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Evidence Report/Technology AssessmentNumber 153<strong>Breastfeed<strong>in</strong>g</strong> <strong>and</strong> <strong>Maternal</strong> <strong>and</strong> <strong>Infant</strong> <strong>Health</strong><strong>Outcomes</strong> <strong>in</strong> Developed CountriesPrepared for:Agency for <strong>Health</strong>care Research <strong>and</strong> QualityU.S. Department of <strong>Health</strong> <strong>and</strong> Human Services540 Gaither RoadRockville, MD 20850www.ahrq.govContract No. 290-02-0022Prepared by:Tufts-New Engl<strong>and</strong> Medical Center Evidence-Based Practice CenterBoston, MassachusettsInvestigatorsStanley Ip, M.D., Project LeaderMei Chung, M.P.H.Gowri Raman, M.D.Priscilla Chew, M.P.H.Nombulelo Magula, M.D.Deirdre DeV<strong>in</strong>e, M.Litt., Project ManagerThomas Trikal<strong>in</strong>os, M.D., Ph.D.Joseph Lau, M.D., Pr<strong>in</strong>cipal InvestigatorAHRQ Publication No. 07-E007April 2007
This report is based on research conducted by the Tufts-New Engl<strong>and</strong> Medical CenterEvidence-based Practice Center (EPC) under contract to the Agency for <strong>Health</strong>care Research<strong>and</strong> Quality (AHRQ), Rockville, MD (Contract No. 290-02-0022). The f<strong>in</strong>d<strong>in</strong>gs <strong>and</strong>conclusions <strong>in</strong> this document are those of the author(s), who are responsible for its content,<strong>and</strong> do not necessarily represent the views of AHRQ. No statement <strong>in</strong> this report should beconstrued as an official position of AHRQ or of the U.S. Department of <strong>Health</strong> <strong>and</strong> HumanServices.The <strong>in</strong>formation <strong>in</strong> this report is <strong>in</strong>tended to help cl<strong>in</strong>icians, employers, policymakers, <strong>and</strong>others make <strong>in</strong>formed decisions about the provision of health care services. This report is<strong>in</strong>tended as a reference <strong>and</strong> not as a substitute for cl<strong>in</strong>ical judgment.This report may be used, <strong>in</strong> whole or <strong>in</strong> part, as the basis for the development of cl<strong>in</strong>icalpractice guidel<strong>in</strong>es <strong>and</strong> other quality enhancement tools, or as a basis for reimbursement <strong>and</strong>coverage policies. AHRQ or U.S. Department of <strong>Health</strong> <strong>and</strong> Human Services endorsement ofsuch derivative products may not be stated or implied.
This document is <strong>in</strong> the public doma<strong>in</strong> <strong>and</strong> may be used <strong>and</strong> repr<strong>in</strong>ted without permission exceptthose copyrighted materials noted for which further reproduction is prohibited without thespecific permission of copyright holders.Suggested Citation:Ip S, Chung M, Raman G, Chew P, Magula N, DeV<strong>in</strong>e D, Trikal<strong>in</strong>os T, Lau J. <strong>Breastfeed<strong>in</strong>g</strong> <strong>and</strong><strong>Maternal</strong> <strong>and</strong> <strong>Infant</strong> <strong>Health</strong> <strong>Outcomes</strong> <strong>in</strong> Developed Countries. Evidence Report/TechnologyAssessment No. 153 (Prepared by Tufts-New Engl<strong>and</strong> Medical Center Evidence-based PracticeCenter, under Contract No. 290-02-0022). AHRQ Publication No. 07-E007. Rockville, MD:Agency for <strong>Health</strong>care Research <strong>and</strong> Quality. April 2007.No <strong>in</strong>vestigators have any affiliations or f<strong>in</strong>ancial <strong>in</strong>volvement (e.g., employment, consultancies,honoraria, or stock options, expert testimony, grants, or patents received or pend<strong>in</strong>g, or royalties)that conflict with material presented <strong>in</strong> this report.ii
PrefaceThe Agency for <strong>Health</strong>care Research <strong>and</strong> Quality (AHRQ), through its Evidence-BasedPractice Centers (EPCs), sponsors the development of evidence reports <strong>and</strong> technologyassessments to assist public- <strong>and</strong> private-sector organizations <strong>in</strong> their efforts to improve thequality of health care <strong>in</strong> the United States. The Office on Women’s <strong>Health</strong>, Department of <strong>Health</strong><strong>and</strong> Human Services, requested <strong>and</strong> provided fund<strong>in</strong>g for this report. The reports <strong>and</strong>assessments provide organizations with comprehensive, science-based <strong>in</strong>formation on common,costly medical conditions <strong>and</strong> new health care technologies. The EPCs systematically review therelevant scientific literature on topics assigned to them by AHRQ <strong>and</strong> conduct additionalanalyses when appropriate prior to develop<strong>in</strong>g their reports <strong>and</strong> assessments.To br<strong>in</strong>g the broadest range of experts <strong>in</strong>to the development of evidence reports <strong>and</strong> healthtechnology assessments, AHRQ encourages the EPCs to form partnerships <strong>and</strong> enter <strong>in</strong>tocollaborations with other medical <strong>and</strong> research organizations. The EPCs work with these partnerorganizations to ensure that the evidence reports <strong>and</strong> technology assessments they produce willbecome build<strong>in</strong>g blocks for health care quality improvement projects throughout the Nation. Thereports undergo peer review prior to their release.AHRQ expects that the EPC evidence reports <strong>and</strong> technology assessments will <strong>in</strong>form<strong>in</strong>dividual health plans, providers, <strong>and</strong> purchasers as well as the health care system as a whole byprovid<strong>in</strong>g important <strong>in</strong>formation to help improve health care quality.We welcome comments on this evidence report. They may be sent by mail to the Task OrderOfficer named below at: Agency for <strong>Health</strong>care Research <strong>and</strong> Quality, 540 Gaither Road,Rockville, MD 20850, or by e-mail to epc@ahrq.hhs.gov.Carolyn M. Clancy, M.D.DirectorAgency for <strong>Health</strong>care Research <strong>and</strong> QualitySuzanne Haynes, Ph.D.Office on Women’s <strong>Health</strong>Department of <strong>Health</strong> <strong>and</strong> Human ServicesJean Slutsky, P.A., M.S.P.H.Director, Center for <strong>Outcomes</strong> <strong>and</strong> EvidenceAgency for <strong>Health</strong>care Research <strong>and</strong> QualityBeth Coll<strong>in</strong>s Sharp, Ph.D., R.N.Director, EPC ProgramAgency for <strong>Health</strong>care Research <strong>and</strong> QualityErnest<strong>in</strong>e Murray, M.A.S., R.N.EPC Program Task Order OfficerAgency for <strong>Health</strong>care Research <strong>and</strong> Qualityiii
AcknowledgmentsWe acknowledge with appreciation the members of the Technical Expert Panel for theiradvice <strong>and</strong> consultation to the Evidence-based Practice Center (EPC) dur<strong>in</strong>g preparation of thisreport. In design<strong>in</strong>g the study questions <strong>and</strong> methodology at the outset of this report, the EPCconsulted these technical <strong>and</strong> content experts. Broad expertise <strong>and</strong> perspectives aresought. Divergent <strong>and</strong> conflicted op<strong>in</strong>ions are common <strong>and</strong> perceived as healthy scientificdiscourse that results <strong>in</strong> a thoughtful, relevant systematic review. Therefore, <strong>in</strong> the end, studyquestions, design <strong>and</strong>/or methodologic approaches do not necessarily represent the views of<strong>in</strong>dividual technical <strong>and</strong> content experts.Technical Expert PanelDavid Chelmow, M.D.Obstetrician-GynecologistTufts-New Engl<strong>and</strong> Medical CenterTufts University School of Medic<strong>in</strong>eKathryn G. Dewey, Ph.D.Department of NutritionUniversity of California, DavisGillman Grave, M.D.Endocr<strong>in</strong>ology, Nutrition & GrowthNational Institute of Child <strong>Health</strong> <strong>and</strong> HumanDevelopmentLarry Grummer-Strawn, Ph.D.National Center for Chronic Disease Prevention<strong>and</strong> <strong>Health</strong> PromotionCenters for Disease Control <strong>and</strong> PreventionKather<strong>in</strong>e E. Hartmann, M.D., Ph.D.Obstetrician-GynecologistV<strong>and</strong>erbilt UniversityRepresentative, American College ofObstetricians <strong>and</strong> GynecologistsSuzanne Haynes, Ph.D.Senior Science AdvisorOffice on Women’s <strong>Health</strong>U.S. Department of <strong>Health</strong> <strong>and</strong> Human ServicesJill Janke, RNC, D.NSc.University of AlaskaRepresentative, Association of Women’s <strong>Health</strong>,Obstetrical <strong>and</strong> Neonatal NursesRonald E. Kle<strong>in</strong>man, M.D.Pediatric Gastroenterology <strong>and</strong> NutritionDepartment of PediatricsMassGeneral Hospital for ChildrenMichael Kramer, M.D.McGill University Faculty of Medic<strong>in</strong>eInstitute of Human Development, Child <strong>and</strong> Youth <strong>Health</strong>The Montreal Children's HospitalKaty Lebb<strong>in</strong>g, B.S., IBCLC, RLCCenter for <strong>Breastfeed<strong>in</strong>g</strong> InformationLa Leche League InternationalArdythe L. Morrow, Ph.D., M.Sc.C<strong>in</strong>c<strong>in</strong>nati Children's Hospital Medical CenterDavid Meyers, M.D.Center for Primary Care, Prevention, <strong>and</strong> Cl<strong>in</strong>icalPartnerships, (CPPO)Agency for <strong>Health</strong>care Research <strong>and</strong> QualityBarbara L. Philipp, M.D.The <strong>Breastfeed<strong>in</strong>g</strong> CenterBoston Medical CenterLori Feldman-W<strong>in</strong>ter, M.D., M.P.H., IBCLC, FAAP,FABMRobert Wood Johnson Medical SchoolUniversity of Medic<strong>in</strong>e <strong>and</strong> Dentistry of New JerseyRepresentative, AAP <strong>and</strong> the Section on <strong>Breastfeed<strong>in</strong>g</strong>iv
Structured AbstractObjectives: We reviewed the evidence on the effects of breastfeed<strong>in</strong>g on short- <strong>and</strong> long-term<strong>in</strong>fant <strong>and</strong> maternal health outcomes <strong>in</strong> developed countries.Data Sources: We searched MEDLINE®, CINAHL, <strong>and</strong> the Cochrane Library <strong>in</strong> November of2005. Supplemental searches on selected outcomes were conducted through May of 2006. Wealso identified additional studies <strong>in</strong> bibliographies of selected reviews <strong>and</strong> by suggestions fromtechnical experts.Review Methods: We <strong>in</strong>cluded systematic reviews/meta-analyses, r<strong>and</strong>omized <strong>and</strong> nonr<strong>and</strong>omizedcomparative trials, prospective cohort, <strong>and</strong> case-control studies on the effects ofbreastfeed<strong>in</strong>g <strong>and</strong> relevant outcomes published <strong>in</strong> the English language. Included studies musthave a comparative arm of formula feed<strong>in</strong>g or different durations of breastfeed<strong>in</strong>g. Only studiesconducted <strong>in</strong> developed countries were <strong>in</strong>cluded <strong>in</strong> the updates of previous systematic reviews.The studies were graded for methodological quality.Results: We screened over 9,000 abstracts. Forty-three primary studies on <strong>in</strong>fant healthoutcomes, 43 primary studies on maternal health outcomes, <strong>and</strong> 29 systematic reviews or metaanalysesthat covered approximately 400 <strong>in</strong>dividual studies were <strong>in</strong>cluded <strong>in</strong> this review. Wefound that a history of breastfeed<strong>in</strong>g was associated with a reduction <strong>in</strong> the risk of acute otitismedia, non-specific gastroenteritis, severe lower respiratory tract <strong>in</strong>fections, atopic dermatitis,asthma (young children), obesity, type 1 <strong>and</strong> 2 diabetes, childhood leukemia, sudden <strong>in</strong>fant deathsyndrome (SIDS), <strong>and</strong> necrotiz<strong>in</strong>g enterocolitis. There was no relationship between breastfeed<strong>in</strong>g<strong>in</strong> term <strong>in</strong>fants <strong>and</strong> cognitive performance. The relationship between breastfeed<strong>in</strong>g <strong>and</strong>cardiovascular diseases was unclear. Similarly, it was also unclear concern<strong>in</strong>g the relationshipbetween breastfeed<strong>in</strong>g <strong>and</strong> <strong>in</strong>fant mortality <strong>in</strong> developed countries. For maternal outcomes, ahistory of lactation was associated with a reduced risk of type 2 diabetes, breast, <strong>and</strong> ovariancancer. Early cessation of breastfeed<strong>in</strong>g or not breastfeed<strong>in</strong>g was associated with an <strong>in</strong>creasedrisk of maternal postpartum depression. There was no relationship between a history of lactation<strong>and</strong> the risk of osteoporosis. The effect of breastfeed<strong>in</strong>g <strong>in</strong> mothers on return-to-pre-pregnancyweight was negligible, <strong>and</strong> the effect of breastfeed<strong>in</strong>g on postpartum weight loss was unclear.Conclusions: A history of breastfeed<strong>in</strong>g is associated with a reduced risk of many diseases <strong>in</strong><strong>in</strong>fants <strong>and</strong> mothers from developed countries. Because almost all the data <strong>in</strong> this review weregathered from observational studies, one should not <strong>in</strong>fer causality based on these f<strong>in</strong>d<strong>in</strong>gs. Also,there is a wide range of quality of the body of evidence across different health outcomes. Forfuture studies, clear subject selection criteria <strong>and</strong> def<strong>in</strong>ition of “exclusive breastfeed<strong>in</strong>g”, reliablecollection of feed<strong>in</strong>g data, controll<strong>in</strong>g for important confounders <strong>in</strong>clud<strong>in</strong>g child-specific factors,<strong>and</strong> bl<strong>in</strong>ded assessment of the outcome measures will help. Sibl<strong>in</strong>g analysis provides a method tocontrol for hereditary <strong>and</strong> household factors that are important <strong>in</strong> certa<strong>in</strong> outcomes. In addition,cluster r<strong>and</strong>omized controlled studies on the effectiveness of various breastfeed<strong>in</strong>g promotion<strong>in</strong>terventions will provide further opportunity to <strong>in</strong>vestigate any disparity <strong>in</strong> health outcomes as aresult of the <strong>in</strong>tervention.v
ContentsExecutive Summary.....................................................................................................................1Evidence Report.........................................................................................................................11Chapter 1. Introduction ................................................................................................................11Chapter 2. Methods......................................................................................................................13Overview...............................................................................................................................13Key Questions Addressed <strong>in</strong> This Report.............................................................................13Def<strong>in</strong>itions of <strong>Breastfeed<strong>in</strong>g</strong> <strong>in</strong> This Report.........................................................................14Literature Search Strategy.....................................................................................................14Study Selection .....................................................................................................................15Meta-Analysis.......................................................................................................................16Grad<strong>in</strong>g of Studies Analyzed <strong>in</strong> This Report........................................................................17Grad<strong>in</strong>g of Systematic Reviews/Meta-Analyses. .................................................................17Grad<strong>in</strong>g of Individual Primary Studies <strong>in</strong> Updates <strong>and</strong> New Reviews.................................18Report<strong>in</strong>g of the Evidence ....................................................................................................20Chapter 3. Results ........................................................................................................................21Overview...............................................................................................................................21Literature Search Results ......................................................................................................23Organization of Results.........................................................................................................24Part I. Term <strong>Infant</strong> <strong>Outcomes</strong> – Relationship of <strong>Breastfeed<strong>in</strong>g</strong> to <strong>Outcomes</strong> .....................27Acute Otitis Media........................................................................................................27Atopic Dermatitis..........................................................................................................35Gastro<strong>in</strong>test<strong>in</strong>al Infections ............................................................................................37Lower Respiratory Tract Diseases................................................................................40Asthma....................................…………………..………………………………… ....42Cognitive Development <strong>in</strong> Terms <strong>Infant</strong>s.....................................................................50Obesity ..........................................................................................................................62Cardiovascular Diseases ...............................................................................................68Type 1 Diabetes ............................................................................................................75Type 2 Diabetes ............................................................................................................81Childhood Leukemia.....................................................................................................84<strong>Infant</strong> Mortality.............................................................................................................90Sudden <strong>Infant</strong> Death Syndrome (SIDS)........................................................................93Part II. Preterm <strong>Infant</strong> <strong>Outcomes</strong> – Relationship with Human milk feed<strong>in</strong>g........................98Necrotiz<strong>in</strong>g Enterocolitis ............................................................................................98Cognitive Development ..............................................................................................103Part III. <strong>Maternal</strong> <strong>Outcomes</strong> – Relationship of <strong>Breastfeed<strong>in</strong>g</strong> to <strong>Outcomes</strong> .........................111Return to Pre-pregnancy Weight or Postpartum Weight Change...............................111Type 2 Diabetes ..........................................................................................................119vii
Osteoporosis................................................................................................................124Postpartum Depression ...............................................................................................130Breast Cancer..............................................................................................................136Ovarian Cancer ...........................................................................................................141Other Research......................................................................................................................155Chapter 4. Discussion ..................................................................................................................157Future Research ....................................................................................................................162References <strong>and</strong> Included Studies .................................................................................................165Acronyms <strong>and</strong> Abbreviations ......................................................................................................185FiguresFigure 1. The relationship between breastfeed<strong>in</strong>g <strong>and</strong> health outcomes <strong>in</strong> term <strong>in</strong>fants –meta-analysis results ..............................................................................................................21Figure 2. The relationship between exclusive breastfeed<strong>in</strong>g <strong>and</strong> health outcomes <strong>in</strong> term<strong>in</strong>fants - meta-analysis results................................................................................................22Figure 3. The relationship between breastfeed<strong>in</strong>g <strong>and</strong> maternal outcomes - meta-analysisresults .....................................................................................................................................23Figure 4. Primary studies available to assess the relationship between breastfeed<strong>in</strong>g <strong>and</strong><strong>in</strong>fant health outcomes ...........................................................................................................25Figure 5. Primary studies available to assess the relationship between breastfeed<strong>in</strong>g <strong>and</strong>maternal health outcomes ......................................................................................................26Figure 6. Meta-analysis of the association between breastfeed<strong>in</strong>g <strong>and</strong> the risk of AOMcompared to exclusive bottle-feed<strong>in</strong>g <strong>in</strong> cohort studies.........................................................30Figure 7. Meta-Analysis of prospective cohort studies of the association between asthma risk<strong>and</strong> breastfeed<strong>in</strong>g ≥ 3 months for children with positive family history of asthma or atopy(exclud<strong>in</strong>g Wright 2001)........................................................................................................44Figure 8. Meta-Analysis of prospective cohort studies of the association between asthma risk<strong>and</strong> breastfeed<strong>in</strong>g ≥ 3 months for children with positive family history of asthma or atopy(<strong>in</strong>clud<strong>in</strong>g Wright 2001) ........................................................................................................45Figure 9. Meta-Analysis of prospective cohort studies of the association between asthmarisk <strong>and</strong> breastfeed<strong>in</strong>g ≥ 3 months for children without family history of asthma oratopy.......................................................................................................................................45Figure 10. R<strong>and</strong>om effects model of summary estimate evaluat<strong>in</strong>g the association ofbreastfeed<strong>in</strong>g <strong>and</strong> SIDS..........................................................................................................95Figure 11. Meta-Analysis of four RCTs on the effects of breast milk feed<strong>in</strong>g <strong>and</strong> NEC<strong>in</strong> preterm <strong>in</strong>fants ...................................................................................................................100Figure 12. Meta-Analysis of case-control studies on the relationship between breastfeed<strong>in</strong>g<strong>and</strong> maternal ovarian cancer risk: ever breastfed versus never breastfed.............................143Figure 13. Meta-Analysis of case-control studies on the relationship between breastfeed<strong>in</strong>g<strong>and</strong> maternal ovarian cancer risk: breastfed less than 12 months (cumulative duration)versus never breastfed............................................................................................................144viii
Figure 14. Meta-Analysis of case-control studies on the relationship between breastfeed<strong>in</strong>g<strong>and</strong> maternal ovarian cancer risk: breastfed at least 12 months (cumulative duration)versus never breastfed…………………………………........................................................145TablesTable 1. Summary of systematic review/meta-analysis on the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> acute otitis media (AOM).........................................................................31Table 2. Summary table for cohort studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong>acute otitis media ...................................................................................................................32Table 3. Summary of systematic review/meta-analysis on the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> the risk of develop<strong>in</strong>g atopic dermatitis ...................................................36Table 4. Summary of systematic review/meta-analysis on the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> gastro<strong>in</strong>test<strong>in</strong>al (GI) <strong>in</strong>fection...................................................................39Table 5. Summary of systematic review/meta-analysis on the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> lower respiratory tract disease ..................................................................41Table 6. Summary of systematic review/meta-analysis on the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> asthma.......................................................................................................47Table 7. Summary of prospective cohort studies on the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> asthma.......................................................................................................48Table 8. Summary of systematic reviews/meta-analyses on the relationship of breastfeed<strong>in</strong>g<strong>and</strong> cognitive development ....................................................................................................54Table 9. Summary of studies on the relationship of breast milk feed<strong>in</strong>g <strong>and</strong> cognitivedevelopment...........................................................................................................................56Table 10. Summary of systematic reviews/meta-analyses on the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> overweight or obesity ...............................................................................66Table 11. Summary of systematic reviews/meta-analyses on the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> total cholesterol <strong>and</strong> low-density lipoprote<strong>in</strong> cholesterol.........................69Table 12. Summary table for systematic reviews/meta-analyses on the relationship betweenbreastfeed<strong>in</strong>g <strong>in</strong> <strong>in</strong>fancy <strong>and</strong> blood pressure levels later <strong>in</strong> life.............................................71Table 13. Summary of systematic review/meta-analysis on the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> long-term cardiovascular disease mortality..............................................74Table 14. Summary of systematic reviews/meta-analyses on the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> type 1 diabetes ..........................................................................................79Table 15. Summary of case-control studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong>type 1 diabetes........................................................................................................................80Table 16. Summary of systematic reviews/meta-analyses on the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> type 2 diabetes ..........................................................................................83Table 17. Comb<strong>in</strong>ed SES-adjusted ORs of ALL for the three case-control studies rated asgood <strong>and</strong> fair methodological quality <strong>in</strong> the systematic review by Guise et al. (2005).........87Table 18. Summary of systematic reviews/meta-analyses on the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> childhood leukemia...................................................................................88Table 19. Summary of case-control study on the relationship between breastfeed<strong>in</strong>g <strong>and</strong><strong>in</strong>fant mortality.......................................................................................................................92Table 20. Summary of systematic review/meta-analysis on the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> Sudden <strong>Infant</strong> Death Syndrome (SIDS) ...................................................96ix
Table 21. Summary of case-control studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong>sudden <strong>in</strong>fant death syndrome (SIDS) <strong>in</strong>cluded <strong>in</strong> the meta-analysis ...................................97Table 22. Meta-Analysis of four RCTs on the effects of breast milk feed<strong>in</strong>g <strong>and</strong> NEC <strong>in</strong>preterm <strong>in</strong>fants: R<strong>and</strong>om Effects Model (D&L)....................................................................99Table 23. Summary of systematic review/meta-analyse on the relationship between breastmilk feed<strong>in</strong>g <strong>and</strong> necrotiz<strong>in</strong>g enterocolitis (NEC) <strong>in</strong> preterm <strong>in</strong>fants....................................101Table 24. Summary of studies on the relationship between breast milk feed<strong>in</strong>g <strong>and</strong>necrotiz<strong>in</strong>g enterocolitis (NEC) <strong>in</strong> preterm <strong>in</strong>fants................................................................102Table 25. Summary of primary studies on the relationship of breast milk feed<strong>in</strong>g <strong>and</strong>cognitive development <strong>in</strong> preterm <strong>in</strong>fants..............................................................................106Table 26. Summary of prospective cohort studies on the relationship between breastfeed<strong>in</strong>g<strong>and</strong> return<strong>in</strong>g to pre-pregnancy weights ................................................................................114Table 27. Summary of prospective cohort studies on the relationship between breastfeed<strong>in</strong>g<strong>and</strong> postpartum weight/BMI changes ....................................................................................116Table 28. Summary of systematic review/meta-analyse on the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> maternal type 2 diabetes ...........................................................................122Table 29. Summary of studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> maternaltype 2 diabetes (NIDDM) ......................................................................................................123Table 30. Summary of case-control studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong>risk of fracture <strong>in</strong> post-menopausal women...........................................................................127Table 31. Summary of prospective cohort studies on the relationship between duration ofbreastfeed<strong>in</strong>g <strong>and</strong> the long-term changes of bone m<strong>in</strong>eral density (BMD) or bonem<strong>in</strong>eral content (BMC)..........................................................................................................129Table 32. Summary of the studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong>postpartum depression ...........................................................................................................132Table 33. Summary of systematic reviews/meta-analyses on the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> the risk of breast cancer............................................................................139Table 34. Summary of case-control studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong>breast cancer...........................................................................................................................140Table 35. Summary of case-control studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong>maternal ovarian cancer .........................................................................................................147Table 36. Summary of case-control studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong>maternal ovarian cancer by menopausal status......................................................................151Table 37. Summary of case-control studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong>maternal ovarian cancer by histologic type ...........................................................................152Table 38. Summary of pooled-analysis of case-control studies on the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> ovarian cancer by population subgroups ..................................................154x
AppendixesAppendix A. MEDLINE ® Search StrategyAppendix B. Sample data abstraction formsAppendix C. Evidence TablesAppendix D. List of Excluded StudiesAppendix E. Peer ReviewersAppendixes <strong>and</strong> Evidence Tables are provided electronically athttp://www.ahrq.gov/downloads/pub/evidence/pdf/brfout/brfout.pdfxi
Executive SummaryIntroductionThe purpose of this report is to summarize the literature concern<strong>in</strong>g the relationship ofbreastfeed<strong>in</strong>g <strong>and</strong> various <strong>in</strong>fant <strong>and</strong> maternal health outcomes. This report was requested by theDepartment of <strong>Health</strong> <strong>and</strong> Human Services (DHHS) Office on Women’s <strong>Health</strong> <strong>and</strong> wasconducted through the Evidence-based Practice Center (EPC) program at the Agency for<strong>Health</strong>care Research <strong>and</strong> Quality (AHRQ).Two key questions are addressed:Methods1. What are the benefits <strong>and</strong> harms for <strong>in</strong>fants <strong>and</strong> children <strong>in</strong> terms of short-term outcomes,such as <strong>in</strong>fectious diseases (<strong>in</strong>clud<strong>in</strong>g otitis media, diarrhea, <strong>and</strong> lower respiratory tract<strong>in</strong>fections), sudden <strong>in</strong>fant death syndrome (SIDS) <strong>and</strong> <strong>in</strong>fant mortality, <strong>and</strong> longertermoutcomes such as cognitive development, childhood cancer (<strong>in</strong>clud<strong>in</strong>g leukemia),type I <strong>and</strong> II diabetes, asthma, atopic dermatitis, cardiovascular disease (<strong>in</strong>clud<strong>in</strong>ghypertension), hyperlipidemia, <strong>and</strong> obesity, compared among those who mostlybreastfeed, mostly formula feed, <strong>and</strong> mixed feed; <strong>and</strong> how are these outcomes associatedwith duration of the type of feed<strong>in</strong>g? Do the harms <strong>and</strong> benefits differ for any specificsubpopulations based on socio-demographic factors?2. What are the benefits <strong>and</strong> harms on maternal health short-term outcomes, such as postpartumdepression <strong>and</strong> return to pre-pregnancy weight, <strong>and</strong> long-term outcomes, such asbreast cancer, ovarian cancer, diabetes <strong>and</strong> osteoporosis, compared among breastfeed<strong>in</strong>g,formula feed<strong>in</strong>g, <strong>and</strong> mixed feed<strong>in</strong>g, <strong>and</strong> how are these associated with duration of thetype of feed<strong>in</strong>g? Do the harms <strong>and</strong> benefits differ for any specific subpopulations basedon socio-demographic factors?Approach to Evaluat<strong>in</strong>g the LiteratureInclusion Criteria. As it was not feasible to review the large number of primary studies thatare relevant to all the outcomes of <strong>in</strong>terest, we consulted the Office on Women’s <strong>Health</strong> <strong>and</strong> thetechnical expert panel (TEP) <strong>and</strong> developed an approach that capitalized on the exist<strong>in</strong>g largenumber of systematic reviews/meta-analyses. For outcomes of <strong>in</strong>terest that have previously beenreviewed systematically, we have summarized the f<strong>in</strong>d<strong>in</strong>gs from those reviews. For acute otitismedia, childhood asthma, cognitive development, SIDS, <strong>in</strong>fant mortality, NEC, maternal breastcancer, return to pre-pregnancy weight, <strong>and</strong> maternal type 2 diabetes, we have also updated thosesystematic reviews with data from primary studies published subsequent to those reviews. Foroutcomes that have not been previously evaluated systematically (osteoporosis, ovarian cancer,postpartum depression, <strong>in</strong>fant mortality), we have reviewed those primary studies that met our<strong>in</strong>clusion criteria. Studies that exam<strong>in</strong>ed only formula-fed <strong>in</strong>fants were excluded.1
Def<strong>in</strong>itions of <strong>Breastfeed<strong>in</strong>g</strong>. The majority of the studies did not dist<strong>in</strong>guish betweenexclusive <strong>and</strong> partially breastfed <strong>in</strong>fants, or expla<strong>in</strong> the difference between “breastfeed<strong>in</strong>g” <strong>and</strong>“feed<strong>in</strong>g of expressed breast milk.” We elected to use the term “breastfeed<strong>in</strong>g” for studies <strong>in</strong> fullterm<strong>in</strong>fants <strong>and</strong> the term “human milk feed<strong>in</strong>g” for studies <strong>in</strong> preterm <strong>in</strong>fants. We elected toaccept all def<strong>in</strong>itions of “exclusive breastfeed<strong>in</strong>g” as provided by the different study authors butqualified our conclusions with respect to those specific def<strong>in</strong>itions.Literature Search Strategy. Comprehensive literature searches of MEDLINE ® , CINAHL,<strong>and</strong> the Cochrane Database of Systemic Reviews took place <strong>in</strong> November of 2005. Search terms<strong>in</strong>cluded subject head<strong>in</strong>gs <strong>and</strong> text words relevant to breastfeed<strong>in</strong>g <strong>and</strong> the different outcomes.Supplemental searches on selected outcomes were conducted through May of 2006. Otherrelevant studies were identified by technical experts or <strong>in</strong> bibliographies of selected reviews.Specific Inclusion Criteria for <strong>Health</strong> Conditions Evaluated. We <strong>in</strong>cluded systematicreviews, meta-analyses, observational studies, r<strong>and</strong>omized controlled trials, <strong>and</strong> comparativestudies that evaluated the effects or associations of breastfeed<strong>in</strong>g on outcomes of <strong>in</strong>terest. Allstudies must have either a comparator arm that evaluated formula feed<strong>in</strong>g or a comparator armthat evaluated different durations of breastfeed<strong>in</strong>g. Only studies conducted <strong>in</strong> developedcountries were used <strong>in</strong> updates of systematic reviews/meta-analyses <strong>and</strong> de novo reviews ofprimary studies.Report<strong>in</strong>g of EvidenceMethodological Quality Grade of Individual Studies. We used a three category grad<strong>in</strong>gsystem (A, B, C) to denote methodological quality of each primary study. We did not evaluatethe methodological quality of the <strong>in</strong>dividual studies <strong>in</strong> the systematic reviews/meta-analyses.A (good): Least bias <strong>and</strong> results are valid; a primary study that adheres mostly to thecommonly held concepts of high qualityB (fair/moderate): Susceptible to some bias, but not sufficient to <strong>in</strong>validate the results; aprimary study that does not meet all the criteria <strong>in</strong> category AC (poor): Significant biases that may <strong>in</strong>validate the results; a primary study with seriouserrors <strong>in</strong> design, analysis or report<strong>in</strong>gMethodological Quality Grade of Systematic reviews/Meta-analyses. We used a similarscheme as above for grad<strong>in</strong>g systematic reviews/meta-analyses. But we supplemented thescheme with the MOOSE guidel<strong>in</strong>e (st<strong>and</strong>ards for report<strong>in</strong>g for meta-analysis <strong>in</strong> observationalstudies <strong>in</strong> epidemiology) <strong>and</strong> an additional checklist of items that we devised to evaluate thequality of the systematic review of observational studies. Items <strong>in</strong> this checklist <strong>in</strong>cludedquestions on the follow<strong>in</strong>g: appropriate search strategy; justification for <strong>in</strong>clusion/exclusioncriteria for studies; description of well-def<strong>in</strong>ed population, <strong>in</strong>tervention/exposure, comparator,outcomes <strong>and</strong> study designs; effort to m<strong>in</strong>imize errors <strong>in</strong> data extraction; assessment of quality of<strong>in</strong>dividual studies; consideration on the effect of confounders; comb<strong>in</strong>ability of the data formeta-analysis; assessment of statistical <strong>and</strong> cl<strong>in</strong>ical heterogeneity; report<strong>in</strong>g accuracies; <strong>and</strong>appropriateness of the conclusions based on the reported data.2
ResultsWe screened over 9,000 abstracts. Forty-three primary studies on <strong>in</strong>fant health outcomes, 43primary studies on maternal health outcomes, <strong>and</strong> 29 systematic reviews or meta-analyses thatcovered approximately 400 <strong>in</strong>dividual studies were <strong>in</strong>cluded <strong>in</strong> this review.The association studies of breastfeed<strong>in</strong>g <strong>and</strong> health outcomes mostly presented results as oddsratios. To facilitate <strong>in</strong>terpretation of the odds ratio, we chose to present these data as a reduction <strong>in</strong>relative risk, estimated as “(1 – odds ratio) x 100%,” along with the correspond<strong>in</strong>g 95% confidence<strong>in</strong>terval (CI).Full term <strong>Infant</strong> <strong>Outcomes</strong>Acute Otitis Media. Our meta-analysis of five cohort studies of good <strong>and</strong> moderatemethodological quality showed that breastfeed<strong>in</strong>g was associated with a significant reduction <strong>in</strong> therisk of acute otitis media. Compar<strong>in</strong>g ever breastfeed<strong>in</strong>g with exclusive formula feed<strong>in</strong>g, the riskreduction of acute otitis media was 23 percent (95% CI 9% to 36%). When compar<strong>in</strong>g exclusivebreastfeed<strong>in</strong>g with exclusive formula feed<strong>in</strong>g, either for more than 3 or 6 months duration, thereduction was 50 percent (95% CI 30% to 64%). These results were adjusted for potentialconfounders.Atopic Dermatitis. One good quality meta-analysis of 18 prospective cohort studies on full term<strong>in</strong>fants reported a reduction <strong>in</strong> the risk of atopic dermatitis by 42 percent (95% CI 8% to 59%) <strong>in</strong>children with a family history of atopy <strong>and</strong> exclusively breastfed for at least 3 months compared withthose who were breastfed for less than 3 months. The meta-analysis did not dist<strong>in</strong>guish betweenatopic dermatitis of <strong>in</strong>fancy (under 2 years of age) <strong>and</strong> persistent or new atopic dermatitis at olderages. It has been postulated that the diagnosis of atopic dermatitis <strong>in</strong> patients younger than 2 years ofage could be attributed to <strong>in</strong>fectious etiologies, which may be prevented by breastfeed<strong>in</strong>g. However,a stratified analysis by duration of followup found the risk reduction from breastfeed<strong>in</strong>g was similar<strong>in</strong> subjects with less than 2 years compared with more than 2 years of followup.Gastro<strong>in</strong>test<strong>in</strong>al Infections. For non-specific gastroenteritis, one systematic review identifiedthree primary studies that controlled for potential confounders. These studies reported that there wasa reduction <strong>in</strong> the risk of non-specific gastro<strong>in</strong>test<strong>in</strong>al <strong>in</strong>fections dur<strong>in</strong>g the first year of life <strong>in</strong>breastfed <strong>in</strong>fants from developed countries. But a summary adjusted estimate tak<strong>in</strong>g <strong>in</strong>to accountpotential confounders could not be determ<strong>in</strong>ed because the studies did not provide usable quantitativedata. However, a recent case-control study from Engl<strong>and</strong> that took <strong>in</strong>to account the role of potentialconfounders reported that <strong>in</strong>fants who were breastfeed<strong>in</strong>g had a 64 percent (95% CI 26% to 82%)reduction <strong>in</strong> the risk of non-specific gastroenteritis compared with <strong>in</strong>fants who were notbreastfeed<strong>in</strong>g.Lower Respiratory Tract Diseases. The summary estimate from a good quality meta-analysisof seven studies reported an overall 72 percent (95% CI 46% to 86%) reduction <strong>in</strong> the risk ofhospitalization due to lower respiratory tract diseases <strong>in</strong> <strong>in</strong>fants less than 1 year of age who wereexclusively breastfed for 4 months or more. The results rema<strong>in</strong>ed consistent after adjustment forpotential confounders.Asthma. The studies on asthma were equivocal. A previously published good quality metaanalysisreported a moderate protective effect <strong>and</strong> four recent primary studies reach<strong>in</strong>g mixedconclusions, <strong>in</strong>clud<strong>in</strong>g two studies f<strong>in</strong>d<strong>in</strong>g an <strong>in</strong>creased risk of asthma associated with breastfeed<strong>in</strong>g.We updated the meta-analysis with the new studies. Our analysis showed that breastfeed<strong>in</strong>g for atleast 3 months was associated with a 27 percent (95% CI 8% to 41%) reduction <strong>in</strong> the risk of asthma3
<strong>in</strong> those subjects without a family history of asthma compared with those who were not breastfed.For those with a family history of asthma, there was a 40 percent (95% CI 18% to 57%) reduction <strong>in</strong>the risk of asthma <strong>in</strong> children less than 10 years of age who were breastfed for at least 3 monthscompared with those who were not breastfed. However, the relationship between breastfeed<strong>in</strong>g <strong>and</strong>the risk of asthma <strong>in</strong> older children <strong>and</strong> adolescents rema<strong>in</strong>s unclear <strong>and</strong> will need further<strong>in</strong>vestigation.Cognitive Development. One well-performed sibl<strong>in</strong>g analysis <strong>and</strong> three prospective cohortstudies of full-term <strong>in</strong>fants, all conducted <strong>in</strong> developed countries, adjusted their analyses specificallyfor maternal <strong>in</strong>telligence. The studies found little or no evidence for an association betweenbreastfeed<strong>in</strong>g <strong>in</strong> <strong>in</strong>fancy <strong>and</strong> cognitive performance <strong>in</strong> childhood. Most of the published studiesadjusted their analyses for socioeconomic status <strong>and</strong> maternal education but not specifically formaternal <strong>in</strong>telligence. For those studies that reported a significant effect after specific adjustment formaternal <strong>in</strong>telligence, residual confound<strong>in</strong>g from other factors such as different home environmentscannot be ruled out.Obesity. Three meta-analyses of good <strong>and</strong> moderate methodological quality reported anassociation of breastfeed<strong>in</strong>g <strong>and</strong> a reduction <strong>in</strong> the risk of obesity <strong>in</strong> adolescence <strong>and</strong> adult lifecompared with those who were not breastfed. One study reported the reduction <strong>in</strong> the risk ofoverweight/obesity <strong>in</strong> breastfeeders compared with non-breastfeeders was 24 percent (95% CI 14%to 33%); another study reported 7 percent (95% CI 1% to 12%). Both of these estimates took <strong>in</strong>toaccount the role of potential confounders. Furthermore, they also showed that the magnitude ofassociation decreased when more confounders were entered <strong>in</strong>to the analyses. The third study usedmeta-regression <strong>and</strong> found a 4 percent reduction <strong>in</strong> the risk of be<strong>in</strong>g overweight <strong>in</strong> adult life for eachadditional month of breastfeed<strong>in</strong>g <strong>in</strong> <strong>in</strong>fancy. Overall, there is an association between a history ofbreastfeed<strong>in</strong>g <strong>and</strong> a reduction <strong>in</strong> the risk of be<strong>in</strong>g overweight or obese <strong>in</strong> adolescence <strong>and</strong> adult life.One should be cautious <strong>in</strong> <strong>in</strong>terpret<strong>in</strong>g all these associations because of the possibility of residualconfound<strong>in</strong>g.Risk of Cardiovascular Diseases. Results from two moderate quality meta-analyses concludedthat there was a small reduction of less than 1.5 mm Hg <strong>in</strong> systolic blood pressures <strong>and</strong> no more than0.5 mm Hg <strong>in</strong> diastolic blood pressures among adults who were breastfed <strong>in</strong> their <strong>in</strong>fancy comparedwith those who were formula-fed. The association weakened after stratification by study size,suggest<strong>in</strong>g the possibility of bias <strong>in</strong> the smaller studies.One meta-analysis of cohort <strong>and</strong> case-control studies reported that there was a reduction <strong>in</strong> total<strong>and</strong> LDL cholesterol levels by 7.0 mg/dL <strong>and</strong> 7.7 mg/dL, respectively, <strong>in</strong> adults who were breastfeddur<strong>in</strong>g <strong>in</strong>fancy compared with those who were not. However, these f<strong>in</strong>d<strong>in</strong>gs were based on data fromadults with a wide age range. The analysis did not segregate the data accord<strong>in</strong>g to gender <strong>and</strong>potential confounders were not explicitly analyzed. Detailed <strong>in</strong>formation (e.g., fast<strong>in</strong>g or non-fast<strong>in</strong>g)on the collection of specimen for cholesterol test<strong>in</strong>g was not <strong>in</strong>cluded. Because of these deficiencies,the correct characterization of a relationship between breastfeed<strong>in</strong>g <strong>and</strong> adult cholesterol levelscannot be determ<strong>in</strong>ed at this time.One meta-analysis found little or no difference <strong>in</strong> all-cause <strong>and</strong> cardiovascular mortality betweenadults who were breastfed dur<strong>in</strong>g <strong>in</strong>fancy <strong>and</strong> those who were not. There were possible biases <strong>and</strong>limitations <strong>in</strong> the studies reviewed, however. Presence of statistical heterogeneity across studiessuggests that it may not have been appropriate to comb<strong>in</strong>e estimates from <strong>in</strong>dividual studies <strong>in</strong>to onesummary estimate. Because of these reasons, no def<strong>in</strong>itive conclusion could be drawn regard<strong>in</strong>g therelationship between a history of breastfeed<strong>in</strong>g <strong>and</strong> cardiovascular mortality.In summary, the relationship between breastfeed<strong>in</strong>g <strong>in</strong> <strong>in</strong>fancy <strong>and</strong> the risk of cardiovasculardiseases cannot be confidently characterized at this time <strong>and</strong> will need further <strong>in</strong>vestigation.4
Type 1 Diabetes. Two moderate quality meta-analyses suggest that breastfeed<strong>in</strong>g for at least 3months reduced the risk of childhood type 1 diabetes compared with breastfeed<strong>in</strong>g for less than 3months. One reported a 19 percent (95% CI 11% to 26%) reduction; the other reported a 27 percent(95% CI 18% to 35%) reduction. In addition, f<strong>in</strong>d<strong>in</strong>gs from five of six studies published s<strong>in</strong>ce themeta-analyses reported similar results. However, these results must be <strong>in</strong>terpreted with cautionbecause of the possibility of recall biases <strong>and</strong> suboptimal adjustments for potential confounders <strong>in</strong> thestudies.Type 2 Diabetes. In one well-performed meta-analysis of seven studies of various designs,breastfeed<strong>in</strong>g <strong>in</strong> <strong>in</strong>fancy was associated with a 39 percent (95% CI 15% to 56%) reduced risk of type2 diabetes <strong>in</strong> later life compared with those who were not. However, only three of seven studiesadjusted for all the important confounders such as birth weight, parental diabetes, socioeconomicstatus, <strong>and</strong> <strong>in</strong>dividual or maternal body size. Though the crude <strong>and</strong> adjusted estimates did not differ<strong>in</strong> these three studies, the lack of adjustments for potential confounders such as birth weight <strong>and</strong>maternal factors by all studies could exaggerate the magnitude of an association.Childhood Leukemia. The published studies on childhood acute lymphocytic leukemia (ALL)were equivocal; a good quality meta-analysis reported a moderate protective effect frombreastfeed<strong>in</strong>g <strong>and</strong> the other good quality systematic review reached the opposite conclusion. Weconducted a meta-analysis <strong>in</strong>clud<strong>in</strong>g only good <strong>and</strong> fair quality case-control studies identified <strong>in</strong> thesystematic review, s<strong>in</strong>ce the meta-analysis did not provide methodological quality grad<strong>in</strong>g of primarystudies. We found breastfeed<strong>in</strong>g of at least 6 months duration was associated with a 19 percent (95%CI 9% to 29%) reduction <strong>in</strong> the risk of childhood ALL. The previous meta-analysis also reported anassociation between breastfeed<strong>in</strong>g of at least 6 months duration <strong>and</strong> a 15 percent reduction (95% CI2% to 27%) <strong>in</strong> the risk of acute myelogenous leukemia (AML). Overall there is an associationbetween a history of breastfeed<strong>in</strong>g for at least 6 months duration <strong>and</strong> a reduction <strong>in</strong> the risk of bothleukemias (ALL <strong>and</strong> AML).<strong>Infant</strong> Mortality. One study of moderate methodological quality evaluated the relationshipbetween breastfeed<strong>in</strong>g <strong>and</strong> <strong>in</strong>fant mortality. The study reported a protective effect of breastfeed<strong>in</strong>g <strong>in</strong>reduc<strong>in</strong>g <strong>in</strong>fant mortality after controll<strong>in</strong>g for some of the potential confounders. However, <strong>in</strong>subgroup analyses of the study, the only statistically significant association reported was between“never breastfed” <strong>and</strong> Sudden <strong>Infant</strong> Death Syndrome (SIDS) or the risk of <strong>in</strong>jury-related deaths.Because of the limited data <strong>in</strong> this area, the relationship between breastfeed<strong>in</strong>g <strong>and</strong> <strong>in</strong>fant mortality <strong>in</strong>developed countries rema<strong>in</strong>s unclear. Further <strong>in</strong>vestigation is needed.Sudden <strong>Infant</strong> Death Syndrome (SIDS). We conducted a meta-analysis by <strong>in</strong>clud<strong>in</strong>g onlystudies that reported clear def<strong>in</strong>itions of exposure, outcomes, <strong>and</strong> results adjusted for well-knownconfounders or risk factors for SIDS. Our meta-analysis of seven case-control studies found that ahistory of breastfeed<strong>in</strong>g was associated with a 36 percent (95% CI 19% to 49%) reduction <strong>in</strong> the riskof SIDS compared to those without a history of breastfeed<strong>in</strong>g.Preterm <strong>Infant</strong> <strong>Outcomes</strong>Cognitive Development. No def<strong>in</strong>itive conclusion can be made regard<strong>in</strong>g the relationshipbetween breast milk feed<strong>in</strong>g <strong>and</strong> cognitive development <strong>in</strong> preterm <strong>in</strong>fants. One meta-analysisreported a five po<strong>in</strong>ts advantage <strong>in</strong> st<strong>and</strong>ardized mean score <strong>and</strong> one systematic review identified oneprimary study that reported an eight po<strong>in</strong>ts advantage <strong>in</strong> IQ <strong>in</strong> preterm or low birth weight <strong>in</strong>fantswho received breast milk feed<strong>in</strong>g. In three of four primary studies of moderate quality that controlledfor either maternal education or maternal <strong>in</strong>telligence, the advantage from breastfeed<strong>in</strong>g was reducedto a statistically non-significant level after adjustment. The roles of maternal <strong>in</strong>telligence <strong>and</strong> home5
environment should be accounted for <strong>in</strong> future studies on breastfeed<strong>in</strong>g <strong>and</strong> cognitive development.Keep<strong>in</strong>g <strong>in</strong> m<strong>in</strong>d that cognitive function measured at an early age is not necessarily predictive of latercognitive ability, one should also consider carefully the tim<strong>in</strong>g <strong>and</strong> the selection of appropriatetest<strong>in</strong>g <strong>in</strong>strument <strong>in</strong> future studies.Necrotiz<strong>in</strong>g Enterocolitis (NEC). Our meta-analysis of four r<strong>and</strong>omized controlled trials ofbreast milk versus formula <strong>in</strong> compar<strong>in</strong>g the outcome of NEC demonstrated that there was amarg<strong>in</strong>ally statistically significant association between a history of breast milk feed<strong>in</strong>g <strong>and</strong> areduction <strong>in</strong> the risk of NEC (P = 0.04). The estimate of the reduction <strong>in</strong> relative risk ranged from 4percent to 82 percent. The absolute risk difference between the two groups was 5 percent. Because ofthe high case-fatality rate of NEC, this difference is a mean<strong>in</strong>gful cl<strong>in</strong>ical outcome. The wide rangeof the estimate reflects the relatively small number of total subjects <strong>in</strong> the studies <strong>and</strong> the smallnumber of events. One must also be cognizant of the heterogeneity underly<strong>in</strong>g these trials <strong>in</strong><strong>in</strong>terpret<strong>in</strong>g the f<strong>in</strong>d<strong>in</strong>gs of the meta-analysis. Examples of which <strong>in</strong>cluded gestational age thatranged from 23 to more than 33 weeks; birth weight ranged from less than 1,000 g to more than1,600 g; <strong>and</strong> some trials <strong>in</strong>cluded only “healthy” <strong>in</strong>fants, while others <strong>in</strong>cluded both “healthy” <strong>and</strong>“ill” <strong>in</strong>fants.<strong>Maternal</strong> <strong>Outcomes</strong>Return to Pre-pregnancy Weight. Three moderate quality prospective cohort studies reportedless than 1 kg weight change from pre-pregnancy or first trimester to 1 to 2 year postpartum period <strong>in</strong>mothers who breastfed. Results from four moderate quality prospective cohort studies showed thatthe effects of breastfeed<strong>in</strong>g on postpartum weight loss were unclear. Results from all seven studiesconsistently showed that many factors other than breastfeed<strong>in</strong>g had larger effects on weight retentionor postpartum weight loss. Methodological challenges <strong>in</strong> these studies <strong>in</strong>cluded the accuratemeasurement of weight change, adequate control for numerous covariables <strong>in</strong>clud<strong>in</strong>g the amount ofpregnancy weight ga<strong>in</strong>, <strong>and</strong> quantify<strong>in</strong>g accurately the exclusivity <strong>and</strong> the duration of breastfeed<strong>in</strong>g.<strong>Maternal</strong> Type 2 Diabetes. Two large cohorts from a high quality longitud<strong>in</strong>al study of 150,000parous women <strong>in</strong> the United States exam<strong>in</strong>ed the relationship between breastfeed<strong>in</strong>g <strong>and</strong> the risk ofmaternal type 2 diabetes. In parous women without a history of gestational diabetes, each additionalyear of breastfeed<strong>in</strong>g was associated with a 4 percent (95% CI 1% to 9%) reduced risk of develop<strong>in</strong>gtype 2 diabetes <strong>in</strong> the first cohort <strong>and</strong> a 12 percent (95% CI 6% to 18%) reduced risk <strong>in</strong> the secondcohort. In women with a history of gestational diabetes, breastfeed<strong>in</strong>g had no significant effect on thealready <strong>in</strong>creased risk of diabetes. Because only nurses were <strong>in</strong>cluded <strong>in</strong> the cohorts, generalizationof f<strong>in</strong>d<strong>in</strong>gs to the rest of the population must be done with care.Osteoporosis. There is little or no evidence from six moderate quality case-control studies for anassociation between lifetime breastfeed<strong>in</strong>g duration <strong>and</strong> the risk of fractures due to osteoporosis. Intwo of three moderate or good quality prospective cohort studies us<strong>in</strong>g bone m<strong>in</strong>eral density as asurrogate for osteoporosis, lactation does not appear to have an effect on long-term changes <strong>in</strong> bonem<strong>in</strong>eral densities. The third study found a small decrease <strong>in</strong> the bone m<strong>in</strong>eral contents <strong>in</strong> the distalradius with <strong>in</strong>creased duration of breastfeed<strong>in</strong>g, but no significant changes <strong>in</strong> bone m<strong>in</strong>eral contents<strong>in</strong> the femoral neck or the trochanter.Postpartum Depression. Four prospective cohort studies of moderate methodological qualityreported on the relationship between a history of breastfeed<strong>in</strong>g <strong>and</strong> postpartum depression. None ofthe studies explicitly screened for depression at basel<strong>in</strong>e before the <strong>in</strong>itiation of breastfeed<strong>in</strong>g <strong>and</strong>none of them provided detailed data on breastfeed<strong>in</strong>g. Three of the four studies found an associationbetween a history of short duration of breastfeed<strong>in</strong>g or not breastfeed<strong>in</strong>g with postpartum depression.6
The results were adjusted for socio-demographic <strong>and</strong> obstetric variables. More <strong>in</strong>vestigation will beneeded to determ<strong>in</strong>e the nature of this association. It is plausible that postpartum depression led toearly cessation of breastfeed<strong>in</strong>g, as opposed to breastfeed<strong>in</strong>g alter<strong>in</strong>g the risk of depression. Botheffects might occur concurrently.Breast Cancer. Two meta-analyses of moderate methodological quality concluded that there wasa reduction of breast cancer risk <strong>in</strong> women who breastfed their <strong>in</strong>fants. The reduction <strong>in</strong> breast cancerrisk was 4.3 percent for each year of breastfeed<strong>in</strong>g <strong>in</strong> one meta-analysis <strong>and</strong> 28 percent for 12 ormore months of breastfeed<strong>in</strong>g <strong>in</strong> the other. In addition, one of the two meta-analyses <strong>and</strong> anothersystematic review reported decreased risk of breast cancer primarily <strong>in</strong> premenopausal women.F<strong>in</strong>d<strong>in</strong>gs from primary studies published after the meta-analyses concurred with the f<strong>in</strong>d<strong>in</strong>gsfrom the earlier meta-analyses. In summary, consistent evidence from these studies suggests thatthere is an association between breastfeed<strong>in</strong>g <strong>and</strong> a reduced risk of breast cancer.Ovarian Cancer. We reviewed 15 case-control studies that exam<strong>in</strong>ed the relationshipbetween breastfeed<strong>in</strong>g <strong>and</strong> the risk of ovarian cancer, <strong>and</strong> performed meta-analyses <strong>in</strong> n<strong>in</strong>estudies that adjusted for potential confounders. The overall result from the n<strong>in</strong>e studies showedan association between breastfeed<strong>in</strong>g <strong>and</strong> a 21 percent (95% CI 9% to 32%) reduction <strong>in</strong> the riskof ovarian cancer, compared to never breastfeed<strong>in</strong>g. Because not all the studies reported similarcomparisons of breastfeed<strong>in</strong>g durations, we had to estimate the comparable risks <strong>in</strong> five studies.Exclud<strong>in</strong>g these five studies from the meta-analysis results <strong>in</strong> loss of statistical significance forthis association.There was <strong>in</strong>direct evidence for a dose-response relationship between breastfeed<strong>in</strong>g <strong>and</strong> areduced risk of ovarian cancer. <strong>Breastfeed<strong>in</strong>g</strong> of more than 12 months (cumulative duration) wasassociated with a reduced risk of ovarian cancer, compared to never breastfeed<strong>in</strong>g. The 12-monthcutoff was arbitrary, <strong>and</strong> the odds ratios were estimated <strong>in</strong> half of these studies.Overall, there is evidence to suggest an association between breastfeed<strong>in</strong>g <strong>and</strong> a reduction <strong>in</strong>the risk of maternal ovarian cancer. Because of the aforementioned limitations, one must becautious <strong>in</strong> <strong>in</strong>terpret<strong>in</strong>g this association.LimitationsDiscussionWith the availability of many published systematic reviews on breastfeed<strong>in</strong>g, we used thisliterature as the evidence for a large number of outcomes, supplemented by updates of thesesystematic reviews with new primary studies. Even though we have assessed the report<strong>in</strong>gquality of these systematic reviews (us<strong>in</strong>g st<strong>and</strong>ards of report<strong>in</strong>g of systematic reviews ofobservational studies (MOOSE statement), <strong>and</strong> additional parameters that we devised), wecannot reliably know the validity of the reported summary data without know<strong>in</strong>g the details ofthe primary studies. It should also be stressed that a well-performed systematic review does notnecessarily imply that the body of evidence for a particular outcome of <strong>in</strong>terest is of high quality.Any systematic review is limited by the quality of the primary studies <strong>in</strong>cluded <strong>in</strong> the review.Unless the method used to assess the quality of the primary studies is transparent <strong>and</strong> the detailsmade available for exam<strong>in</strong>ation, it would be difficult to reliably determ<strong>in</strong>e the validity of theconclusions.7
The breastfeed<strong>in</strong>g literature is primarily comprised of observational studies, either cohort orcase-control studies. There are a number of potential deficiencies related to the observationalstudy designs that could limit the <strong>in</strong>ternal validity <strong>and</strong> the generalizability of the f<strong>in</strong>d<strong>in</strong>gs. Someof these potential deficiencies <strong>in</strong>clude (1) misclassification of exposure; (2) confound<strong>in</strong>g fromthe process of self-selection; <strong>and</strong> (3) residual confound<strong>in</strong>g.We have summarized the effects of breastfeed<strong>in</strong>g (or breast milk feed<strong>in</strong>g) on a large numberof <strong>in</strong>fant <strong>and</strong> maternal outcomes. Some of the outcomes are well def<strong>in</strong>ed <strong>and</strong> specific (e.g.,childhood acute lymphocytic leukemia, breast cancer); <strong>and</strong> some are not so well def<strong>in</strong>ed <strong>and</strong>non-specific (e.g., asthma, non-specific gastro<strong>in</strong>test<strong>in</strong>al <strong>in</strong>fections). When the reported outcomeis well def<strong>in</strong>ed <strong>and</strong> specific, it lends confidence that the effect reported is valid for that outcome.When the reported outcome is not well def<strong>in</strong>ed, one might have some reservation regard<strong>in</strong>g thevalidity of the measured effect for that outcome. For all the above reasons, we f<strong>in</strong>d that there is awide range of quality of evidence for the different outcomes exam<strong>in</strong>ed <strong>in</strong> this review.An important area of research that is not systematically reviewed <strong>in</strong> this report is the use ofbreastfeed<strong>in</strong>g promotion <strong>in</strong>tervention trial to measure health effects (this topic is not part of thescope of this report <strong>and</strong> it will be covered <strong>in</strong> a separate report). The best known of these types ofstudies is the Promotion of <strong>Breastfeed<strong>in</strong>g</strong> Intervention Trial (PROBIT) conducted <strong>in</strong> theRepublic of Belarus. Data from this study provided good evidence that breastfeed<strong>in</strong>g isassociated with a reduction <strong>in</strong> the risk of gastro<strong>in</strong>test<strong>in</strong>al <strong>in</strong>fection <strong>and</strong> atopic dermatitis.Lastly, the outcomes analyzed <strong>in</strong> this review represent only a portion of all possible healthoutcomes related to breastfeed<strong>in</strong>g reported by <strong>in</strong>vestigators worldwide. To work with<strong>in</strong> theconstra<strong>in</strong>ts of resources, we relied on the advice from our panel of technical experts <strong>in</strong> f<strong>in</strong>aliz<strong>in</strong>gthe list of outcomes <strong>in</strong>cluded <strong>in</strong> this review. Thus, some important outcomes (e.g., growth <strong>and</strong>nutrition) have, by necessity, not been <strong>in</strong>cluded <strong>in</strong> this review.Future ResearchObservational studies will rema<strong>in</strong> the major source of <strong>in</strong>formation <strong>in</strong> this field. Clear subjectselection criteria, adopt<strong>in</strong>g a common def<strong>in</strong>ition of “exclusive breastfeed<strong>in</strong>g”, reliable collectionof feed<strong>in</strong>g data, specific <strong>and</strong> properly quantifiable outcomes of <strong>in</strong>terest, controll<strong>in</strong>g for importantpotential confounders <strong>in</strong>clud<strong>in</strong>g child-specific factors, <strong>and</strong> bl<strong>in</strong>ded assessment of the outcomemeasures will help immeasurably to improve the quality of these studies.Sibl<strong>in</strong>g analysis provides a method to control for hereditary <strong>and</strong> household factors that areimportant <strong>in</strong> certa<strong>in</strong> outcomes, provided that those factors are similar for the sibl<strong>in</strong>gs of <strong>in</strong>terest.Although such analysis may be less susceptible to confounders <strong>and</strong> effect modifiers that areshared by sibl<strong>in</strong>gs, one must remember that it is not immune to biases. This method should beused when the appropriate data are available.Cluster r<strong>and</strong>omized controlled studies similar to the Belarus trial will provide underst<strong>and</strong><strong>in</strong>gof the effectiveness of various breastfeed<strong>in</strong>g promotion <strong>in</strong>terventions. Any substantialdifferences <strong>in</strong> the degree of breastfeed<strong>in</strong>g between the two groups as a result of the <strong>in</strong>terventionwill provide further opportunity to <strong>in</strong>vestigate any disparity <strong>in</strong> health outcomes between the twogroups.8
Evidence Report
Chapter 1. IntroductionThe Department of <strong>Health</strong> <strong>and</strong> Human Services (DHHS) Office on Women’s <strong>Health</strong> hasrequested an evidence report from the Agency for <strong>Health</strong>care Research <strong>and</strong> Quality (AHRQ)through the Evidence-based Practice Center program (EPC) that would critically exam<strong>in</strong>e theliterature concern<strong>in</strong>g the relationship of breastfeed<strong>in</strong>g <strong>and</strong> various <strong>in</strong>fant <strong>and</strong> maternal healthoutcomes. EPC evidence reports summarize evidence address<strong>in</strong>g specific key questions; thesereports do not make cl<strong>in</strong>ical practice or health policy recommendations.Breast milk is the natural nutrition for all <strong>in</strong>fants. Accord<strong>in</strong>g to the American Academy ofPediatrics (AAP), it is the preferred choice of feed<strong>in</strong>g for all <strong>in</strong>fants. 1 The goals of <strong>Health</strong>yPeople 2010 for breastfeed<strong>in</strong>g are an <strong>in</strong>itiation rate of 75 percent <strong>and</strong> cont<strong>in</strong>uation ofbreastfeed<strong>in</strong>g of 50 percent at 6 months <strong>and</strong> 25 percent at 12 months postpartum. 2 NationalImmunization Survey of U.S. children <strong>in</strong> 2005 (NIS 2005) <strong>in</strong>dicated that 73 percent had everbeen breastfed. The percentage of <strong>in</strong>fants who cont<strong>in</strong>ued to breastfeed to some extent is 39percent at 6 months <strong>and</strong> 20 percent at 12 months (www.cdc.gov/breastfeed<strong>in</strong>g/data/NIS_data/data_2005.htm).In addition to provid<strong>in</strong>g essential nutrients to <strong>in</strong>fants, benefits of breastfeed<strong>in</strong>g for bothchildren <strong>and</strong> their mothers have been reported. Reports of the benefits for children <strong>in</strong>cludedecreases <strong>in</strong> <strong>in</strong>cidence of otitis media <strong>and</strong> gastroenteritis, 3 lower risk of obesity, 4,5 <strong>and</strong> lower riskof asthma. 6 Other benefits reported <strong>in</strong>clude decreased rates of sudden <strong>in</strong>fant death syndrome,reduction <strong>in</strong> the <strong>in</strong>cidence of type 1 <strong>and</strong> type 2 diabetes mellitus, certa<strong>in</strong> types of cancer, <strong>and</strong>improved performance on certa<strong>in</strong> tests of cognitive development. 7Reported benefits for mothers who breastfed their <strong>in</strong>fants <strong>in</strong>clude <strong>in</strong>creased postpartumuter<strong>in</strong>e activity (<strong>in</strong>ferentially this would lead to reduced postpartum blood loss), 8 greater weightloss postpartum compared with mothers who bottle-fed their <strong>in</strong>fants, 9 decreased <strong>in</strong>cidence of premenopausalbreast cancer 10 <strong>and</strong> decreased <strong>in</strong>cidence of ovarian cancer. 11In 2000, the DHHS Office on Women’s <strong>Health</strong>, <strong>in</strong> cooperation with the Surgeon General ofthe United States <strong>and</strong> several governmental <strong>and</strong> non-governmental agencies, published the firstdepartmental policy on breastfeed<strong>in</strong>g, the HHS Bluepr<strong>in</strong>t for Action on <strong>Breastfeed<strong>in</strong>g</strong>(www.womenshealth.gov). The DHHS Office on Women’s <strong>Health</strong> endorses the recommendationfrom the American Academy of Pediatrics (AAP), American Academy of Family Physicians(AAFP), American College of Obstetricians <strong>and</strong> Gynecologists (ACOG), Association ofWomen’s <strong>Health</strong>, Obstetrical, <strong>and</strong> Neonatal Nurses (AWHONN), Le Leche LeagueInternational, National Medical Association (NMA), <strong>and</strong> many other health organizations, thatmothers exclusively breastfeed for 6 months. The DHHS Office on Women’s <strong>Health</strong> hascommissioned a review to systematically exam<strong>in</strong>e the evidence for the effects of breastfeed<strong>in</strong>g.The DHHS Office on Women’s <strong>Health</strong> has also requested that the focus of the review be onstudies from developed countries (i.e., “high <strong>in</strong>come” classification by World Bank) ∗ as thef<strong>in</strong>d<strong>in</strong>gs from those studies are deemed more directly applicable to population <strong>in</strong> this country.As it is unethical to r<strong>and</strong>omize subjects <strong>in</strong>to breastfeed<strong>in</strong>g versus non-breastfeed<strong>in</strong>g groups(although there were some r<strong>and</strong>omized controlled trials (RCTs) <strong>in</strong> the 1980s on preterm <strong>in</strong>fantswhose mothers desired not to breastfeed, their <strong>in</strong>fants were r<strong>and</strong>omized <strong>in</strong>to those who received∗ http://web.worldbank.org/WBSITE/EXTERNAL/DATASTATISTICS/0,,contentMDK:20421402~pagePK:64133150~piPK:64133175~theSitePK:239419,00.html#High_<strong>in</strong>come11
donor breast milk versus those who received preterm formula 12,13 ), much of the evidence on thebenefits of breastfeed<strong>in</strong>g came from observational studies. Observational studies are subject toconfound<strong>in</strong>g. One of the well-known confounders <strong>in</strong> breastfeed<strong>in</strong>g research is demographicdifference between mothers who breastfeed <strong>and</strong> those who chose not to breastfeed due to selfselection.Consistent with previously reported data, 14 NIS 2005 showed that mothers whobreastfeed tend to be white (versus non-Hispanic black or African American), older, moreeducated, <strong>and</strong> <strong>in</strong> a higher socioeconomic stratum (cdc.gov/breastfeed<strong>in</strong>g/data/NIS_data/data_2005.htm). While it is possible to control for some of these demographic factors, it is notpossible to control for behavioral or attitud<strong>in</strong>al factors <strong>in</strong>tr<strong>in</strong>sic <strong>in</strong> the desire to breastfeed. Someauthors have proposed strict st<strong>and</strong>ards <strong>in</strong> evaluat<strong>in</strong>g the quality of observational studies. Thesest<strong>and</strong>ards should <strong>in</strong>clude the quality of the feed<strong>in</strong>g data, a clear def<strong>in</strong>ition of the outcome, theelim<strong>in</strong>ation of systematic differences <strong>in</strong> outcome assessment between comparison groups(detection bias), <strong>and</strong> the control of potential <strong>and</strong> well-known confounders. The feed<strong>in</strong>g datashould clearly def<strong>in</strong>e whether it was prospectively or retrospectively collected, whether therewas a precise def<strong>in</strong>ition of exclusive breastfeed<strong>in</strong>g, <strong>and</strong> whether the duration of breastfeed<strong>in</strong>gwas reported. 15,16Large number of <strong>in</strong>fant <strong>and</strong> maternal outcomes has been exam<strong>in</strong>ed <strong>in</strong> relation to a history ofbreastfeed<strong>in</strong>g. It was not feasible to review all possible outcomes <strong>in</strong> mothers <strong>and</strong> children for thisreport; we sought guidance from our panel of technical experts <strong>in</strong> the field of breastfeed<strong>in</strong>gresearch <strong>in</strong> decid<strong>in</strong>g on the specific outcomes to review. After tak<strong>in</strong>g <strong>in</strong>to consideration thefollow<strong>in</strong>g factors: relevance <strong>and</strong> importance of outcome <strong>in</strong> a developed country, date (recent orold) of the last systematic review on the outcome, availability or non-availability of data from adeveloped country, consistency or <strong>in</strong>consistency of outcomes <strong>in</strong> previously reported studies, <strong>and</strong>consideration of the possibility that breastfeed<strong>in</strong>g may have potential harms as well as benefits,the follow<strong>in</strong>g outcomes from developed countries have been designated for review: for term<strong>in</strong>fants, <strong>in</strong>fectious diseases (<strong>in</strong>clud<strong>in</strong>g otitis media, diarrhea, <strong>and</strong> lower respiratory tract<strong>in</strong>fections), sudden <strong>in</strong>fant death syndrome, <strong>in</strong>fant mortality, cognitive development, childhoodcancer (<strong>in</strong>clud<strong>in</strong>g leukemia), type 1 <strong>and</strong> 2 diabetes, asthma, atopic dermatitis, cardiovasculardisease (<strong>in</strong>clud<strong>in</strong>g hypertension), hyperlipidemia, <strong>and</strong> obesity; for preterm <strong>in</strong>fants, necrotiz<strong>in</strong>genterocolitis (NEC) <strong>and</strong> cognitive development; for mothers, post-partum depression, return topre-pregnancy weight, breast cancer, ovarian cancer, diabetes <strong>and</strong> osteoporosis.It is also outside the scope of this report to exam<strong>in</strong>e the biological mechanisms underp<strong>in</strong>n<strong>in</strong>gthe effects of breast milk <strong>and</strong> therefore, studies on <strong>in</strong>dividual components of breast milk will notbe part of this report. Lastly, studies on the effectiveness of <strong>in</strong>terventions to promote <strong>and</strong> supportbreastfeed<strong>in</strong>g are not systematically covered <strong>in</strong> this review, as this topic will be reviewed for asubsequent report. However, there is good quality evidence to support that some of these<strong>in</strong>terventions do lead to an <strong>in</strong>crease <strong>in</strong> breastfeed<strong>in</strong>g rates <strong>and</strong> also an improvement of certa<strong>in</strong>health outcomes <strong>in</strong> the study populations. Details of one l<strong>and</strong>mark study 17 <strong>and</strong> its implicationsfor future research <strong>in</strong> the study of the effects of breastfeed<strong>in</strong>g will be discussed <strong>in</strong> some details <strong>in</strong>this report.12
Chapter 2. MethodsOverviewThis evidence report on breastfeed<strong>in</strong>g <strong>and</strong> health outcomes <strong>in</strong> <strong>in</strong>fants <strong>and</strong> mothers is based ona systematic review of the literature. To identify the specific issues central to this report, theTufts-New Engl<strong>and</strong> Medical Center (Tufts-NEMC) Evidence-based Practice Center (EPC) heldteleconferences with a panel of technical experts (TEP) <strong>and</strong> various stakeholders. Acomprehensive search of the medical literature was conducted to identify studies address<strong>in</strong>g thekey questions. Evidence tables of study characteristics <strong>and</strong> results were compiled, <strong>and</strong> themethodological quality of the studies was appraised. Study results were summarized withqualitative reviews of the evidence, summary tables, <strong>and</strong> quantitative summary data, whenappropriate.A number of <strong>in</strong>dividuals <strong>and</strong> groups supported the Tufts-NEMC EPC <strong>in</strong> prepar<strong>in</strong>g this report.The TEP served as our science partner. Technical experts <strong>and</strong> representatives from the Agencyfor <strong>Health</strong>care Research <strong>and</strong> Quality (AHRQ), DHHS Office on Women’s <strong>Health</strong>, The NationalInstitute of Child <strong>Health</strong> <strong>and</strong> Human Development (NICHD), Centers for Disease Control <strong>and</strong>Prevention (CDC), American Academy of Pediatrics (AAP), American College of Obstetrics <strong>and</strong>Gynecology (ACOG), Association of Women’s <strong>Health</strong>, Obstetrics <strong>and</strong> Neonatal Nurses(AWHONN), <strong>and</strong> La Leche League worked with the EPC staff to ref<strong>in</strong>e key questions, identifyimportant issues, <strong>and</strong> def<strong>in</strong>e parameters for literature review <strong>in</strong> this report.In the early phase of explor<strong>in</strong>g the literature available for this report, it was soon discoveredthat there was a large number of primary studies <strong>and</strong> systematic reviews/meta-analyses on thevarious outcomes of <strong>in</strong>terest. As it was not feasible to review all the primary studies address<strong>in</strong>gthe outcomes of <strong>in</strong>terest, therefore, <strong>in</strong> consultation with the Office on Women’s <strong>Health</strong> <strong>and</strong> theTEP, we developed an approach that capitalized on the exist<strong>in</strong>g systematic reviews/metaanalyses.For outcomes of <strong>in</strong>terest that had previously been reviewed systematically, we assessedthe quality of those reviews <strong>and</strong> summarized their f<strong>in</strong>d<strong>in</strong>gs. For selected <strong>in</strong>fant (necrotiz<strong>in</strong>genterocolitis, cognitive development, acute otitis media, asthma, type 1 <strong>and</strong> 2 diabetes, SIDS)<strong>and</strong> maternal (weight changes, type 2 diabetes, breast cancer) outcomes, <strong>in</strong> addition to report<strong>in</strong>gon the exist<strong>in</strong>g systematic reviews, we also updated them by summariz<strong>in</strong>g the relevant primarystudies that were published after those reviews. For outcomes of <strong>in</strong>terest (osteoporosis, ovariancancer, postpartum depression, <strong>in</strong>fant mortality) that had not been reviewed systematically, wereviewed all the relevant primary studies that met our <strong>in</strong>clusion criteria.Key Questions Addressed <strong>in</strong> This ReportTwo key questions are addressed <strong>in</strong> this report. Question 1 perta<strong>in</strong>s to <strong>in</strong>fant outcomes <strong>and</strong>question 2 perta<strong>in</strong>s to maternal outcomes. The key questions are:1. What are the benefits <strong>and</strong> harms for <strong>in</strong>fants <strong>and</strong> children <strong>in</strong> terms of short-term outcomes,such as <strong>in</strong>fectious diseases (<strong>in</strong>clud<strong>in</strong>g otitis media, diarrhea, <strong>and</strong> lower respiratory tract<strong>in</strong>fections), sudden <strong>in</strong>fant death syndrome <strong>and</strong> <strong>in</strong>fant mortality, <strong>and</strong> longer-term outcomessuch as cognitive development, childhood cancer (<strong>in</strong>clud<strong>in</strong>g leukemia), type 1 <strong>and</strong> 2diabetes, asthma, atopic dermatitis, cardiovascular disease (<strong>in</strong>clud<strong>in</strong>g hypertension),hyperlipidemia, <strong>and</strong> obesity, compared among those who mostly breastfeed, mostly13
formula feed, <strong>and</strong> mixed feed; <strong>and</strong> how are these outcomes associated with duration ofthe type of feed<strong>in</strong>g? Do the harms <strong>and</strong> benefits differ for any specific subpopulationsbased on socio-demographic factors?2. What are the benefits <strong>and</strong> harms on maternal health short-term outcomes, such as postpartumdepression <strong>and</strong> return to pre-pregnancy weight, <strong>and</strong> long-term outcomes, such asbreast cancer, ovarian cancer, type 2 diabetes mellitus <strong>and</strong> osteoporosis, compared amongbreastfeed<strong>in</strong>g, formula feed<strong>in</strong>g, <strong>and</strong> mixed feed<strong>in</strong>g, <strong>and</strong> how are these associated withduration of the type of feed<strong>in</strong>g? Do the harms <strong>and</strong> benefits differ for any specificsubpopulations based on socio-demographic factors?It should be emphasized that the focus of this review is on the effects of breast milk feed<strong>in</strong>g,not formula feed<strong>in</strong>g. However, many studies did not dist<strong>in</strong>guish between exclusive <strong>and</strong> partiallybreastfed <strong>in</strong>fants; presumably, some of the effects reported from observational studies were from<strong>in</strong>fants who received both breast milk <strong>and</strong> formula milk feed<strong>in</strong>gs. Studies that exam<strong>in</strong>ed onlyformula fed <strong>in</strong>fants were not <strong>in</strong>cluded <strong>in</strong> this report. Lastly, studies on <strong>in</strong>fant <strong>and</strong> maternal healthoutcomes of <strong>in</strong>terventions to promote <strong>and</strong> support breastfeed<strong>in</strong>g were not systematically covered<strong>in</strong> this review as that subject will be covered <strong>in</strong> a separate report. However, our panel oftechnical experts felt that the study of breastfeed<strong>in</strong>g promotion <strong>in</strong> <strong>in</strong>fants from Belarus 17 was al<strong>and</strong>mark study <strong>and</strong> offered new directions <strong>in</strong>to research on effects from breast milk that itwarrants discussion <strong>in</strong> this report. The details of that study are described <strong>in</strong> the section OtherResearch <strong>in</strong> the results chapter.Def<strong>in</strong>itions of <strong>Breastfeed<strong>in</strong>g</strong> <strong>in</strong> This ReportNone of the studies <strong>in</strong> this review explicitly exam<strong>in</strong>ed the difference between “breastfeed<strong>in</strong>g”an <strong>in</strong>fant (<strong>in</strong>fant suckl<strong>in</strong>g at her/his mother’s nipple) <strong>and</strong> “feed<strong>in</strong>g of expressed breast milk” to an<strong>in</strong>fant. To dist<strong>in</strong>guish between the two forms of feed<strong>in</strong>gs, we elected to use the term“breastfeed<strong>in</strong>g” when the studies concerned primarily full-term <strong>in</strong>fants (presumably they were,<strong>in</strong>deed, breastfed) <strong>and</strong> the term “breast milk feed<strong>in</strong>g” when the studies concerned primarilypreterm <strong>in</strong>fants (as most of them received breast milk <strong>in</strong>itially either by gavage- or by bottlefeed<strong>in</strong>g).For term <strong>in</strong>fants, “bottle-feed<strong>in</strong>g” is used synonymously with “formula feed<strong>in</strong>g.”Def<strong>in</strong>itions of “exclusive breastfeed<strong>in</strong>g” varied widely <strong>in</strong> the literature. They ranged from“no supplement of any k<strong>in</strong>d <strong>in</strong>clud<strong>in</strong>g water while breastfeed<strong>in</strong>g” to “occasional formula ispermissible while breastfeed<strong>in</strong>g.” We elected to accept all def<strong>in</strong>itions of “exclusivebreastfeed<strong>in</strong>g” as provided by the different study authors, but we qualified our f<strong>in</strong>d<strong>in</strong>gs by thedetails regard<strong>in</strong>g those def<strong>in</strong>itions.Literature Search StrategyWe conducted a comprehensive literature search to address the two key questions. The EPCused the Ovid search eng<strong>in</strong>e to conduct searches on the MEDLINE ® database, CINAHLdatabase, <strong>and</strong> the Cochrane Database of Systemic Reviews. A wide variety of search terms wereused to capture the many potential sources of <strong>in</strong>formation related to the myriad of differentoutcomes (see Appendix A). * But the different outcomes were always searched <strong>in</strong> conjunction* Appendixes <strong>and</strong> Evidence Tables cited <strong>in</strong> this report are provided electronically at http://www.ahrq.gov/cl<strong>in</strong>ic/tp/ brfouttp.htm14
with the follow<strong>in</strong>g: “breastfeed<strong>in</strong>g,” “breast milk feed<strong>in</strong>g,” “breast milk,” “human milk,”“nurs<strong>in</strong>g”, <strong>and</strong> “lactation”. Literature search of the outcomes alone without references to breastmilk feed<strong>in</strong>g was not conducted. The search <strong>in</strong>cluded citations from 1966 to November of 2005.Updated searches on selected outcomes took place <strong>in</strong> April <strong>and</strong> May of 2006. We alsosupplemented our computer search by exam<strong>in</strong><strong>in</strong>g the bibliographies of the review articles. Wealso <strong>in</strong>cluded articles suggested by reviewers, provided that the articles met the <strong>in</strong>clusion criteriafor this review. For outcomes that were not slated for updates, additional articles suggested byreviewers were also <strong>in</strong>cluded as an addendum if they provided useful <strong>in</strong>formation. We did notmake efforts to identify unpublished studies.Study SelectionSelection of <strong>Outcomes</strong> for This ReviewThe TEP offered advice on selection of outcomes for review. F<strong>in</strong>al selection of the list ofoutcomes for review took <strong>in</strong>to account the follow<strong>in</strong>g factors: the importance of the outcome,whether a systematic review of the outcome has previously been reported from a developedcountry, whether the exist<strong>in</strong>g systematic review of the outcome is outdated, whether therelationship between breastfeed<strong>in</strong>g <strong>and</strong> the outcome is thought to be equivocal, whether a largenumber of primary studies has been published recently on the outcome, <strong>and</strong> the total number ofoutcomes that could be adequately reviewed for this report given the time constra<strong>in</strong>t.We <strong>in</strong>cluded the follow<strong>in</strong>g outcomes <strong>in</strong> this report:Term <strong>in</strong>fant outcomes: acute otitis media, hospitalization for lower respiratory tract <strong>in</strong>fection,gastro<strong>in</strong>test<strong>in</strong>al <strong>in</strong>fection, hypertension, cardiovascular diseases, hyperlipidemia, asthma, atopicdermatitis, type 1 <strong>and</strong> 2 diabetes, obesity, sudden <strong>in</strong>fant death syndrome (SIDS), <strong>in</strong>fant mortality,cognitive development, <strong>and</strong> childhood cancer (<strong>in</strong>clud<strong>in</strong>g leukemia)Preterm <strong>in</strong>fant outcomes: necrotiz<strong>in</strong>g enterocolitis (NEC) <strong>and</strong> cognitive development<strong>Maternal</strong> outcomes: maternal weight changes, breast cancer, ovarian cancer, post-partumdepression, osteoporosis, <strong>and</strong> type 2 diabetesAbstract Screen<strong>in</strong>gAll abstracts identified through the literature search were screened. At this stage, eligiblestudies <strong>in</strong>cluded all English language primary experimental or observational studies that reportedany health outcomes <strong>in</strong> human subjects <strong>in</strong> relation to a history of breast milk feed<strong>in</strong>g. As the<strong>in</strong>clusion criteria were broad at this stage, the abstracts rejected at this stage did not undergo asecond rescreen<strong>in</strong>g process. Abstracts that were accepted at this stage were exam<strong>in</strong>ed a secondtime by different reviewers <strong>and</strong> categorized <strong>in</strong>to the different outcomes of <strong>in</strong>terest.Full Article Inclusion/Exclusion CriteriaArticles that passed the abstract screen<strong>in</strong>g process were retrieved <strong>and</strong> the full articles werereviewed for eligibility. Full articles were exam<strong>in</strong>ed only once unless the articles were equivocalfor <strong>in</strong>clusion or exclusion. In that event, the article <strong>in</strong> question was screened aga<strong>in</strong> by a differentreviewer <strong>and</strong> a consensus was reached after discussion with the first reviewer.15
Meta-AnalysisWe used meta-analysis to exp<strong>and</strong> on the <strong>in</strong>dividual studies’ f<strong>in</strong>d<strong>in</strong>gs, if it was appropriate<strong>and</strong> feasible to do so. M<strong>in</strong>imal criteria for meta-analysis are comparable group<strong>in</strong>gs, similar studydesigns, <strong>and</strong> quantifiable outcome data. Secondary criteria for consideration of meta-analysis aresimilar study quality, similar statistical adjustment of outcomes, <strong>and</strong> other factors. Beforecomb<strong>in</strong><strong>in</strong>g the reported odds ratios or risk ratios reported <strong>in</strong> the <strong>in</strong>dividual studies from theprevious meta-analysis with the estimates from the updated primary studies <strong>in</strong>to a new summaryodds ratio or risk ratio, we verified the previous reported odds ratios or risk ratios by exam<strong>in</strong><strong>in</strong>gthe data from the orig<strong>in</strong>al studies.We used the DerSimonian <strong>and</strong> Laird’s r<strong>and</strong>om effects model for all meta-analyses. 18 Ther<strong>and</strong>om effects model assigns a weight to each study based both on the <strong>in</strong>dividual study variance<strong>and</strong> the between-study heterogeneity. Compared with the fixed effect model, the r<strong>and</strong>om effectsmodel is more conservative <strong>in</strong> that it generally results <strong>in</strong> broader confidence <strong>in</strong>tervals whenbetween-study heterogeneity is present. We tested for heterogeneity us<strong>in</strong>g Cochran’s Q <strong>and</strong>assessed its extent with I 2 , which evaluates the proportion of between study variability that isattributed to heterogeneity rather than chance. 19,20 Intercooled Stata 8.2 was used for thecalculations <strong>and</strong> graphics.Grad<strong>in</strong>g of Studies Analyzed <strong>in</strong> This Evidence ReportStudies accepted <strong>in</strong> evidence reports have been designed, conducted, analyzed, <strong>and</strong> reportedwith various degrees of methodological rigor <strong>and</strong> completeness. Deficiencies <strong>in</strong> any of theseprocesses may lead to biased report<strong>in</strong>g or <strong>in</strong>terpretation of the results. While it is desirable tohave a simple evidence grad<strong>in</strong>g system us<strong>in</strong>g a s<strong>in</strong>gle quantity, the quality of evidence is multidimensional.A s<strong>in</strong>gle metric cannot adequately capture <strong>in</strong>formation needed to <strong>in</strong>terpret a cl<strong>in</strong>icalstudy. However, grad<strong>in</strong>g of <strong>in</strong>formation can help the reader to <strong>in</strong>terpret the studies properly.Grad<strong>in</strong>g of Systematic Reviews/Meta-AnalysesWe assessed the methodological quality of studies based on predef<strong>in</strong>ed criteria. For theassessment of systematic reviews, the criteria for methodological quality was based on theQUOROM guidel<strong>in</strong>es for meta-analyses <strong>and</strong> systematic reviews of RCTs (a checklist organized<strong>in</strong>to 21 head<strong>in</strong>gs <strong>and</strong> subhead<strong>in</strong>gs for the preferred way to present the abstract, <strong>in</strong>troduction,methods, results, <strong>and</strong> discussion sections of a report of a meta-analysis), 21 <strong>and</strong> report<strong>in</strong>gguidel<strong>in</strong>es for meta-analysis <strong>in</strong> observational studies <strong>in</strong> epidemiology (MOOSE) (a checklist forthe specifications for present<strong>in</strong>g background, search strategy, methods, results, discussion,conclusion, <strong>and</strong> assessment of quality of <strong>in</strong>dividual studies <strong>and</strong> bias (e.g., publication bias) a ). 22As the QUOROM <strong>and</strong> the MOOSE statements were primarily concerned with the report<strong>in</strong>gst<strong>and</strong>ards of the reviews, we have also supplemented those criteria with our own checklist ofitems designed to evaluate the quality of the systematic review of observational studies (seeAppendix B b for details). Items <strong>in</strong> this checklist consisted of questions on appropriate search strategy;a Publication bias refers to selective publication of studies accord<strong>in</strong>g to results. When studies with non-significant or negativeresults are not published, the available studies may overestimate the effect.b Appendixes <strong>and</strong> Evidence Tables cited <strong>in</strong> this report are provided electronically at http://www.ahrq.gov/cl<strong>in</strong>ic/tp/ brfouttp.htm.17
justification for <strong>in</strong>clusion/exclusion criteria; how well-def<strong>in</strong>ed were the population, <strong>in</strong>tervention,comparator, outcomes <strong>and</strong> study design; effort to m<strong>in</strong>imize errors <strong>in</strong> data extraction; assessment of<strong>in</strong>dividual study quality; consideration on the effect of confounders; comb<strong>in</strong>ability of the data formeta-analysis; assessment of statistical <strong>and</strong> cl<strong>in</strong>ical heterogeneity; report<strong>in</strong>g accuracies; <strong>and</strong>appropriateness of the conclusions based on the reported data.We applied a three category summary grad<strong>in</strong>g system (A, B, C) to each systematic review/metaanalysis:A (good)Category A studies have the least bias <strong>and</strong> results are considered valid. A study that adheresmostly to the commonly held concepts of high quality <strong>in</strong>clud<strong>in</strong>g the follow<strong>in</strong>g: a rigorouslyconducted systematic review or meta-analysis; clear description of the population, sett<strong>in</strong>g,<strong>in</strong>terventions <strong>and</strong> comparison groups; clear description of the content of the comparisongroups; appropriate measurement of outcomes; appropriate statistical assumptions <strong>and</strong>analytic methods <strong>and</strong> report<strong>in</strong>g; appropriate consideration <strong>and</strong> adjustment for potentialconfounders; rigorous assessment of <strong>in</strong>dividual study quality; no report<strong>in</strong>g errors; <strong>and</strong> wellreasonedconclusions based on the data reported.B (fair/moderate)Category B studies are susceptible to some bias, but not sufficient to <strong>in</strong>validate the results.They do not meet all the criteria <strong>in</strong> category A because they have some deficiencies, but noneof which are likely to cause major biases. The study may have suboptimal adjustment forpotential confounders. The study may also be miss<strong>in</strong>g <strong>in</strong>formation, mak<strong>in</strong>g it difficult toassess limitations <strong>and</strong> potential problems.C (poor)Category C studies have significant biases that may <strong>in</strong>validate the results. The study eitherdid not consider potential confounders or did not adjust for them appropriately. These studieshave serious errors <strong>in</strong> design, analysis or report<strong>in</strong>g; have large amounts of miss<strong>in</strong>g<strong>in</strong>formation, or discrepancies <strong>in</strong> report<strong>in</strong>g.It should be noted that while we assessed the methodological quality of the systematic reviews ormeta-analyses, it was not possible to evaluate the quality of the primary studies <strong>in</strong>cluded <strong>in</strong> thosereviews/analyses, as we did not exam<strong>in</strong>e those studies first h<strong>and</strong>. For systematic reviews/metaanalysesthat had equivocal grad<strong>in</strong>g between moderate <strong>and</strong> poor, the results <strong>and</strong> the reasons for the<strong>in</strong>itial grade assignments were presented to the entire group of project <strong>in</strong>vestigators <strong>and</strong> the f<strong>in</strong>algrades were adjudicated.Grad<strong>in</strong>g of Individual Primary Studies <strong>in</strong> Updates <strong>and</strong>New ReviewsA well-performed RCT with proper r<strong>and</strong>omization, allocation concealment, clear def<strong>in</strong>itions ofbreastfeed<strong>in</strong>g exposure compared with non-breastfeed<strong>in</strong>g, <strong>and</strong> bl<strong>in</strong>ded assessment of outcomes willyield the best evidence <strong>in</strong> support<strong>in</strong>g the causality of breast milk <strong>in</strong> affect<strong>in</strong>g health outcomes.But with the recognized benefits of breast milk, this approach is ethically not feasible. Othertypes of studies <strong>in</strong>volve follow<strong>in</strong>g the health outcomes from r<strong>and</strong>omization of <strong>in</strong>tervention topromote <strong>and</strong> support breastfeed<strong>in</strong>g (e.g., Belarus study 17 ), this type of study will yield <strong>in</strong>directevidence for the relationship between breastfeed<strong>in</strong>g <strong>and</strong> health18
outcomes provided that there is a differential effect from the <strong>in</strong>tervention on breastfeed<strong>in</strong>g ratesbetween the comparison groups. Prospective observational cohort studies with proper adjustmentof potential confounders provide the bulk of data <strong>in</strong> this field. However, the possibility ofresidual confound<strong>in</strong>g that could expla<strong>in</strong> the observed association between breastfeed<strong>in</strong>g <strong>and</strong> thespecific health outcomes can never be completely ruled out. Case-controlled design is an evenless attractive option because of the concern for case selection bias <strong>and</strong> suboptimal match<strong>in</strong>g tocontrol subjects.For the assessment of RCTs, the criteria were based on the CONSORT statement forreport<strong>in</strong>g RCTs (a checklist with specifications for report<strong>in</strong>g all aspects of a trial). 23,24 We ma<strong>in</strong>lyconsidered the methods used for r<strong>and</strong>omization, allocation concealment, <strong>and</strong> bl<strong>in</strong>d<strong>in</strong>g as well asthe use of <strong>in</strong>tention-to-treat analysis, the report of well-described valid primary outcomes, <strong>and</strong>the dropout rate. For non-r<strong>and</strong>omized trials, we used the report of eligibility criteria <strong>and</strong> assessedthe adequacy of controll<strong>in</strong>g for differences between comparative groups <strong>in</strong> terms of basel<strong>in</strong>echaracteristics <strong>and</strong> prognostic factors. We also considered the report of <strong>in</strong>tention-to-treatanalysis, <strong>and</strong> the crossovers when so designed, as well as important differential loss to followupbetween the comparative groups or overall high loss to followup. The validity <strong>and</strong> the adequatedescription of outcomes <strong>and</strong> results were also assessed. For the assessment of prospectivecohorts <strong>and</strong> case-control studies (cross-over design <strong>and</strong> retrospective cohort studies wereexcluded from this review), we used a rat<strong>in</strong>g checklist largely based on the Newcastle-OttawaQuality Assessment scales for cohort <strong>and</strong> case-control studies(www.ohri.ca/programs/cl<strong>in</strong>ical_epidemiology/oxford.htm). Items assessed <strong>in</strong>cluded selection ofcases <strong>and</strong> controls or cohorts, comparability, <strong>in</strong>formation concern<strong>in</strong>g exposure/<strong>in</strong>tervention,consideration for potential confounders, <strong>and</strong> percentage of withdrawals or dropouts. In particular,we paid close attention to the quality of the breastfeed<strong>in</strong>g data, whether they were obta<strong>in</strong>edprospectively or by retrospective recall, whether a dist<strong>in</strong>ction was made between exclusive <strong>and</strong>partial breastfeed<strong>in</strong>g, <strong>and</strong> whether the duration of breastfeed<strong>in</strong>g was reported. We also paid closeattention to consideration of <strong>and</strong> appropriate adjustment for potential confounders.We applied a three category summary grad<strong>in</strong>g system (A, B, C) to each study. This systemdef<strong>in</strong>es a generic grad<strong>in</strong>g system that is applicable to each type of study design <strong>in</strong>clud<strong>in</strong>gr<strong>and</strong>omized controlled trials, cohort, <strong>and</strong> case-control studies:A (good)Category A studies have the least bias <strong>and</strong> results are considered valid. A study that adheresmostly to the commonly held concepts of high quality <strong>in</strong>clud<strong>in</strong>g the follow<strong>in</strong>g: cleardescription of the population, sett<strong>in</strong>g, <strong>in</strong>terventions <strong>and</strong> comparison groups; clear descriptionof the comparison groups; appropriate measurement of outcomes; appropriate statistical <strong>and</strong>analytic methods <strong>and</strong> report<strong>in</strong>g; no report<strong>in</strong>g errors; less than 20 percent dropout; clearreport<strong>in</strong>g of dropouts; <strong>and</strong> appropriate consideration <strong>and</strong> adjustment for potentialconfounders.B (fair/moderate)Category B studies are susceptible to some bias, but not sufficient to <strong>in</strong>validate the results.They do not meet all the criteria <strong>in</strong> category A because they have some deficiencies, but noneof which are likely to cause major biases. The study may have suboptimal adjustment forpotential confounders. The study may also be miss<strong>in</strong>g <strong>in</strong>formation, mak<strong>in</strong>g it difficult toassess limitations <strong>and</strong> potential problems.19
C (poor)Category C studies have significant biases that may <strong>in</strong>validate the results. The study eitherdid not consider potential confounders or did not adjust for them appropriately. These studieshave serious errors <strong>in</strong> design, analysis or report<strong>in</strong>g; have large amounts of miss<strong>in</strong>g<strong>in</strong>formation, or discrepancies <strong>in</strong> report<strong>in</strong>g.For primary studies that had equivocal grad<strong>in</strong>g between moderate <strong>and</strong> poor, those studieswere reviewed <strong>and</strong> graded aga<strong>in</strong> by different reviewers <strong>and</strong> consensus was reached afterdiscussion among the reviewers. Lastly, it should be noted that the summary quality grad<strong>in</strong>gsystem evaluates <strong>and</strong> grades the studies with<strong>in</strong> their own design strata. It does not attempt toassess the comparative validity of studies across different design strata. Thus, one should becognizant of the study design when <strong>in</strong>terpret<strong>in</strong>g the methodological quality grade of a study.Report<strong>in</strong>g of the EvidenceWe reported each outcome separately <strong>in</strong> its own section <strong>in</strong> the results chapter. A briefexplanation of the importance of the outcome is followed by a description of <strong>in</strong>clusion/exclusioncriteria of studies exam<strong>in</strong>ed that are specific to that outcome. A description of the relevantsystematic review is followed by a description of the primary studies that were published afterthe latest search date of the systematic review. A summary table highlighted important f<strong>in</strong>d<strong>in</strong>gs.A summary conclusion regard<strong>in</strong>g breast milk <strong>and</strong> that particular outcome is made <strong>in</strong> the lastsection. Conclusions were drawn only from studies of high or moderate (grade A or B)methodological quality. For dichotomous outcome, either the summary risk ratio or odds ratio isreported. For cont<strong>in</strong>uous outcome, the comparative difference <strong>in</strong> the actual measurement for thatoutcome is reported (e.g., IQ po<strong>in</strong>ts, mm Hg of blood pressure). When only studies of C qualityare available, we summarize the f<strong>in</strong>d<strong>in</strong>gs from those studies <strong>and</strong> expla<strong>in</strong> the reasons for the “C’rat<strong>in</strong>g, but we do not draw conclusions from them.Extracted data are compiled <strong>in</strong> evidence tables. The tables offer a detailed description of thestudies that addressed each of the key questions. The tables (see Appendix C) a provide detailed<strong>in</strong>formation about the study design, the sample size, the patient characteristics, the <strong>in</strong>tervention<strong>and</strong> comparison group feed<strong>in</strong>g methods, the followup, the major outcomes, <strong>and</strong> themethodological quality. In addition, for systematic reviews <strong>and</strong> meta-analyses, we reported thedatabases searched <strong>and</strong> for which time period, the number <strong>and</strong> the type of primary studies<strong>in</strong>cluded, <strong>and</strong> the type of comparison addressed.Summary tables succ<strong>in</strong>ctly report summary measures of the ma<strong>in</strong> outcomes evaluated. They<strong>in</strong>clude <strong>in</strong>formation regard<strong>in</strong>g study design, <strong>in</strong>tervention <strong>and</strong> comparison group, feed<strong>in</strong>gmethods, study duration or followup, sample size (subjects enrolled <strong>and</strong> analyzed <strong>in</strong> each arm),potential confounders, results of major outcomes, <strong>and</strong> methodological quality. These tables weredeveloped by condens<strong>in</strong>g <strong>in</strong>formation from the evidence tables. They are designed to facilitatecomparisons <strong>and</strong> synthesis across studies. A methodological quality was assigned to each studyas described previously.a Appendixes <strong>and</strong> Evidence Tables cited <strong>in</strong> this report are provided electronically at http://www.ahrq.gov/cl<strong>in</strong>ic/tp/ brfouttp.htm.20
†Four historical cohort studies reported data on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> both CVD <strong>and</strong> IHDmortality.Figure 2. The relationship between exclusive breastfeed<strong>in</strong>g <strong>and</strong> health outcomes <strong>in</strong> term <strong>in</strong>fants - metaanalysisresultsMA, meta-analysis; AOM, acute otitis media; FH, family history; Hosp, hospitalization; exclu, exclusive; LRTI, lowerrespiratory track <strong>in</strong>fection*18 studies <strong>in</strong> total were <strong>in</strong>cluded <strong>in</strong> Gdalevich 2001 meta-analyses. The number of studies per comparison was notreported.22
Figure 3. The relationship between breastfeed<strong>in</strong>g <strong>and</strong> maternal outcomes - meta-analysis resultsMA, meta-analysis; BC, breast cancer; RR, relative risk; OC, ovarian cancer; adj, adjustedLiterature Search ResultsIn the early phase of explor<strong>in</strong>g the literature available for this report, a large number ofpublished systematic reviews or meta-analyses were identified for various outcomes of <strong>in</strong>terest.We screened over 300 abstracts for published systematic reviews <strong>and</strong> meta-analysis. We<strong>in</strong>cluded all relevant systematic reviews <strong>and</strong> meta-analyses, although some of them <strong>in</strong>cludedprimary studies that were conducted <strong>in</strong> develop<strong>in</strong>g countries. A total of 29 systematic reviews ormeta-analyses met our <strong>in</strong>clusion criteria. These systematic reviews or meta-analyses <strong>in</strong>cluded atotal m<strong>in</strong>imum of 343 to a maximum of 494 unique primary studies (as some of the same studieswere covered <strong>in</strong> multiple reviews). In this chapter, we summarized the f<strong>in</strong>d<strong>in</strong>gs <strong>and</strong> authors’conclusions from these systematic reviews <strong>and</strong> meta-analyses. If multiple systematic reviews <strong>and</strong>meta-analyses were available on the same outcome of <strong>in</strong>terest, we also compared the differences<strong>and</strong> similarities between them.We screened over 9,000 abstracts for potential relevant articles on the relationship betweenbreastfeed<strong>in</strong>g or breast milk feed<strong>in</strong>g <strong>and</strong> various <strong>in</strong>fant <strong>and</strong> maternal outcomes. After the <strong>in</strong>itialscreen<strong>in</strong>g, we categorized the abstracts accord<strong>in</strong>g to the populations <strong>and</strong> outcomes of <strong>in</strong>terest.For outcomes of <strong>in</strong>terest that had previously been reviewed systematically, we excluded abstractsthat were published before the search dates of previous systematic reviews or meta-analyses. Forthe rema<strong>in</strong><strong>in</strong>g abstracts, we retrieved the correspond<strong>in</strong>g full articles <strong>and</strong> applied additional<strong>in</strong>clusion or exclusion criteria tailored for the specific outcomes. For outcomes of <strong>in</strong>terest thathad not been reviewed systematically, we performed a new systematic review on all relevantprimary studies that were conducted <strong>in</strong> developed countries.23
F<strong>in</strong>ally, a total of 43 unique primary studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong><strong>in</strong>fant health outcomes, <strong>and</strong> a total of 43 unique primary studies on the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> maternal health outcomes were <strong>in</strong>cluded. Details of the <strong>in</strong>clusion <strong>and</strong>exclusion of abstracts <strong>and</strong> full article screen<strong>in</strong>gs were summarized <strong>in</strong> Figures 1 <strong>and</strong> 2. The fullarticle <strong>in</strong>clusion or exclusion criteria were described <strong>in</strong> Chapter 2, <strong>and</strong> the additional <strong>in</strong>clusion orexclusion criteria tailored for the specific outcomes were described under each outcome section<strong>in</strong> this chapter.Organization of ResultsIn this chapter, we grouped studies <strong>in</strong>to one of the three parts of this report accord<strong>in</strong>g to thetarget population – Part I: term <strong>in</strong>fant outcomes, Part II: preterm <strong>in</strong>fant outcomes, Part III:maternal outcomes.In Part I, we summarized the results for health outcomes <strong>in</strong> term <strong>in</strong>fants, <strong>in</strong>clud<strong>in</strong>g acuteotitis media, atopic dermatitis, gastro<strong>in</strong>test<strong>in</strong>al <strong>in</strong>fections, lower respiratory <strong>in</strong>fection, asthma,cognitive development, obesity, cardiovascular diseases, cholesterols, blood pressure,cardiovascular mortality, type 1 <strong>and</strong> 2 diabetes, childhood leukemia, <strong>in</strong>fant mortality, <strong>and</strong> sudden<strong>in</strong>fant death syndrome.In Part II, we summarized the results for necrotiz<strong>in</strong>g enterocolitis (NEC) <strong>and</strong> cognitivedevelopment <strong>in</strong> relationship to breast milk feed<strong>in</strong>g <strong>in</strong> preterm <strong>in</strong>fants, respectively.In Part III, we summarized the results for maternal health outcomes, <strong>in</strong>clud<strong>in</strong>g return<strong>in</strong>g topre-pregnancy weight, postpartum weight changes, maternal type 2 diabetes, osteoporosis,postpartum depression, breast cancer, <strong>and</strong> ovarian cancer.24
Figure 4. Primary studies available to assess the relationship between breastfeed<strong>in</strong>g <strong>and</strong> <strong>in</strong>fant health outcomes.9318 abstracts wereidentified <strong>in</strong> the searchAbstract screen<strong>in</strong>g~400 abstracts werescreened-<strong>in</strong><strong>Maternal</strong>outcomesSee next page*Exclusion criteria:1. Conducted <strong>in</strong> develop<strong>in</strong>gcountries2. Published before thesearch dates of the latestsystematic review or metaanalysis3. Non-human studies4. Non-English publications5. No outcome of <strong>in</strong>terest6. <strong>Outcomes</strong> that are notdesignated for update~8,800Excluded*~240 Excluded*for both <strong>in</strong>fant<strong>and</strong> maternaloutcomes<strong>Infant</strong> outcomesFull-textscreen<strong>in</strong>gArticles from h<strong>and</strong>search,bibliography, oridentified by fieldexpertsAOM12Asthma27Cognitivefunction39Diabetes18NEC10<strong>Infant</strong>mortality2SIDS725Term30Preterm9Type 115Type 23Meet<strong>in</strong>g specific <strong>in</strong>clusion criteriafor the outcome?YesNoExcludedAOM6Asthma4Cognitive functionTerm8Preterm8Type 1DM6Type 2DM0NEC3<strong>Infant</strong>mortality2SIDS4A total of 43 unique studies were <strong>in</strong>cluded for updates of <strong>in</strong>fant outcomes
Figure 5. Primary studies available to assess the relationship between breastfeed<strong>in</strong>g <strong>and</strong> maternal health outcomes.See previous page<strong>Infant</strong>outcomes~400 abstracts werescreened-<strong>in</strong>Yes<strong>Maternal</strong> outcomesIs there a published sytematicreviews or meta-analyses?*Exclusion criteria:1. Conducted <strong>in</strong> develop<strong>in</strong>gcountries3. Non-human studies4. Non-English publications5. No outcome of <strong>in</strong>terestNoBreastcancer35Diabetes4Perform de novo systematic reviewsFull-textscreen<strong>in</strong>gExcluded*26**Exclusion criteria:1. Conducted <strong>in</strong>develop<strong>in</strong>g countries2. Published beforethe search dates ofthe latest systematicreview or metaanalysis3. Non-human studies4. Non-EnglishpublicationFull-textscreen<strong>in</strong>gExcluded**Postpartumdepression35Fractures6Osteoporosis44BMD/BMC38Return to prepregnancyweight /postpartum weightchanges54Ovarian cancer26Meet specific <strong>in</strong>clusion criteria?ExcludedYesBreastcancer3Type 2DM1Postpartumdepression6Fracture6BMD/BMC4Weight8Ovariancancer15A total of 43 unique studies were <strong>in</strong>cluded for updates of maternal outcomes
Part I. Term <strong>Infant</strong> <strong>Outcomes</strong>Relationship between Acute Otitis Media <strong>and</strong> <strong>Breastfeed<strong>in</strong>g</strong>BackgroundAcute otitis media (AOM) is a common childhood <strong>in</strong>fection. It often beg<strong>in</strong>s with an upperrespiratory tract <strong>in</strong>fection. The viral <strong>in</strong>fection predisposes the child to the development of AOMby caus<strong>in</strong>g eustachian tube dysfunction. The eustachian tube dysfunction enhancesnasopharyngeal colonization with middle ear pathogens. The prevalence of a first attack of AOM<strong>in</strong> children under l year of age was estimated to be 44 percent. 25 Almost 70 percent of childrenunder 6 years of age have had an episode of AOM. 25 Several risk factors have been identified for<strong>in</strong>creas<strong>in</strong>g the occurrence <strong>and</strong> recurrence of AOM. 26 There is a general consensus thatbreastfeed<strong>in</strong>g protects aga<strong>in</strong>st many <strong>in</strong>fections, <strong>in</strong>clud<strong>in</strong>g AOM. Breast milk conta<strong>in</strong>simmunoglobul<strong>in</strong>s with antibody activity aga<strong>in</strong>st common bacteria such as Haemophilus<strong>in</strong>fluenzae <strong>and</strong> Streptococcus pneumoniae. It also conta<strong>in</strong>s components that <strong>in</strong>terfere with theattachment of Haemophilus <strong>in</strong>fluenzae <strong>and</strong> Streptococcus pneumoniae to nasopharyngealepithelial cells. The <strong>in</strong>termittent adm<strong>in</strong>istration of milk with anti-adhesive substances <strong>in</strong>to thenasopharynx of the nurs<strong>in</strong>g child may reduce the extent of colonization <strong>and</strong> protect aga<strong>in</strong>st<strong>in</strong>fection. 27Commonly considered confounders <strong>in</strong> the studies of the relationship between breastfeed<strong>in</strong>g<strong>and</strong> AOM were parental history of allergy, number of sibl<strong>in</strong>gs, use of day care, maternalsmok<strong>in</strong>g, gender, ethnicity, <strong>and</strong> socioeconomic status.We identified one meta-analysis of risk factors for AOM that aimed to further clarifypossible means of prevent<strong>in</strong>g AOM <strong>in</strong> childhood. 28 Duration of breastfeed<strong>in</strong>g was one of thefactors exam<strong>in</strong>ed. S<strong>in</strong>ce this meta-analysis, we identified six studies <strong>in</strong> seven publications thatexam<strong>in</strong>ed the relationship between breastfeed<strong>in</strong>g <strong>and</strong> AOM.Additional Methodological CommentsUhari 1996 compared the risk of AOM among children who were breastfed for variousdurations – breastfeed<strong>in</strong>g for 3 or more months versus less than 3 months, 6 or more monthsversus less than 6 months, <strong>and</strong> ever breastfeed<strong>in</strong>g versus never breastfeed<strong>in</strong>g. 28 The cl<strong>in</strong>ical <strong>and</strong>statistical heterogeneity of the studies <strong>in</strong>cluded were not reported. The methodological quality ofthe meta-analysis was rated grade C, because there was no consideration for potentialconfound<strong>in</strong>g <strong>and</strong> poor report<strong>in</strong>g of study characteristics (Table 1).S<strong>in</strong>ce the meta-analysis was of poor quality, we decided to conduct a new meta-analysiscomb<strong>in</strong><strong>in</strong>g adjusted odds ratios or risk ratios of AOM compar<strong>in</strong>g breastfed <strong>in</strong>fants with nonbreastfed<strong>in</strong>fants from the studies identified <strong>in</strong> Uhari 1996 <strong>and</strong> from the update search. We only<strong>in</strong>cluded studies that reported the relationship between breastfeed<strong>in</strong>g <strong>and</strong> the occurrence of AOM<strong>in</strong> <strong>in</strong>fants without co-morbidities (e.g., cleft palate). Of the 10 studies <strong>in</strong>cluded <strong>in</strong> Uhari 1996meta-analysis, only three reported adjusted odds ratios or risk ratios of AOM compar<strong>in</strong>gbreastfed <strong>in</strong>fants with non-breastfed <strong>in</strong>fants. 29-31 Those studies are summarized <strong>in</strong> Table 2.27
Studies Identified after the Systematic Review/Meta-analysis (Table 2)A total of five cohort studies (<strong>in</strong> 6 publications) 3,32-36 <strong>and</strong> one case-control study 37 thatevaluated the relationship of breastfeed<strong>in</strong>g <strong>and</strong> AOM published after the search dates of Uhari’smeta-analysis met our <strong>in</strong>clusion criteria. We <strong>in</strong>cluded only studies conducted <strong>in</strong> developedcountries among children without co-morbidity. In cohort studies, subjects <strong>in</strong> the studies werefollowed from birth to a mean of 6 to 24 months. The number of subjects evaluated ranged from289 to 15,113 at basel<strong>in</strong>e. Four of the five cohort studies were of methodological quality gradeB, while the other one was of grade C. In the case-control study, the children were between theages of 3 <strong>and</strong> 7 years at the time of exam<strong>in</strong>ation. A total of 179 AOM cases <strong>and</strong> 305 controlswere analyzed. The methodological quality of the case-control study was rated C because theanalysis did not control for potential confound<strong>in</strong>g.Studies varied <strong>in</strong> the def<strong>in</strong>itions of breastfeed<strong>in</strong>g <strong>and</strong> comparison groups. All studies weredesigned to evaluate a broad range of potential risk factors <strong>in</strong> AOM, except for Scariati 1997 <strong>in</strong>which the study specifically aimed to exam<strong>in</strong>e the relationship between breastfeed<strong>in</strong>g <strong>and</strong><strong>in</strong>fections. We focused only on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> AOM. The studiesalso varied <strong>in</strong> their def<strong>in</strong>itions of the disease conditions. In most studies, def<strong>in</strong>itions of AOMwere based on cl<strong>in</strong>ical features comb<strong>in</strong>ed with otoscopic f<strong>in</strong>d<strong>in</strong>gs. The data were collected frommedical records <strong>and</strong> confirmed by a physician <strong>in</strong> all studies except for Vernacchio 2004 <strong>and</strong>Scariati 1997 where a mother was asked to report ear <strong>in</strong>fection <strong>in</strong> a list of diagnoses orsymptoms.All cohort studies adjusted for potential confounders <strong>and</strong> the case-control study did not.Confound<strong>in</strong>g factors considered <strong>in</strong> the studies <strong>in</strong>cluded gender, number of sibl<strong>in</strong>gs, family daycare, nursery day care, number of children <strong>in</strong> the home, maternal age, parental race or ethnicity,parity, maternal marital status, <strong>and</strong> parental smok<strong>in</strong>g.<strong>Breastfeed<strong>in</strong>g</strong> was associated with a reduced risk of AOM compared to bottle-feed<strong>in</strong>g aftercontroll<strong>in</strong>g for potential confounders across the five cohort studies, although some studies didnot report a statistically significant result.When exclusive breastfeed<strong>in</strong>g for more than 3 or 6 months was compared with exclusivebottle- or formula- feed<strong>in</strong>g, one study reported 28 percent 33 <strong>and</strong> another study reported 45percent 3 relative risk reduction <strong>in</strong> AOM. The case-control study did not show a significantdifference <strong>in</strong> the risk of AOM between the children who were ever breastfed <strong>and</strong> those who didnot. However, the analysis did not control for any potential confound<strong>in</strong>g factors.Meta-analysis. In addition to the five cohort studies <strong>in</strong> the update search, three additionalcohort studies that reported adjusted odds ratios or risk ratios of AOM from Uhari 1996 werereviewed for possible <strong>in</strong>clusion <strong>in</strong>to our meta-analyses. Studies were heterogeneous <strong>in</strong> thedef<strong>in</strong>itions of breastfeed<strong>in</strong>g <strong>and</strong> comparison groups. In order to m<strong>in</strong>imize the heterogeneity, werestricted our analyses to studies that reported an adjusted odds ratio or risk ratio of AOMcompar<strong>in</strong>g any def<strong>in</strong>ition of breastfeed<strong>in</strong>g duration to exclusive bottle-feed<strong>in</strong>g. Five studies thatreported data from a total of six comparisons met the <strong>in</strong>clusion criteria for our metaanalyses.3,29,31,33,35 Us<strong>in</strong>g a r<strong>and</strong>om effects model, pooled data from five cohort studies of good<strong>and</strong> moderate methodological quality showed an adjusted odds ratio of AOM of 0.60 (95%CI0.46-0.78) compar<strong>in</strong>g breastfeed<strong>in</strong>g to exclusive bottle-feed<strong>in</strong>g. There is a significant difference<strong>in</strong> the risk reduction of AOM between the studies compar<strong>in</strong>g exclusive breastfeed<strong>in</strong>g withexclusive bottle-feed<strong>in</strong>g <strong>and</strong> the studies compar<strong>in</strong>g ever breastfeed<strong>in</strong>g with exclusive bottlefeed<strong>in</strong>g(P
0.91), when compar<strong>in</strong>g children who were ever breastfed with children who were exclusivelybottle-fed <strong>in</strong> two studies. The pooled adjusted odds ratio was 0.50 (95%CI 0.36-0.70), whencompar<strong>in</strong>g children who were exclusively breastfed for at least 3 or 6 months with those whowere exclusively bottle-fed for at least 3 or 6 months <strong>in</strong> three studies (provid<strong>in</strong>g 4 estimates).The three studies that were excluded from our meta-analyses compared breastfeed<strong>in</strong>g formore than 13 weeks, 4 months, <strong>and</strong> 6 months with breastfeed<strong>in</strong>g for less than 13 weeks, 4months, <strong>and</strong> less than 6 months, respectively. 29,30,32 There was no significant association betweenthe risk of AOM <strong>and</strong> breastfeed<strong>in</strong>g for more than 13 weeks, while a significant risk reduction <strong>in</strong>AOM was found when compar<strong>in</strong>g children who were breastfed for more than 4 months or 6months with those who were breastfed for less than 4 months or 6 months, respectively.29
Figure 6. Meta-analysis of the association between breastfeed<strong>in</strong>g <strong>and</strong> the risk of AOM compared to exclusivebottle-feed<strong>in</strong>g <strong>in</strong> cohort studies* Exclusive breastfeed<strong>in</strong>g ≥ 6 months vs. exclusive bottle-feed<strong>in</strong>g <strong>and</strong> breastfeed<strong>in</strong>g < 4 moConclusionThe results from our meta-analyses of cohort studies of good <strong>and</strong> moderate methodologicalquality showed that breastfeed<strong>in</strong>g was associated with a significant reduction <strong>in</strong> the risk ofAOM. Compar<strong>in</strong>g ever breastfeed<strong>in</strong>g with exclusive bottle-feed<strong>in</strong>g, the pooled adjusted oddsratio of AOM was 0.77 (95%CI 0.64 - 0.91). When compar<strong>in</strong>g exclusive breastfeed<strong>in</strong>g withexclusive bottle-feed<strong>in</strong>g, either for more than 3 or 6 months duration, the pooled odds ratio was0.50 (95%CI 0.36 - 0.70).30
31Table 1. Summary of systematic review/meta-analysis on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> acute otitis media (AOM)Author YearStudy Intervention ConfoundersPopulationdescription /Comparator consideredResultsUhari 1996 MA of 2 casecontrolAny measures of ND<strong>and</strong> 8 breastfeed<strong>in</strong>gcohort studies <strong>in</strong> <strong>and</strong> comparatorsdevelopedcountriesAOM <strong>in</strong>children.Specific agegroups notspecified <strong>in</strong>the cohortsCase- control:671Cohort: 4,455AOM, Acute Otitis Media; SR, systematic review; MA, meta-analysis10 studies evaluated the risk of AOM <strong>and</strong> recurrence of AOMassociated with breastfeed<strong>in</strong>g. The diagnosis of AOM varied,but pneumatic otoscopy was used <strong>in</strong> the diagnosis. There wasno restriction on study <strong>in</strong>clusion accord<strong>in</strong>g to the diagnosticcriteria used. 22 studies evaluat<strong>in</strong>g an array of risk factors fordevelopment <strong>and</strong> recurrence of AOM were <strong>in</strong>cluded <strong>in</strong> themeta-analysis. Seven of the twenty-two studies specificallyevaluated the association between breastfeed<strong>in</strong>g <strong>and</strong> AOM,while another 3 studies <strong>in</strong>cluded breastfeed<strong>in</strong>g among otherrisk factors that were evaluated.<strong>Breastfeed<strong>in</strong>g</strong> for at least 3 months reduced the risk of AOM(RR=0.87; 95%CI: 0.79-0.95)Children who were breastfed for 3 or more months had a nonstatisticallysignificant reduced risk of recurrent AOMcompared with those who were breastfed less than 3 months(RR 0.69, 95%CI 0.46 - 1.03).When children who were breastfed for 6 months or more werecompared to those who were breastfed for less than 6 months,a statistically significant reduced risk of recurrent AOM wasfound (RR=0.69; 95%CI: 0.49-0.97).Quality of SR/MA <strong>and</strong>limitationsCNo consideration for potentialconfound<strong>in</strong>g, no restriction on<strong>in</strong>clusion accord<strong>in</strong>g to thediagnostic criteria used forAOM; unclear howbreastfeed<strong>in</strong>g data wascollected
Table 2. Summary table for cohort studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> acute otitis mediaNumber ofAuthor YearMeanOR (95% CI)subjects Def<strong>in</strong>ition of<strong>Breastfeed<strong>in</strong>g</strong> ComparatorCountryduration(Basel<strong>in</strong>e AOMgroup (n) group (n)DesignFollowupCrude Adjusted/Followup)Confounders / riskfactors adjustedQuality <strong>and</strong>limitations32Studies <strong>in</strong> update searchVernacchio2004USAProspectivecohortScariati 1997USProspectivecohortSassen 1994Netherl<strong>and</strong>sProspectivecohort15,113/11,3491,743 /1410289 /232Mother selectsear <strong>in</strong>fection froma list of diagnosesby physician <strong>in</strong>the past monthMother reportedsymptomsCl<strong>in</strong>ical diagnosisby physician.Tympanometryresults not used.6 mo7 mo23.6 moBF at 6 mo(2,771)Exclusive BF at 6mo (299)Overall effectbefore stopp<strong>in</strong>gBF (OR permonth)No BF at 6mo (8,558)Exclusiveformula at 6mo (891)1-57% mixedfeed<strong>in</strong>g (81)58-88%mixedfeed<strong>in</strong>g (80)89-99%mixedfeed<strong>in</strong>g (59)Up to 4 moafterstopp<strong>in</strong>g BF0.66(0.59-0.74)0.69(0.61-0.78)0.45 0.56, p
33Table 2. Cont<strong>in</strong>uedAuthor YearCountryDesignDuffy 1997F<strong>in</strong>l<strong>and</strong> cProspectivecohortAlho 1996 (2papers)F<strong>in</strong>l<strong>and</strong>RetrospectivecohortStenstrom,1997SwedenNumber ofsubjects(Basel<strong>in</strong>e/Followup)Exclusivebreast: 178/ 53 @ 3mo / 28 @6 moComb<strong>in</strong>edBF <strong>and</strong>formula: 18@ basel<strong>in</strong>eExclusiveformula:110 @basel<strong>in</strong>e2,512 / 825Def<strong>in</strong>ition ofAOMExclusive formula:110 @ basel<strong>in</strong>e>1 acutesymptoms <strong>and</strong>onepneumatoscopicf<strong>in</strong>d<strong>in</strong>g up to age2 yrsCase-controlstudyAOMcases: 179Control d :305> 5 episodes ofAOM (Otoscopicdiagnosis) beforeage of 30 moStudies <strong>in</strong> MA that reported adjusted OR / RRDuncan 1993USProspectivecohort1220 /1013Diagnosed byexperiencedcl<strong>in</strong>icians with anaverage of > 9 yrs<strong>in</strong> pediatricpracticeMe<strong>and</strong>urationFollowupExclusiveformula:110 @basel<strong>in</strong>e22 mo<strong>Breastfeed<strong>in</strong>g</strong>group (n)Exclusive 3-moBFExclusive 6-moBF6-mo mixedfeed<strong>in</strong>gEver BF (nd)BF > 3 mo (735)Comparatorgroup (n)Exclusive 3-mo formulaExclusive 6-mo formulaExclusive 6-mo formulaNever BF(nd)BF < 3 mo(90)Crude0.72(0.52-1.00)0.550.34-0.87)0.71(0.53-0.96)0.9 (0.8-1.0)OR (95% CI)RR (95% CI)Adjusted0.72(0.52-1.00)0.550.34-0.87)0.30(0.19-0.48)0.8 (0.7-0.9) eConfounders / riskfactors adjustedAge at colonization, daycare, maternal smok<strong>in</strong>gGender, number ofsibl<strong>in</strong>gs, atopy, age,season of birth, daycare, parental smok<strong>in</strong>gN/A Ever BF Never BF NS None12 moExclusive BF ≥ 6mo (154)BF ≥ 4 mo, suppl4-6 mo (199)BF ≥ 4 mo, suppl
34Table 2. Cont<strong>in</strong>uedAuthor YearCountryDesignTeele 1989USProspectivecohortHowie 1990Scotl<strong>and</strong>ProspectivecohortNumber ofsubjects(Basel<strong>in</strong>e/Followup)1067 / 877750 / 617Def<strong>in</strong>ition ofAOMEffusion <strong>in</strong> one orboth middle earsaccompanied by≥ 1 signs of acuteillness bMother reportedthat <strong>in</strong>fantexperiencedpa<strong>in</strong>ful ordischarg<strong>in</strong>g earlast<strong>in</strong>g for 48 hrsor moreMe<strong>and</strong>urationFollowup<strong>Breastfeed<strong>in</strong>g</strong>group (n)12 mo Ever BF (292)12 moExclusive BF ≥ 13wk (89) or partialBF ≥ 13 wk (121)Comparatorgroup (n)Never BF(585)Bottlefeeders (246)<strong>and</strong> BF < 13wk(161)Crude≥ 1 episode ofAOM: 0.830.7 (0.5–1.0)OR (95% CI)Adjusted≥ 1 episode ofAOM: 0.64(0.44-0.91)≥ 3 episode ofAOM: 0.51(0.30-0.89)NS <strong>in</strong> the %<strong>in</strong>fantsexperiencedear <strong>in</strong>fectionBF, breastfeed<strong>in</strong>g; excl, exclusive; ROM, recurrent otitis media; SES, socioeconomic statusa Mean duration of exclusive BF (95% CI)b Signs of acute illness <strong>in</strong>clud<strong>in</strong>g earache, otorrhea, ear tugg<strong>in</strong>g, fever, irritability, lethargy, anorexia, vomit<strong>in</strong>g or diarrheac Proportion of <strong>in</strong>fants <strong>in</strong> the <strong>in</strong>dividual categories of feed<strong>in</strong>g method at different time cut-offs is not availableConfounders / riskfactors adjustedSite of health care,season of birth, birthweight, gender, SES,number of sibl<strong>in</strong>gs,sibl<strong>in</strong>g or parental historyof <strong>in</strong>fection, parentalsmok<strong>in</strong>gFather’s social class,maternal age, <strong>and</strong>parental smok<strong>in</strong>gQuality <strong>and</strong>limitationsBBd Matched to the case by age <strong>and</strong> gendere Values were estimated from figure. Statistically modeled to fit the whole sample.
Relationship between Atopic Dermatitis <strong>and</strong> <strong>Breastfeed<strong>in</strong>g</strong>BackgroundAtopic dermatitis is a common problem with an estimated lifetime prevalence <strong>in</strong> children of10-20 percent. 38 Many studies have <strong>in</strong>vestigated the possible protective effect of breastfeed<strong>in</strong>gon the development of atopic dermatitis. The results have been conflict<strong>in</strong>g. 16,38,39 Potentialconfounders considered <strong>in</strong> the studies <strong>in</strong>cluded gender, socioeconomic status, family history ofatopy, parental smok<strong>in</strong>g, <strong>and</strong> presence of furry animals <strong>in</strong> the home. 40Published Systematic Review/Meta-Analysis (Table 3)We identified one systematic review/meta-analysis that exam<strong>in</strong>ed the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> the development of atopic dermatitis. 40 The methodological quality of thissystematic review/meta-analysis was rated grade A.Us<strong>in</strong>g the MEDLINE database from 1966 to 2000, Gdalevich 2001 identified 18 prospectivestudies from developed countries that qualified for <strong>in</strong>clusion <strong>in</strong> the review. Sample size of thestudies ranged from 17 to 991. A total of 4,158 participants were <strong>in</strong>cluded. Mean followupduration was 4.5 years. Study selection criteria <strong>in</strong>cluded term <strong>in</strong>fant, restriction of maternal recallof the child’s feed<strong>in</strong>g history limited to the first 12 months of the <strong>in</strong>fants’ life, the breastfeed<strong>in</strong>ggroup <strong>in</strong> the study were exclusively breastfed for at least 3 months, bl<strong>in</strong>d<strong>in</strong>g of the feed<strong>in</strong>ghistory dur<strong>in</strong>g outcome assessment, strict diagnostic criteria of atopic dermatitis provided by theauthors, <strong>and</strong> control for confound<strong>in</strong>g variables like socioeconomic status <strong>and</strong> family history ofatopy.Us<strong>in</strong>g a fixed effect model, the overall summary odds ratio for the development of atopicdermatitis was 0.68 (95% CI 0.52 - 0.88) <strong>in</strong> those subjects with at least 3 months of exclusivebreastfeed<strong>in</strong>g versus subjects without 3 months of exclusive breastfeed<strong>in</strong>g. When the analysiswas restricted to those studies with positive family history of atopy, the odds ratio was 0.58(95%CI 0.41 - 0.92). When the analysis was restricted to those studies without a family historyof atopy, the odds ratio was 0.84 (95%CI 0.59 - 1.19).The systematic review did not make a dist<strong>in</strong>ction between atopic dermatitis of <strong>in</strong>fancy (under2 years of age) <strong>and</strong> persistent or new atopic dermatitis at older ages. However, <strong>in</strong> a primaryanalysis, the data were stratified accord<strong>in</strong>g to different durations of followup (because thediagnosis of atopic dermatitis <strong>in</strong> patients younger than 2 years of age are sometimes attributed tosymptoms of <strong>in</strong>fectious orig<strong>in</strong> <strong>and</strong> breastfeed<strong>in</strong>g may have a protective effect aga<strong>in</strong>st <strong>in</strong>fections).The summary odds ratio <strong>in</strong> the group with less than 2 years of followup was 0.74 (95%CI 0.61 –0.90), whereas the summary odds ratio <strong>in</strong> the group with 2 or more years of followup was 0.78(95%CI 0.62 – 0.99).The authors of the review concluded that there was a substantial protective effect ofbreastfeed<strong>in</strong>g aga<strong>in</strong>st atopic dermatitis <strong>in</strong> children with a family history of atopy.ConclusionAvailable evidence from one well-performed systematic review/meta-analysis on full term<strong>in</strong>fants <strong>in</strong> developed countries suggests that exclusive breastfeed<strong>in</strong>g for at least 3 months was35
associated with a reduction <strong>in</strong> the risk of atopic dermatitis <strong>in</strong> those subjects with a family historyof atopy.Table 3. Summary of systematic review/meta-analysis on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> the riskof develop<strong>in</strong>g atopic dermatitisAuthorYearGdalevich2001Term<strong>in</strong>fants4,158(17-991)Studiesdescription18 prospectivecohort studies<strong>in</strong> developedcountriesIntervention/Comparator≥ 3 mo ofexclusivebreastfeed<strong>in</strong>g vs.without ≥ 3 mo ofexclusivebreastfeed<strong>in</strong>gConfoundersconsideredSES, gender, familyhistory of atopy, parentalsmok<strong>in</strong>g, <strong>and</strong> presence offurry animals at home;also considered disease<strong>in</strong> < 2 yr of age vs. ≥ 2 yr(to sort out the possibleconfound<strong>in</strong>g protectiveeffect of breastfeed<strong>in</strong>g forsk<strong>in</strong> rash that is <strong>in</strong>fectious<strong>in</strong> etiology which might beconfused with thediagnosis of atopicdermatitis)SR, systematic review; MA, meta-analysis; SES, socioeconomic statusResultsOverall OR 0.68 (95% CI 0.52 -0.88, fixed effect model);When restricted to those withpositive family history, OR 0.58(95%CI 0.41 - 0.92)When restricted to those withoutfamily history, OR 0.84 (95%CI0.59 - 1.19)Authors’ conclusion: “There is asubstantial protective effect ofbreastfeed<strong>in</strong>g aga<strong>in</strong>st atopicdermatitis <strong>in</strong> children with afamily history of atopy.”QualityofSR/MAA36
Relationship between Gastro<strong>in</strong>test<strong>in</strong>al Infections <strong>and</strong><strong>Breastfeed<strong>in</strong>g</strong>BackgroundGastro<strong>in</strong>test<strong>in</strong>al <strong>in</strong>fections are common <strong>in</strong> <strong>in</strong>fants <strong>and</strong> children. Rate of diarrheal disease <strong>in</strong>US was estimated to be 1.1 episodes per person-year <strong>in</strong> children less than 5 years old. 41 Manystudies have <strong>in</strong>vestigated the possible protective effect of breastfeed<strong>in</strong>g on the development ofgastro<strong>in</strong>test<strong>in</strong>al <strong>in</strong>fections. A previous review of diarrhea morbidity <strong>in</strong> both developed <strong>and</strong>develop<strong>in</strong>g countries reported that the risk of diarrhea <strong>in</strong> <strong>in</strong>fants who did not receive breast milkwere 3.5 to 4.9 times higher than <strong>in</strong>fants who had exclusive breastfeed<strong>in</strong>g <strong>in</strong> the first 6 months oflife. 42 Factors like secretory IgA, oligosaccharides, lactoferr<strong>in</strong> <strong>and</strong> others available <strong>in</strong> breast milkmay protect the <strong>in</strong>fant from various <strong>in</strong>fections through passive immunity. 1 In vitro <strong>and</strong> <strong>in</strong> vivob<strong>in</strong>d<strong>in</strong>g studies have demonstrated that fucosylated glycans <strong>in</strong> breast milk <strong>in</strong>hibit b<strong>in</strong>d<strong>in</strong>g bycampylobacter jejuni, stable tox<strong>in</strong> of enterotoxigenic Escherichia coli, <strong>and</strong> major stra<strong>in</strong>s ofcalciviruses (e.g., noroviruses (also known as Norwalk-like viruses)) to their target host cellreceptors. 43 One report suggests that glycoprote<strong>in</strong> lactadher<strong>in</strong> found <strong>in</strong> breast milk protectsaga<strong>in</strong>st rotavirus <strong>in</strong>fection. 44 Socioeconomic status <strong>and</strong> child care variables (e.g., home versusday care, degree of crowd<strong>in</strong>g at home) are thought to be important confound<strong>in</strong>g factors <strong>in</strong>observational studies on gastro<strong>in</strong>test<strong>in</strong>al <strong>in</strong>fection <strong>and</strong> breastfeed<strong>in</strong>g. As the aforementionedreview also <strong>in</strong>cluded studies before 1950, it would be <strong>in</strong>structive to review the more recentliterature <strong>and</strong> assess the relationship between breastfeed<strong>in</strong>g <strong>and</strong> gastro<strong>in</strong>test<strong>in</strong>al <strong>in</strong>fections <strong>in</strong><strong>in</strong>fants from developed countries.Published Systematic Review/Meta-Analysis (Table 4)We identified one systematic review/meta-analysis that exam<strong>in</strong>ed the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> the development of gastro<strong>in</strong>test<strong>in</strong>al <strong>in</strong>fections <strong>in</strong> children less than 1 year ofage from developed countries. 45 The methodological quality of this systematic review/metaanalysiswas rated grade B.Us<strong>in</strong>g the MEDLINE database from 1966 to 1998, <strong>and</strong> supplement<strong>in</strong>g the results withsearches of the bibliographies of the primary <strong>and</strong> review articles, Chien 2001 identified 16studies from developed countries that qualified for <strong>in</strong>clusion <strong>in</strong> the review. There were 12prospective cohort studies total<strong>in</strong>g 5,473 subjects, 2 retrospective cohort studies total<strong>in</strong>g 504subjects, <strong>and</strong> 2 case-control studies with 331 pairs of subjects. For the review, gastro<strong>in</strong>test<strong>in</strong>al<strong>in</strong>fection was def<strong>in</strong>ed to be “any illness associated with vomit<strong>in</strong>g, change <strong>in</strong> consistency orfrequency of stools, or isolation of a known enteropathogenic bacterial or viral agent.” For thef<strong>in</strong>al data analysis, <strong>in</strong>fant feed<strong>in</strong>g practices were dichotomized <strong>in</strong>to two groups: exclusivebreastfeed<strong>in</strong>g <strong>and</strong> partial/mixed feed<strong>in</strong>g, or exclusive artificial feed<strong>in</strong>g.Results were conflict<strong>in</strong>g. N<strong>in</strong>e of 16 studies (56 percent) yielded a statistically significantprotective effect of breastfeed<strong>in</strong>g on gastro<strong>in</strong>test<strong>in</strong>al <strong>in</strong>fections. Majority of the studies sufferedfrom methodological deficiencies. Four studies fulfilled criteria of controll<strong>in</strong>g for detection bias,analyses of confounders, hav<strong>in</strong>g a clear def<strong>in</strong>ition of <strong>in</strong>fant feed<strong>in</strong>g practices <strong>and</strong> <strong>in</strong>fectiousoutcomes. Three of the studies reported breastfeed<strong>in</strong>g was protective aga<strong>in</strong>st non-specificgastro<strong>in</strong>test<strong>in</strong>al <strong>in</strong>fection. The fourth study reported that differences <strong>in</strong> feed<strong>in</strong>g practice did not37
affect the attack rates of rotavirus gastroenteritis. The potential confounders exam<strong>in</strong>ed <strong>in</strong> thesestudies <strong>in</strong>cluded <strong>in</strong>fant sex, race, maternal education, family liv<strong>in</strong>g st<strong>and</strong>ards, marital status,paternal social class, <strong>and</strong>/or parental smok<strong>in</strong>g. Even though these studies adjusted for potentialconfounders, the actual quantitative adjusted odds ratio or risk ratio were not reported.The authors of the systematic review stated that “it was not possible to pool the adjustedrelative measures of association” <strong>in</strong> the cohort studies reviewed. Us<strong>in</strong>g a fixed effect model, thesummary crude odds ratio of the 14 cohort studies for the development of gastro<strong>in</strong>test<strong>in</strong>al<strong>in</strong>fection was 0.36 (95% CI 0.32, 0.41; heterogeneity P
Table 4. Summary of systematic review/meta-analysis on the relationship between breastfeed<strong>in</strong>g <strong>and</strong>gastro<strong>in</strong>test<strong>in</strong>al (GI) <strong>in</strong>fectionAuthor YearPopulationChien 2001Prospectivecohorts:5,473Retrospectivecohorts: 504Case-control:331 pairsStudiesdescription12prospectivecohortstudies, 2retrospectivecohortstudies; 2case-controlstudiesIntervention/ComparatorEitherexclusivebreastfeed<strong>in</strong>g<strong>and</strong>partial/mixedfeed<strong>in</strong>g orexclusiveartificialfeed<strong>in</strong>gConfoundersconsidered<strong>Maternal</strong> education,s<strong>in</strong>gle or dualparent<strong>in</strong>g, familyliv<strong>in</strong>g st<strong>and</strong>ards,<strong>in</strong>fant sex, race,maternal parity,marital status,paternal socialclass, maternal age,parental smok<strong>in</strong>gResultsConflict<strong>in</strong>g results on the effect ofbreastfeed<strong>in</strong>g on GI <strong>in</strong>fection: 9/16 studies(56%) yielded a statistically significantprotective effect of breastfeed<strong>in</strong>g on GI<strong>in</strong>fections;Majority of studies suffered frommethodological deficiencies;4 studies fulfilled criteria of controll<strong>in</strong>g fordetection bias, analyses of confounders,hav<strong>in</strong>g a clear def<strong>in</strong>ition of <strong>in</strong>fant feed<strong>in</strong>gpractices <strong>and</strong> <strong>in</strong>fectious outcomes; 3 ofthese studies reported breastfeed<strong>in</strong>g wasprotective aga<strong>in</strong>st non-specific GI<strong>in</strong>fection;Unadjusted pooled estimate of the cohortstudies: OR 0.36 (95% CI 0.32, 0.41;heterogeneity P
Relationship of Hospitalization Secondary to LowerRespiratory Tract Diseases <strong>in</strong> Infancy <strong>and</strong> <strong>Breastfeed<strong>in</strong>g</strong>BackgroundRespiratory <strong>in</strong>fection is the most common medical problem among <strong>in</strong>fants <strong>and</strong> children. Eachyear <strong>in</strong> the United States, three percent of all <strong>in</strong>fants are hospitalized with moderate to severerespiratory <strong>in</strong>fection. 47 Severe lower respiratory tract diseases may <strong>in</strong>crease the risk of childhoodasthma. Viral <strong>in</strong>fections, especially respiratory syncytial virus (RSV) <strong>in</strong>fection, are the mostcommon cause of lower respiratory tract disease <strong>in</strong> developed countries. RSV <strong>in</strong>fection occursmost frequently between 2 <strong>and</strong> 8 months of age. The risk factors associated with rates ofrespiratory illness <strong>in</strong>clude age, smoke exposure, day care, race/ethnicity, family size, education,<strong>and</strong> socioeconomic status. We identified one meta-analysis published <strong>in</strong> 2003 that compared therisk of hospitalization for respiratory diseases <strong>in</strong> healthy full term <strong>in</strong>fants who were breastfedwith those who were not. 48Published Systematic Review/Meta-Analysis (Table 5)Bachrach 2003’s meta-analysis <strong>in</strong>cluded seven cohort (five prospective <strong>and</strong> tworetrospective) studies that evaluated the relationship between breastfeed<strong>in</strong>g <strong>and</strong> hospitalizationrisk secondary to respiratory diseases. 48 Primary studies published before April 2002 <strong>and</strong>evaluated healthy full-term <strong>in</strong>fants less than 1 year of age from developed countries were<strong>in</strong>cluded. Only data from exclusive breastfeed<strong>in</strong>g of at least 2 months or any breastfeed<strong>in</strong>gtotal<strong>in</strong>g 9 months or more were <strong>in</strong>cluded. Exclusive breastfeed<strong>in</strong>g was def<strong>in</strong>ed as little or noformula feed<strong>in</strong>g. Studies on cystic fibrosis <strong>and</strong> allergic conditions were excluded. Unpublisheddata were also exam<strong>in</strong>ed. The primary outcome variable was hospitalization for lower respiratorytract disease secondary to bronchiolitis, asthma, pneumonia, empyema, <strong>and</strong> <strong>in</strong>fections due tospecific agents (e.g., RSV). The meta-analysis was restricted to first hospitalization. The analysisevaluated the risk of hospitalization <strong>in</strong> 3,201 breastfed subjects <strong>and</strong> 1,324 non-breastfed subjects.The meta-analysis used a r<strong>and</strong>om effects model. There was an overall 72 percent reduction <strong>in</strong>the risk of hospitalization <strong>in</strong> <strong>in</strong>fants who were exclusively breastfed for 4 or more monthscompared with those who were formula-fed (summary relative risk 0.28, 95% CI 0.14 - 0.54).There was no change <strong>in</strong> summary relative risk <strong>in</strong> the subgroup analyses of studies that alsoreported relative risk adjusted for the effects of smok<strong>in</strong>g or socioeconomic status. There was nostatistical heterogeneity across the studies. The authors performed sensitivity analyses to assessthe appropriateness of comb<strong>in</strong><strong>in</strong>g studies <strong>and</strong> found no changes <strong>in</strong> summary risk. In addition, thenumber needed to treat (NNT) was calculated to be 26. This implies that at least 26 <strong>in</strong>fants willhave to breastfeed exclusively for 4 or more months to prevent one <strong>in</strong>fant from hospitalizationsecondary to respiratory diseases. The methodological quality of the meta-analysis was ratedgrade A.ConclusionThe meta-analysis showed an overall 72 percent reduction <strong>in</strong> the risk of hospitalizationsecondary to respiratory diseases <strong>in</strong> <strong>in</strong>fants who were exclusively breastfed for 4 or more months40
compared with those who were formula-fed. This f<strong>in</strong>d<strong>in</strong>g rema<strong>in</strong>ed statistically significant afteradjustment for potential confounders. There could be differences across studies with regard toduration of followup, diagnosis of respiratory disease, <strong>and</strong> other factors. However, there was nostatistically significant heterogeneity detected across the studies. Tak<strong>in</strong>g <strong>in</strong>to account themethodological quality of the meta-analysis <strong>and</strong> the consistent f<strong>in</strong>d<strong>in</strong>gs reported, we concludethat breastfeed<strong>in</strong>g for 4 or more months is associated with a reduction <strong>in</strong> the risk ofhospitalization secondary to lower respiratory tract diseases.Table 5. Summary of systematic review/meta-analysis on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> lowerrespiratory tract diseaseConfoundersQualityconsidered<strong>Outcomes</strong>ofAuthor yearPopulationBachrach 2003<strong>Infant</strong>s
BackgroundRelationship between Asthma <strong>and</strong> <strong>Breastfeed<strong>in</strong>g</strong>Asthma is a bronchial disorder accompanied by breath<strong>in</strong>g difficulties, wheez<strong>in</strong>g, cough<strong>in</strong>g,<strong>and</strong> production of thick mucus. Trigger<strong>in</strong>g factors have been attributed to foreign substances,tobacco smoke or pollutants, exercise, <strong>in</strong>fection, <strong>and</strong> emotional stress. An <strong>in</strong>crease <strong>in</strong> theprevalence of asthma has been reported <strong>in</strong> some countries dur<strong>in</strong>g the second half of the 20 thcentury. 49 In 2002-2003, about six percent of the children <strong>in</strong> the United States had an asthmaattack (www.cdc.gov/nchs/data/hus/hus05.pdf). In addition, the hygiene hypothesis (a lack ofearly childhood exposure to <strong>in</strong>fectious agents <strong>in</strong>creases susceptibility to allergic diseases 50,51 ) hasbeen proffered as a possible explanation for some of the <strong>in</strong>crease <strong>in</strong> <strong>in</strong>cidence <strong>and</strong> prevalence ofasthma, but that hypothesis rema<strong>in</strong>s a matter of debate. 49 Potential confounders considered <strong>in</strong> thestudies of breastfeed<strong>in</strong>g <strong>and</strong> asthma <strong>in</strong>clude age, socioeconomic status, family history of atopy,<strong>and</strong> parental smok<strong>in</strong>g.F<strong>in</strong>d<strong>in</strong>gs from primary studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> thedevelopment of asthma have been conflict<strong>in</strong>g. One meta-analysis published <strong>in</strong> 2001 aimed toexam<strong>in</strong>e this relationship. 52 We identified three relevant prospective longitud<strong>in</strong>al cohort studies<strong>and</strong> one followup study (to one of the primary studies <strong>in</strong> the meta-analysis) published subsequentto the meta-analysis. 53-56 Three of the four studies met the <strong>in</strong>clusion criteria of the orig<strong>in</strong>al metaanalysis<strong>and</strong> an updated meta-analysis stratified by family history of asthma was conducted.Published Systematic Review/Meta-Analysis (Table 6)Gdalevich 2001 conducted a meta-analysis that <strong>in</strong>cluded 12 prospective observational studieswith 8,183 term <strong>in</strong>fants followed for a mean of 4.1 years. Study <strong>in</strong>clusion criteria <strong>in</strong>cludedsubjects from developed countries, exclusive of breastfeed<strong>in</strong>g for at least 3 months, bl<strong>in</strong>d<strong>in</strong>g ofdiagnos<strong>in</strong>g physician to feed<strong>in</strong>g status, <strong>and</strong> maternal recall of child’s feed<strong>in</strong>g history of not morethan 12 months. Exclusive breastfeed<strong>in</strong>g was def<strong>in</strong>ed as hav<strong>in</strong>g no substitutes or additions.Critical appraisal of the studies was conducted based on the st<strong>and</strong>ards suggested by Kramer. 16Potential confounders <strong>in</strong>clud<strong>in</strong>g age, socioeconomic status, family history of atopy, <strong>and</strong> parentalsmok<strong>in</strong>g were controlled for by means of multivariate analysis. The outcome of asthma wasdiagnosis by a physician.Meta-analysis of the 12 studies with followup of 2 or more years reported a summary oddsratio of 0.70 (95% CI 0.60 - 0.81), suggest<strong>in</strong>g an association of breastfeed<strong>in</strong>g <strong>and</strong> a reduction <strong>in</strong>the risk of the development of asthma. Subgroup analysis reported that children with a familyhistory of asthma or atopy benefited more from breastfeed<strong>in</strong>g (OR 0.52, 95% CI 0.35 - 0.79) <strong>in</strong>the risk reduction of the development of asthma, compared with children who did not have afamily history of asthma or atopy. There was no statistical heterogeneity <strong>in</strong> the studies.Sensitivity analysis <strong>in</strong>dicated the exclusion of any one study did not change the overall results.Methodological quality for the meta-analysis was rated grade A.42
Studies Identified after the Published Systematic Review/Meta-Analysis (Table 7)We identified three prospective cohort studies, <strong>in</strong>clud<strong>in</strong>g one that had both prospective <strong>and</strong>retrospective analyses, <strong>and</strong> one followup publication exam<strong>in</strong><strong>in</strong>g the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> risk of the development of asthma. 53-55 Methodological quality of these fourstudies ranged from grade C to grade A.Subjects selected <strong>in</strong> these studies ranged from healthy full-term <strong>in</strong>fants to any live birthsfrom ma<strong>in</strong>ly population-based samples. Sample sizes at followup ranged from 1,037 to 4,964with zero to 31 percent dropouts or withdrawals. Verification of asthma varied from parentalconfirmation through questionnaires to cl<strong>in</strong>ic assessment <strong>and</strong> physician diagnosis. Although allfour studies adjusted for confound<strong>in</strong>g, the only variable common to all studies was maternalsmok<strong>in</strong>g, either dur<strong>in</strong>g pregnancy or after birth.Two of the studies were population-based, one was hospital-based, <strong>and</strong> one study was done<strong>in</strong> a large health ma<strong>in</strong>tenance organization (HMO). Wright 2001 <strong>and</strong> Kull 2004 looked atexclusive breastfeed<strong>in</strong>g whereas Burgess 2006 did not def<strong>in</strong>e breastfeed<strong>in</strong>g but acknowledgedthat exclusive breastfeed<strong>in</strong>g was <strong>in</strong> practice difficult to verify. Another issue is that there were nogold st<strong>and</strong>ards for the diagnosis of asthma <strong>in</strong> population studies. To confirm the diagnosis ofasthma, Kull 2004 relied on cl<strong>in</strong>ical exam<strong>in</strong>ations as well as blood sampl<strong>in</strong>g <strong>and</strong> pulmonaryfunction tests. Burgess 2006 used data from a questionnaire that asked about medications,symptoms, hospitalization, <strong>and</strong> family history to formulate the diagnosis. Sears 2002 based thediagnosis on pulmonary function tests with the addition of maternal description of symptoms.Wright 2001 <strong>and</strong> Kull 2004 appeared to have the most rigorous criteria for diagnosis of asthmaby consider<strong>in</strong>g recent symptoms, results from test<strong>in</strong>gs, <strong>and</strong> confirmation by a physician. Twostudies gathered feed<strong>in</strong>g data post-delivery by recall, first study at 6 months, 53 <strong>and</strong> the secondstudy at 2 months with another followup at 12 months. 54 Two studies relied on objective data forfeed<strong>in</strong>g history; Sears 2002 relied on data from nurs<strong>in</strong>g program records, 55 <strong>and</strong> Wright 2001relied on breastfeed<strong>in</strong>g data from cl<strong>in</strong>ic visits. 56 The methodological quality of the studies byKull, Wright, <strong>and</strong> Sears were rated grade B, <strong>and</strong> Burgess was rated grade C.Study f<strong>in</strong>d<strong>in</strong>gs. Kull 2004 followed 3,384 newborns for the first 4 years of life <strong>and</strong> reportedthat there was a statistically significant association of exclusive breastfeed<strong>in</strong>g for 4 months ormore <strong>and</strong> a reduction <strong>in</strong> the risk of the development of asthma (OR 0.72, 95%CI 0.53 - 0.97). 54Furthermore, subgroup analysis showed that the association was stronger for children whoseparents did not have a history of allergic diseases.Sears 2002 enrolled 1,037 subjects at age 3 years <strong>and</strong> a retrospective record review foundthat approximately half were breastfed <strong>and</strong> half were not (533 breastfed, 504 not breastfed). 55The subjects were followed prospectively until 21 or 26 years of age. The study found an<strong>in</strong>creased risk of asthma <strong>in</strong> those subjects who were breastfed compared with those who were notfor all time po<strong>in</strong>ts assessed. Length of breastfeed<strong>in</strong>g duration had no protective effect aga<strong>in</strong>stasthma. Family history of asthma did not significantly affect these results. Even though“exclusive breastfeed<strong>in</strong>g” rate was reported <strong>in</strong> the study, the authors acknowledged that it wascommon practice for the hospital staff to feed the newborns with formula for the first few nightspost-delivery to allow the mothers to sleep.Wright 2001 is a followup publication to one of the primary studies from the Gdalevich 2001meta-analysis. This study reported that there was no association between duration of exclusivebreastfeed<strong>in</strong>g <strong>and</strong> asthma for 926 children by age 13 years followed s<strong>in</strong>ce birth, except <strong>in</strong> those43
children who were atopic <strong>and</strong> whose mothers had a history of asthma. 56 This was the only studyto report that a family history of asthma is an effect modifier of breastfeed<strong>in</strong>g <strong>in</strong> the <strong>in</strong>creasedrisk of the development of asthma <strong>in</strong> children.Burgess 2006 <strong>in</strong>vestigated 4,964 children at 14 years of age concern<strong>in</strong>g their history ofasthma (“yes” or “no”) as reported by their mothers. This study found that there was nosignificant relationship between the duration of breastfeed<strong>in</strong>g <strong>and</strong> the prevalence of asthma. Therates of asthma were the same for any given rates of breastfeed<strong>in</strong>g regardless of the maternalhistory concern<strong>in</strong>g asthma. 53 Data on feed<strong>in</strong>g were collected at 6 months after birth.Updat<strong>in</strong>g the Previous Meta-AnalysisWe performed an update meta-analysis stratified by family history of asthma us<strong>in</strong>g ther<strong>and</strong>om effects model <strong>in</strong>clud<strong>in</strong>g three of the four recent publications. 53,54,56 The fourth study didnot qualify for <strong>in</strong>clusion because it did not have a comparison group of at least 3 months durationof breastfeed<strong>in</strong>g. In the subgroup analysis of those children with a positive family history ofasthma, two studies (Wright 56 <strong>and</strong> Kull 54 ) met the <strong>in</strong>clusion criteria set by Gdalevich. One of thestudies reported a very large adjusted odds ratio (OR 8.7, 95%CI 3.4 – 22.2) <strong>in</strong> a followup of 13year olds, compared with the other studies. 56 Sensitivity analyses were conducted to exam<strong>in</strong>e thesource of heterogeneity by <strong>in</strong>clud<strong>in</strong>g or exclud<strong>in</strong>g this study. Exclud<strong>in</strong>g Wright, a history ofexclusive breastfeed<strong>in</strong>g for more than 3 months was associated with a reduction <strong>in</strong> the risk ofasthma (OR adj 0.60; 95%CI 0.43 - 0.82), compared with no breastfeed<strong>in</strong>g. Includ<strong>in</strong>g Wright,there was no longer a statistically significant association between a history of breastfeed<strong>in</strong>g <strong>and</strong>the risk of asthma (OR adj 0.81, 95%CI 0.41 – 1.60). This result suggests that the heterogeneitycan be expla<strong>in</strong>ed by a s<strong>in</strong>gle study. Compared with the other studies <strong>in</strong> the analyses, the age offollowup was 13 years <strong>in</strong> Wright 2001, while it ranged from 2 to 9 years <strong>in</strong> the other studies.In the analysis of those children without a family history of asthma, the addition of the twosubsequent studies (Kull 54 <strong>and</strong> Burgess 53 ) did not alter the statistically significant association ofbreastfeed<strong>in</strong>g <strong>and</strong> the reduction <strong>in</strong> the risk of asthma (OR 0.73, 95%CI 0.59 – 0.92) comparedwith the orig<strong>in</strong>al results reported by Gdalevich. It should be noted that Burgess reported only theunadjusted odds ratio, stat<strong>in</strong>g that the adjusted was “m<strong>in</strong>imally altered”.44
Figure 7. Meta-Analysis of prospective cohort studies of the association between asthma risk <strong>and</strong>breastfeed<strong>in</strong>g ≥ 3 months for children with positive family history of asthma or atopy (exclud<strong>in</strong>g Wright 2001)Figure 8. Meta-Analysis of prospective cohort studies of the association between asthma risk <strong>and</strong>breastfeed<strong>in</strong>g ≥ 3 months for children with positive family history of asthma or atopy (<strong>in</strong>clud<strong>in</strong>g Wright 2001)45
Figure 9. Meta-Analysis of prospective cohort studies of the association between asthma risk <strong>and</strong>breastfeed<strong>in</strong>g ≥ 3 months for children without family history of asthma or atopyConclusionA well-performed meta-analysis from 2001 concluded that breastfeed<strong>in</strong>g was associated witha reduction <strong>in</strong> the risk of develop<strong>in</strong>g asthma. This association was stronger <strong>in</strong> those subjects witha positive family history. However, three new primary studies <strong>and</strong> one followup study reportedconflict<strong>in</strong>g results. With our new meta-analyses <strong>in</strong>clud<strong>in</strong>g three of these studies, it is clear thatthere rema<strong>in</strong>ed an association between breastfeed<strong>in</strong>g <strong>and</strong> a reduction <strong>in</strong> the risk of asthma <strong>in</strong>those subjects without a family history of asthma. This association was also found <strong>in</strong> subjectsunder 10 years of age with a positive family history of asthma. It is unclear whether thisassociation changes for older children. It should also be noted that the fourth study, which didnot qualify for <strong>in</strong>clusion <strong>in</strong> our new meta-analyses, reported an <strong>in</strong>crease <strong>in</strong> asthma risk with<strong>in</strong>creased duration of breastfeed<strong>in</strong>g <strong>in</strong> those subjects with a maternal history of asthma. Furtherstudies concern<strong>in</strong>g the effect of a family history of asthma on long-term outcome of asthma iswarranted.46
Table 6. Summary of systematic review/meta-analysis on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> asthmaAuthor YearInterventionConfoundersStudies descriptionPopulation/ComparatorconsideredResultsGdalevich MA of 12 prospective2001studies <strong>in</strong> developedTerm <strong>in</strong>fants countriesSR, systematic review; MA, meta-analysis≥ 3 mo exclusivebreastfeed<strong>in</strong>g vs.without ≥ 3 mo ofexclusivebreastfeed<strong>in</strong>gSES, gender, familyhistory of atopy, parentalsmok<strong>in</strong>g, <strong>and</strong> presence offurry animals at home≥ 2 years followup, breast feed<strong>in</strong>g had protectiveeffect aga<strong>in</strong>st asthma, summary OR 0.72 (95% CI0.62 – 0.84)Subgroup analysis of children from family withasthma or atopy showed higher protective effect ofbreast feed<strong>in</strong>g OR 0.52 (95% CI, 0.35 - 0.79)Subgroup analysis of children from family withoutasthma or atopy, OR 0.73 (95% CI, 0.62 - 0.86Quality of SR/MA<strong>and</strong> limitationsA47
48Table 7. Summary of prospective cohort studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> asthmaAuthor YearBreast milk feed<strong>in</strong>g Assessment of ConfoundersCountryStudy Descriptionexposureasthmaadjusted forPopulationKull2004SwedenEnrolled: 4,089Follow-up: 3,384All newbornsfrom catchmentsarea ofStockholmSears2002New Zeal<strong>and</strong>Enrolled: 1,037Followup:1,037Populationbasedcohortfrom s<strong>in</strong>glehospital centerWright2001USAEnrolled: 1,246Followup: 1,043<strong>Health</strong>ynewborns fromlarge HMOProspective,longitud<strong>in</strong>al cohortwith questionnaires atchild’s age of 2months, 1, 2, <strong>and</strong> 4years. Cl<strong>in</strong>icassessment at 4years.Both prospective <strong>and</strong>retrospective cohortstudy design enrolledat age 3 <strong>and</strong> datacollectedretrospective <strong>and</strong>prospective, followedprospectively up to21 yearsProspective,longitud<strong>in</strong>al newborncohort withquestionnaires at 2,3, 6, 9, 11, 13 years;Additional datacollection by MDhealth surveillanceExclusivebreastfeed<strong>in</strong>g wasdichotomized with the25 th percentile as thecutoff po<strong>in</strong>t ( 4 weeksExclusivebreastfeed<strong>in</strong>gcategorized byduration: neverbreastfedbreastfed 4monthsAt age 4 years, 4episodes of wheez<strong>in</strong>gdur<strong>in</strong>g the last 12months or at least 1episode of wheez<strong>in</strong>gdur<strong>in</strong>g the sameperiod if the child wasreceiv<strong>in</strong>g <strong>in</strong>haledsteroidsAsthma as reportedby child or parentPhysician diagnosedasthma, wheez<strong>in</strong>g orasthma symptomsreported ≥ 2questionnaires fromages 6 to 13 years<strong>Maternal</strong> age,maternal smok<strong>in</strong>gdur<strong>in</strong>g pregnancy orat 2 months of age,<strong>and</strong> heredity ofallergic diseasesSES, birth order,sheepsk<strong>in</strong> use <strong>in</strong><strong>in</strong>fancy, maternalsmok<strong>in</strong>g<strong>Maternal</strong> education,smok<strong>in</strong>g status <strong>in</strong> 1 styear, sex, ethnicity, 2or more sibl<strong>in</strong>gs athome or day care useversus neither first 6months, paternalasthma<strong>Outcomes</strong>• Overall exclusivebreastfeed<strong>in</strong>g for ≥ 4month associated withlower risk than those whobreastfed
Table 7. Cont<strong>in</strong>uedAuthor YearCountry Study DescriptionPopulationBurgess2006AustraliaEnrolled: 7,223Followup: 4,964S<strong>in</strong>gleton termdeliveries frompublic cl<strong>in</strong>ic ofUniversityHospitalProspective,longitud<strong>in</strong>al cohortwith questionnairesat birth, 6 months, 5<strong>and</strong> 14 years.SES, socioeconomic statusBreast milkfeed<strong>in</strong>gexposure<strong>Breastfeed<strong>in</strong>g</strong>categorized byduration:Neverbreastfed< 3 weeks3 – 6 weeks7 weeks – 3months≥ 4 monthsAssessment of asthmaFrom questionnaire:episodes of asthma <strong>in</strong> past6 months, frequency ofasthma meds, asthmarelatedsick days fromschool, asthma-relatedhospital admissionsConfoundersadjusted for<strong>Maternal</strong> asthma,paternal asthma,smok<strong>in</strong>g early <strong>and</strong>late pregnancy,frequency of coughs<strong>and</strong> cold first 6months, annual family<strong>in</strong>come<strong>Outcomes</strong>• <strong>Breastfeed<strong>in</strong>g</strong> at least 4months not associated withasthma compared to nobreastfeed<strong>in</strong>g, unadjustedOR 1.03 (0.9-1.2)Quality <strong>and</strong> limitationsCAdjusted OR notreported,dropout/withdrawals >30%, significantdifferences betweencompleters <strong>and</strong>noncompleters, nodef<strong>in</strong>ition or descriptionof breastfeed<strong>in</strong>g,discrepancy for %males <strong>in</strong> table.49
BackgroundRelationship between Cognitive Development <strong>and</strong><strong>Breastfeed<strong>in</strong>g</strong> <strong>in</strong> Term <strong>Infant</strong>sMany studies have exam<strong>in</strong>ed the relationship between breastfeed<strong>in</strong>g <strong>and</strong> cognitivedevelopment. Results have been conflict<strong>in</strong>g. Many of them did not have a clear def<strong>in</strong>ition ofbreastfeed<strong>in</strong>g or breast milk exposure. Different cognitive assessment tools were used. <strong>Outcomes</strong>were measured anywhere from less than 2 years of age to adulthoods. Confounders commonlyconsidered <strong>in</strong> these studies were socioeconomic status, maternal education, birthweight,gestational age, birth order <strong>and</strong> gender. 57 Ja<strong>in</strong> et al. considered SES <strong>and</strong> quality <strong>and</strong> quantity ofstimulation of the child (<strong>in</strong>clud<strong>in</strong>g social <strong>in</strong>teractions) to be crucial confounders. 58 These authorsdid not consider maternal or paternal <strong>in</strong>telligence, marital status, number of children, <strong>and</strong>maternal age to be crucial because to “some degree, they are markers of socioeconomic status,<strong>and</strong> are not clearly related to both feed<strong>in</strong>g method <strong>and</strong> <strong>in</strong>telligence <strong>in</strong>dependent ofsocioeconomic status”. Three systematic reviews from 1999 to 2002 have tried to either establishmethodological st<strong>and</strong>ards to assess the observational studies or adjust for covariates <strong>in</strong> pooledanalysis. S<strong>in</strong>ce the last systematic review by Ja<strong>in</strong> et al. <strong>in</strong> 2002, 58 there have been eightprospective cohort studies on healthy term <strong>in</strong>fants that exam<strong>in</strong>ed the relationship of breastfeed<strong>in</strong>gto some aspects of cognitive development.Additional Methodological CommentsWe searched for systematic reviews on breastfeed<strong>in</strong>g <strong>and</strong> cognitive development us<strong>in</strong>g termslike “cognitive”, “neurodevelopment”, “<strong>in</strong>telligence”…etc. Us<strong>in</strong>g similar terms, we searchedMEDLINE <strong>and</strong> CINAHL <strong>in</strong> January <strong>and</strong> April of 2006, respectively, for additional primarystudies published after 2000. We also identified additional articles based on reviews of thebibliographies cited <strong>in</strong> the relevant retrieved studies from the search <strong>and</strong> from suggestions by thereviewers for this report. For primary studies, qualify<strong>in</strong>g study designs <strong>in</strong>cluded prospectivecohort <strong>and</strong> case-control studies; only studies from developed countries were <strong>in</strong>cluded. For thehealthy term <strong>in</strong>fants, subgroups like <strong>in</strong>fants of diabetic mothers <strong>and</strong> small-for-gestational age<strong>in</strong>fants were not <strong>in</strong>cluded. For preterm <strong>in</strong>fants, no subgroups were excluded. Studies concernedexclusively with <strong>in</strong>dividual breast milk factor supplements (e.g., long cha<strong>in</strong> polyunsaturated fattyacids, nucleotides) were not <strong>in</strong>cluded. There was no restriction on tim<strong>in</strong>g of <strong>and</strong> the tools usedfor cognitive assessment. Only data on cognitive outcomes were extracted, data from motor,psychomotor, or visual development were not extracted.Published Meta-Analyses/Systematic Reviews (Table 8)Ja<strong>in</strong> 2002 identified 40 relevant publications (30 birth cohorts, five RCTs, five schoolregistry cohorts, <strong>and</strong> three case-control studies) from 1929 to 2001. Most of them studied term<strong>in</strong>fants. A few studies <strong>in</strong>cluded only preterm <strong>in</strong>fants <strong>in</strong> their analyses. Each study was assessedaccord<strong>in</strong>g to a set of eight cl<strong>in</strong>ical epidemiological st<strong>and</strong>ards: study design, target population,sample size, quality of feed<strong>in</strong>g data (suitable def<strong>in</strong>ition <strong>and</strong> duration of breastfeed<strong>in</strong>g, <strong>and</strong>appropriate tim<strong>in</strong>g <strong>and</strong> source of feed<strong>in</strong>g data), whether studies controlled for socioeconomic50
status <strong>and</strong> stimulation of the child, whether observers of the outcome were bl<strong>in</strong>d to feed<strong>in</strong>gstatus, whether a st<strong>and</strong>ardized <strong>in</strong>dividual test of general <strong>in</strong>telligence at older than 2 years of agewas used, <strong>and</strong> whether studies reported an effect size. Two studies on term <strong>in</strong>fants met all theproposed methodological st<strong>and</strong>ards. One concluded that the effect of breastfeed<strong>in</strong>g on <strong>in</strong>tellectwas significant (4.6 po<strong>in</strong>ts <strong>in</strong> IQ at age 3 years <strong>in</strong> children who breastfed compared with thosewho bottle-fed), 59 <strong>and</strong> the other concluded that the effect on cognitive performance wasstatistically non-significant. 60Drane 2000 exam<strong>in</strong>ed 24 studies from 1966 to 1998. 57 Twenty-one <strong>in</strong>cluded term <strong>in</strong>fants,two <strong>in</strong>cluded low birthweight <strong>in</strong>fants, <strong>and</strong> one <strong>in</strong>volved small-for-gestational age <strong>in</strong>fants. Eachstudy was assessed accord<strong>in</strong>g to a set of three methodological st<strong>and</strong>ards: def<strong>in</strong>ition of outcome,correct classification of type of <strong>in</strong>fant feed<strong>in</strong>g, <strong>and</strong> control of potential confound<strong>in</strong>g variables(socioeconomic status, maternal education, birthweight, gestational age, birth order, gender).Five of the 24 studies met all three methodological st<strong>and</strong>ards. These studies <strong>in</strong>dicated anadvantage <strong>in</strong> IQ to breastfed <strong>in</strong>fants <strong>in</strong> the range of two to five po<strong>in</strong>ts for term <strong>in</strong>fants <strong>and</strong> eightpo<strong>in</strong>ts for low birth weight <strong>in</strong>fants.Interest<strong>in</strong>gly, of the two studies that were identified by Ja<strong>in</strong> 2002 to have met all theproposed methodological report<strong>in</strong>g st<strong>and</strong>ards, the feed<strong>in</strong>g data from one did not meet the feed<strong>in</strong>gdata report<strong>in</strong>g st<strong>and</strong>ard put forth <strong>in</strong> the review by Drane 2000. The study at issue was Wigg1998, <strong>in</strong> which the follow<strong>in</strong>g statement could be found: “Feed<strong>in</strong>g methods (i.e., breast, bottle-fedor mixed) <strong>and</strong> duration of breastfeed<strong>in</strong>g <strong>in</strong> <strong>in</strong>fancy were recorded at age 6 months by the tra<strong>in</strong>edresearch nurse”. 60 Ja<strong>in</strong> 2002 <strong>in</strong>terpreted that study to have met their requirement of adequatereport<strong>in</strong>g of feed<strong>in</strong>g data (“whether <strong>in</strong>fants received breast milk exclusively or with supplementalformula or other foods”), while Drane 2000 <strong>in</strong>terpreted that study not to have adequatelydist<strong>in</strong>guished between partial <strong>and</strong> exclusive breastfeed<strong>in</strong>g. The other study that met all themethodological st<strong>and</strong>ards accord<strong>in</strong>g to Ja<strong>in</strong> 2002 was published <strong>in</strong> 1996, 59 but it was not<strong>in</strong>cluded <strong>in</strong> Drane 2000’s review; reason of which was not readily apparent.Anderson 1999 exam<strong>in</strong>ed 11 studies from 1978 to 1995 that controlled for at least fivecovariates (breastfeed<strong>in</strong>g duration, sex, maternal smok<strong>in</strong>g history, maternal age, maternal<strong>in</strong>telligence, maternal education, maternal tra<strong>in</strong><strong>in</strong>g, paternal education, race or ethnicity,socioeconomic status, family size, birth order, birth weight, gestational age, <strong>and</strong> childhoodexperiences) <strong>and</strong> presented unadjusted <strong>and</strong> adjusted results. 61 Eight studies <strong>in</strong>cluded term <strong>in</strong>fants;three studies <strong>in</strong>cluded only preterm <strong>in</strong>fants. The results were comb<strong>in</strong>ed <strong>in</strong> a meta-analysis. Theadjusted (fixed effects) pooled mean difference was 3.16 po<strong>in</strong>ts (st<strong>and</strong>ardized effect estimate ofcognitive developmental mean score, 95% CI 2.35 - 3.98) <strong>in</strong> favor of the breastfeed<strong>in</strong>g group.Low birthweight <strong>in</strong>fants showed larger differences (5.18 po<strong>in</strong>ts <strong>in</strong> cognitive developmentalscore; 95%CI 3.59 - 6.77) than did normal birth weight <strong>in</strong>fants (2.66 po<strong>in</strong>ts; 95%CI 2.15 - 3.17).Other methodological quality of the studies was not assessed.Studies Identified after the Published Meta-Analysis/SystematicReview <strong>in</strong> Term <strong>Infant</strong>s (Table 9)Prospective cohort. One secondary analysis of a prospectively collected data set 62 <strong>and</strong> sevenprospective cohort studies rang<strong>in</strong>g from 44 to 3880 term subjects reported on the relationshipbetween breast milk feed<strong>in</strong>g <strong>and</strong> some aspects of cognitive development s<strong>in</strong>ce 2002. 63-71None of the cohort studies made a clear dist<strong>in</strong>ction between partial <strong>and</strong> exclusivebreastfeed<strong>in</strong>g. Two studies stated to have a prospective design, but the breastfeed<strong>in</strong>g <strong>in</strong>formation51
was collected retrospectively. Subjects were breastfed from less than 3 weeks to 12 months.Three studies reported the proportion of subjects who breastfed for more than 6 to 7 months, theyranged from 9 percent to 62 percent.Bayley Mental Development Index Scale (MDI) was the cognitive assessment tool forsubjects under 2 years of age. Peabody Picture Vocabulary Test (PPVT-R) <strong>and</strong> WechslerPreschool <strong>and</strong> Primary Scale of Intelligence (WPPSI-R) were used <strong>in</strong> subjects under 7 years ofage. Wechsler Adult Intelligence Scale (WAIS), Raven’s st<strong>and</strong>ard progressive matrices, st<strong>and</strong>ardread<strong>in</strong>g, verbal, <strong>and</strong> mathematical reason<strong>in</strong>g tests were used <strong>in</strong> adults up to 27 years of age. Timeof assessment ranged from 1 to 27 years.Der 2006 analyzed the database from the US National Longitud<strong>in</strong>al Survey of Youth 1979(NLSY79). 62 This database has <strong>in</strong>formation on the participants <strong>and</strong> their offspr<strong>in</strong>gs. The studyreported that the adjusted effect of breastfeed<strong>in</strong>g on Peabody <strong>in</strong>dividual achievement test(st<strong>and</strong>ardized mean of 100 <strong>and</strong> SD of 15) at 14 years was reduced to +0.52 from +4.7 afteradjustment for maternal IQ, education, age, family poverty, home stimulation, <strong>and</strong> birth order.Further analysis of 332 pairs of sibl<strong>in</strong>gs discordant for breastfeed<strong>in</strong>g status found non-significantdifference between groups <strong>in</strong> both status <strong>and</strong> duration of breastfeed<strong>in</strong>g. Meta-regression of n<strong>in</strong>eunique studies (<strong>in</strong>clud<strong>in</strong>g the data from NLSY79) reported an advantage of breastfeed<strong>in</strong>g of 0.16cognitive po<strong>in</strong>ts after controll<strong>in</strong>g for maternal IQ <strong>and</strong> other confounders. This study was ratedgood methodological quality (grade A).Der 2006 also comb<strong>in</strong>ed its estimate with the estimate from the only other sibl<strong>in</strong>g analysis <strong>in</strong>the literature to date (Evenhouse 2005, 72 this study did not qualify for <strong>in</strong>clusion <strong>in</strong> this reviewbecause it was an analysis of data obta<strong>in</strong>ed from a cross-sectional design study). Evenhouse 2005analyzed the database from the National Longitud<strong>in</strong>al Study of Adolescent <strong>Health</strong> (Add <strong>Health</strong>)1994 (This database oversamples low-<strong>in</strong>come, African-American, <strong>and</strong> Hispanic children <strong>and</strong>provided <strong>in</strong>formation on an abbreviated Peabody Picture Vocabulary Test results. There were523 pairs of sibl<strong>in</strong>gs with different breastfeed<strong>in</strong>g history <strong>in</strong> this data set). The comb<strong>in</strong>ed estimatefrom NLSY79 <strong>and</strong> Add <strong>Health</strong> was 0.025 (P=0.54) for breastfeed<strong>in</strong>g status <strong>and</strong> 0.04 (P=0.271)for duration of breastfeed<strong>in</strong>g.Of the six prospective cohort studies of moderate (grade B) methodological quality, fivereported an advantage <strong>in</strong> cognitive development <strong>in</strong> subjects who breastfed. Specifically, Lawlor2006 reported that the adjusted score (for sex, parental characteristics, birthweight, <strong>and</strong> per<strong>in</strong>atalcharacteristics) <strong>in</strong> Raven’s st<strong>and</strong>ard progressive matrices at age 14 years showed a me<strong>and</strong>ifference of 6.79 (95%CI, 5.33-8.26) <strong>in</strong> less than 4 months of breastfeed<strong>in</strong>g versus neverbreastfeed<strong>in</strong>g (compared to an unadjusted mean of 8.20). 71 Qu<strong>in</strong>n 2001 reported that the meanPPVT-R at 5 years for those breastfed for at least 6 months was 8.2 po<strong>in</strong>ts (95%CI, 6.5-9.9)higher for females <strong>and</strong> 5.8 po<strong>in</strong>ts (95%CI, 4.1-7.5) higher for males when compared to thosenever breastfed. PPVT-R was adjusted for birthweight, poverty, maternal education, maternalage, time <strong>in</strong> daycare or preschool, the number of children <strong>in</strong> the household at 5 years, Englishspeak<strong>in</strong>g background <strong>in</strong> parents, <strong>and</strong> <strong>in</strong>fant stimulation. 70 Similarly, Oddy 2003 <strong>and</strong> 2004,reported that the PPVT-R score at 6 years was 3.56 po<strong>in</strong>t higher for children breastfed more than6 months compared with children never breastfed (F=8.59, P=0.003). 68,69 The result was adjustedfor gender, gestational age, maternal age <strong>and</strong> education, parental smok<strong>in</strong>g, <strong>and</strong> the presence ofolder sibl<strong>in</strong>gs. Mortensen 2002 reported that the duration of breastfeed<strong>in</strong>g was associated withsignificantly higher scores on the verbal, performance, <strong>and</strong> full scale WAIS at 27 years. 67 Withregression adjustment for parental social status <strong>and</strong> education, s<strong>in</strong>gle mother status, mother’sheight, age, <strong>and</strong> weight ga<strong>in</strong> dur<strong>in</strong>g pregnancy, cigarette smok<strong>in</strong>g dur<strong>in</strong>g 3 rd trimester, number of52
pregnancies, estimated gestational age, birth weight, birth length, <strong>and</strong> <strong>in</strong>dices of pregnancy <strong>and</strong>delivery complications, the mean full scale WAIS were 99.4, 101.7, 102.3, 106.0, <strong>and</strong> 104.0 forbreastfeed<strong>in</strong>g durations of < 1 month, 2 to 3 months, 4 to 6 months, 7 to 9 months, <strong>and</strong> > 9months, respectively (P=0.003). GomezSanchiz 2004 reported that the Bayley MDI at 24 monthswas 4.3 po<strong>in</strong>ts higher <strong>in</strong> those breastfed more than 4 months compared with those breastfed lessthan 4 months after multiple l<strong>in</strong>ear regression adjust<strong>in</strong>g for parental IQ. 66 Angelsen 2001reported that adjustment for differences <strong>in</strong> maternal <strong>in</strong>telligence reduced the odds ratio of hav<strong>in</strong>ga low IQ score among children who were breastfed for
54Table 8. Summary of systematic reviews/meta-analyses on the relationship of breastfeed<strong>in</strong>g <strong>and</strong> cognitive developmentAuthor YearPopulationJa<strong>in</strong> 200250 to >11,000Term <strong>and</strong>pretermDrane 2000N <strong>in</strong> <strong>in</strong>dividualstudies notprovided <strong>in</strong> thereviewTerm <strong>and</strong>pretermStudies description30 birth cohorts; 2RCTs; 5 school registrycohorts; 3 case-controlstudies24 studies (1 RCT <strong>and</strong>23 cohorts) met<strong>in</strong>clusion criteria: birth1960-98, Englishlanguage, exam<strong>in</strong>edcognitive developmentIntervention/Comparator<strong>Breastfeed<strong>in</strong>g</strong>,breast milk, orchoice to breastfeedActual breastfeed<strong>in</strong>g<strong>in</strong>tervention <strong>in</strong><strong>in</strong>dividual studies notdescribed <strong>in</strong> thereviewConfoundersconsideredSES (parental education,occupation, <strong>in</strong>come or anycomb<strong>in</strong>ation), quality <strong>and</strong>quantity of stimulation ofthe child (<strong>in</strong>clud<strong>in</strong>g social<strong>in</strong>teractions)SES, maternal education,birthweight, gestationalage, birth order, genderResultsQuality of feed<strong>in</strong>g data evaluated by 4 criteria (exclusivebreastfeed<strong>in</strong>g or not, tim<strong>in</strong>g of feed<strong>in</strong>g data collection,source of feed<strong>in</strong>g data, duration of breastfeed<strong>in</strong>g): 9 articlesmet all 4 criteria (8 full-term cohorts).22 studies used an appropriate measure of cognition.Only 2 studies met all the methodological st<strong>and</strong>ards. Onestudy concluded that “any beneficial effect of breastfeed<strong>in</strong>gon cognitive development is quite small <strong>in</strong> magnitude”,another study found that children who were breastfed hadmean IQ scores 4.6 po<strong>in</strong>ts higher than those neverbreastfed after controll<strong>in</strong>g for socioeconomic status <strong>and</strong>other factors. Among the studies that controlled forsocioeconomic status <strong>and</strong> stimulation/<strong>in</strong>teraction of thechild, three concluded that breastfeed<strong>in</strong>g promotes cognitivedevelopment, <strong>and</strong> four did not.5 studies met the 3 methodological st<strong>and</strong>ards (operationaldef<strong>in</strong>ition of cognitive outcome <strong>and</strong> outcome measure us<strong>in</strong>gst<strong>and</strong>ardized tests; correct classification of type of feed<strong>in</strong>g:measure breastfeed<strong>in</strong>g as a cont<strong>in</strong>uous variable or at leastas a 3-level categorical variable (exclusive breast orformula-fed; partial breastfed) <strong>and</strong> control for potentialconfound<strong>in</strong>g variables.The only RCT did not f<strong>in</strong>d statistical significant difference <strong>in</strong>Bayley MDI <strong>in</strong> <strong>in</strong>fants fed solely on a diet of donor breastmilk compared with <strong>in</strong>fants fed solely on a diet of termformula.Advantages <strong>in</strong> IQ as measured by the WISC-R, Bayley <strong>and</strong>McCarthy were observed <strong>in</strong> 4 cohort studies.In term <strong>in</strong>fants, effects on IQ <strong>in</strong> the range of 2-5 po<strong>in</strong>ts (0.2-0.3SD) were found.Quality ofSR/MA <strong>and</strong>limitationsAB
Table 8. Cont<strong>in</strong>uedAuthor Year StudiesPopulation descriptionAnderson, 11 cohort studies1999 with resultsadjusted for7,081 covariatesTerm <strong>and</strong> lowbirthweightIntervention/Comparator<strong>Breastfeed<strong>in</strong>g</strong> vs.formula feed<strong>in</strong>g (nodetailed <strong>in</strong>formation)Confounders consideredbreastfeed<strong>in</strong>g duration, sex, maternal smok<strong>in</strong>g,age, <strong>in</strong>telligence, education, tra<strong>in</strong><strong>in</strong>g, paternaleducation, race or ethnicity, SES, family size,birth order, birth weight, gestational age, <strong>and</strong>childhood experiencesMDI, Bayley Mental Development Index; SR, systematic review; MA, meta-analysis; SES, socioeconomic statusResultsAdjusted (fixed effects) pooled me<strong>and</strong>ifference of st<strong>and</strong>ardized effectestimate of cognitive developmentalscore was 3.16 (95% CI 2.35, 3.98) <strong>in</strong>favor of breastfeed<strong>in</strong>g;An average adjusted benefit frombreastfeed<strong>in</strong>g of 5.18 po<strong>in</strong>ts <strong>in</strong>cognitive developmental score wasobta<strong>in</strong>ed for low-birth weight childrenacross 6 available observations.Quality of SR/MA<strong>and</strong> limitationsBNo additionalqualityassessments ofprimary studies55
56Table 9. Summary of studies on the relationship of breast milk feed<strong>in</strong>g <strong>and</strong> cognitive developmentAssessmentAuthor YearBreast milkStudytools for ConfoundersCountryfeed<strong>in</strong>gDescriptioncognitive adjusted forPopulationexposuredevelopmentDatabase analysis of a prospective cohort studyDer 2006USDatabasefrom the USnationallongitud<strong>in</strong>alsurvey ofyouth 1979(NLSY79)<strong>and</strong> childrenof thewomen <strong>in</strong>the survey,Full term<strong>in</strong>fantsDatabaseanalysis of aprospectivestudy; sibl<strong>in</strong>gpairs analysis,<strong>and</strong> metaanalysis;Cognitive testadm<strong>in</strong>istered tochildrenbetween 5 yr<strong>and</strong> 14 yrbiennially from1986 to 2002;For metaanalysis,only<strong>in</strong>cluded studiesthat quantifiedthe effect ofbreastfeed<strong>in</strong>g oncognitive abilityafter controll<strong>in</strong>gfor parental<strong>in</strong>telligence<strong>Breastfeed<strong>in</strong>g</strong>historyobta<strong>in</strong>edwith<strong>in</strong> a yearof birth <strong>in</strong>most casesPeabody<strong>in</strong>dividualachievementtest (PIAT)wasadm<strong>in</strong>isteredto childrenAdjustment forvariables associatedwith breastfeed<strong>in</strong>g <strong>in</strong>the survey, homeenvironment (HOME-SF), childdemographics,maternalcharacteristics<strong>Outcomes</strong>PIAT (all outcomes st<strong>and</strong>ardized to a mean of 100 <strong>and</strong> SD of15)Unadjusted effect of breastfeed<strong>in</strong>g +4.7 compared to nonbreastfeed<strong>in</strong>g(3,161 mothers, 5,475 children, 16,744assessments); after adjustment for maternal Armed ForcesQualification Test (AFQT) score, education, age, familypoverty, HOME stimulation score, <strong>and</strong> birth order, thedifference became +0.52 (P=0.149)332 pairs of sibl<strong>in</strong>g discordant for breastfeed<strong>in</strong>g status <strong>and</strong>545 discordant for duration of breastfeed<strong>in</strong>g, differencebetween groups (status) = -0.63 (P=0.506); (duration) =-0.13 (P=0.866)Meta-regression of 9 unique studies (<strong>in</strong>clud<strong>in</strong>g the data fromNLSY79): an advantage of breastfeed<strong>in</strong>g of 0.16 aftercontroll<strong>in</strong>g for IQ <strong>and</strong> 8 additional confounders.Comb<strong>in</strong>ed data from NLSY79 <strong>and</strong> sibl<strong>in</strong>g analysis study byEvenhouse 2005 (see separate extraction): estimate 0.025(P=0.54) for breastfeed<strong>in</strong>g status <strong>and</strong> 0.04 (P=0.271) forduration of breastfeed<strong>in</strong>gQuality <strong>and</strong>limitationsANo detailsregard<strong>in</strong>gbreastfeed<strong>in</strong>ghistory
57Table 9. Cont<strong>in</strong>uedAuthor YearCountryPopulationProspective cohortLawlor 2006AustraliaEnrolled7,223Followup3,794 (>98%term)StudyDescriptionEnrolledsubjects at birth<strong>and</strong> didPeabody PictureVocabulary testat 5 yr <strong>and</strong>Raven’sst<strong>and</strong>ardprogressivematrices (nonverbalreason<strong>in</strong>gor general<strong>in</strong>telligence) at14 yr, most ofthe datareported werefrom age 14(see Qu<strong>in</strong>n 2001for 5-yr data)Breast milkfeed<strong>in</strong>gexposureClassified bynever, < 4mo, ≥ 4 mo(obta<strong>in</strong>edfrom mothersat the 6-mofollowup)Assessmenttools forcognitivedevelopmentRaven’sst<strong>and</strong>ardprogressivematrices at 14yearsConfoundersadjusted forSex, parentalcharacteristics(maternal age,ethnicity, education,paternal education,family <strong>in</strong>come,gravidity, maternalsmok<strong>in</strong>g), labor,Apgar scores,birthweight, height,BMI<strong>Outcomes</strong>At age 14 yr, Never breastfed = 694,
58Table 9. Cont<strong>in</strong>uedAuthor YearCountryPopulationQu<strong>in</strong>n 2001AustraliaEnrolled7,357Followup3,880S<strong>in</strong>gleton;children withmajorneurologicalabnormalities <strong>and</strong> thosefor whom thedata were<strong>in</strong>completewereexcludedStudyDescriptionEnrolled womenattend<strong>in</strong>gantenatal cl<strong>in</strong>ic;data collected atbasel<strong>in</strong>e, afterbirth, 6 mo <strong>and</strong>5 yrBreast milkfeed<strong>in</strong>gexposureNo dist<strong>in</strong>ctionwas madebetweenpartial orcompletebreastfeed<strong>in</strong>g;classified bynever,< 3 wk, 3 to
59Table 9. Cont<strong>in</strong>uedAuthor YearCountryPopulationOddy, 2003,2004 (samedata)Australia2,393 atbirth, 1,444at 6 yr, 1,371at 8 yr37-39 wkgestationStudyDescriptionCompar<strong>in</strong>g nobreastfeed<strong>in</strong>g,6 mo ofbreastfeed<strong>in</strong>gBreast milkfeed<strong>in</strong>gexposure90% ofchildren werebreastfed atsome po<strong>in</strong>t,28% werebreastfed for>6 mo, solidfoods were<strong>in</strong>troduced at≤6 mo <strong>in</strong> 88%of <strong>in</strong>fants.Assessmenttools forcognitivedevelopmentPeabodyPictureVocabularyTest (PPVT-R) wasadm<strong>in</strong>isteredat 6 y/o <strong>and</strong> aPerformancesubtest(PerceptualorganizationWISC- BlockDesign) at 8y/oConfoundersadjusted forGender, gestationalage, maternal age<strong>and</strong> education,parental smok<strong>in</strong>g,<strong>and</strong> the presence ofolder sibl<strong>in</strong>gs.<strong>Outcomes</strong>Both verbal IQ <strong>and</strong> performance scores <strong>in</strong>crease with<strong>in</strong>creas<strong>in</strong>g maternal education comb<strong>in</strong>ed with a longerduration of breastfeed<strong>in</strong>g, with the most profound effect ofbreastfeed<strong>in</strong>g occurr<strong>in</strong>g <strong>in</strong> the highest education groups(P6mo had mean verbal IQ scores 6.44 po<strong>in</strong>ts higher <strong>and</strong>Block Design scores that were 1.13 po<strong>in</strong>ts higher thanchildren never breastfed.After adjustment for covariates, there was an associationbetween duration of breastfeed<strong>in</strong>g <strong>and</strong> verbal IQ with a3.56 po<strong>in</strong>t advantage for children breastfed >6 mocompared with children never breastfed (P=0.003). Theadjusted association of full breastfeed<strong>in</strong>g with thePerformance subtest was not significant (P=0.223).There was an association of low PPVT-R <strong>and</strong> non-Englishmaternal language; children of non-English speak<strong>in</strong>gparents (n=100) were excluded from further analyses.Quality <strong>and</strong>limitationsBLarge drop out
60Table 9. Cont<strong>in</strong>uedAuthorYearStudy DescriptionCountryPopulationMortensen2002DenmarkEnrolled9,125(4668males)973 hadWAIS;2,280 hadBPP & BFdataGomezSanchiz, 2003,2004Spa<strong>in</strong>296 atbirth; 249at 18 mo;238 at 24mo37-42 wkgestationProspective cohort;but breastfeed<strong>in</strong>g<strong>in</strong>formationcollectedretrospectively at 1-year exam1 rural <strong>and</strong> 1 urbansites, compar<strong>in</strong>gbreastfed > 4 mo, 9 mo 3%≤ 4 mo49%> 4 mo28%(nodist<strong>in</strong>ctionbetweenexclusive orpartialbreastfeed<strong>in</strong>g)Formula-fed23%Assessmenttools forcognitivedevelopment2 sub-cohorts;one (50%male) took theWAIS at 27yr; the other(100% male)took the draftboard<strong>in</strong>telligencetest: BorgePriens Prove(BPP) at 18.7yrBayley wasadm<strong>in</strong>isteredat 18 <strong>and</strong> 24moConfoundersadjusted forParental social status<strong>and</strong> education, s<strong>in</strong>glemother status,mother’s height, age,<strong>and</strong> weight ga<strong>in</strong>dur<strong>in</strong>g pregnancy,cigarette dur<strong>in</strong>g 3 rdtrimester, number ofpregnancies,estimated gestationalage, birthweight, birthlength, <strong>and</strong> <strong>in</strong>dices ofpregnancy <strong>and</strong>deliverycomplicationsParental IQ, socialclass, parentaleducation, number ofsibl<strong>in</strong>gs<strong>Outcomes</strong><strong>Breastfeed<strong>in</strong>g</strong> duration (mo) 9Unadjusted 98.1 101.3 103.3 108.2 102.8Adjusted 99 102 102 106 104WAIS P=0.003 for overall FUnadjusted 36.9 39 40.8 43.1 40.2Adjusted 38 39 40 40 40BPP P=0.01 for overall FParental IQ was obta<strong>in</strong>ed only for 164 couples; their childrenhad MDI 2.3 po<strong>in</strong>ts higher than the children whose parentsdid not take part <strong>in</strong> IQ test<strong>in</strong>g (P
61Table 9. Cont<strong>in</strong>uedAuthor YearCountryPopulationAngelsen,2001Norway<strong>and</strong>SwedenEnrolled521Followup291 (5 yr)TermExcludedcongenitalmalformationsStudy DescriptionProspective cohort;but duration ofbreastfeed<strong>in</strong>gretrospectivelyrecorded at 13 moBreast milkfeed<strong>in</strong>gexposure< 3 mo17%;3-6 mo21%;≥ 6 mo62%Assessmenttools forcognitivedevelopmentBayley MDI at13 moWechslerPreschool<strong>and</strong> PrimaryScales ofIntelligence(WPPSI-R) at5 y/oConfoundersadjusted for<strong>Maternal</strong> IQ, age,education, smok<strong>in</strong>g<strong>Outcomes</strong>Bayley MDI at 13 mo: 117.7 (SD11.7) <strong>in</strong> ≥ 6 mobreastfeed<strong>in</strong>g compared to 109.9 (SD13.1) <strong>in</strong> < 3 mo(P
BackgroundRelationship between Obesity <strong>and</strong> <strong>Breastfeed<strong>in</strong>g</strong>The prevalence of overweight or obesity among children <strong>and</strong> adolescents has rapidly<strong>in</strong>creased <strong>in</strong> the past two decades. Results from the 1999-2002 National <strong>Health</strong> <strong>and</strong> NutritionExam<strong>in</strong>ation Survey (NHANES) showed that an estimated 16 percent of children <strong>and</strong>adolescents ages 6-19 years were overweight. This represents a 45 percent <strong>in</strong>crease from theoverweight estimate of 11 percent obta<strong>in</strong>ed from NHANES III (1988-94).(www.cdc.gov/nchs/products/pubs/pubd/hestats/overwght99.htm) It is <strong>in</strong>creas<strong>in</strong>gly recognizedthat nutrition <strong>in</strong> early life may have long-term physiologic effects. Relationships between thetypes of postnatal feed<strong>in</strong>g <strong>and</strong> the subsequent development of fat <strong>and</strong> fat-free mass are quitecomplex <strong>and</strong> are dependent on multiple factors <strong>in</strong>clud<strong>in</strong>g differences <strong>in</strong> food composition(human milk versus formula), food delivery (breast versus bottle), food “lifestyle” (breastfeed<strong>in</strong>gversus formula feed<strong>in</strong>g) <strong>and</strong> food behavior (self-regulation <strong>and</strong> feed<strong>in</strong>g on dem<strong>and</strong> versus setschedules of feed<strong>in</strong>g of predeterm<strong>in</strong>ed amounts). 73 It is known that <strong>in</strong>fants fed breast milk differ<strong>in</strong> their growth k<strong>in</strong>etics from formula-fed <strong>in</strong>fants. Formula-fed <strong>in</strong>fants demonstrate higher weight<strong>and</strong> length ga<strong>in</strong>s compared with breastfed <strong>in</strong>fants. A systematic review of 19 studies <strong>in</strong>developed countries concluded that by the age of 12 months, the cumulative difference <strong>in</strong> bodyweight amounted to approximately 400 g less <strong>in</strong> <strong>in</strong>fants breastfed for 9 months compared withformula-<strong>in</strong>fants, <strong>and</strong> as much as 600-650 g less <strong>in</strong> <strong>in</strong>fants breastfed for 12 months compared withformula-fed <strong>in</strong>fants. 74 Differences <strong>in</strong> feed<strong>in</strong>g behavior <strong>and</strong> mother-child <strong>in</strong>teraction betweenbreast- <strong>and</strong> formula-fed <strong>in</strong>fants may account for some of the differences reported. For <strong>in</strong>stance,breastfed <strong>in</strong>fants showed a different suckl<strong>in</strong>g pattern, <strong>and</strong> appeared to have greater degree ofcontrol on meal sizes <strong>and</strong> feed<strong>in</strong>g <strong>in</strong>tervals than <strong>in</strong>fants who were formula-fed. 75 Diet-relateddifferences <strong>in</strong> the circulat<strong>in</strong>g levels of biochemical markers (such as lept<strong>in</strong>, ghrel<strong>in</strong>, <strong>in</strong>sul<strong>in</strong>-likegrowth factors, <strong>and</strong> other compounds) implicated <strong>in</strong> energy metabolism dur<strong>in</strong>g <strong>in</strong>fancy mightexpla<strong>in</strong> some of the anthropometric <strong>and</strong> behavioral differences between breastfed <strong>and</strong> formulafed<strong>in</strong>fants. These observed differences may have potential long-term consequences. 73Commonly considered confounders <strong>in</strong> the studies of relationship between obesity oroverweight <strong>and</strong> breastfeed<strong>in</strong>g were birth weight, parental overweight, parental smok<strong>in</strong>g, dietaryfactors, physical activity, socioeconomic status (SES), age, sex, birth order, <strong>and</strong> number ofsibl<strong>in</strong>gs.Additional Methodological CommentsWe identified three systematic reviews <strong>and</strong> meta-analyses that exam<strong>in</strong>ed the relationshipbetween breastfeed<strong>in</strong>g <strong>and</strong> childhood obesity or obesity across all ages. 76-78 Although theoutcomes of <strong>in</strong>terest were similar among these systematic reviews <strong>and</strong> meta-analyses, theyanswered slightly different research questions because of the differences <strong>in</strong> their study eligibilitycriteria <strong>and</strong> analyses. Thus, we have summarized <strong>and</strong> discussed these systematic reviews <strong>and</strong>meta-analyses separately.62
Published Systematic Reviews/Meta-Analyses (Table 10)Arenz 2004 was a meta-analysis of studies from 1966 to December 2003 that exam<strong>in</strong>ed therelationship between breastfeed<strong>in</strong>g <strong>and</strong> childhood obesity <strong>in</strong> children at least one year of age.Inclusion criteria for the meta-analysis were: obesity def<strong>in</strong>ed by a body mass <strong>in</strong>dex (BMI)greater than 90 th , 95 th or 97 th percentile; adjustment for at least three potential confound<strong>in</strong>g or<strong>in</strong>teract<strong>in</strong>g factors; reported either odds ratio or relative risk; <strong>and</strong> last followup between 5 <strong>and</strong> 18years of age. N<strong>in</strong>e of 28 studies reviewed met the eligibility criteria for meta-analysis. Therewere two prospective cohort <strong>and</strong> seven cross-sectional studies total<strong>in</strong>g more than 69,000 childrenfrom developed countries. The meta-analysis used both fixed- <strong>and</strong> r<strong>and</strong>om-effects models <strong>and</strong>pooled crude <strong>and</strong> adjusted odds ratios from the <strong>in</strong>dividual studies. Def<strong>in</strong>itions of breastfeed<strong>in</strong>g<strong>and</strong> comparative feed<strong>in</strong>gs were heterogeneous across studies. Sensitivity analyses wereperformed to assess for heterogeneity. The factors analyzed were cohort study or cross-sectionalstudy, different def<strong>in</strong>itions of breastfeed<strong>in</strong>g, different def<strong>in</strong>itions of obesity, different age groups<strong>and</strong> number of potential confounders considered for adjustment. The methodological quality ofthis meta-analysis was grade A.The pooled crude odds ratio for breastfeed<strong>in</strong>g <strong>and</strong> obesity def<strong>in</strong>ed as a BMI > 90th, 95th or97th percentile could be calculated for six of the n<strong>in</strong>e studies <strong>in</strong>cluded. The odds ratio was 0.67(95% CI 0.62 - 0.73). The adjusted odds ratio for the n<strong>in</strong>e studies was 0.78 (95% CI 0.71 - 0.85)for both the fixed <strong>and</strong> r<strong>and</strong>om-effects models, suggest<strong>in</strong>g that there was no heterogeneitybetween the studies. Sensitivity analyses showed that the protective effect of breastfeed<strong>in</strong>g wasmore pronounced <strong>in</strong> studies with adjustment for less than seven potential confound<strong>in</strong>g factorscompared with adjustment for seven or more potential confound<strong>in</strong>g factors (adjusted OR 0.69 vs.0.78, respectively). Other criteria (e.g., cohort study or cross-sectional study, different def<strong>in</strong>itionsof breastfeed<strong>in</strong>g, different def<strong>in</strong>itions of obesity, different age-groups) did not affect thesummary estimates significantly. For example, the pooled adjusted odds ratio of obesity was 0.76(95%CI 0.67-0.86) <strong>in</strong> studies compar<strong>in</strong>g ever breastfeed<strong>in</strong>g to never breastfeed<strong>in</strong>g, versus 0.74(95%CI 0.64-0.85) <strong>in</strong> studies that used other def<strong>in</strong>itions of breastfeed<strong>in</strong>g <strong>and</strong> comparativefeed<strong>in</strong>gs.Eight studies analyzed the relationship between breastfeed<strong>in</strong>g duration <strong>and</strong> the risk ofoverweight or obesity <strong>in</strong> later childhood. Exclusivity of breastfeed<strong>in</strong>g was not reported. Fourstudies reported an <strong>in</strong>verse association of breastfeed<strong>in</strong>g duration <strong>and</strong> the prevalence of obesityboth <strong>in</strong> the crude <strong>and</strong> the adjusted estimates. One of the studies lost statistical significance afteradjustment. Three studies found no significant effect of duration of breastfeed<strong>in</strong>g on obesity.Harder 2005 was a meta-analysis of 17 qualify<strong>in</strong>g studies published from 1966 to December2003. A total of 120,831 subjects (66 to 32,200 subjects per study) from developed countrieswere <strong>in</strong>cluded. Eligibility criteria <strong>in</strong>cluded any orig<strong>in</strong>al report compar<strong>in</strong>g breastfed subjects withexclusively formula-fed subjects at any age, the reports must have either reported odds ratio orconta<strong>in</strong>ed data for the calculation of odds ratio for the risk of overweight or obesity <strong>in</strong>relationship to the feed<strong>in</strong>g history, <strong>and</strong> the duration of breastfeed<strong>in</strong>g must have been reported.All def<strong>in</strong>itions of overweight or obesity were <strong>in</strong>cluded. Three different meta-analytic techniquesthat specifically required the use of crude odds ratios <strong>and</strong> 95% confidence <strong>in</strong>tervals wereemployed. Because of suboptimal consideration for potential confound<strong>in</strong>g, we rated themethodological quality of this meta-analyses grade B.Fourteen studies provided data for more than one category of duration of breastfeed<strong>in</strong>g,lead<strong>in</strong>g to 52 estimates <strong>in</strong>cluded <strong>in</strong> the meta-regression analysis. In the analysis, duration of63
eastfeed<strong>in</strong>g was significantly negatively related to the risk of overweight (regressioncoefficient: 0.94, 95%CI 0.89 - 0.98). Categorical analysis showed that from 1 month ofbreastfeed<strong>in</strong>g onward (the reference group), the risk of subsequent overweight cont<strong>in</strong>ued todecrease, reach<strong>in</strong>g a plateau of more than 30 percent risk reduction at 9 months of breastfeed<strong>in</strong>g.Us<strong>in</strong>g the “pool-first method” (that is to calculate a study-specific regression coefficient <strong>and</strong>correspond<strong>in</strong>g 95 percent confidence <strong>in</strong>terval for each study us<strong>in</strong>g a log-l<strong>in</strong>ear model <strong>and</strong> thenpooled all studies with a r<strong>and</strong>om effects model) to quantify the dose-response relationship, theresults showed that each month of breastfeed<strong>in</strong>g was associated with a four percent decrease <strong>in</strong>risk of overweight per month of breastfeed<strong>in</strong>g exposure (OR 0.96/month of breastfeed<strong>in</strong>g,95%CI 0.94 - 0.98). A fixed effect model reported a similar pooled odds ratio (OR 0.96/month ofbreastfeed<strong>in</strong>g, 95%CI 0.95 - 0.98). The age at exam<strong>in</strong>ation had little <strong>in</strong>fluence on the magnitudeof the effect of duration of breastfeed<strong>in</strong>g on the risk of overweight. The pooled odds ratio fromfive studies <strong>in</strong>vestigat<strong>in</strong>g subjects up to 5 years of age was 0.97 (95%CI 0.94 - 0.99); while forsix studies on subjects 6 or more years of age, it was 0.96 (95%CI 0.93 - 0.99).The effect of the duration of exclusive breastfeed<strong>in</strong>g was analyzed <strong>in</strong> two studies. The pooledodds ratio for the risk of overweight per month of exclusive breastfeed<strong>in</strong>g was 0.94 (95%CI 0.89- 0.99, r<strong>and</strong>om effects model).Subgroup analyses showed that the different def<strong>in</strong>itions of overweight <strong>in</strong>fluenced theestimate of odds ratio only slightly. In eight studies that used BMI to def<strong>in</strong>e overweight, thepooled odds ratio was 0.96 (95%CI 0.94 - 0.98); while <strong>in</strong> three studies that used anothermeasures (e.g., percentile of weight for length, or weight for age) to def<strong>in</strong>e overweight orobesity, the odds ratio was 0.93 (95%CI 0.87 - 0.99).Lastly, Owen 2005 was a systematic review of 61 observational studies from 1966 toSeptember 2003 that exam<strong>in</strong>ed the effects of <strong>in</strong>fant feed<strong>in</strong>g on a measure of adiposity(quantitatively or narratively) <strong>in</strong> later life. Twenty-eight studies (total<strong>in</strong>g 298,900 subjects) thatprovided 29 unadjusted odds ratios relat<strong>in</strong>g the <strong>in</strong>itial <strong>in</strong>fant feed<strong>in</strong>g method <strong>and</strong> obesity were<strong>in</strong>cluded <strong>in</strong> a meta-analysis. A fixed effect model was used. Meta-regression <strong>and</strong> sensitivityanalyses were used to exam<strong>in</strong>e the <strong>in</strong>fluence of various factors def<strong>in</strong>ed a priori, <strong>in</strong>clud<strong>in</strong>g theeffects of adjustment for factors such as parental body size (mostly BMI), SES, <strong>and</strong> maternalsmok<strong>in</strong>g. Because of suboptimal consideration for potential confound<strong>in</strong>g, we rated themethodological quality of this systematic review <strong>and</strong> meta-analyses grade B.Twenty-eight of 29 estimates related breastfeed<strong>in</strong>g to a lower risk of obesity <strong>in</strong> later life.Four estimates were for <strong>in</strong>fants, 23 for children, <strong>and</strong> two for adults. There was evidence ofmarked heterogeneity among studies (P < 0.001). In a fixed-effect meta-analysis, breastfedsubjects were less likely to be def<strong>in</strong>ed as obese than were formula-fed subjects (OR 0.87, 95% CI0.85 - 0.89). In six studies, it was possible to exam<strong>in</strong>e the effect of adjustment for the follow<strong>in</strong>gpotential confounders: SES (based on parental education <strong>in</strong> two studies), parental BMI, <strong>and</strong>current maternal smok<strong>in</strong>g or maternal smok<strong>in</strong>g <strong>in</strong> early life. The pooled odds ratio <strong>in</strong> thesestudies changed from 0.86 (95% CI 0.81 - 0.91) before adjustment to 0.93 (95% CI 0.88 - 0.99)after comb<strong>in</strong>ed adjustment. The effect of adjustment for birth weight (based on either actual birthweight or prevalence of low birth weight) was exam<strong>in</strong>ed <strong>in</strong> 10 studies; this had no appreciableeffect on the odds ratios.There was no clear evidence that the protective effect of breastfeed<strong>in</strong>g altered with <strong>in</strong>creas<strong>in</strong>gage of outcome assessment. Odds ratios of 0.50 (95% CI 0.26 - 0.94) for <strong>in</strong>fants, 0.90 (95% CI0.87 - 0.92) for young children, 0.66 (95% CI 0.60 - 0.72) for older children, <strong>and</strong> 0.80 (95% CI0.71 - 0.91) for adults were observed (test for trend, P = .85, adjusted for study size; P = .99 with64
the exclusion of <strong>in</strong>fants). The protective effect of breastfeed<strong>in</strong>g on obesity was stronger <strong>and</strong> morehomogeneous among four studies <strong>in</strong> which <strong>in</strong>itial feed<strong>in</strong>g groups were exclusive (OR 0.76; 95%CI 0.70 - 0.83; test for heterogeneity between estimates, P= .143), compared with all otherstudies. In 14 studies that provided data on breastfeed<strong>in</strong>g duration, the protective effect ofbreastfeed<strong>in</strong>g over formula feed<strong>in</strong>g was greater among subjects breastfed for at least 2 months(OR 0.81, 95% CI 0.77 - 0.84), compared with those breastfed for any duration (OR 0.89, 95%CI 0.86 - 0.91). In six studies, it was possible to exam<strong>in</strong>e the effect of adjustment for thefollow<strong>in</strong>g potentially important confounders: socioeconomic status, parental BMI, <strong>and</strong> currentmaternal smok<strong>in</strong>g or maternal smok<strong>in</strong>g <strong>in</strong> early life. The pooled odds ratio <strong>in</strong> these studies wasreduced from 0.86 (95% CI: 0.81– 0.91) before adjustment to 0.93 (95% CI: 0.88–0.99) afteradjustment.Thirty-three studies total<strong>in</strong>g 12,505 subjects explored the relationship between breastfeed<strong>in</strong>g<strong>and</strong> obesity even though they did not provide odds ratio. However, they provided 35 reports ofdirections of association; of these, breastfeed<strong>in</strong>g was unrelated to the risk of obesity <strong>in</strong> 33,related to a reduced risk <strong>in</strong> one, <strong>and</strong> related to an <strong>in</strong>creased risk <strong>in</strong> another. Studies that did notprovide odds ratios were much less likely to report that breastfeed<strong>in</strong>g was associated with areduced risk of obesity, compared with studies that did provide odds ratios (1 of 35 studies <strong>and</strong>18 of 29 studies, respectively; P < .001).ConclusionF<strong>in</strong>d<strong>in</strong>gs from three systematic reviews <strong>and</strong> meta-analyses of good <strong>and</strong> moderatemethodological quality suggest that a history of breastfeed<strong>in</strong>g is associated with a reduction <strong>in</strong>the risk of obesity <strong>in</strong> later life. The pooled adjusted odds ratio of overweight/obesity compar<strong>in</strong>gever breastfeeders to never breastfeeders was 0.76 (95%CI 0.67-0.86) <strong>and</strong> 0.93 (95%CI: 0.88–0.99) <strong>in</strong> Arenz 2004 <strong>and</strong> Owen 2006 meta-analysis, respectively. In Harder 2005 meta-analysis,duration of breastfeed<strong>in</strong>g was significantly negatively related to the unadjusted risk ofoverweight (regression coefficient: 0.94, 95%CI 0.89 - 0.98), <strong>and</strong> each month of breastfeed<strong>in</strong>gwas found to be associated with a four percent decrease <strong>in</strong> risk (unadjusted OR 0.96/month ofbreastfeed<strong>in</strong>g, 95%CI 0.94 - 0.98). However, the results from Harder 2005 meta-analysisemployed techniques that required the use of crude odds ratios from the primary studies for itssummary estimates. Therefore, those estimates may not be accurate because potentialconfounders could not be accounted for <strong>in</strong> the analysis. As demonstrated <strong>in</strong> the sensitivityanalyses <strong>in</strong> both Arenz 2004 <strong>and</strong> Owen 2005, the magnitude of effects was reduced when moreconfounders were adjusted for <strong>in</strong> the analyses. The observed association between breastfeed<strong>in</strong>g<strong>and</strong> a reduced risk of obesity could also reflect selective report<strong>in</strong>g <strong>and</strong>/or publication bias. Theexclusivity of breastfeed<strong>in</strong>g was not described <strong>in</strong> the majority of the studies.65
66Table 10. Summary of systematic reviews/meta-analyses on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> overweight or obesityAuthor yearInterventionStudy descriptionPopulation/ComparatorConfounders consideredResultsArenz 2004 MA of 7 crosssectionalStudies with > 3 the<strong>and</strong> 2follow<strong>in</strong>g relevantChildren <strong>and</strong> prospective cohortconfound<strong>in</strong>g factors birthadolescents. studies <strong>in</strong>weight, parental overweight,One study developedparental smok<strong>in</strong>g, dietary<strong>in</strong>cluded some countriesfactors, physical activity <strong>and</strong>adult subjects.SES were <strong>in</strong>cluded.N=69,000Harder 2005Children <strong>and</strong>adolescents.Two studies<strong>in</strong>cluded adultsubjects.N=120,831(ranged from66 to 32,200)MA of 16 cohort orcross-sectionalstudies <strong>and</strong> 1 casecontrolstudy <strong>in</strong>developedcountriesNever BF or partly BF 6 months, BF groups: 9 months(exclusivity of BF notreported)Median duration ofbreastfeed<strong>in</strong>gcategories: < 1 month(reference), 1-3 month,4-6 months, 7-9 months,> 9month.To studies that provideddata for more than twocategories of duration ofbreastfeed<strong>in</strong>g, “pool-firstmethod” was used toquantify the doseresponserelation (permonth of breastfeed<strong>in</strong>g).Other confounders <strong>in</strong> the<strong>in</strong>cluded studies: age, sex,diet <strong>and</strong> weight concerns,Tanner stadium, birth order,race, <strong>in</strong>troduction of solidfoods, number of sibl<strong>in</strong>gsAge, sex, birth weight, SES,Tanner stage, physicalactivity, eat<strong>in</strong>g habits,concerns to ga<strong>in</strong> weight,birth order, dietary <strong>in</strong>takes,maternal BMI, maternalsmok<strong>in</strong>g• The pooled adjusted OR for breastfeed<strong>in</strong>g<strong>and</strong> obesity def<strong>in</strong>ed as BMI >90th, 95th or 97thpercentile calculated for n<strong>in</strong>e studies was 0.78(95%CI 0.71-0.85) for both fixed <strong>and</strong> r<strong>and</strong>omeffectsmodel.• Protective effect of breastfeed<strong>in</strong>g wasmore pronounced <strong>in</strong> studies with adjustment forless than 7 (but more than 3) potentialconfound<strong>in</strong>g factors compared to adjustment forseven or more potential confound<strong>in</strong>g factors (OR0.69 vs. 0.78 respectively).• Pooled adjusted OR of obesity was 0.76(95%CI 0.67-0.86) compared ever breastfeed<strong>in</strong>gto never breastfeed<strong>in</strong>g, while it was 0.74 (95%CI0.64-0.85) <strong>in</strong> studies us<strong>in</strong>g other def<strong>in</strong>itions ofbreastfeed<strong>in</strong>g.• In the weighted meta-regression (52estimates from 14 gave data for more than onecategory of duration of breastfeed<strong>in</strong>g), duration ofbreastfeed<strong>in</strong>g was significantly negatively relatedto risk of overweight (regression coefficient: 0.94,95%CI 0.89-0.98).• From 1 month of breastfeed<strong>in</strong>g onward,the risk of subsequent overweight cont<strong>in</strong>uouslydecreased up to a reduction of more than 30%,reach<strong>in</strong>g a plateau at 9 months of breastfeed<strong>in</strong>g.• Each month of breastfeed<strong>in</strong>g was found tobe associated with a 4% decrease <strong>in</strong> risk (OR:0.96/month of breastfeed<strong>in</strong>g, 95%CI 0.94-0.98).Quality of SR/MA<strong>and</strong> limitationsA aBOnly unadjusted ORswere comb<strong>in</strong>ed,although someprimary studies hadadjustments forpotential confound<strong>in</strong>g
67Table 10. Cont<strong>in</strong>uedAuthor yearPopulationOwen 200528 studies provided 29unadjusted odds ratiosrelat<strong>in</strong>g the <strong>in</strong>itial <strong>in</strong>fantfeed<strong>in</strong>g method <strong>and</strong>obesity. Fourobservations were for<strong>in</strong>fants, 23 for children,<strong>and</strong> 2 for adults.N=298,900 <strong>in</strong> metaanalysesN=12,505 <strong>in</strong> the studiesthat did not provide anestimate of relative riskStudy descriptionSR of 61 studies thatcompared a measure ofobesity (quantitatively ornarratively) amongbreastfed <strong>and</strong> formula-fedsubjects; with metaanalysesof 28 studiesreported sufficient dataIntervention/ComparatorBreastfed vs.formula-fedConfoundersconsideredParental body size(mostly BMI),socioeconomicstatus, maternalsmok<strong>in</strong>g, physicalactivity, weight ga<strong>in</strong>dur<strong>in</strong>g pregnancy,<strong>in</strong>troduction of solidfoods, birth order,dietary <strong>in</strong>takes,maternal BMI,maternal smok<strong>in</strong>g,<strong>and</strong> parentalobesity/overweightResults• In a fixed-effects model <strong>in</strong>clud<strong>in</strong>g all 28studies, breastfed subjects were less likely to bedef<strong>in</strong>ed as obese than were formula-fed subjects(OR: 0.87; 95% CI: 0.85–0.89). There was evidenceof marked heterogeneity among studies (p
Relationship between the Risk of Cardiovascular Diseases<strong>and</strong> <strong>Breastfeed<strong>in</strong>g</strong>BackgroundAbnormal levels of total cholesterol, low-density lipoprote<strong>in</strong> (LDL) cholesterol, <strong>and</strong> bloodpressure <strong>in</strong> adults are major risk factors for cardiovascular disease (CVD). Observational studiesof large cohorts of men <strong>and</strong> women have consistently reported that serum cholesterol level >200mg/dL was associated with an <strong>in</strong>creased risk of all-cause <strong>and</strong> CVD mortality. 79,80 Each <strong>in</strong>crementof 20 mm Hg of systolic blood pressure <strong>and</strong> 10 mm Hg of diastolic blood pressure doubles therisk for CVD. 81 Diet modification, weight reduction, <strong>and</strong> pharmacotherapy can reduce the risk ofCVD. We identified one meta-analysis that evaluated the relationship of breastfeed<strong>in</strong>g dur<strong>in</strong>g<strong>in</strong>fancy with cholesterol levels <strong>in</strong> adolescents <strong>and</strong> adults, 82 two meta-analyses that evaluated therelationship of breastfeed<strong>in</strong>g with adult blood pressure, 83,84 <strong>and</strong> one systematic review <strong>and</strong> metaanalysisthat exam<strong>in</strong>ed the relationship between breastfeed<strong>in</strong>g <strong>and</strong> cardiovascular diseasemortality <strong>in</strong> later life. 85CholesterolsPublished Systematic Reviews/Meta-Analyses (Table 11)One meta-analysis of 37 cohort <strong>and</strong> cross-sectional studies evaluated the effect ofbreastfeed<strong>in</strong>g on total <strong>and</strong> LDL cholesterol levels among <strong>in</strong>fants, adolescents, <strong>and</strong> adults. 82 Allprimary studies published <strong>in</strong> English language from both developed <strong>and</strong> develop<strong>in</strong>g countriesthat reported estimates of a mean difference <strong>and</strong> st<strong>and</strong>ard error <strong>in</strong> cholesterol levels betweenbreastfed <strong>and</strong> formula-fed <strong>in</strong>fants were <strong>in</strong>cluded <strong>in</strong> the meta-analysis. The meta-analysis utilizeda r<strong>and</strong>om effects model. A total of 5,829 breastfed <strong>and</strong> 4,852 formula-fed subjects wereevaluated. Data from the <strong>in</strong>cluded primary studies were categorized <strong>in</strong>to three age strata: <strong>in</strong>fancy(< 1 year of age), children <strong>and</strong> adolescents (1 to 16 years), <strong>and</strong> adults (17 years to 65 years).<strong>Outcomes</strong> <strong>in</strong>cluded total <strong>and</strong> LDL cholesterol levels. No <strong>in</strong>formation was provided on the tim<strong>in</strong>gof the sample collection <strong>in</strong> relation to fast<strong>in</strong>g or not fast<strong>in</strong>g. Of the 37 studies, there were 26outcomes (total or LDL cholesterol levels) <strong>in</strong> <strong>in</strong>fants, 17 <strong>in</strong> children <strong>and</strong> adolescents, <strong>and</strong> n<strong>in</strong>e <strong>in</strong>adults. The analysis comb<strong>in</strong>ed data from a broad age category for the adult participants. It wasunclear if there were adjustments for potential confounders such as body mass <strong>in</strong>dex, height, <strong>and</strong>socioeconomic status for the data on cholesterol. The methodological quality of the metaanalysiswas rated grade C.In 25 of 26 observations, <strong>in</strong>fants who were breastfed reported higher mean total cholesterollevels compared with <strong>in</strong>fants who were formula-fed. The overall mean difference was +24.75mg/dL (95% CI 18.95 to 30.55). There was a statistically significant heterogeneity across thestudies. The meta-analysis did not f<strong>in</strong>d an association between total cholesterol level <strong>and</strong> age orgender. There were only seven reported observations on LDL cholesterol levels <strong>in</strong> <strong>in</strong>fants, six ofwhich reported higher mean levels of LDL cholesterol <strong>in</strong> breastfed <strong>in</strong>fants compared withformula-fed <strong>in</strong>fants. The mean difference was +22 mg/dL (95% CI 15.47 to 29.0 mg/dL). Therewas no statistical heterogeneity.68
In 16 of 17 observations, the mean total cholesterol levels <strong>in</strong> children or adolescents whowere breastfed <strong>in</strong> their <strong>in</strong>fancy were similar to those who were formula-fed. The overall me<strong>and</strong>ifference was 0.0 mg/dL (95% CI −2.7 to 2.7 mg/dL). A statistically significant heterogeneitywas observed across studies. There was no association between total cholesterol level <strong>and</strong> age orgender. There were only four observations of LDL cholesterol levels <strong>in</strong> children or adolescents.The mean levels of LDL cholesterol <strong>in</strong> children or adolescents who were breastfed <strong>in</strong> their<strong>in</strong>fancy were similar to those who were formula-fed. The mean difference was +0.39 mg/dL(95% CI −2.7 to 3.09 mg/dL). There was no statistical heterogeneity between the studies.The mean age of adults evaluated <strong>in</strong> the primary studies ranged from 17 to 64 years. Lowermean total cholesterol levels <strong>in</strong> adults who were breastfed <strong>in</strong> their <strong>in</strong>fancy compared with thosewho were formula-fed <strong>in</strong> their <strong>in</strong>fancy were reported <strong>in</strong> seven of n<strong>in</strong>e observations. The overallmean difference was −6.96 mg/dL (95% CI −2.32 to −11.6 mg/dL). There was no statisticallysignificant heterogeneity between the studies. There were only four observations of LDLcholesterol reported <strong>in</strong> adults. Adults who were breastfed <strong>in</strong> their <strong>in</strong>fancy had lower mean LDLcholesterol levels compared with those who were formula-fed. The mean difference was −7.7mg/dL (95% CI −3.09 to −12.37 mg/dL). There was no statistical heterogeneity between thestudies.ConclusionResults from the meta-analysis of cohort <strong>and</strong> case-control studies reported that there was areduction <strong>in</strong> total <strong>and</strong> LDL cholesterol levels <strong>in</strong> adults who were breastfed dur<strong>in</strong>g <strong>in</strong>fancycompared with those who were formula-fed. While higher serum lipid levels were observed <strong>in</strong><strong>in</strong>fancy, the meta-analysis found that breastfeed<strong>in</strong>g was associated with a reduction <strong>in</strong> serumlipid level <strong>in</strong> adult life. The significance of higher serum lipid levels observed <strong>in</strong> <strong>in</strong>fancy isunclear <strong>and</strong> studies have neither shown benefit nor harm from such high levels. 86 These f<strong>in</strong>d<strong>in</strong>gswere based on data from adults with a wide age range. The analysis did not segregate the dataaccord<strong>in</strong>g to gender. Potential confounders were not explicitly analyzed. Detailed <strong>in</strong>formation(e.g., fast<strong>in</strong>g or non-fast<strong>in</strong>g) on the collection of specimen for cholesterol test<strong>in</strong>g was not<strong>in</strong>cluded. The methodological quality of the meta-analysis was rated grade C. Because of thepoor methodological quality of the meta-analysis, we f<strong>in</strong>d that the conclusions drawn by theauthors were suspect. We conclude that the relationship between breastfeed<strong>in</strong>g <strong>and</strong> adultcholesterol levels cannot be correctly characterized at this time.69
Table 11. Summary of systematic reviews/meta-analyses on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> totalcholesterol <strong>and</strong> low-density lipoprote<strong>in</strong> cholesterolAuthoryearOwen2002Numberofsubjects5,829 vs.4,852Population3 agestrata:ConfoundersconsideredStudydescription70Intervention/ComparatorResultsComb<strong>in</strong>ed mean difference (95%CI)LDLTotal cholesterolcholesterol(mg/dL)(mg/dL)+22.0(15.47 toMA of 37<strong>Breastfeed<strong>in</strong>g</strong>cohort <strong>and</strong>Age
utilized a r<strong>and</strong>om effects model. Subgroup analyses evaluated the effect of heterogeneity <strong>in</strong> studysize, age of assessment of outcomes, <strong>and</strong> year of birth. Mean systolic blood pressures werereduced by 1.10 mm Hg (95% CI 0.42 to 1.78) <strong>in</strong> adulthood among subjects who were breastfed<strong>in</strong> <strong>in</strong>fancy compared with those who were formula-fed. When stratified by age groups (≤1 year,>1 to 16 years, ≥17 years), a similar association was observed among age groups that rangedfrom more than 1 year to 16 years. There was a statistically significant heterogeneity for thisoutcome. Mean diastolic blood pressures were reduced by 0.36 mm Hg (95% CI – 0.08 to 0.79)among subjects who were breastfed compared with subjects who were formula-fed. There wasno statistical heterogeneity for this outcome.Both meta-analyses observed smaller association of breastfeed<strong>in</strong>g on systolic blood pressure<strong>in</strong> large studies (>300 <strong>and</strong>/or >1000 participants) compared with smaller studies. Both metaanalysesattributed this observation to publication bias. Similar effect size reduction ofbreastfeed<strong>in</strong>g on diastolic blood pressure was not observed. In studies that adjusted for potentialconfounders, results rema<strong>in</strong>ed similar before <strong>and</strong> after adjustment for potential confounders.ConclusionResults from both meta-analyses concluded that there was a small reduction <strong>in</strong> systolic bloodpressures among adults who were breastfed <strong>in</strong> their <strong>in</strong>fancy compared with those who wereformula-fed. The association weakened after stratification by study size, suggest<strong>in</strong>g thepossibility of bias. Although both analyses had moderate methodological quality <strong>and</strong> reportedsimilar f<strong>in</strong>d<strong>in</strong>gs, the authors had different appraisals of the public health importance of the smallreduction <strong>in</strong> systolic blood pressure. In conclusion, there is an association between a history ofbreastfeed<strong>in</strong>g dur<strong>in</strong>g <strong>in</strong>fancy <strong>and</strong> a small reduction <strong>in</strong> adult blood pressure, but the cl<strong>in</strong>ical orpublic health implication of this f<strong>in</strong>d<strong>in</strong>g is unclear.Table 12. Summary table for systematic reviews/meta-analyses on the relationship between breastfeed<strong>in</strong>g <strong>in</strong><strong>in</strong>fancy <strong>and</strong> blood pressure levels later <strong>in</strong> lifeAuthoryearPopulationConfoundersconsideredStudydescriptionIntervention /ComparatorResultsQuality ofSR/MALimitationsMart<strong>in</strong>2005N=17,503Age > 1to60 yrOwen 2003N=8471 vs.11,292Age > 1to71 yrConsidered butnot pooled: age,gender, race,height, <strong>and</strong>body mass<strong>in</strong>dexMeta-analysis of15 studies(Observationswith<strong>in</strong> 2RCTs, 8prospectivecohorts, 1retrospectivecohort, <strong>and</strong> 4cross-sectionalstudies)Meta-analysis of24 studies(Observationswith<strong>in</strong> 1RCT, 12cross-sectional,<strong>and</strong> 11 cohortstudies)<strong>Breastfeed<strong>in</strong>g</strong> vs.formula feed<strong>in</strong>g<strong>in</strong> <strong>in</strong>fancy<strong>Breastfeed<strong>in</strong>g</strong> vs.formula feed<strong>in</strong>g<strong>in</strong> <strong>in</strong>fancyComb<strong>in</strong>ed mean difference (95%CI)SBP mmHg DBP mmHg–1.4(–2.2, –0.6)p=0.001–0.5(–0.9, –0.04)p=0.03Comb<strong>in</strong>ed mean difference (95%CI)SBP mmHg DBP mmHg–1.10(–1.8, –0.4)– 0.36(–0.79, 0.08)SBP, systolic blood pressure; DBP, diastolic blood pressure; SR, systematic review; MA,meta-analysisBNo pooledadjustedestimateBNo pooledadjustedestimate71
Cardiovascular Disease MortalityPublished Systematic Review/Meta-Analysis (Table 13)We identified one systematic review <strong>and</strong> meta-analysis that exam<strong>in</strong>ed the relationshipbetween breastfeed<strong>in</strong>g <strong>and</strong> cardiovascular disease (CVD) mortality <strong>in</strong> later life. 85 Articles were<strong>in</strong>cluded <strong>in</strong> the systematic review if breastfed <strong>in</strong>fants were compared with bottle-fed <strong>in</strong>fants, ifthe outcome was cardiovascular disease or ischemic heart disease mortality, <strong>and</strong> if estimates ofthe association between hav<strong>in</strong>g been breastfed <strong>and</strong> cardiovascular disease or ischemic heartdisease mortality could be obta<strong>in</strong>ed from the paper or after correspondence with the authors. Atotal of four historical cohort studies from developed countries were identified, <strong>in</strong>volv<strong>in</strong>g 25,166subjects at basel<strong>in</strong>e <strong>and</strong> 10,785 subjects at followup. The studies were not graded for theirmethodological quality. The meta-analysis used a r<strong>and</strong>om-effects model. Heterogeneity acrossstudies was assessed. The methodological quality of this systematic review <strong>and</strong> meta-analysiswas rated grade B due to <strong>in</strong>complete consideration of the heterogeneity across studies <strong>in</strong> themeta-analyses.The four historical cohorts <strong>in</strong>cluded <strong>in</strong> the systematic review <strong>and</strong> meta-analysis wereW<strong>in</strong>gard cohort, 1,373 birth children <strong>in</strong> California (85 percent <strong>in</strong> followup); Hertfordshirecohort, 5,908 women <strong>and</strong> 10,374 men born <strong>in</strong> Hertfordshire (43 percent <strong>in</strong> followup); Boyd Orrcohort, 4,999 men <strong>and</strong> women from a survey of diet <strong>and</strong> health <strong>in</strong> pre-war Brita<strong>in</strong> (71 percent <strong>in</strong>followup); <strong>and</strong> Caerphilly cohort, 2,512 middle-aged men liv<strong>in</strong>g <strong>in</strong> Caerphilly, South Wales (63percent <strong>in</strong> followup). Subjects from these four cohorts were born between 1904 <strong>and</strong> 1939.Potential confounders considered <strong>in</strong> the association between the risk of CVD mortality <strong>and</strong>breastfeed<strong>in</strong>g <strong>in</strong> the four studies were age, birth weight, <strong>in</strong>fant health, socioeconomic status,<strong>and</strong>/or birth order.R<strong>and</strong>om-effects model showed little difference <strong>in</strong> all cause mortality between breast- <strong>and</strong>bottle-fed subjects (pooled rate ratio = 1.01; 95% CI: 0.91 - 1.13, P=0.8), <strong>and</strong> there was littleevidence of heterogeneity. Five observations from three studies suggested little or no associationbetween breastfeed<strong>in</strong>g <strong>and</strong> cardiovascular disease mortality <strong>in</strong> both males <strong>and</strong> females, <strong>and</strong> onesuggested a possible adverse effect (Caerphilly cohort). In r<strong>and</strong>om effects meta-analysis, CVDmortality was similar <strong>in</strong> breastfed versus bottle-fed subjects (pooled rate ratio = 1.06; 95% CI:0.94 – 1.20), <strong>and</strong> there was no statistical evidence of between-study heterogeneity.Ischemic heart disease mortality was 6 percent lower among males who had been breastfed <strong>in</strong>the Hertfordshire cohort, but 56 percent higher among breastfed females. This result was <strong>in</strong>agreement with po<strong>in</strong>t estimates from the Boyd Orr cohort, suggest<strong>in</strong>g that ischemic heart diseasemortality was 10 percent lower among males who had been breastfed, but 40 percent higheramong breastfed females (although there was little statistical evidence of <strong>in</strong>teraction: P = 0.2). InCaerphilly, however, ischemic heart disease mortality was 73 percent higher among breastfedmales. In a r<strong>and</strong>om effects meta-analysis (pooled rate ratio = 1.19; 95% CI 0.89 - 1.58, P = 0.3),<strong>and</strong> there was evidence of heterogeneity.Similar analyses were also performed to exam<strong>in</strong>e the association between prolongedbreastfeed<strong>in</strong>g (> 1 year duration) <strong>and</strong> the risk of all-cause, CVD, <strong>and</strong> ischemic heart diseasemortality <strong>in</strong> later life. There was little evidence that prolonged breastfeed<strong>in</strong>g was associated withall-cause mortality (pooled rate ratio: 0.94; 95% CI 0.71 – 1.24), although there was moderatestatistical evidence of heterogeneity. There was some evidence that prolonged breastfeed<strong>in</strong>g wasassociated with a 16 percent <strong>in</strong>crease (95% CI 0.99 – 1.36; P = 0.06) <strong>in</strong> CVD mortality, <strong>and</strong> no72
evidence of <strong>in</strong>consistency <strong>in</strong> estimates. There was little evidence that prolonged breastfeed<strong>in</strong>gwas associated with ischemic heart disease mortality (rate ratio: 1.08; 95% CI 0.88 – 1.31; P =0.5) <strong>and</strong> there was no heterogeneity.ConclusionThe authors concluded that the data reviewed did not provide evidence that breastfeed<strong>in</strong>gwas related to all-cause or CVD mortality. The confidence limits around the po<strong>in</strong>t estimates <strong>and</strong>the observed between-study heterogeneity for associations between breastfeed<strong>in</strong>g <strong>and</strong> ischemicheart disease, however, do not rule out important beneficial or adverse cardiovascular effects ofbreastfeed<strong>in</strong>g.There were some possible sources of bias <strong>and</strong> limitations <strong>in</strong> the studies reviewed. Two of thefour studies had followup rate of less than 70 percent of the orig<strong>in</strong>al population; therefore,selection bias cannot be ruled out. Recall bias was possible <strong>in</strong> the three studies wherebreastfeed<strong>in</strong>g data were collect retrospectively. As confound<strong>in</strong>g <strong>and</strong> biases may have distortedresults from <strong>in</strong>dividual studies, the statistical comb<strong>in</strong>ation of estimates <strong>in</strong>to a s<strong>in</strong>gle rate rationeeds to be <strong>in</strong>terpreted with caution. All four studies <strong>in</strong> the meta-analyses were historical cohorts(born between 1904 <strong>and</strong> 1939). Given the statistical heterogeneity across studies, comb<strong>in</strong><strong>in</strong>gstudy results might not be appropriate. For the outcome of ischemic heart disease mortality, itmay not be appropriate to comb<strong>in</strong>e results for men <strong>and</strong> women <strong>in</strong>to a s<strong>in</strong>gle analysis because ofapparent effect modification by gender.Because of the above limitations, no def<strong>in</strong>itive conclusions can be drawn regard<strong>in</strong>g therelationship between breastfeed<strong>in</strong>g <strong>and</strong> CVD mortality. Further <strong>in</strong>vestigation is warranted.73
74Table 13. Summary of systematic review/meta-analysis on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> long-term cardiovascular disease mortalityAuthor yearStudy Intervention ConfoundersQuality of SR/MAResultsPopulationdescription /Comparator considered<strong>and</strong> limitationsMart<strong>in</strong> 2004MA of 4 Any or exclusively Age, birth weight,Bhistorical cohort breastfed vs. bottlefed;<strong>in</strong>fant health,studies <strong>in</strong>prolonged (>1 socioeconomic status,developed yr) breastfed vs. number of sibl<strong>in</strong>gs,countries bottle-fed<strong>and</strong>/or birth orderW<strong>in</strong>gard (1994) cohort:1373 birth children <strong>in</strong>California (85% <strong>in</strong>follow-up)Hertfordshire cohort(update to 1999): 5908women <strong>and</strong> 10374men born <strong>in</strong> 11 of 12districts <strong>in</strong>Hertfordshire (43% <strong>in</strong>followup)Boyd Orr (2003): 4999men <strong>and</strong> women froma survey of diet <strong>and</strong>health <strong>in</strong> pre-warBrita<strong>in</strong> (71% <strong>in</strong>followup)Caerphilly (2003): 2512middle-aged menliv<strong>in</strong>g <strong>in</strong> Caerphilly,South Wales (63% <strong>in</strong>followup)Total N=25,166 atbasel<strong>in</strong>e;13,302 at followupIHD, Ischemic heart disease; CVD, cardiovascular disease; SR, systematic review; MA, meta-analysisAll four studies were historical cohorts born between1904 <strong>and</strong> 1939.Five observations from three studies suggested little orno association between breastfeed<strong>in</strong>g <strong>and</strong> CVDmortality <strong>in</strong> both males <strong>and</strong> females (pooled rate ratio:1.06; 95% CI: 0.94–1.20), <strong>and</strong> one suggested apossible adverse effect (Caerphilly cohort). There wasno statistical evidence of between-study heterogeneity.IHD mortality was 6% lower amongst males who hadbeen breastfed <strong>in</strong> the Hertfordshire cohort, but 56%higher amongst breastfed females. This result is <strong>in</strong> l<strong>in</strong>ewith po<strong>in</strong>t estimates from the Boyd Orr cohortsuggest<strong>in</strong>g that IHD mortality was 10% lower amongstmales who had been breastfed, but 40% higheramongst breastfed females (although there was littlestatistical evidence of <strong>in</strong>teraction: p=0.2). In Caerphilly,however, IHD mortality was 73% higher amongstbreastfed males. In a r<strong>and</strong>om effects meta-analysis(pooled rate ratio: 1.19; 95% CI 0.89-1.58, p=0.3), therewas evidence of heterogeneity.There was weak evidence that prolonged breastfeed<strong>in</strong>gwas associated with a 16% <strong>in</strong>crease (95% CI: 0.99–1.36; p=0.06) <strong>in</strong> CVD mortality, <strong>and</strong> no evidence of<strong>in</strong>consistency <strong>in</strong> estimates.There was little evidence that prolonged breastfeed<strong>in</strong>gwas associated with IHD mortality (rate ratio: 1.08; 95%CI: 0.88–1.31; p=0.5) <strong>and</strong> there was no heterogeneity.Men <strong>and</strong> womenshould beconsideredseparately becauseof apparent effectmodification bygender
Relationship between Type 1 Diabetes <strong>and</strong> <strong>Breastfeed<strong>in</strong>g</strong>BackgroundType 1 diabetes results from destruction of the <strong>in</strong>sul<strong>in</strong>-produc<strong>in</strong>g β cells of the pancreatic islets.Various exogenous triggers, such as certa<strong>in</strong> dietary factors <strong>and</strong> viruses, are thought to <strong>in</strong>duce theimmune-mediated process lead<strong>in</strong>g to extensive β cell destruction. 87 Putative mechanisms ofprotection aga<strong>in</strong>st type 1 diabetes afforded by breast milk <strong>in</strong>clude passive immunity provided bysecretory immunoglobul<strong>in</strong> A antibodies, <strong>in</strong>creased β cell proliferation observed <strong>in</strong> breastfedcompared with formula-fed <strong>in</strong>fants, or delayed exposure to foreign food antigens <strong>in</strong> exclusivelybreastfed <strong>in</strong>fants. 87 In addition, hypotheses have been proposed to expla<strong>in</strong> the putativediabetogenicity of cow milk. 87 For example, β-lactoglobul<strong>in</strong>, a cow milk-specific prote<strong>in</strong>, has beenimplicated as a possible trigger of the immune defect, lead<strong>in</strong>g to type 1 diabetes. Therefore,concerns regard<strong>in</strong>g the safety <strong>and</strong> advisability of feed<strong>in</strong>g cow milk-based products to <strong>in</strong>fants havebeen raised. 88 Gerster<strong>in</strong> 1994 conducted a systematic review of the epidemiological <strong>and</strong> cl<strong>in</strong>icalliterature that explored a possible l<strong>in</strong>k between cow milk <strong>and</strong> type 1 diabetes. 89 Subsequently,Norris <strong>and</strong> Scott 1996 performed meta-analyses on all published case-control studies from 1966 to1994 that exam<strong>in</strong>ed <strong>in</strong>fant diet exposures <strong>and</strong> type 1 diabetes. 90 S<strong>in</strong>ce this meta-analysis, weidentified six case-control studies that reported outcome of type 1 diabetes <strong>in</strong> relation tobreastfeed<strong>in</strong>g dur<strong>in</strong>g <strong>in</strong>fancy.Commonly considered confounders <strong>in</strong> the relationship between type 1 diabetes <strong>and</strong>breastfeed<strong>in</strong>g were maternal/parental education, maternal age at birth, birth order, household<strong>in</strong>come, race/ethnicity, social class, family history of type 1 diabetes, neonatal illness, <strong>and</strong> type ofdelivery.Published Systematic Reviews/Meta-Analyses (Table 14)Gerster<strong>in</strong> 1994 conducted a systematic review on literature that explored a possible l<strong>in</strong>k betweencow milk <strong>and</strong> type 1 diabetes. Articles were excluded if they exclusively used surrogate markers foreither type 1 diabetes or cow milk exposure. A total of three ecological <strong>and</strong> time-series studies, 13case-control studies, one cohort study, <strong>and</strong> one case series were <strong>in</strong>cluded. Meta-analysis of all<strong>in</strong>cluded case-control studies was performed, us<strong>in</strong>g a fixed effect model. Both adjusted <strong>and</strong>unadjusted odds ratios were used, but there was no further analysis or discussion on potentialimpacts of confound<strong>in</strong>g by comb<strong>in</strong><strong>in</strong>g unadjusted odds ratios. The methodological quality of thesystematic review <strong>and</strong> meta-analysis was rated grade B, due to <strong>in</strong>sufficient consideration for thepotential confound<strong>in</strong>g <strong>in</strong> the primary studies.In the <strong>in</strong>cluded time-series <strong>and</strong> ecological studies, the results showed an <strong>in</strong>verse association(geographical <strong>and</strong> temporal) between the rate/prevalence of breastfeed<strong>in</strong>g <strong>and</strong> the rate/prevalence oftype 1 diabetes.The cohort study was an analysis of two groups of children born <strong>in</strong> the UK <strong>in</strong> 1958 <strong>and</strong> 1970,who were followed for 16 <strong>and</strong> 10 years, respectively. This study did not f<strong>in</strong>d any associationbetween breastfeed<strong>in</strong>g for less than 1 month <strong>and</strong> the risk of development of type 1 diabetes.In the 13 case-control studies <strong>in</strong> which the neonatal feed<strong>in</strong>g history of patients with type 1diabetes <strong>and</strong> <strong>in</strong>dividually matched non-diabetic control subjects were compared, the results weremixed. A total of 3,708 type 1 diabetes cases <strong>and</strong> 20,340 non-diabetic controls were <strong>in</strong>cluded. Noneof these studies satisfied all six methodological criteria def<strong>in</strong>ed by the author. Four of the 13 case-75
control studies fulfilled five of six methodological criteria (e.g., <strong>in</strong>clusion of ≥75 percent of eligiblediabetic patients, unbiased selection of unrelated nondiabetic control subjects, control subjectsderived from the same population as diabetic subjects, an identical means of determ<strong>in</strong>ation of <strong>in</strong>fantfeed<strong>in</strong>g practices <strong>in</strong> both diabetic <strong>and</strong> nondiabetic groups, bl<strong>in</strong>d determ<strong>in</strong>ation of early feed<strong>in</strong>ghistory, <strong>and</strong> identification of diabetic patients from <strong>in</strong>cident cases). When these four studies werecomb<strong>in</strong>ed, the overall odds ratio (adjusted odds ratios were used) for type 1 diabetes <strong>in</strong> patientsexposed to less than 3 months of breastfeed<strong>in</strong>g was 1.43 (95%CI 1.15 - 1.77; P=0.3 forhomogeneity). When all 13 <strong>in</strong>cluded case-control studies were comb<strong>in</strong>ed, the overall odds ratio(mixed crude <strong>and</strong> adjusted odds ratios were used) for type 1 diabetes <strong>in</strong> patients exposed to less than3 months of breastfeed<strong>in</strong>g was 1.37 (95%CI 1.22-1.53; P=0.11 for homogeneity).In 1996, Norris <strong>and</strong> Scott performed a meta-analysis of <strong>in</strong>fant diet <strong>and</strong> type 1 diabetes toexam<strong>in</strong>e further the <strong>in</strong>consistent results reported <strong>in</strong> the literature. A total of 17 case-control studieswith appropriate data for meta-analysis were <strong>in</strong>cluded. The analysis <strong>in</strong>cluded 4,656 type 1 diabetescases <strong>and</strong> 16,383 non-diabetic controls. The authors abstracted case <strong>and</strong> control data for fourseparate exposures: breastfeed<strong>in</strong>g status (ever/never), total breastfeed<strong>in</strong>g duration, exposure tobreast-milk substitutes, <strong>and</strong> exposure to cow milk-based substitutes. Due to the limitation of themeta-analytic technique, only unadjusted odds ratios were calculated <strong>and</strong> comb<strong>in</strong>ed, although someprimary studies had adjustments for maternal education, maternal age at birth, birth order,household <strong>in</strong>come, race/ethnicity, <strong>and</strong>/or social class. Authors performed sensitivity analyses onvarious characteristics of study methodological quality to explore the impacts of potential biases onthe summary odds ratios. The methodological quality of this meta-analysis was rated grade B, dueto <strong>in</strong>sufficient consideration for the potential confound<strong>in</strong>g <strong>in</strong> the primary studies.The overall odds ratio of all <strong>in</strong>cluded case-control studies that exam<strong>in</strong>ed the association betweennever breastfed <strong>and</strong> type 1 diabetes was 1.13 (95%CI 1.04 - 1.23). Among these studies, fourteenalso exam<strong>in</strong>ed type 1 diabetes risk by months of breastfeed<strong>in</strong>g duration. The duration categories <strong>in</strong>the analysis were cumulative, rather than mutually exclusive (i.e., some studies provided data onboth 3-month <strong>and</strong> 6 month breastfeed<strong>in</strong>g data <strong>in</strong> the same subjects). The summary odds ratiosshowed consistently elevated risks of type 1 diabetes associated with age at first exposure to anybreast milk substitutes before 6 months of age. S<strong>in</strong>ce the majority of the studies reported odds ratiosus<strong>in</strong>g a cutoff of 3 months when exam<strong>in</strong><strong>in</strong>g cont<strong>in</strong>uous exposures, this cutoff was used for the metaanalysis.The summary odds ratio for type 1 diabetes <strong>in</strong> subjects who were breastfed for less than 3months compared with those who were breastfed for at least 3 months was 1.23 (95%CI 1.12 -1.35).Stratified analyses of studies by methodological <strong>and</strong> study population characteristics wereperformed to see whether differences <strong>in</strong> these characteristics might expla<strong>in</strong> the heterogeneity. Thecharacteristics were prevalent versus <strong>in</strong>cident case-control study design, adequate versus <strong>in</strong>adequateresponse rates of the cases <strong>and</strong> controls, the breastfeed<strong>in</strong>g prevalence <strong>in</strong> the background population,the type 1 diabetes risk <strong>in</strong> the background population, <strong>and</strong> retrospective versus concurrent <strong>in</strong>fantdiet assessment. All of these factors had differential impacts on the summary odds ratios for the riskof type 1 diabetes associated with <strong>in</strong>fant diet exposures.Norris <strong>and</strong> Scott concluded that their meta-analysis showed that the <strong>in</strong>creased risk of type 1diabetes associated with any of the <strong>in</strong>fant diet exposures was small. Accord<strong>in</strong>g to these authors,<strong>in</strong>terpretation of weak associations (i.e., an odds ratio of less than 2.0) can be problematic, s<strong>in</strong>ceweak associations can more readily be expla<strong>in</strong>ed by biases.76
Studies Identified after the Published Systematic Reviews/Meta-Analyses/Systematic Review (Table 15)We only <strong>in</strong>cluded all studies that exam<strong>in</strong>ed the outcome of type 1 diabetes <strong>in</strong> relation tobreastfeed<strong>in</strong>g <strong>in</strong> developed countries. To be consistent with previous meta-analyses, articles wereexcluded if they only used surrogate markers for type 1 diabetes (e.g., the presence of islet cellantibodies). A total of six case-control studies were identified, 91-96 The studies <strong>in</strong>cluded 1,293patients with type 1 diabetes <strong>and</strong> 3,262 control subjects. Five studies were conducted <strong>in</strong> Europe, <strong>and</strong>one <strong>in</strong> Taiwan. Four studies were rated grade B <strong>in</strong> methodological quality; two studies were ratedgrade C. Commonly considered confounders <strong>in</strong> these studies were family history of type 1 diabetes,neonatal illness, maternal age at birth, birth order, maternal/parental education, <strong>and</strong> type of delivery.In four studies, the def<strong>in</strong>ition of type 1 diabetes cases was children with juvenile-onset diabetes(or develop<strong>in</strong>g diabetes before 17 years of age). In the other two studies, the cases were registeredtype 1 diabetes patients who were younger than 30 years of age <strong>and</strong> children with diabetes whowere identified through hospital records. Matched controls were those without type 1 diabetesselected from various sources <strong>in</strong> the same population as the cases.Three studies reported odds ratio of type 1 diabetes compar<strong>in</strong>g subjects who were ever breastfedwith those who were never breastfed. Two studies found a reduced risk of type 1 diabetes <strong>in</strong>subjects who were ever breastfed (ORs 0.56 95 <strong>and</strong> 0.75 91 ), while the third study reported an<strong>in</strong>creased risk (OR 2.44 94 ).Three studies compared subjects who were breastfed for more than 3 months or 6 months withthose who were never breastfed. Two studies reported a reduced risk of type 1 diabetes <strong>in</strong> subjectswho were breastfed for more than 3 or 6 months (adjusted OR 0.57 96 <strong>and</strong> 0.25 95 , respectively). Thethird study 94 reported an opposite f<strong>in</strong>d<strong>in</strong>g (this was the same study that reported an <strong>in</strong>creased riskwith ever breastfed). A reduced risk of type 1 diabetes was found when compar<strong>in</strong>g subjects whowere never breastfed with those who were breastfed for more than 6 months (adjusted OR 0.36,95%CI 0.14 - 0.94). The data also showed a slight <strong>in</strong>crease <strong>in</strong> the risk of type 1 diabetes with longerduration of breastfeed<strong>in</strong>g (1 month <strong>in</strong>crement). The control subjects <strong>in</strong> this study were selected fromchildren admitted to the same hospital as the cases, whether this expla<strong>in</strong>ed the f<strong>in</strong>d<strong>in</strong>g was unclear.One study reported a reduced risk of type 1 diabetes compar<strong>in</strong>g subjects who were <strong>in</strong>itiallyexclusively breastfed with those who were not (adjusted OR 0.6, 95%CI 0.41 - 0.89). 93 Anotherstudy found a small, but non-significant <strong>in</strong>creased risk of type 1 diabetes with not breastfeed<strong>in</strong>g atdischarge (RR 1.33, 95%CI 0.76 - 2.31). 92 This study was rated to have poor methodological qualitybecause only univariate analysis was performed <strong>and</strong> potential confounders were not considered.ConclusionOur f<strong>in</strong>d<strong>in</strong>gs from the six additional case-control studies are similar to the f<strong>in</strong>d<strong>in</strong>gs from the twometa-analyses. However, the exclusivity of breastfeed<strong>in</strong>g was not addressed <strong>in</strong> all studies, <strong>and</strong> theassessment of <strong>in</strong>fant diet was based on long-term recall <strong>in</strong> five of six studies. We elected not toperform a meta-analysis, because it is unlikely to change the pooled estimates from the previousmeta-analyses by add<strong>in</strong>g additional three studies from the updates that compared subjects who werebreastfed for more than 3 or 6 months with those who were never breastfed.Two meta-analyses of moderate methodological quality reported statistically significant oddsratios of 1.23 <strong>and</strong> 1.43, respectively, for the risk of type 1 diabetes <strong>in</strong> subjects exposed to lessthan 3 months compared with more than 3 months of breastfeed<strong>in</strong>g. S<strong>in</strong>ce case-control studies areprone to recall biases, Norris <strong>and</strong> Scott compared the odds ratios <strong>in</strong> studies relied on long-77
term recall to assess <strong>in</strong>fant diet with studies that did not. The results showed that studies us<strong>in</strong>gexist<strong>in</strong>g <strong>in</strong>fant records to determ<strong>in</strong>e breastfeed<strong>in</strong>g <strong>in</strong>itiation <strong>and</strong> duration failed to show theassociations reported <strong>in</strong> the studies rely<strong>in</strong>g on long-term recall for their exposure data. Thissuggests that subjects with type 1 diabetes were more likely to report shorter duration ofbreastfeed<strong>in</strong>g than control subjects.In conclusion, even though there is some evidence to suggest that breastfeed<strong>in</strong>g for morethan 3 months is associated with a reduced risk of type 1 diabetes, this evidence must be<strong>in</strong>terpreted with caution because of the possibility of recall biases <strong>and</strong> suboptimal adjustmentsfor potential confounders <strong>in</strong> the primary studies.78
79Table 14. Summary of systematic reviews/meta-analyses on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> type 1 diabetesAuthor YearInterventionConfoundersStudy descriptionResultsPopulation/ComparatorconsideredNorris 1996MA of 17 casecontrolstudiespublished from 1966to 1994.Case-control studies <strong>in</strong>which the neonatalfeed<strong>in</strong>g histories ofpatients with type 1 DM<strong>and</strong> <strong>in</strong>dividuallymatched non-DMcontrol subjects werecomparedCases: 4,656Controls: 16,383Gerste<strong>in</strong> 1994Case-control studies <strong>in</strong>which the neonatalfeed<strong>in</strong>g histories ofpatients with type 1 DM<strong>and</strong> <strong>in</strong>dividuallymatched non-DMcontrol subjects werecomparedCases: 3,708Controls: 20,340A SR review of 3ecological <strong>and</strong> timeseriesstudies, 13case-control studies,one cohort study,<strong>and</strong> one case series.MA was performedfor the case-controlstudies.MA, meta-analyses; SR, systematic reviewA=breastfeed<strong>in</strong>g status(ever/never)B=total breastfeed<strong>in</strong>gdurationC=exposure to breastmilksubstitutesD=exposure to cow’smilk-based substitutesCow’s milk exposure(<strong>and</strong> therefore nonexclusivebreastfeed<strong>in</strong>g)vs. Cow’s milk avoidance(<strong>and</strong> thereforebreastfeed<strong>in</strong>g)<strong>Maternal</strong> education,maternal age at birth,birth order,household <strong>in</strong>come,race/ethnicity, socialclassNDThe summary OR for type 1 DM <strong>in</strong> patients whowere never be<strong>in</strong>g breast-fed was 1.13 (95% CI1.04-123).The summary OR for type 1 DM <strong>in</strong> subjects whowere breast-fed for < 3 mo compared with thosewho were breast-fed for at least 3 mo was 1.23(95%CI 1.12-1.35).Stratified analyses of studies were performed byprevalent vs. <strong>in</strong>cident case-control study design,adequate vs. <strong>in</strong>adequate response rates of thecases <strong>and</strong> controls, the breastfeed<strong>in</strong>gprevalence <strong>in</strong> the background population, thetype 1 DM risk <strong>in</strong> the background population,<strong>and</strong> retrospective vs. concurrent <strong>in</strong>fant dietassessment. All of these factors had impacts onthe summary ORs for the risk of type 1 DMassociated with <strong>in</strong>fant diet exposures.Results from the 13 case-control studies weremixed. The comb<strong>in</strong>ed OR for type 1 DM <strong>in</strong>patients exposed to < 3 mo of breastfeed<strong>in</strong>gwas 1.38 (95% CI 1.22-1.53; p=0.11 forhomogeneity).An analysis of 2 cohorts of children born <strong>in</strong> the UK<strong>in</strong> 1958 <strong>and</strong> 1970 followed for 16 <strong>and</strong> 10 yr,respectively, failed to show any associationbetween breastfeed<strong>in</strong>g for < 1 mo <strong>and</strong> type 1DM.None of the 13 case-control studies fulfilled all sixmethodological criteria. Four case-controlstudies (31%) fulfilled five out of the six criteria(considered high quality)Quality of SR/MA<strong>and</strong> limitationsBOnly unadjustedORs were comb<strong>in</strong>edalthough someprimary studies hadadjustments forpotentialconfound<strong>in</strong>gBComb<strong>in</strong>e both crude<strong>and</strong> adj. ORs withoutperform<strong>in</strong>gsensitivity analyseson potentialconfound<strong>in</strong>g or studyquality
80Table 15. Summary of case-control studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> type 1 diabetesAuthorCases ControlDef<strong>in</strong>ition Mean<strong>Breastfeed<strong>in</strong>g</strong> ComparatorOR* (95% CI)year(N) (N)of type 1 Age atgroup group Crude AdjustCountryDM Dx (year)EURODIAS2002EuropeMcK<strong>in</strong>ney1999UKTai 1998TaiwanMeloni1997ItalyVisalli 2003ItalyJones,1998UK610 1616196 325177 193100 100150 75060 458Onset < 15yr <strong>in</strong> 1989-1995Onset < 16yr <strong>in</strong> 1993-1994Registeredtype 1 DM,age < 30 yr,born <strong>in</strong>1984-1993Onset < 17yr <strong>in</strong> 1983-1994Onset < 15yr, born<strong>in</strong>1977-1989Dx atdischarge,born <strong>in</strong>1976-1986ND Ever BF Never BF0-158.36 (1-15)Initial exclusiveBFEver BFBF < 6 moBF ≥ 6 moInitial notexclusive BFNever BFNever BFEver BF Never BFBF 3-5 moBF > 6 mo BF 1-2 moBF 0 moBF as cont<strong>in</strong>uous coefficient (1mo <strong>in</strong>crement)ND BF ≥ 3 mo BF < 3 moNDBF atdischargeNot BF atdischarge0.75(0.58-0.96)0.68p=0.040.56(0.40-1.2)0.82(0.47-1.42)0.39(0.16-0.94)0.47(0.31-0.72)0.75(0.43-1.32)0.59(0.35-0.97)0.60(0.41-0.89)0.84(0.45-1.59)0.25(0.09-0.69)2.44(1.10-7.14)0.85(0.37-1.92)2.08(0.18-5.26)2.78(1.06-7.14)1.10(0.99-1.22)0.57(041-0.74)Potential confoundersadjustedHt SDS, Wt SDS,maternal age, jaundice,RTI, Vit D suppl, asthma[Sex, age] a , maternal age,maternal type 1 DM,preeclampsia, C-section,neonatal illnesses[Age, sex, parentaleducation] a , birth order,paternal age, GA, type ofdelivery, BW, monthlyfamily <strong>in</strong>come[Age, sex] a , mother’seducation, number ofsibl<strong>in</strong>gs[Age] a , family history oftype 1 DM, <strong>in</strong>fectiousdisease dur<strong>in</strong>g pregnancy,eczema[Age, sex] aQuality <strong>and</strong>LimitationsBNo demographicdata; No adj. for SESBNo adj. for SESBInconsistent methodsfor ascerta<strong>in</strong>ment ofBF exposureBHospital controlsCInadequate responserate (>20%); No adj.For SESCPoor adj. forconfound<strong>in</strong>gDx, diagnosis; BF, breastfeed<strong>in</strong>g; SR, systematic review; MA, meta-analysis; SDS, st<strong>and</strong>ard deviation score; Ht, height; Wt, weight; RTI, respiratory <strong>in</strong>fection; VitD suppl, Vitam<strong>in</strong> D supplementation; C-section, delivery by cesarean section; GA, gestational age; BW, birth weight; LTC, long-term recalls; adj, adjustment;SES, socioeconomic status*Odds ratio of type 1 DM, compared the breastfeed<strong>in</strong>g group to the comparator group (or the reference group), unless noteda Match<strong>in</strong>g factors for controls
Relationship between Type 2 Diabetes <strong>and</strong> <strong>Breastfeed<strong>in</strong>g</strong>BackgroundIn 2002, it was estimated that a total of 18.2 million people, or 6.3 percent of the USpopulation carried a diagnosis of diabetes (cdc.gov/diabetes/pubs/estimates.htm#prev). No dataare currently available on the prevalence of type 2 diabetes <strong>in</strong> children <strong>and</strong> adolescents. TheCenters for Disease Control <strong>and</strong> Prevention (CDC) estimated that among new cases of childhooddiabetes, the proportion of those with type 2 diabetes ranges between eight percent <strong>and</strong> 43percent (www.cdc.gov/diabetes/pubs/factsheets/search.htm). Type 2 diabetes beg<strong>in</strong>s when thebody develops a resistance to <strong>in</strong>sul<strong>in</strong> <strong>and</strong> no longer uses <strong>in</strong>sul<strong>in</strong> properly. Adults <strong>and</strong> childrenwho develop type 2 diabetes are typically overweight or obese <strong>and</strong> have a family history of thedisease. Furthermore, offspr<strong>in</strong>gs of mothers who had diabetes dur<strong>in</strong>g pregnancy had higher ratesof type 2 diabetes <strong>and</strong> obesity. 97 It is <strong>in</strong>creas<strong>in</strong>gly recognized that nutrition <strong>in</strong> early postnatal lifemay have long-term physiologic effects. Studies have suggested that breastfeed<strong>in</strong>g may beprotective aga<strong>in</strong>st later obesity. 77,78 Therefore, it seems biologically plausible that there may be arelationship between breastfeed<strong>in</strong>g <strong>and</strong> long-term glucose <strong>and</strong> <strong>in</strong>sul<strong>in</strong> metabolism.We identified one systematic review by Taylor et al. 98 <strong>in</strong> our <strong>in</strong>itial literature search <strong>and</strong> wealso identified one additional systematic review by Owen et al. 99 dur<strong>in</strong>g f<strong>in</strong>al phase for thepreparation of this report. We did not identify any additional systematic reviews.Commonly considered confounders <strong>in</strong> the studies of relationship between type 2 diabetes <strong>and</strong>breastfeed<strong>in</strong>g were age, sex, BMI, birth weight, socioeconomic status, history of parentaldiabetes, maternal diabetes dur<strong>in</strong>g pregnancy, maternal diet <strong>and</strong> smok<strong>in</strong>g, <strong>and</strong> prepregnancyBMI.Additional Methodological CommentsWe have elected to describe <strong>in</strong> details only the Owen 2006 systematic review because itsuperseded the Taylor 2005 systematic review. Owen 2006 <strong>in</strong>cluded two of the three primarystudies that were covered <strong>in</strong> Taylor 2005. In addition, Taylor 2005 was of poor methodologicalquality because there was no synthesis of results <strong>and</strong> it was unclear how conclusions were drawn.Published Systematic Reviews/Meta-Analyses (Table 16)Owen 2006 conducted a systematic review <strong>and</strong> meta-analyses to exam<strong>in</strong>e the <strong>in</strong>fluence ofbreastfeed<strong>in</strong>g on type 2 diabetes <strong>and</strong> blood glucose <strong>and</strong> <strong>in</strong>sul<strong>in</strong> concentrations. 99 Studies that didnot provide the odds ratios of type 2 diabetes compar<strong>in</strong>g breastfed to formula-fed subjects wereexcluded. In addition to two of the three studies <strong>in</strong>cluded <strong>in</strong> the Taylor 2005 review (the thirdstudy was excluded from Owen 2006 because it did not provide odds ratio of the disease), fiveadditional studies were identified <strong>in</strong> the Owen 2006 review. Seven studies (six <strong>in</strong> adults <strong>and</strong> one<strong>in</strong> adolescents) total<strong>in</strong>g 76,744 subjects provided odds ratios that related <strong>in</strong>itial <strong>in</strong>fant feed<strong>in</strong>gmethods <strong>and</strong> type 2 diabetes were <strong>in</strong>cluded <strong>in</strong> the meta-analyses. There were three historicalcohort, two cross-sectional, one prospective cohort, <strong>and</strong> one case-control studies. All sevenstudies were conducted <strong>in</strong> developed countries. The effects of study size, year of birth, themethod of ascerta<strong>in</strong>ment of <strong>in</strong>fant feed<strong>in</strong>g status (whether contemporary or recalled up to 7181
years after birth), type of formula feed<strong>in</strong>g, study response rate, study design, <strong>and</strong> whether <strong>in</strong>fantswere born pre- or full-term were exam<strong>in</strong>ed by us<strong>in</strong>g meta-regression <strong>and</strong> sensitivity analyses.Sensitivity analyses were also used to exam<strong>in</strong>e the effect of adjustment for importantconfounders <strong>and</strong> of fast<strong>in</strong>g status. The methodological quality of this systematic review <strong>and</strong>meta-analyses was rated grade A.Six of seven studies related breastfeed<strong>in</strong>g to a lower risk of type 2 diabetes, <strong>and</strong> there was noevidence of heterogeneity across studies. Overall, the subjects who were breastfed showed alower risk of type 2 diabetes than those who were formula-fed (pooled adjusted OR 0.61; 95%CI0.44-0.85, P=0.003). Three studies considered the effects of potential confound<strong>in</strong>g by birthweight, parental diabetes, socioeconomic status, <strong>and</strong> <strong>in</strong>dividual or maternal body size, while theother four studies only considered the effects of confound<strong>in</strong>g by age, sex <strong>and</strong>/or birth weight.However, the odds ratio relat<strong>in</strong>g breastfeed<strong>in</strong>g <strong>and</strong> diabetes risk was similar before (OR 0.55;95% CI: 0.35-0.86; P=0.009) <strong>and</strong> after adjustment for all the important confounders (OR 0.55,95% CI 0.34-0.90; P=0.017) <strong>in</strong> the three studies. The method of ascerta<strong>in</strong><strong>in</strong>g feed<strong>in</strong>g exposurewas unrelated to the odds ratios, although there was <strong>in</strong>sufficient power to detect appreciabledifferences <strong>in</strong> exam<strong>in</strong><strong>in</strong>g the effect of potential biases (such as study size, year of birth, themethod of ascerta<strong>in</strong><strong>in</strong>g <strong>in</strong>fant feed<strong>in</strong>g status, type of formula feed<strong>in</strong>g, study response rate, studydesign, <strong>and</strong> whether <strong>in</strong>fants were born pre- or full-term) by us<strong>in</strong>g meta-regression <strong>and</strong> sensitivityanalyses.Studies Identified after the Published Meta-Analysis/SystematicReviewNone was found.ConclusionResults from a high-quality systematic review <strong>and</strong> meta-analyses of seven studies suggestthat breastfeed<strong>in</strong>g is associated with a lower risk of type 2 diabetes <strong>in</strong> later life, compared withformula feed<strong>in</strong>g. Compar<strong>in</strong>g subjects who were ever breastfed to those who were formula fed,the pooled adjusted odds ratio of type 2 diabetes <strong>in</strong> later life was 0.61 (95%CI 0.44-0.85).However, only three studies appropriately adjusted for all the important confounders, <strong>in</strong>clud<strong>in</strong>gbirth weight, parental diabetes, socioeconomic status, <strong>and</strong> <strong>in</strong>dividual or maternal body size. Eventhough these three studies found that adjustment did not alter the crude estimate, we cannot becompletely confident that potential confound<strong>in</strong>g by birth weight <strong>and</strong> maternal factors has beenruled out for the overall pooled estimate. This could lead to an overestimate of the association.Publication bias is also a possible explanation for the consistent associations observed <strong>in</strong> thesestudies.82
83Table 16. Summary of systematic reviews/meta-analyses on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> type 2 diabetesAuthor YearInterventionStudy descriptionPopulation/ComparatorConfounders consideredResultsOwen 2006 MA of 7 studies (3 Ever breastfed vs. Age, sex, BMI, birth weight,historical cohort, 2 formula fed <strong>in</strong> all 7 socioeconomic status, parentalN=76,744 cross-sectional, 1 studies.diabetes, maternal diabetes <strong>in</strong>prospective cohortpregnancy, hospital duration <strong>in</strong><strong>and</strong> 1 case-control<strong>in</strong>fancy, maternal diet <strong>and</strong>studies)smok<strong>in</strong>g, <strong>and</strong> prepregnancy BMI6 studiesconducted <strong>in</strong>adults <strong>and</strong> 1 studyconducted <strong>in</strong>adolescentsTaylor 2005N=1,430People of all agesSystematic review of 2cohort studies <strong>and</strong> 1case-control studyFeed<strong>in</strong>g status wasreported as be<strong>in</strong>gexclusive <strong>in</strong> one ofthese studies.VariableAge, sex, birth date, parentaldiabetes, <strong>and</strong> birth weightGDM, use of traditional diet,smok<strong>in</strong>g, <strong>and</strong> alcohol dur<strong>in</strong>gpregnancy, mother’sprepregnancy BMI, <strong>and</strong> birthweight• Overall, the subjects who were breastfedshowed a lower risk of type 2 diabetes th<strong>and</strong>id those who were formula fed (pooled OR:0.61; 95%CI 0.44-0.85; p=0.003).• OR relat<strong>in</strong>g breastfeed<strong>in</strong>g <strong>and</strong> diabetesrisk was similar before (0.55; 95% CI: 0.35-0.86; p=0.009) <strong>and</strong> after (0.55, 95% CI 0.34-0.90; p=0.017) adjustment <strong>in</strong> 3 studies thathad <strong>in</strong>formation on relevant confounders.• In a retrospective cohort study of 720 peopleage 10-39 years old, type 2 diabetes (def<strong>in</strong>edby OGTT test<strong>in</strong>g) was 59% less common <strong>in</strong>exclusively breastfed people compared withthose who were exclusively bottle-fed(adjusted OR: 0.41; 95%CI 0.18-0.93)• In a case-control study of native Canadian,Some breastfeed<strong>in</strong>g for one year or longerwas a significant <strong>in</strong>dependent predictor offuture diabetes (adjusted OR: 0.24; 95%CI0.07-0.84) as was some breastfeed<strong>in</strong>g for 6months of longer (adjusted OR: 0.36; 95%CI0.13-0.99).None • Type 2 diabetes (def<strong>in</strong>ed by OGTT test<strong>in</strong>g)<strong>in</strong> the next generation was less commonamong children who were breastfedexclusively for > 2 months (6.9% vs. 30.1%among offspr<strong>in</strong>g of women without diabetes<strong>and</strong> women with diabetes, respectively) thanamong bottle-fed children (11.9% vs. 43.6%,respectively).GDM, gestational diabetes; OGTT, oral glucose tolerance test; BMI, body mass <strong>in</strong>dex (kg/m 2 ); SR, systematic review; MA, meta-analysisQuality of SR/MA<strong>and</strong> limitationAPooled differentstudy designsCNo synthesis ofresults <strong>and</strong>unclear how theconclusions werereached
BackgroundRelationship between Childhood Leukemia <strong>and</strong><strong>Breastfeed<strong>in</strong>g</strong>Leukemia, the most common cancer <strong>in</strong> children, encompasses multiple diseases <strong>in</strong>clud<strong>in</strong>gthree types: acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), <strong>and</strong>chronic myelogenous leukemia. In the United States, approximately 3,250 children are diagnosedwith leukemia each year <strong>and</strong> 2,400 (74 percent) of them have ALL. With the exception ofprenatal exposure to x-rays <strong>and</strong> specific genetic syndromes, little is known about the causes ofchildhood ALL (National Cancer Institute: seer.cancer.gov/publications/childhood/leukemia.pdf). Although the majority of human leukemias or lymphomas have no readilyidentifiable <strong>in</strong>fectious etiologies, viral causes have been identified for Burkitt’s lymphoma <strong>and</strong> arare form of adult leukemia/lymphoma. 100,101 Because breast milk is noted for provid<strong>in</strong>g passiveimmunity <strong>and</strong> protection of newborns from some early <strong>in</strong>fections, <strong>in</strong>vestigators havehypothesized that breastfeed<strong>in</strong>g may reduce the risk of childhood leukemia. 102Some of the confounders that had been considered <strong>in</strong> the studies of the relationship betweenchildhood leukemia <strong>and</strong> breastfeed<strong>in</strong>g were age, sex, race, socioeconomic status (such asmother’s education, region of residence at the time of diagnosis, parental occupation, deprivation<strong>in</strong>dex, <strong>and</strong>/or annual household <strong>in</strong>come), parental alcohol consumption, parental smok<strong>in</strong>g, birthorder, birth weight, parity, <strong>and</strong> age of mother at birth of <strong>in</strong>dex child.Additional Methodological CommentsWe identified four systematic reviews or meta-analyses that exam<strong>in</strong>ed the relationshipbetween breastfeed<strong>in</strong>g <strong>and</strong> childhood leukemia 103-106 We have elected to describe <strong>in</strong> details onlythe Guise 2005 104 systematic review <strong>and</strong> Kwan 2004 106 meta-analysis because they supersededthe Beral 2001 103 meta-analysis <strong>and</strong> Davis 1998 105 systematic review. All studies <strong>in</strong>cluded <strong>in</strong>Beral 2001 <strong>and</strong> Davis 10998 were also <strong>in</strong>cluded <strong>in</strong> Kwan 2004 or Guise 2005, except that Guise2005 review excluded studies published before 1990, unpublished data, <strong>and</strong> studies conducted <strong>in</strong>develop<strong>in</strong>g countries. Kwan 2004 also <strong>in</strong>cluded three additional studies published after 2001. Inaddition, the report<strong>in</strong>g <strong>and</strong> analysis <strong>in</strong> Beral 2001 <strong>and</strong> Davis 1998 were poor due to deficiency <strong>in</strong>report<strong>in</strong>g of the meta-analysis methods, search strategy <strong>and</strong>/or study eligibility criteria, <strong>and</strong> therewas a lack of consideration of potential confound<strong>in</strong>g <strong>in</strong> the <strong>in</strong>cluded studies.Guise 2005’s systematic review was the only study that reported methodological grad<strong>in</strong>g for<strong>in</strong>dividual studies. Guise 2005 did not perform a meta-analysis. Kwan 2004 comb<strong>in</strong>ed all casecontrolstudies regardless of their study quality <strong>in</strong>to a meta-analyses. To underst<strong>and</strong> further howstudy quality can affect the effect estimate, we decided to perform meta-analyses on the effectestimates from the four studies graded as good or fair quality <strong>in</strong> Guise 2005’s systematic review.Published Systematic Reviews/Meta-Analyses (Table 18)Guise 2005 conducted a systematic review of case-control studies related to breastfeed<strong>in</strong>g<strong>and</strong> the risk of childhood leukemia. Ten case-control studies total<strong>in</strong>g 9,653 subjects withleukemia were <strong>in</strong>cluded. All the studies were conducted <strong>in</strong> developed countries. Study quality84
was rated by the authors <strong>in</strong> a three-levels scale: good, fair, or poor. The follow<strong>in</strong>g aspects of thestudy quality were assessed: reliability of the diagnoses of leukemia, comparability of the case<strong>and</strong> control groups, differences <strong>in</strong> nonrespondents <strong>in</strong> cases versus controls, <strong>and</strong> the conduct ofcontroll<strong>in</strong>g for confound<strong>in</strong>g. There were two good, two fair, <strong>and</strong> six poor quality studies. Allstudies but one focused solely on childhood leukemia. There was no meta-analysis or statisticalanalysis performed. The methodological quality of this systematic review was rated grade A.Many of the studies <strong>in</strong> Guise 2005 systematic review did not provide data on exclusivity ofbreastfeed<strong>in</strong>g <strong>and</strong> did not consider potential confounders such as <strong>in</strong>fectious exposures fromhousehold or school contacts. Six of the ten studies explicitly sought to characterize therelationship between breastfeed<strong>in</strong>g <strong>and</strong> leukemia.Guise 2005 concluded that the few high-quality studies disagreed <strong>in</strong> regards to theassociation between breastfeed<strong>in</strong>g <strong>and</strong> the risk of ALL. Specifically, the two good-qualitystudies, or UKCCS <strong>and</strong> CCG study, 103,107 presented “conflict<strong>in</strong>g results” (Table 17). Similarly,the two fair-quality studies disagreed on the protective effect of breastfeed<strong>in</strong>g.Kwan 2004 conducted a meta-analysis of 14 case-control studies on breastfeed<strong>in</strong>g <strong>and</strong> therisk of childhood leukemia. A total of 8,051 subjects with leukemia were <strong>in</strong>cluded <strong>in</strong> theanalysis. The meta-analysis exam<strong>in</strong>ed the relationship between short-term breastfeed<strong>in</strong>g (def<strong>in</strong>edas breastfeed<strong>in</strong>g for 6 months or less) or long-term breastfeed<strong>in</strong>g (def<strong>in</strong>ed as breastfeed<strong>in</strong>g formore than 6 months) <strong>and</strong> the risk of childhood leukemias. Twelve studies from developedcountries <strong>and</strong> two studies from develop<strong>in</strong>g countries, <strong>in</strong>clud<strong>in</strong>g any type of leukemia <strong>in</strong> children15 years or younger that reported odds ratio <strong>and</strong> duration of breastfeed<strong>in</strong>g, were <strong>in</strong>cluded <strong>in</strong> themeta-analysis. Kwan 2004 did not formally assess the <strong>in</strong>dividual study quality. However, thepotential for confound<strong>in</strong>g <strong>in</strong> each study was considered <strong>in</strong> the meta-analysis. The methodologicalquality of this meta-analysis was rated grade A.For each of the 14 primary studies <strong>in</strong> the meta-analysis, Kwan 2004 selected odds ratioadjusted for SES when available. The meta-analysis showed a statistically significant reducedrisk of ALL with short- <strong>and</strong> long-term breastfeed<strong>in</strong>g (OR 0.88, 95%CI 0.80 - 0.96; OR 0.76,95%CI 0.68 - 0.84, respectively). The analysis reported a statistically significant reduction <strong>in</strong>AML for long-term breastfeed<strong>in</strong>g (OR 0.85, 95%CI 0.73 - 0.98) but not for short-termbreastfeed<strong>in</strong>g (OR 0.90, 95%CI 0.80 - 1.02). The unadjusted <strong>and</strong> adjusted odds ratios forreduction of the risk of ALL <strong>in</strong> short-term breastfeed<strong>in</strong>g were both statistically significant. Forreduction of the risk of ALL <strong>in</strong> long-term breastfeed<strong>in</strong>g, only the adjusted odds ratio wasstatistically significant. The same sensitivity analyses were performed for the reduction of therisk of AML <strong>in</strong> short- <strong>and</strong> long-term breastfeed<strong>in</strong>g, <strong>and</strong> similar results were found.Studies <strong>in</strong>cluded <strong>in</strong> the additional analysis. Guise 2005 identified two good <strong>and</strong> two fairmethodological quality studies. We have analyzed these studies further as detailed below.The two good studies were the UKCCS <strong>and</strong> the CCG studies. The UKCCS <strong>in</strong>cluded 1,401(87 percent) ALL <strong>and</strong> 214 (13 percent) AML case patients recruited from health programs thatenrolled 98 percent of the total childhood cancers throughout Engl<strong>and</strong>, Scotl<strong>and</strong> <strong>and</strong> Wales overthe period 1991-1998; control subjects were selected from population-based health rosters. Incontrast, the CCG study <strong>in</strong>cluded 1,744 (79 percent) ALL <strong>and</strong> 456 (21 percent) AML casepatients enrolled from specific CCG centers, <strong>and</strong> control subjects were selected via r<strong>and</strong>omdigit-dial<strong>in</strong>g.Both studies excluded leukemia diagnoses less than 1 year of age because mostleukemias occurr<strong>in</strong>g dur<strong>in</strong>g <strong>in</strong>fancy are thought to have different etiologies from childhoodleukemias. Both studies found that long-term breastfeed<strong>in</strong>g (> 6 months duration) was protectivefor ALL, but the confidence <strong>in</strong>terval for the risk estimate from the UKCCS did not exclude unity85
(1.00), whereas the confidence <strong>in</strong>terval for the risk estimate reported by the CCG study clearlyexcluded unity (1.00), <strong>in</strong>dicat<strong>in</strong>g statistical significance. The UKCCS, however, found noassociation between short- or long-term breastfeed<strong>in</strong>g <strong>and</strong> the risk of AML, while the CCG studyfound a significant protective effect of long-term breastfeed<strong>in</strong>g for AML.The two fair quality studies were Dockerty 1999 <strong>and</strong> Rosenbaum 2000. They were gradedfair quality due to potential selection biases. 108,109 Dockerty 1999 <strong>in</strong>cluded 121 newly diagnosedleukemia cases (ages 0-14 years) <strong>and</strong> 121 age- <strong>and</strong> sex-matched control subjects selectedr<strong>and</strong>omly from the New Zeal<strong>and</strong> national birth records. The primary purpose of the study was toexam<strong>in</strong>e the relationship between <strong>in</strong>fections, vacc<strong>in</strong>ations, <strong>and</strong> the risk of childhood leukemia.<strong>Breastfeed<strong>in</strong>g</strong> was one of the secondary factors exam<strong>in</strong>ed <strong>in</strong> the study. Compared with childrenwho never breastfed, those who breastfed for more than 6 months to 1 year had about a 20percent reduced risk of ALL; those who were breastfed for more than 1 year had the lowest risk(OR 0.47; 95%CI 0.15 – 1.43). Even though these estimates were not statistically significant(Table 22), a trend analysis <strong>in</strong>dicated a statistically significant effect <strong>in</strong> reduc<strong>in</strong>g the risk of ALLwith <strong>in</strong>creas<strong>in</strong>g duration of breastfeed<strong>in</strong>g (P = 0.04). Rosenbaum 2000 <strong>in</strong>cluded 255 ALL casesfrom hospital registries <strong>and</strong> 760 matched control r<strong>and</strong>omly selected from birth certificates <strong>in</strong> US.This study aimed to exam<strong>in</strong>e the relationship between early child-care (<strong>in</strong>clud<strong>in</strong>g breastfeed<strong>in</strong>g)<strong>and</strong> the risk of childhood ALL. Like Dockerty 1999, children under 1 year of age were <strong>in</strong>cluded<strong>in</strong> Rosenbaum 2000. The analysis of the relationship between breastfeed<strong>in</strong>g <strong>and</strong> the risk ofchildhood ALL did not adjust for any other potential confounders, except for the factors used toidentify matched controls (gender, race, <strong>and</strong> birth year). They found that 47 percent of cases ofALL <strong>and</strong> 51 percent of control were breastfed at birth (OR 1.20, 95%CI was not reported). Thisassociation was not statistically significant.Meta-analysis. We used a r<strong>and</strong>om-effects model to comb<strong>in</strong>e SES-adjusted odds ratios ofALL <strong>in</strong> relation to short-term (≤ 6 months) <strong>and</strong> long-term (> 6 months) breastfeed<strong>in</strong>g fromUKCCS 103 , CCG 107 study, <strong>and</strong> Dockerty 1999 (Table 17). Rosenbaum 2000 was excluded fromthe analysis because the duration of breastfeed<strong>in</strong>g was not reported. The results from our metaanalysissuggest that long-term breastfeed<strong>in</strong>g is associated with a reduction <strong>in</strong> the risk of ALL(OR 0.80; 95%CI 0.71 - 0.91).86
Table 17. Comb<strong>in</strong>ed SES-adjusted ORs of ALL for the three case-control studies rated as good <strong>and</strong> fairmethodological quality <strong>in</strong> the systematic review by Guise et al. (2005)Study OR (≤ 6 mo vs. never BF) Lower CI Upper CIUKCCS 2001 6 mo vs. never BF) Lower CI Upper CIUKCCS 2001 0.89 0.75 1.05CCG study 1999 0.72 0.60 0.87Dockerty 1999>6 mo to 1 yr 0.82 0.29 2.27>1 yr 0.47 0.15 1.43Pooled 0.80 0.71 0.91Kwan 2004meta-analysis results 0.76 0.68 0.84ConclusionOur meta-analyses of the three case-control studies concern<strong>in</strong>g breastfeed<strong>in</strong>g <strong>and</strong> the risk ofALL were consistent with the results from Kwan 2004’s meta-analysis, but with smaller effectsize <strong>and</strong> smaller statistical significance (Table 17). Kwan 2004 also found an associationbetween a history of breastfeed<strong>in</strong>g <strong>and</strong> a reduced risk of AML. We conclude that there isassociation between a history of breastfeed<strong>in</strong>g of at least 6 months duration <strong>and</strong> a reduction <strong>in</strong>the risk of both ALL <strong>and</strong> AML.Further evaluation of the biological mechanisms underly<strong>in</strong>g this relationship while tak<strong>in</strong>g<strong>in</strong>to consideration potential biases can be achieved with more large-scale case-control studiesutiliz<strong>in</strong>g population-based <strong>and</strong> socioeconomic status-matched controls.87
88Table 18. Summary of systematic reviews/meta-analyses on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> childhood leukemiaAuthor Year StudyInterventionPopulation description /ComparatorConfounders consideredResultsGuise 2005 SR of 10 casecontrolAny measures ofstudies <strong>in</strong> breastfeed<strong>in</strong>g <strong>and</strong>developed comparatorscountriesChildhood ALLor all childhoodleukemias:9,653Kwan 2004Children withALL, AML orANLL: 6,835(Note: 8 of the14 studiesexcluded casesof leukemia <strong>in</strong><strong>in</strong>fants)Beral 2001Children with allleukemia,<strong>in</strong>clud<strong>in</strong>g ALL:7,401MA of 14 casecontrolstudies <strong>in</strong>both developed<strong>and</strong> develop<strong>in</strong>gcountriesMA of 15 casecontrolstudies <strong>in</strong>both developed<strong>and</strong> develop<strong>in</strong>gcountriesCompared short-termbreastfeed<strong>in</strong>g (≤6months) or long-termbreastfeed<strong>in</strong>g (>6months) to nobreastfeed<strong>in</strong>g or neverbeen breastfedCompared everbreastfeed<strong>in</strong>g,breastfeed<strong>in</strong>g duration≤ 6 months, orbreastfeed<strong>in</strong>g duration> 6 months to neverbeen breastfedGender, year of birth, race,SES (region of residence,maternal education, family<strong>in</strong>come), gestational age,birthweight, maternal age,<strong>and</strong> smok<strong>in</strong>gAge, sex, race, SES(mother’s education, regionof residence at the time ofdiagnosis, parentaloccupation, deprivation<strong>in</strong>dex, <strong>and</strong>/or annualhousehold <strong>in</strong>come),parental alcoholconsumption, parentalsmok<strong>in</strong>g, birth order,birthweight, parity, age ofmother at birth of <strong>in</strong>dexchild.• Six studies were conducted <strong>in</strong> European countries.Six of the studies explicitly sought to characterizethe relationship between breastfeed<strong>in</strong>g <strong>and</strong>leukemia as the primary objective, whereas theothers <strong>in</strong>cluded breastfeed<strong>in</strong>g measures from theperspective measur<strong>in</strong>g broader characteristics ofthe immune system <strong>and</strong> early <strong>in</strong>fections <strong>in</strong> theetiology. Of the 10 studies, 2 were of good quality,2 were of fair quality, <strong>and</strong> 6 were of poor quality.• The 2 good-quality studies (UKCCS <strong>and</strong> CCGstudies) present “conflict<strong>in</strong>g results” regard<strong>in</strong>g theassociation between breastfeed<strong>in</strong>g <strong>and</strong> leukemia.• Similarly, the 2 fair-quality studies disagreed onthe protective effect of breastfeed<strong>in</strong>g.• A significant negative association was observedbetween short-term breastfeed<strong>in</strong>g <strong>and</strong> ALL(OR=0.88, 95% CI 0.80-0.96), but the AML results(OR=0.90, 95% CI 0.80-1.02) were not significant.• A significant negative association was observedbetween long-term breastfeed<strong>in</strong>g <strong>and</strong> ALL(OR=0.76, 95% CI 0.68-0.84), <strong>and</strong> AML(OR=0.85, 95% CI 0.73-0.98).ND • There is evidence of a statistically significantreduction <strong>in</strong> the OR associated with ever hav<strong>in</strong>gbeen breastfed (OR=0.86, 95%CI 0.81-0.92) <strong>and</strong>hav<strong>in</strong>g been breastfed for more than 6 months(OR=0.78, 95% CI 0.71-0.85).Quality of SR/MA<strong>and</strong> limitationsAInterpretation of“conflict<strong>in</strong>g results” forthe 2 good-qualitystudies was based onstatistical significanceonlyA2 studies fromdevelop<strong>in</strong>g countriesCNo methods of metaanalysis;nodescription of searchstrategy <strong>and</strong> studyeligibility; noconsideration ofpotential confound<strong>in</strong>g
Table 18. Cont<strong>in</strong>uedAuthor Year StudyPopulation descriptionDavis 1998 SR of 5 casecontrolstudiesChildren with <strong>in</strong> developedall leukemia, countriesALL or ANLL:1,656Intervention/ComparatorCompared anybreastfeed<strong>in</strong>g, or longtermbreastfeed<strong>in</strong>g (6-8months) to artificial <strong>in</strong>fantfeed<strong>in</strong>g (or never beenbreastfed)Confounders consideredResultsNone • None of the <strong>in</strong>cluded studies reported a significantassociation between all leukemia, ALL or ANLL<strong>and</strong> <strong>in</strong>fant feed<strong>in</strong>g.Quality of SR/MA<strong>and</strong> limitationsCPoor report<strong>in</strong>g ofsearch strategy <strong>and</strong>study eligibility; noconsideration ofpotential confound<strong>in</strong>gALL, acute lymphocytic leukemia; ANLL, Acute non-lymphocytic leukemia; AML, acute myeloid leukemia; SES, socioeconomic status; SR, systematic review; MA,meta-analysis89
Relationship between <strong>Infant</strong> Mortality <strong>and</strong> <strong>Breastfeed<strong>in</strong>g</strong>Background<strong>Infant</strong> mortality (both neonatal <strong>and</strong> post-neonatal mortality) is on the decl<strong>in</strong>e <strong>in</strong> bothdevelop<strong>in</strong>g <strong>and</strong> developed countries dur<strong>in</strong>g the past four decades. In the United States, thenational average of <strong>in</strong>fant mortality was 7.0 deaths per 1000 live births <strong>in</strong> 2002. 110 Lead<strong>in</strong>gcauses of <strong>in</strong>fant death <strong>in</strong> a developed country <strong>in</strong>clude congenital abnormalities, pre-term births,low birth weight, Sudden <strong>Infant</strong> Death Syndrome (SIDS), problems related to complications ofpregnancy, <strong>and</strong> respiratory distress syndrome. 110 The common risk factors that are associatedwith <strong>in</strong>fant mortality <strong>in</strong>clude <strong>in</strong>fant <strong>and</strong> maternal age, gender, race, socioeconomic status, birthorder, birth weight, congenital malformation at birth, <strong>and</strong> maternal smok<strong>in</strong>g dur<strong>in</strong>g pregnancy.<strong>Breastfeed<strong>in</strong>g</strong> protects aga<strong>in</strong>st <strong>in</strong>fectious diarrhea <strong>and</strong> respiratory diseases, which are the lead<strong>in</strong>gcauses of <strong>in</strong>fant mortality <strong>in</strong> develop<strong>in</strong>g countries. 111 However, the role of breastfeed<strong>in</strong>g <strong>in</strong>prevent<strong>in</strong>g <strong>in</strong>fant deaths <strong>in</strong> developed countries is less clear. We elect to review the relationshipbetween breastfeed<strong>in</strong>g <strong>and</strong> post-neonatal mortality.Additional Methodological CommentsFor this section, <strong>in</strong>fant mortality is def<strong>in</strong>ed as any death that occurred more than 1 month butless than 12 months after birth. Neonatal mortality (death < 1 month of age) is not considered <strong>in</strong>this review. No published meta-analysis was identified that evaluated the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> <strong>in</strong>fant mortality. We <strong>in</strong>cluded only studies conducted <strong>in</strong> developed countriesthat evaluated the relationship between breastfeed<strong>in</strong>g <strong>and</strong> <strong>in</strong>fant mortality (exclud<strong>in</strong>g SIDS).Results (Table 19)We identified two studies conducted <strong>in</strong> the United States that evaluated the role ofbreastfeed<strong>in</strong>g <strong>in</strong> <strong>in</strong>fant deaths other than SIDS. 112,113 ; one study did not qualify for <strong>in</strong>clusion <strong>in</strong>this review because it was an analysis based on data collected from cross-sectional surveys. 113The study that qualified for <strong>in</strong>clusion was a case-control study that selected subjects fromnationally representative samples. 112 The study excluded <strong>in</strong>fants who died at less than one monthof age. The methodological quality of the study was rated grade B.Chen 2004 analyzed the 1988 US National <strong>Maternal</strong> <strong>and</strong> <strong>Infant</strong> <strong>Health</strong> Survey (NMIHS) dataus<strong>in</strong>g a case-control study design. Their sample <strong>in</strong>cluded 1,204 <strong>in</strong>fants who died between 28days <strong>and</strong> 1 year of age. The authors excluded <strong>in</strong>fants who died from congenital anomalies ormalignant tumors. In an attempt to address the issue of reverse causality, only <strong>in</strong>fants whosurvived beyond the neonatal period were <strong>in</strong>cluded <strong>and</strong> feed<strong>in</strong>g status was categorized based onthe assessments undertaken some time before death occurred. The controls <strong>in</strong>cluded 7,740 livebirths who were alive <strong>and</strong> older than 1 year of age at the time of survey. Mothers were surveyedus<strong>in</strong>g a mailed questionnaire. <strong>Breastfeed<strong>in</strong>g</strong> was assessed as “ever breastfed” or “neverbreastfed.” The study did not report the mean or the range of duration of maternal recall forbreastfeed<strong>in</strong>g. Overall <strong>and</strong> cause-specific odds ratios were calculated to evaluate “ever” versus“never” breastfeed<strong>in</strong>g. S<strong>in</strong>ce there was an oversampl<strong>in</strong>g of black <strong>and</strong> low birth weight <strong>in</strong>fants <strong>in</strong>the orig<strong>in</strong>al sample, <strong>in</strong> order for the study population to be more representative of the US90
population, additional analyses were performed with SUDAAN software adjusted samples. Thisadjusted sample <strong>in</strong>cluded a total of 9,145 cases <strong>and</strong> 3,186,497 controls. The analyses wereadjusted for sampl<strong>in</strong>g strategy <strong>and</strong> potential confounders such as maternal age, education,smok<strong>in</strong>g, <strong>in</strong>fant gender, race, birth weight, congenital malformation, live birth order, plurality,<strong>and</strong> status of enrollment <strong>in</strong> the Special Supplemental Nutrition Program for Women, <strong>Infant</strong>, <strong>and</strong>Children program (WIC). The study reported that the odds of death <strong>in</strong> the postneonatal periodwere 21 percent lower for “ever breastfed” compared with “never breastfed” <strong>in</strong>fants. However,<strong>in</strong> subgroup analyses of cause-specific death, the only statistically significant association wasreported between SIDS (<strong>in</strong> the orig<strong>in</strong>al sample) or <strong>in</strong>jury-related death (<strong>in</strong> the SUDAANadjustedsample) <strong>and</strong> “never breastfed” status.ConclusionOne study of moderate methodological quality us<strong>in</strong>g a large sample of <strong>in</strong>fants reported aprotective effect of breastfeed<strong>in</strong>g <strong>in</strong> reduc<strong>in</strong>g <strong>in</strong>fant mortality after controll<strong>in</strong>g for some of thepotential confounders. However, <strong>in</strong> subgroup analyses of the study, the only statisticallysignificant association reported was between “never breastfeed<strong>in</strong>g” <strong>and</strong> SIDS or the risk of<strong>in</strong>jury-related deaths. Because of the limited data <strong>in</strong> this area, the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> post-neonatal <strong>in</strong>fant mortality rema<strong>in</strong>s unclear. Further research is warranted.91
Table 19. Summary of case-control study on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> <strong>in</strong>fant mortalityDef<strong>in</strong>itionMeanOR* (95% CI)Author year Cases Controlof <strong>in</strong>fantAge at <strong>Breastfeed<strong>in</strong>g</strong> ComparatorCountry(N)(N)mortalityDx group group Crude Adjust(year)Chen 2004USANational<strong>Maternal</strong> <strong>and</strong><strong>Infant</strong> <strong>Health</strong>Survey 1998(NMIHS)Postneonataldeath a(9145)Postneonataldeath b(1204)Live birth a(3 186 497)Live birth b(7740)a SUDAAN software adjusted samplebOrig<strong>in</strong>al sampleDeath> 28dof age% Ever % Neverndnd0.79(0.67-0.93)0.76(0.65-0.88)Potentialconfoundersadjusted<strong>Maternal</strong>: age,education,smok<strong>in</strong>g<strong>Infant</strong>: gender,race, birth weight,congenitalmalformation, livebirth order,plurality, <strong>and</strong> WICstatusQuality <strong>and</strong>limitationsB(<strong>in</strong> subgroupanalysesstatisticallysignificantassociation wasreported between<strong>in</strong>jury-relateddeath or SIDS<strong>and</strong> “neverbreastfed” status)92
Relationship between Sudden <strong>Infant</strong> Death Syndrome (SIDS)<strong>and</strong> <strong>Breastfeed<strong>in</strong>g</strong>BackgroundSudden <strong>in</strong>fant death syndrome (SIDS) is the lead<strong>in</strong>g cause of mortality among <strong>in</strong>fants aged1 to 12 months <strong>in</strong> the United States. 114 SIDS accounted for a death rate of 0.55 per 1000 livebirths for the year 2004 accord<strong>in</strong>g to the National Center for <strong>Health</strong> Statistics (NCHS) at CDC(www.cdc.gov/nchs/deaths.htm.). Several modifiable risk factors for SIDS are sleep<strong>in</strong>gpositions, maternal smok<strong>in</strong>g, <strong>and</strong> bed shar<strong>in</strong>g. Other potential risk factors <strong>in</strong>clude birth weight,gender, <strong>and</strong> socioeconomic status. The relationship of breastfeed<strong>in</strong>g <strong>and</strong> SIDS has beenevaluated among a broad range of potential risk factors. However, the role of breastfeed<strong>in</strong>g as aprotective factor <strong>in</strong> SIDS is unclear. One meta-analysis published <strong>in</strong> 2000 assessed therelationship of breastfeed<strong>in</strong>g <strong>and</strong> SIDS.Additional Methodological CommentsWe identified four eligible studies conducted <strong>in</strong> developed countries that evaluated the roleof breastfeed<strong>in</strong>g <strong>in</strong> SIDS, <strong>and</strong> published s<strong>in</strong>ce 1997, the cutoff date for the literature search of thepublished meta-analysis. .Published Systematic Review/Meta-Analysis (Table 20)One meta-analysis 115 of 23 studies (18 case-control; four nested case-control; <strong>and</strong> oneobservational cohort) evaluated the relationship of breastfeed<strong>in</strong>g <strong>and</strong> SIDS. All studies wereconducted <strong>in</strong> developed countries from 1965 to 1997. Studies that reported a m<strong>in</strong>imal def<strong>in</strong>itionof SIDS – sudden unexpla<strong>in</strong>ed death of an <strong>in</strong>fant or young child – met the eligibility criteria. Themeta-analysis analyzed a total of 4,251 cases of SIDS <strong>and</strong> 58,055 controls. Seventeen studies<strong>in</strong>cluded subjects from birth to 2 years old when SIDS occurred; eight studies did not provideage data. The studies differed <strong>in</strong> their def<strong>in</strong>ition of breastfeed<strong>in</strong>g exposure. Also, the studiesvaried <strong>in</strong> their description of SIDS. Of these, only 14 studies reported autopsy-confirmeddiagnoses of SIDS. Three studies were specifically designed to exam<strong>in</strong>e the relationship ofbreastfeed<strong>in</strong>g <strong>and</strong> SIDS. The rest of the studies exam<strong>in</strong>ed multiple risk factors <strong>and</strong> theirassociation with SIDS, of which feed<strong>in</strong>g history would be one.The meta-analysis utilized a r<strong>and</strong>om effects model. It reported an overall risk of SIDS twiceas great for formula-fed <strong>in</strong>fants compared with breastfed <strong>in</strong>fants (crude odds ratio (OR) of 2.11;95% CI 1.66 to 2.68). The methodological quality of <strong>in</strong>dividual studies was appraised. Theauthors conducted a separate meta-analysis for those studies published s<strong>in</strong>ce 1988 when moreadvanced epidemiological <strong>and</strong> autopsy procedures were available. A separate analysis was alsoperformed for those studies with “high” quality scores. The results from these meta-analysesconcurred with the overall result. Heterogeneity was not explored, i.e., no subgroup analyseswere performed to account for the different def<strong>in</strong>itions of <strong>in</strong>terventions or outcomes. The authorsreported “no publication bias”. Differences <strong>in</strong> case match<strong>in</strong>g precluded them from comb<strong>in</strong><strong>in</strong>gadjusted odds ratios <strong>in</strong> the meta-analysis. Four of the 16 studies showed a dose response trend93
with the risk of SIDS <strong>in</strong>creas<strong>in</strong>g with <strong>in</strong>creas<strong>in</strong>g formula feed<strong>in</strong>g. The overall methodologicalquality of the meta-analysis was rated grade C.Studies Identified after the Published Meta-Analysis (Table 21)We identified four eligible studies from five publications conducted <strong>in</strong> developed countries<strong>and</strong> published s<strong>in</strong>ce 1997 that evaluated the relationship of breastfeed<strong>in</strong>g <strong>and</strong> SIDS. 116-120 Threewere case-control studies <strong>and</strong> the fourth, a case-cohort study (a cohort study analyzed as a casecontrolstudy). The methodological quality ranged from grades B to C. There were a total of 769cases of SIDS <strong>and</strong> 2,681 controls.All studies were designed to evaluate a broad range of potential risk factors for SIDS. Thestudies differed <strong>in</strong> their description of the duration of breastfeed<strong>in</strong>g. Similarly, the studies varied<strong>in</strong> their def<strong>in</strong>ition of the time <strong>in</strong>terval when SIDS occurs <strong>in</strong> <strong>in</strong>fants, but all studies reportedautopsy-confirmed diagnoses. The mean age of the <strong>in</strong>fants with SIDS ranged from 2 to 19weeks. All studies provided adjusted odds ratios for the association of breastfeed<strong>in</strong>g <strong>and</strong> SIDS.Three of the four studies identified statistically significant <strong>in</strong>creased risk of SIDS <strong>in</strong> bottle-fed<strong>in</strong>fants. 117,119,120 Two studies reported that the risk of SIDS was twice or more for non-breastfed<strong>in</strong>fants compared with some or ever breastfed <strong>in</strong>fants. 117,119 One study reported an approximatelytwo times <strong>in</strong>creased risk of SIDS among those breastfed less than 2 weeks compared with thosebreastfed more than 2 weeks. 120 One case-cohort study (a cohort study analyzed as case-controlstudy) did not f<strong>in</strong>d a statistically significant <strong>in</strong>creased risk of SIDS <strong>in</strong> bottle fed <strong>in</strong>fants. 118Meta-analysis results. Because of the limitations of the previous meta-analysis, we electedto conduct our own meta-analysis us<strong>in</strong>g only studies that provided an objective def<strong>in</strong>ition ofSIDS (autopsy confirmed SIDS among <strong>in</strong>fants 1 week to 1 year of age), clear report<strong>in</strong>g ofbreastfeed<strong>in</strong>g data, <strong>and</strong> outcomes adjusted for important confounders or risk factors (e.g.,sleep<strong>in</strong>g positions, maternal smok<strong>in</strong>g, <strong>and</strong> socioeconomic status). Four studies <strong>in</strong>cluded <strong>in</strong> thepreviously published meta-analysis 121-124 <strong>and</strong> two studies published s<strong>in</strong>ce 1997 met the eligibilitycriteria. 118,120 The majority of the studies provided data on ever versus never breastfeed<strong>in</strong>g <strong>and</strong>this was comb<strong>in</strong>ed us<strong>in</strong>g a r<strong>and</strong>om effects model. The results from our meta-analysis found thatever breastfeed<strong>in</strong>g was associated with a reduction <strong>in</strong> both crude <strong>and</strong> adjusted risk of SIDS(crude OR 0.41; 95%CI (0.28, 0.58), <strong>and</strong> adjusted OR 0.64; 95%CI (0.51, 0.81), respectively);both estimates were statistically significant with a reduction <strong>in</strong> SIDS for the ever breastfed<strong>in</strong>fants.94
Figure 10. R<strong>and</strong>om effects model of summary estimate evaluat<strong>in</strong>g the association of breastfeed<strong>in</strong>g <strong>and</strong> SIDSAdjusted OR of SIDSStudy(95% CI) % W eight Q ualityBrooke 1997 0.99 ( 0.37, 2.56) 5.1 AW ennergren 1997 0.50 ( 0.45, 0.77) 28.6 AFlem<strong>in</strong>g 1996 1.06 ( 0.57, 1.98) 10.6 AMitchell 1993 0.53 ( 0.38, 0.74) 23.6 BVennemann 2005 0.59 ( 0.36, 0.94) 15.5 BMitchell 1997 0.76 ( 0.40, 1.47) 9.9 BM itchell2 1997 1.07 ( 0.47, 2.43) 6.7 BOverall 0.64 ( 0.51, 0.81) 100.0.1 .5 .8 1 1.5 2 5Reduction <strong>in</strong> risk with breastfeed<strong>in</strong>g Adjusted OR of SIDS Increase <strong>in</strong> risk with breastfeed<strong>in</strong>gConclusionResults from the previously published meta-analysis of case-control studies concluded thatan overall crude risk of SIDS was twice as great for formula-fed <strong>in</strong>fants compared with breastfed<strong>in</strong>fants. The conclusion may be biased because the reported association was not adjusted forpotential confounders. Misclassification biases may occur because of differences among studieswith regard to def<strong>in</strong>itions of breastfeed<strong>in</strong>g exposure, def<strong>in</strong>itions of SIDS, <strong>and</strong> the wide age rangeof population <strong>in</strong>cluded <strong>in</strong> the studies.F<strong>in</strong>d<strong>in</strong>gs from the four studies published subsequent to the meta-analysis <strong>in</strong> developedcountries concurred with the f<strong>in</strong>d<strong>in</strong>gs from the meta-analysis. All studies reported autopsyconfirmeddiagnoses of SIDS <strong>and</strong> adjusted for potential confounders. However, the def<strong>in</strong>itions ofbreastfeed<strong>in</strong>g exposure <strong>and</strong> the time <strong>in</strong>tervals accepted for def<strong>in</strong><strong>in</strong>g SIDS varied across studies.Three of four studies reported statistically significant <strong>in</strong>creased risk of SIDS associated with nonbreastfeed<strong>in</strong>gor reduced duration of breastfeed<strong>in</strong>g <strong>and</strong> the fourth study reported a statisticallynon-significant <strong>in</strong>creased risk.Our meta-analysis <strong>in</strong>cluded only studies that reported clear def<strong>in</strong>itions of exposure,outcomes, <strong>and</strong> results adjusted for well-known confounders or risk factors for SIDS. Thesummary estimate found a statistically significant adjusted odds ratio for an association betweenbreastfeed<strong>in</strong>g <strong>and</strong> a reduced risk of SIDS (adjusted OR 0.64, 95%CI 0.51 - 0.81). We concludethat there is a relationship between breastfeed<strong>in</strong>g <strong>and</strong> a reduced risk of SIDS.95
Table 20. Summary of systematic review/meta-analysis on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> Sudden <strong>Infant</strong> Death Syndrome (SIDS)Author Study Number ofInterventionPopulationResultsyear description subjects/ComparatorMcVea2000MA of 23observationalstudiesCases 4,251Controls 58,055SR, systematic review; MA, meta-analysisChildren whowere diagnosedof SIDS<strong>Breastfeed<strong>in</strong>g</strong>(any)The pooled OR for the 23 studies us<strong>in</strong>g r<strong>and</strong>om effects model resulted<strong>in</strong> an OR = 2.11 (95% CI 1.66-2.68) i.e., the overall risk of SIDS wastwice as great for bottle-fed <strong>in</strong>fants compared to breastfed <strong>in</strong>fants.The pooled OR from the higher quality studies also demonstrated a twofold <strong>in</strong>crease <strong>in</strong> risk among bottle fed <strong>in</strong>fants OR = 2.24The pooled OR from studies after 1988 OR = 2.32Confounders: Individual studies adjusted for potential confounders; 6studies reported adjusted OR; 4 studies reported no protective effectof breastfeed<strong>in</strong>g, while 2 reported adjusted OR that rema<strong>in</strong>edsignificant.Dose-response relationship: 4 out of 9 studies showed a dose responsetrend with the risk of SIDS <strong>in</strong>creas<strong>in</strong>g with <strong>in</strong>creas<strong>in</strong>g formula feed<strong>in</strong>g.None of the studies had sufficient power to demonstrate a statisticallysignificant difference between partial vs. no breastfeed<strong>in</strong>g.Qualityof SR/MAC96
97Table 21. Summary of case-control studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> sudden <strong>in</strong>fant death syndrome (SIDS) <strong>in</strong>cluded <strong>in</strong> the metaanalysisOR* (95% CI)Author year Cases Control Def<strong>in</strong>ition<strong>Breastfeed<strong>in</strong>g</strong> ComparatorPotential confounders adjustedCountry (N) (N) of SIDSgroupgroup Crude AdjustWennegran,1997Alm 2002Sc<strong>and</strong><strong>in</strong>aviaFlem<strong>in</strong>g,1996UKBrooke,1992UK(Scotl<strong>and</strong>)Mitchell,1993NewZeal<strong>and</strong>Population1987-1990Vennemann2005Germany244 869Mitchell 79 6791997 aNewZeal<strong>and</strong> 38 588a A case-cohort studyValidateddef<strong>in</strong>itionMeanAge atDx(week)16Ever(At the time ofdeath)Never195 780 7d-1y nd Ever Never147 275 7d-1y 15-18460 1757 >28d-1yr ndEver(At the time ofdeath)Ever(At the time ofdischarge fromobstetric dept)NeverNever333 998 8d-1 yr 19 >2 wk
Part II. Preterm <strong>Infant</strong> <strong>Outcomes</strong>Relationship between Necrotiz<strong>in</strong>g Enterocolitis <strong>and</strong> BreastMilk Feed<strong>in</strong>g <strong>in</strong> Preterm <strong>Infant</strong>sBackgroundNecrotiz<strong>in</strong>g enterocolitis (NEC) is a serious gastro<strong>in</strong>test<strong>in</strong>al disease <strong>in</strong> the preterm <strong>in</strong>fants.No def<strong>in</strong>itive causes have been identified. A population-based epidemiological study published<strong>in</strong> 2002 reported that the highest <strong>in</strong>cidence occurred <strong>in</strong> <strong>in</strong>fants with birth weights 750 to 1000 g<strong>and</strong> decreased with <strong>in</strong>creas<strong>in</strong>g birth weights. 125 Observational studies have suggested that breastmilk might be protective. There have been very few r<strong>and</strong>omized controlled trials (RCTs) thatexam<strong>in</strong>ed this issue. McGuire 2001 performed a meta-analysis of RCTs of breast milkcompar<strong>in</strong>g with formula milk <strong>in</strong> preterm <strong>in</strong>fants to reduce the risk of NEC. 126 S<strong>in</strong>ce that metaanalysis,we identified one RCT 127 <strong>and</strong> two prospective cohort studies 128,129 that reportedoutcome of NEC <strong>in</strong> preterm <strong>in</strong>fants <strong>in</strong> relation to a history of breast milk feed<strong>in</strong>g. Some of thepotential confounders that may affect the results of neonatal morbidity <strong>and</strong> mortality <strong>in</strong>cludebirth weight, ethnicity, <strong>and</strong> sex. 128Published Systematic Review/Meta-Analysis (Table 23)McGuire 2001’s meta-analysis compared formula feed<strong>in</strong>g with term breast milk feed<strong>in</strong>g <strong>in</strong>low birth weight or preterm <strong>in</strong>fants. Three RCTs published <strong>in</strong> 1983 <strong>and</strong> 1984 total<strong>in</strong>g 308preterm <strong>in</strong>fants were <strong>in</strong>cluded: Gross 1983 compared formula with unfortified term donor breastmilk; 12 Tyson 1983 compared preterm formula with pooled banked term breast milk; 13 <strong>and</strong> Lucas1984 130 (results for NEC reported <strong>in</strong> 1990 131 ) compared preterm formula with banked term breastmilk as the sole diet. In the meta-analysis compar<strong>in</strong>g formula with breast milk, the risk ratio fordevelop<strong>in</strong>g NEC was 2.5 (95% CI 0.9 - 7.3); risk difference was 0.05 (95% CI 0.00 - 0.1). Theauthors concluded that there was no statistically significant difference <strong>in</strong> the risk of NEC witheither form of milk feed<strong>in</strong>g.Studies Identified after the Published Systematic Review/Meta-Analysis (Table 24)R<strong>and</strong>omized controlled trial. Schanler 2005 enrolled 243 <strong>in</strong>fants ≤ 29-week gestationwhose mothers were expected to breastfeed. 127 If these <strong>in</strong>fants’ own mothers’ milk wereunavailable, the <strong>in</strong>fants were then r<strong>and</strong>omly assigned to receive either pasteurized donor milk orpreterm formula. However, both groups cont<strong>in</strong>ued to receive mother’s milk partially if they wereavailable dur<strong>in</strong>g the study. The <strong>in</strong>fants who were fed mother’s milk exclusively were notr<strong>and</strong>omized <strong>and</strong> served as a reference group. The <strong>in</strong>cidence of NEC <strong>in</strong> Donor milk versusPreterm formula was 5/78 versus 10/88 (P = 0.27). The non-r<strong>and</strong>omized group “mother’s milk”had fewer repeated episodes of late-onset sepsis <strong>and</strong>/or NEC (OR 0.18, 95% CI 0.04 - 0.79)compared with comb<strong>in</strong>ed groups “donor milk” <strong>and</strong> “preterm formula”. The methodologicalquality of this study was rated B.98
Prospective cohort. Furman 2003 was a prospective cohort study on 119 <strong>in</strong>fants withgestational age < 33 weeks <strong>and</strong> birth weight 600-1499 g. 128 Enteral feed<strong>in</strong>g was begun by day 2or 3 of life, parenteral nutrition was cont<strong>in</strong>ued until a daily enteral <strong>in</strong>take of 120 mL/kg of bodyweight was reached. <strong>Infant</strong>s received their mother’s milk <strong>in</strong> the sequence it was expressed,except that fresh rather than frozen milk was given if available. <strong>Maternal</strong> milk was fortified, <strong>and</strong>preterm <strong>in</strong>fant formula was offered when the <strong>in</strong>fant reached a daily oral <strong>in</strong>take of at least 110mL/kg. Limited availability of maternal milk was the sole reason <strong>in</strong>fants were fed pretermformula <strong>in</strong> addition to maternal milk. Four subgroups were analyzed: no maternal milk, dailymaternal milk of 1-24 mL/kg, 25-49 mL/kg, <strong>and</strong> ≥ 50 mL/kg. Rates of NEC did not differaccord<strong>in</strong>g to the amounts of maternal milk received. The results of the regression analysis wereadjusted for birth weight, ethnicity, <strong>and</strong> sex. The methodological quality of this study was ratedB.Ronnestad 2005 was a prospective cohort study of late-onset sepsis on 462 <strong>in</strong>fants withgestational age
Figure 11. Meta-Analysis of four RCTs on the effects of breast milk feed<strong>in</strong>g <strong>and</strong> NEC <strong>in</strong> preterm <strong>in</strong>fantsConclusionEven though the observational study by Furman et al. did not f<strong>in</strong>d a difference <strong>in</strong> the rates ofNEC accord<strong>in</strong>g to the amount of maternal milk received by the <strong>in</strong>fants, our meta-analysis of fourRCTs demonstrated that there was a marg<strong>in</strong>ally statistically significant association betweenbreast milk feed<strong>in</strong>g <strong>and</strong> the reduction <strong>in</strong> the risk of NEC. The confidence <strong>in</strong>terval for the estimate<strong>in</strong> the relative risk reduction ranged from four percent to 82 percent. The absolute risk differencewas five percent. The wide confidence of the estimate reflects the relatively small number oftotal subjects <strong>in</strong> the studies <strong>and</strong> the small number of events. One must be cognizant of the cl<strong>in</strong>icalheterogeneity underly<strong>in</strong>g these RCTs <strong>in</strong> <strong>in</strong>terpret<strong>in</strong>g the f<strong>in</strong>d<strong>in</strong>gs of the meta-analysis. Some ofthem were: different time periods when the studies were conducted; different preterm formulasas comparators; wide range of gestational ages <strong>and</strong> birth weights <strong>in</strong> the subjects; different degreeof illnesses <strong>in</strong> the subjects; <strong>and</strong> others. How the heterogeneity <strong>in</strong> the studies affected the f<strong>in</strong>d<strong>in</strong>gsis unclear. Lastly, one may question the importance of an absolute risk difference of five percentbetween groups. Tak<strong>in</strong>g <strong>in</strong>to account the high case-fatality rate of NEC, we consider thisestimate is of mean<strong>in</strong>gful cl<strong>in</strong>ical difference. In conclusion, there is evidence to support anassociation between breast milk feed<strong>in</strong>g <strong>and</strong> a reduction <strong>in</strong> the risk of NEC <strong>in</strong> preterm <strong>in</strong>fants.100
Table 23. Summary of systematic review/meta-analysis on the relationship between breast milk feed<strong>in</strong>g <strong>and</strong> necrotiz<strong>in</strong>g enterocolitis (NEC) <strong>in</strong> preterm<strong>in</strong>fantsAuthor StudyQuality forN Population Intervention/Comparator Resultsyear descriptionSR or MAMcGuire2001MA of 3 RCTs 310Gross 1983 27-33wk, < 1600 gN=67USUnfortified term donor breast milk, fed until 1800 g or untilwithdrawal secondary to feed <strong>in</strong>tolerance or NEC; compared tost<strong>and</strong>ard calorie, prote<strong>in</strong> enriched formulaformula vs. breast milk,RR: 2.5 (95% CI 0.9, 7.3);RD: 0.05 (95% CI 0.0, 0.1)BTyson 1983 “verylow birth weight<strong>in</strong>fants”N=81USLucas 1984 preterm<strong>in</strong>fants < 1850 gN=162UKPooled banked term breast milk, allocation at 10 th day of life, feduntil 2000 g or until withdrawal secondary to illness requir<strong>in</strong>gparenteral fat or prote<strong>in</strong>; compared to enriched calorie <strong>and</strong> prote<strong>in</strong>formulaBanked term breast milk 200 mL/kg/d, fed until 2000 g or until d/c;compared to enriched calorie <strong>and</strong> prote<strong>in</strong> formula101SR, systematic review; MA, meta-analysis
102Table 24. Summary of studies on the relationship between breast milk feed<strong>in</strong>g <strong>and</strong> necrotiz<strong>in</strong>g enterocolitis (NEC) <strong>in</strong> preterm <strong>in</strong>fantsAuthoryearN Population Intervention/Comparator <strong>Outcomes</strong> QualityR<strong>and</strong>omized Controlled TrialSchanler2005Incidence of NEC:DM vs. PF: 5/78 vs. 10/88 (P=0.27)B243
Relationship between Cognitive Development <strong>and</strong> BreastMilk Feed<strong>in</strong>g <strong>in</strong> Preterm <strong>Infant</strong>sBackgroundMany studies have exam<strong>in</strong>ed the relationship between breastfeed<strong>in</strong>g <strong>and</strong> cognitivedevelopment. Results have been conflict<strong>in</strong>g. Most of the studies were observational <strong>in</strong> design.Many of them did not have a clear def<strong>in</strong>ition of breastfeed<strong>in</strong>g or breast milk exposure. Differentcognitive assessment tools were used. <strong>Outcomes</strong> were measured anywhere from less than 2 yearsof age to adulthood.Three systematic reviews from 1999 to 2002 have tried to either establish methodologicalst<strong>and</strong>ards to assess the observational studies or adjust for covariates <strong>in</strong> pooled analysis (seediscussion of confounders <strong>in</strong> section on cognitive outcomes <strong>in</strong> term <strong>in</strong>fants). S<strong>in</strong>ce the lastsystematic review by Ja<strong>in</strong> et al. <strong>in</strong> 2002, 58 there have been eight cohort studies on preterm <strong>in</strong>fantsthat exam<strong>in</strong>ed the relationship of breast milk feed<strong>in</strong>g to some aspects of cognitive development.A note of caution is <strong>in</strong> order here. The Mental Developmental Index of the Bayley Scales of<strong>Infant</strong> Development is widely used to assess the cognitive ability of young children <strong>in</strong> the studiesreviewed <strong>in</strong> this report. One must keep <strong>in</strong> m<strong>in</strong>d that the primary purpose of the Bayley Scales isto identify children who may be at risk from developmental delay; it was not the primary purposeto use the results of the Bayley Scales to predict IQ at a later age. Even though some recentstudies on preterm <strong>in</strong>fants have shown some predictive ability of the Bayley Scales, the ability todo so is imperfect. 132,133 Comorbidities (e.g., neurological impairment, extremely low birthweight, other neonatal illnesses), early <strong>in</strong>tervention, environmental, <strong>and</strong> socioeconomic factorsare some of the additional important variables that could affect the prediction of future cognitivefunction.Published Systematic Review/Meta-Analysis (Please Refer To Table 8In Part I)Studies Identified after the Published Systematic Review/Meta-Analysis (Table 25)S<strong>in</strong>ce 2002, five prospective cohort studies, 134-139 two nested case control studies, 140,141 <strong>and</strong>one secondary data analysis of a previous r<strong>and</strong>omized controlled trial on supplementalarachidonic <strong>and</strong> docosahexaenoic acid 142 reported on the relationship between breast milkfeed<strong>in</strong>g <strong>and</strong> some aspects of cognitive development <strong>in</strong> preterm <strong>in</strong>fants. Sample size of the studiesranged from 39 to 1,035. Five of the studies were of moderate methodological quality, 135,137,140-142 <strong>and</strong> three studies were of poor methodological quality. 134,136,138,139 Each study was gradedwith<strong>in</strong> its own study design stratum <strong>and</strong> only with respect to the data on the relationship of breastmilk feed<strong>in</strong>g <strong>and</strong> cognitive development.Gestational age of the <strong>in</strong>fants ranged from 26 to 33 weeks. Except for one study thatspecifically enrolled children who had cerebral ultrasound abnormalities, <strong>in</strong>clud<strong>in</strong>g echodensity,echolucency, <strong>and</strong>/or ventriculomegaly, 140 the rest of the studies excluded <strong>in</strong>fants with severecongenital abnormalities. Some also excluded <strong>in</strong>fants with per<strong>in</strong>atal asphyxia <strong>and</strong> sensor<strong>in</strong>euralabnormalities.103
One study reported that half of the subjects had received breast milk exclusively. 137 Moststudies provided <strong>in</strong>formation on the amount of breast milk <strong>in</strong>take <strong>and</strong> whether the milk hadadded cow-milk based fortifiers or not while the subjects were <strong>in</strong> the neonatal wards, but the<strong>in</strong>formation on breast milk <strong>in</strong>take was less <strong>in</strong>formative after discharge to home. Three studiesreported the proportion of subjects who breastfed for more than 6 to 7 months; they were 20percent, 140 27 percent, 137 <strong>and</strong> 29 percent, 141 respectively.Bayley Mental Development Index Scale (MDI) was the cognitive assessment tool forsubjects up to 2 years of age. Wechsler Preschool <strong>and</strong> Primary Scale of Intelligence (WPPSI-R)was used <strong>in</strong> subjects under 7 years of age. Weschler Intelligence Scale for Children (WISC-R)was used <strong>in</strong> 7 years <strong>and</strong> 11 years old. Kaufman Assessment Battery for children (test for overall<strong>in</strong>tellectual function) <strong>and</strong> Peabody Picture Vocabulary Test (PPVT-R) were adm<strong>in</strong>istered to 6 to8 year old children <strong>in</strong> one study. 140Prospective cohort. Elgen 2003 prospectively studied 130 low birth weight children at 5years <strong>and</strong> 11 years of age us<strong>in</strong>g the Wechsler Preschool <strong>and</strong> Primary Scale of Intelligence(WPPSI-R) <strong>and</strong> the Weschler Intelligence Scale for Children (WISC-R), respectively. 135 Twentysevenpercent of them received less than 30 percent breast milk <strong>in</strong> the neonatal ward. Afteradjustment for parental confound<strong>in</strong>g (paternal <strong>and</strong> maternal education), breast milk was nolonger a statistically significant predictor of IQ.P<strong>in</strong>elli 2003 prospectively studied 128 <strong>in</strong>fants with birth weight 75 percent of nutrition as breast milk) <strong>and</strong> <strong>in</strong>termediate (25-75 percent) or m<strong>in</strong>imal feed<strong>in</strong>ggroups (< 25 percent) (94.2±8.8 vs. 91.7±7.2 vs. 90.5±8.5, respectively). 134,136 <strong>Maternal</strong>education or SES were not adjusted for <strong>in</strong> these results.In a cohort study of subjects from a convenience sample (29 <strong>in</strong> breast milk group; 10 <strong>in</strong>formula group), a regression analysis showed an association between the amount of milk <strong>in</strong>fantsreceived <strong>in</strong> the special care nursery <strong>and</strong> the Bayley MDI at 7 months (r=0.4, R 2 =0.1, P < 0.05)<strong>and</strong> 12 months (r= 0.4, R 2 =0.2, P < 0.025). 139In a prospective study of 775 preterm <strong>in</strong>fants who were fed breast milk <strong>and</strong> 260 preterm<strong>in</strong>fants who were not fed breast milk, the adjusted Bayley MDI at 18 to 22 months of age was79.9 ± 18 (SD) <strong>in</strong> the breast milk group versus 75.8 ± 16 (SD) <strong>in</strong> the no breast milk group (P =0.07). 138 The result was adjusted for maternal (education, age, marital status) <strong>and</strong> per<strong>in</strong>atal (sex,gestational age, oxygen need, birth weight, <strong>and</strong> illnesses) factors. Mothers <strong>in</strong> the breast milkgroup were more likely to have private health <strong>in</strong>surance, be white <strong>and</strong> married, <strong>and</strong> have acollege degree. Mothers who had low household <strong>in</strong>come, higher parity, or were black were lesslikely to provide breast milk feeds. It was unclear if the results were actually adjusted forhousehold <strong>in</strong>come or not. Further analysis of breast milk <strong>in</strong>take by qu<strong>in</strong>tile relative to the no104
east milk group showed that there was a 13.1 po<strong>in</strong>t difference <strong>in</strong> MDI between ≤ 20 th qu<strong>in</strong>tile<strong>and</strong> >80 th qu<strong>in</strong>tile (P
106Table 25. Summary of primary studies on the relationship of breast milk feed<strong>in</strong>g <strong>and</strong> cognitive development <strong>in</strong> preterm <strong>in</strong>fantsAuthor YearStudy Breast milkConfoundersCountryAssessment tools<strong>Outcomes</strong>Description feed<strong>in</strong>g exposureadjusted forPopulationProspective cohortElgen 2003Norway130Low birthweight(
107Table 25. Cont<strong>in</strong>uedAuthor YearCountry Study DescriptionPopulationVohr 2006US1,035Preterm withmeangestation of26.5 wk <strong>and</strong>birth weightof ~790 gEnrolledprospectively <strong>in</strong> theGlutam<strong>in</strong>e Trial at15 sites ofNeonatal ResearchNetwork; survivorswho receivedsome breast milk<strong>and</strong> had cognitivetest<strong>in</strong>gBreast milkfeed<strong>in</strong>gexposureBreast milkgroup– receivedsome breast milkdur<strong>in</strong>ghospitalization;total volumereceivedcalculated perday, values were<strong>in</strong>terpolated fordays of the week<strong>in</strong> which the datawere not collectedAssessment toolsBayley MentalDevelopment Index(MDI) at 18 to 22mos corrected ageConfoundersadjusted formarital status,maternal education,age, race/ethnicity,<strong>in</strong>fant’s gestationalage, gender,culture positivesepsis, grade 3 to 4<strong>in</strong>traventricularhemorrhage,oxygen at 36 wksgestational age,necrotiz<strong>in</strong>genterocolitis, <strong>and</strong>weight
108Table 25. Cont<strong>in</strong>uedAuthor YearCountry Study DescriptionPopulationEidelman,2004Feldman,2003Israel86gestationalage 30.5 wk(26-33 wk)Bier 2002US3928.6 wkgestation(range 23-34wk); 29 <strong>in</strong>breast milkgroup; 10 <strong>in</strong>formulagroup3 groups stratifiedby amount ofbreast milkfeed<strong>in</strong>g; cognitiveassessment at 6mo corrected age;excluded <strong>in</strong>fantswith IVH grade 3 or4, per<strong>in</strong>atalasphyxia,metabolic, geneticdiseaseconveniencesample; excluded<strong>in</strong>fants withmothers who usedillicit drugs, hadmental illness, HIV<strong>in</strong>fection, <strong>and</strong>others;Breast milkfeed<strong>in</strong>gexposure3 groups: >75% ofnutrition as breastmilk; 25-75%; <strong>and</strong>
109Table 25. Cont<strong>in</strong>uedAuthor YearCountry Study DescriptionPopulationNested case-controlSmith, 2003US119 withultrasoundabnormalities;320frequencymatched (1:4)were<strong>in</strong>cluded;gestationalage 27.4 wkBirth subjects fromDevelopmentalEpidemiologyNetwork (n=1442);439 subjects whohad undergoneneuropsychologicaltest<strong>in</strong>g <strong>and</strong> forwhom parentalquestionnaireswere completed by9/2002 were<strong>in</strong>cluded <strong>in</strong> thisstudyBreast milkfeed<strong>in</strong>gexposure153 did notreceive breastmilk; 142 receivedexpressed milkwithoutprogress<strong>in</strong>g todirectbreastfeed<strong>in</strong>g;125 receiveddirectbreastfeed<strong>in</strong>g (themajority of themfirst receivedexpressed breastmilk); 20% of<strong>in</strong>fants receivedbreast milk > 6mo.Assessment toolsKaufman; PeabodyPicture VocabularyTest <strong>and</strong> Cl<strong>in</strong>icalEvaluation ofLanguageFundamentals;CaliforniaChildren’s VerbalLearn<strong>in</strong>g Test; atage 6-8 yrConfoundersadjusted for<strong>Maternal</strong> verbalability, HomeObservation forMeasurement ofthe EnvironmentInventory, SES,duration ofhospitalization<strong>Outcomes</strong>Outcome measures were st<strong>and</strong>ardized with a mean of100 po<strong>in</strong>ts <strong>and</strong> st<strong>and</strong>ard deviation of 15 po<strong>in</strong>ts.Breast milk feed<strong>in</strong>gs were associated with higherunadjusted test scores for each doma<strong>in</strong> of cognitivefunction except memory.In the regression model that <strong>in</strong>cluded social advantage<strong>and</strong> neonatal morbidity, the adjusted score <strong>in</strong> overall<strong>in</strong>tellectual function associated with directbreastfeed<strong>in</strong>g was reduced to 3.6 po<strong>in</strong>ts (95% CI, -0.3to 7.5).Quality <strong>and</strong>limitationsB27% ofsubjects withultrasoundabnormalities;the tim<strong>in</strong>g ofcollection ofbreastfeed<strong>in</strong>gdata was notreportedHorwood,2001New Zeal<strong>and</strong>280Very low birthweightsurvivors of anational birthcohortretrospective recallof breast milkfeed<strong>in</strong>g <strong>and</strong>duration of feed<strong>in</strong>g;assessed at 7 yr;excludedsensor<strong>in</strong>euraldisability <strong>and</strong><strong>in</strong>completebreastfeed<strong>in</strong>g dataBreastfed < 4 mo(n=99) (49%)4-7 mo (n=46)(22%)≥ 8 mo (n=59)(29%)Not breastfed(n=76)WISC-R at 7 yrPer<strong>in</strong>atal, sociodemographic(family <strong>in</strong>come,s<strong>in</strong>gle/two parentfamily, childethnicity), <strong>and</strong>maternal factors(age, education,smok<strong>in</strong>g);Children who were breastfed ≥ 8 mo had mean verbalIQ 10.2 (SD 0.56) higher <strong>and</strong> mean performance IQ6.2 (SD 0.35) higher than children who did not receivebreast milk.After adjustment for covariates, there rema<strong>in</strong>ed asignificant association between duration of receipt ofbreast milk <strong>and</strong> verbal IQ, with a 6 po<strong>in</strong>t advantage for<strong>in</strong>fants who received breast milk for ≥ 8 mo comparedwith no breastfeed<strong>in</strong>g (P
110Table 25. Cont<strong>in</strong>uedAuthorStudyYearDescriptionCountryBreast milkfeed<strong>in</strong>g exposureAssessment toolsConfoundersadjusted forSecondary data analysis of a previous RCT on supplemental arachidonic <strong>and</strong> docosahexaenoic acidO‘Connor,2003Chile, US,UKBayley at 12 mo <strong>Maternal</strong> <strong>in</strong>telligence<strong>and</strong> homeenvironment463
Part III. <strong>Maternal</strong> <strong>Outcomes</strong>Relationship between Return to Pre-Pregnancy Weight orPostpartum Weight Change <strong>and</strong> <strong>Breastfeed<strong>in</strong>g</strong>BackgroundReturn to pre-pregnancy weight is desirable s<strong>in</strong>ce postpartum weight retention is a possiblerisk factor for obesity <strong>and</strong> its ensu<strong>in</strong>g medical complications. 143 The change <strong>in</strong> weight resultsfrom changes <strong>in</strong> energy metabolism dur<strong>in</strong>g pregnancy <strong>and</strong> lactation. This is mediated through thecomplex neuroendocr<strong>in</strong>e <strong>and</strong> biochemical stimuli that follow from conception.Despite the fact that the average weight retention associated with child bear<strong>in</strong>g is modest,estimated at approximately 1.51 kg (s.d.=5.95 kg) 144-146 for some, there is some risk of majorweight ga<strong>in</strong> with pregnancy. Ohl<strong>in</strong> <strong>and</strong> Rossner 1990 reported changes <strong>in</strong> body weight thatranged from –12.3 to +26.5 kg from preconception to 1 year postpartum. 144 In various studies,the proportion of women reta<strong>in</strong><strong>in</strong>g 5 kg or more after 6 months postpartum ranged from 14 to20%. 146-148 Studies of the impact of physiological <strong>and</strong> behavioral <strong>in</strong>fluences, such as dietary<strong>in</strong>take, physical activity, <strong>and</strong> lactation on postpartum weight change reported mixed results.Studies of postpartum weight changes <strong>in</strong> lactat<strong>in</strong>g <strong>and</strong> non-lactat<strong>in</strong>g women also were equivocalwith<strong>in</strong> <strong>and</strong> across populations, with some show<strong>in</strong>g that the length <strong>and</strong> <strong>in</strong>tensity of breastfeed<strong>in</strong>gwere associated with less weight retention after pregnancy, while other studies reported thatwomen who fed their <strong>in</strong>fants formula lost more weight than women who nursed their <strong>in</strong>fants.Commonly considered confounders <strong>in</strong> the relationship between return to pre-pregnancyweight or post-partum weight change <strong>and</strong> breastfeed<strong>in</strong>g were pre-pregnancy weight or BMI, age,educational level, physical activity, parity, smok<strong>in</strong>g status, diet<strong>in</strong>g practice, <strong>and</strong> ethnicity.Additional Methodological CommentsTo assess the relationship between breastfeed<strong>in</strong>g <strong>and</strong> return to pre-pregnancy weight <strong>and</strong>postpartum weight/BMI changes, we relied on Fraser 2003, 149 the only published systematicreview of the effect of lactation on maternal body weight. S<strong>in</strong>ce Fraser 2003 did not provide anydescriptive or summary tables for further analysis, we contacted the authors to obta<strong>in</strong> copies oftheir evidence tables. However, the tables made available lacked the appropriate data foradditional clarification of the authors’ conclusions. Therefore, we decided to perform a primaryanalysis of all the studies cited <strong>in</strong> Fraser 2003. We also screened the references <strong>in</strong> the primarystudies to identify additional studies for <strong>in</strong>clusion <strong>in</strong> our systematic review. In addition, we alsoevaluated primary studies that were published after Fraser 2003 <strong>and</strong> from suggestions by thereviewers of this report. These primary studies had been identified by our general literaturesearch on the <strong>in</strong>tervention of breastfeed<strong>in</strong>g (see Methods chapter). We did not perform a searchon maternal weight change by itself without any reference to breastfeed<strong>in</strong>g.Because of the known methodological problems <strong>in</strong> the studies of the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> maternal weight, 15,150,151 we adopted the follow<strong>in</strong>g <strong>in</strong>clusion criteria for ourreview: prospective cohort studies conducted <strong>in</strong> developed countries which directly compared111
weight changes of nonlactat<strong>in</strong>g women with that of lactat<strong>in</strong>g women <strong>and</strong> for whom theexclusivity or the amount of breastfeed<strong>in</strong>g was clear. The sample size criterion was at least 50women per feed<strong>in</strong>g group <strong>in</strong> the f<strong>in</strong>al analyses (e.g., lactat<strong>in</strong>g versus nonlactat<strong>in</strong>g).For studies of the relationship between postpartum weight change <strong>and</strong> breastfeed<strong>in</strong>g, studiesneed to control for subjects’ gestational weight ga<strong>in</strong> or pre-pregnancy weight <strong>and</strong> have at least 3-months postpartum followup to be <strong>in</strong>cluded.Results (Tables 26-27)A total of 54 potentially relevant articles were retrieved for full-text screen<strong>in</strong>g. Forty-fivearticles were excluded because they were cross-sectional design, non-comparative studies,review articles, sample size less than 50 subjects per group, or had unclear breastfeed<strong>in</strong>g data(exclusivity or amount of breastfeed<strong>in</strong>g not clearly reported).We <strong>in</strong>cluded a total of three prospective cohort studies that exam<strong>in</strong>ed the relationshipbetween exclusive or full breastfeed<strong>in</strong>g <strong>and</strong> return to pre-pregnancy weight 145,152,153 <strong>and</strong> fiveprospective cohort studies (<strong>in</strong> six publications) that exam<strong>in</strong>ed postpartum weight changes <strong>in</strong>relation to exclusive breastfeed<strong>in</strong>g. 144,154-157 One study, L<strong>in</strong>ne 2003, was a 15-year followup ofthe two earlier Ohl<strong>in</strong> <strong>and</strong> Rossner studies of 1990 <strong>and</strong> 1996.The report<strong>in</strong>g of breastfeed<strong>in</strong>g data varied across studies. Some studies reported explicit <strong>and</strong>quantifiable amount of breastfeed<strong>in</strong>g (e.g., provid<strong>in</strong>g at least two-thirds of the needed energy<strong>in</strong>take per kilogram of the <strong>in</strong>fant’s weight <strong>in</strong> breast milk, or <strong>in</strong>fants received 120 mL/day or lessof other milk until at least 1 year of age), while others did not quantify the amount ofbreastfeed<strong>in</strong>g the <strong>in</strong>fants received.Relationship between breastfeed<strong>in</strong>g <strong>and</strong> return to pre-pregnancy weight (Table 26)A total of three prospective cohort studies were identified, <strong>in</strong>volv<strong>in</strong>g 4,318, 540, <strong>and</strong> 95women, with follow up durations of 3 years, 1 year <strong>and</strong> 1.5 years postpartum, respectively. Allstudies were conducted <strong>in</strong> the United States. All studies enrolled nulliparous <strong>and</strong> primiparouswomen between 24 <strong>and</strong> 40 years of age with normal <strong>and</strong> above normal pre-pregnancy weights,<strong>and</strong> all three studies were rated methodological quality grade B.Overall effect of breastfeed<strong>in</strong>g on return to pre-pregnancy weight or weight retention wasnegligible. The average weight retention was only with<strong>in</strong> 1 kg range at 1 to 2 years postpartum.The large study of 4,318 nulliparous <strong>and</strong> primiparous women reported that, compared withwomen who did not breastfeed, exclusive breastfeed<strong>in</strong>g was associated with a weight ga<strong>in</strong> ofapproximately 1 kg from pre-pregnancy to 1 to 2 years postpartum, adjust<strong>in</strong>g for age, physicalactivity <strong>and</strong> pre-pregnancy BMI. 152 This f<strong>in</strong>d<strong>in</strong>g is only statistically significant for nulliparouswomen who had normal pre-pregnancy weight (BMI < 25) <strong>and</strong> for those primiparous womenwho were overweight at basel<strong>in</strong>e (BMI ≥ 25). However, the duration of exclusive breastfeed<strong>in</strong>gwas not related to the magnitude of weight change from pre-pregnancy to 1 to 2 year postpartum.The study of 540 parous women reported that breastfeed<strong>in</strong>g at 1 year was significantly associatedwith less weight retention from first trimester to 1 year postpartum (P = 0.04). The study of 95nulliparous <strong>and</strong> primiparous women found that less weight was reta<strong>in</strong>ed by lactat<strong>in</strong>g women thanby non-lactat<strong>in</strong>g women, <strong>and</strong> this was statistically significant. 153 Exclusive breastfeed<strong>in</strong>g wasassociated with approximately 1 kg weight loss from pre-pregnancy to 1 year postpartum. Bottlefeed<strong>in</strong>gwas associated with a weight retention of 2 kg dur<strong>in</strong>g the same time period. Oncelactation was discont<strong>in</strong>ued, slower rates of weight loss were observed. Exclusively breastfeed<strong>in</strong>g112
women achieved their pre-pregnancy weights about 6 months earlier than women whoexclusively bottle-fed their <strong>in</strong>fants.Relationship between breastfeed<strong>in</strong>g <strong>and</strong> postpartum weight changes (Table 27)Five prospective cohort studies <strong>in</strong>volv<strong>in</strong>g a total of 2,097 parous women were identified.Followup durations ranged from 6 months to 15 years. Two studies were conducted <strong>in</strong> Sweden,two <strong>in</strong> the United States, <strong>and</strong> one <strong>in</strong> Canada. This group of studies measured the post-deliveryweight changes <strong>in</strong> women. Half of the studies did not report women’s pre-pregnancy weights.All studies attempted to control for various confound<strong>in</strong>g factors that could <strong>in</strong>fluence therelationship between breastfeed<strong>in</strong>g <strong>and</strong> postpartum weight changes. Five studies were ofmoderate methodological quality (Grade B), <strong>and</strong> one of poor methodological quality (Grade C).The results from the five studies were <strong>in</strong>consistent. Among the studies utilized a lactationscore to express duration <strong>and</strong> <strong>in</strong>tensity or exclusivity of breastfeed<strong>in</strong>g, amount of breastfeed<strong>in</strong>gwas negatively associated with the postpartum weight change. 144,157 Among the three studies thatexam<strong>in</strong>ed postpartum weight changes <strong>and</strong> compared women who exclusively breastfed withwomen who partially breastfed or exclusively bottle-fed, none of them found a significantrelationship between weight loss <strong>and</strong> breastfeed<strong>in</strong>g among the comparison groups. 155,156,158ConclusionBased on the results from three prospective cohort studies, we concluded that the overalleffect of breastfeed<strong>in</strong>g on return-to-pre-pregnancy weight (weight change from pre-pregnancy orfirst trimester to 1 to 2 year postpartum) was negligible (less than 1 kg). Results from fourprospective cohort studies showed that the effects of breastfeed<strong>in</strong>g on postpartum weight losswere unclear. All seven studies consistently suggested that many other factors have larger effectson weight retention or postpartum weight loss than breastfeed<strong>in</strong>g. Examples of which <strong>in</strong>cludedannual household <strong>in</strong>come, basel<strong>in</strong>e BMI, ethnicity, gestational weight ga<strong>in</strong>, <strong>and</strong> energy <strong>in</strong>take.Undoubtedly, all these factors need to be carefully considered <strong>in</strong> any future <strong>in</strong>vestigation of therelationship between breastfeed<strong>in</strong>g <strong>and</strong> postpartum weight changes.113
114Table 26. Summary of prospective cohort studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> return<strong>in</strong>g to pre-pregnancy weightsAuthor YearCountry(N basel<strong>in</strong>e/followup)Sichieri 2003USNulliparous:1,538/1,538;Primiparous:2,810/2,810Olson, 2003US597/540Studyfollowupperiod(s)3 yr1 yrpostpartum<strong>Breastfeed<strong>in</strong>g</strong>exposureExclusive breastfeed<strong>in</strong>g:<strong>in</strong>troduction of dailyformula/milk wasassumed to represent theend of exclusivebreastfeed<strong>in</strong>g period aComparativefeed<strong>in</strong>ggroupsNeverbreastfeed<strong>in</strong>gPrepregnancyweight (kg) /BMI (kg/m 2 )62 / 82% 26Confounders adjustedforAge, physical activity, BMI,gestational weight ga<strong>in</strong>Age, educational level,smok<strong>in</strong>g status at 1 yrpost-partum, annualhousehold <strong>in</strong>come level,pre-pregnancy BMIcategory, <strong>and</strong> parity,gestational weight ga<strong>in</strong>ResultsAfter adjust<strong>in</strong>g for confounders, lactation wasassociated with a weight ga<strong>in</strong> fromprepregnancy to 1-2 yr postpartum ofapproximately 1 kg (statistically significantonly for women nulliparous with a basel<strong>in</strong>eBMI 0.40).Effect of breastfeed<strong>in</strong>g on maternal weight isnegligible.Women who were breastfeed<strong>in</strong>g at 1 yrreta<strong>in</strong>ed c less weight compared with thewomen who weren’t (P = 0.04).<strong>Breastfeed<strong>in</strong>g</strong> at all other time po<strong>in</strong>ts <strong>and</strong> thebreastfeed<strong>in</strong>g score were not significantlyrelated to postpartum weight retention.Women at < 185% federal poverty <strong>in</strong>dex ratio(PIR) who ga<strong>in</strong>ed more <strong>in</strong> pregnancy thanInstitute of Medic<strong>in</strong>e (IOM) recommendationswere 3.73 kg heavier that low <strong>in</strong>come womenwho ga<strong>in</strong>ed below or with<strong>in</strong> the IOMguidel<strong>in</strong>es for gestational weight ga<strong>in</strong>(P
115Table 26. cont<strong>in</strong>uedAuthor YearCountry(N basel<strong>in</strong>e/followup)Janney 1997US110/95Studyfollowupperiod(s)0.5, 2, 4, 6, 12,<strong>and</strong> 18 mopostpartum<strong>Breastfeed<strong>in</strong>g</strong>exposureFullybreastfeed<strong>in</strong>g wasdef<strong>in</strong>ed asprovid<strong>in</strong>g at least2/3 of the neededenergy <strong>in</strong>take perkilogram of the<strong>in</strong>fant’s weight <strong>in</strong>breast milkComparativefeed<strong>in</strong>g groupsPartialbreastfeed<strong>in</strong>g; fullbottle feed<strong>in</strong>gPrepregnancyweight (kg) /BMI (kg/m2)59.7 / 22.2BMI, Body Mass Index; IOM, Institute of Medic<strong>in</strong>e; ND, not documented; PIR, poverty <strong>in</strong>dex ratioConfoundersadjusted forWeight ga<strong>in</strong>eddur<strong>in</strong>g pregnancy,amount ofeducation, parity,type of delivery,season of delivery,marital status, age,smok<strong>in</strong>g statusbefore <strong>and</strong> dur<strong>in</strong>gpregnancy,physical activityResultsDuration of lactation practice was a significantpredictor of postpartum weight retention overtime (P
116Table 27. Summary of prospective cohort studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> postpartum weight/BMI changesAuthor YearPrepregnancyConfoundersStudy Breastfeed ComparativeCountryfollowup <strong>in</strong>g feed<strong>in</strong>gResults(N basel<strong>in</strong>eweight (kg) / adjusted forperiod(s) exposure groups/followup)BMI (kg/m 2 )Ohl<strong>in</strong> 1990;Ohl<strong>in</strong> 1996Sweden2295/1423Stockholm Pregnancy<strong>and</strong> Women’sNutrition Study(SPAWN)L<strong>in</strong>ne 2003Stockholm1423/563 e(SPAWN)1 yrpostpartum15 yrLactation score (scale 0-48):Every month with full lactationwas given 4 po<strong>in</strong>ts, <strong>and</strong> everymonth with mixed feed<strong>in</strong>g wasgiven 2 po<strong>in</strong>ts.Ohl<strong>in</strong>’s lactation score (scale 0-48)59.6 / 21.5Weight ga<strong>in</strong>dur<strong>in</strong>g pregnancy,lactation score,age, prepregnancyBMI,parity, weightretention afterpreviouspregnancy,diet<strong>in</strong>g,profession,smok<strong>in</strong>g habits,contraceptivepractices, physicalactivity.59.8 / 21.5 As aboveOverall, relationship between the ∆ weight <strong>and</strong> lactationscore is statistically significant though weak (r=-0.09,p20than < 20. However, the total weight loss between 2.5<strong>and</strong> 12 months postpartum did not differ significantlybetween groups.30% lost weight, 56% ga<strong>in</strong> 0-5 kg, 13% ga<strong>in</strong>ed 5-10 kg <strong>and</strong>1.5% ga<strong>in</strong>ed >=10 kg 1 year after delivery. Frequency ofoverweight women (BMI>=23.9) <strong>in</strong>creased from 13%before pregnancy to 21% 1 year post-partum (p
117Table 27. cont<strong>in</strong>uedAuthor YearCountry(N basel<strong>in</strong>e/followup)Walker 2004USND/382Haiek 2001Canada242/236Studyfollowupperiod(s)6 wk, <strong>and</strong> 3, 6,<strong>and</strong> 12 mopostpartum6 wk, 3-5, 6-8mo, <strong>and</strong> 9 mopostpartum<strong>Breastfeed<strong>in</strong>g</strong>exposureFull (exclusive)breastfeed<strong>in</strong>gPredom<strong>in</strong>antlybreastfeed<strong>in</strong>g (i.e.,exclusivebreastfeed<strong>in</strong>g oraverage daily<strong>in</strong>take of formulaof 4 oz or less)Comparativefeed<strong>in</strong>g groupsPartialbreastfeed<strong>in</strong>g; fullbottle feed<strong>in</strong>gMixed-feed<strong>in</strong>g(i.e., average daily<strong>in</strong>take of formula<strong>and</strong> breast milk of> 4 oz);predom<strong>in</strong>antlybottle-feed<strong>in</strong>g (i.e.,exclusive bottlefeed<strong>in</strong>goraverage daily<strong>in</strong>take of breastmilk of 4 oz orless)Prepregnancyweight (kg) /BMI (kg/m 2 )ND22.5Confounders adjustedforEthnicity, maternal education,parity, smok<strong>in</strong>g, physicalactivity, time of weightmeasurement, <strong>in</strong>teraction ofethnicity <strong>and</strong> time, prepregnantBMI, gestationalweight ga<strong>in</strong>, energy <strong>in</strong>takes,fat <strong>in</strong>take, contraception,emotional eat<strong>in</strong>g, depressivesymptomsGestational weight ga<strong>in</strong>,postpartum smok<strong>in</strong>g, <strong>in</strong>fant’ssolid <strong>in</strong>take, maternal placeof birth<strong>Outcomes</strong><strong>Infant</strong> feed<strong>in</strong>g method was not associatedwith postpartum BMI (p=0.140) aEthnicity is associated with BMI (P=0.001).In addition, BMI for the ethnic groups isparallel until 3 months postpartum whenthe African American <strong>and</strong> Hispanic groupsbeg<strong>in</strong> <strong>in</strong>creas<strong>in</strong>g <strong>in</strong> BMI while the Whitegroup beg<strong>in</strong>s decreas<strong>in</strong>g. At 6 months,the White group cont<strong>in</strong>ues to decrease,the African American group cont<strong>in</strong>ues to<strong>in</strong>crease <strong>and</strong> the Hispanic groups beg<strong>in</strong>sto decrease.The unadjusted monthly rate of weightchange was similar among the threefeed<strong>in</strong>g groups for all time periods. Fornone of the time periods was the rate ofweight loss greater <strong>in</strong> the predom<strong>in</strong>antlybreastfeed<strong>in</strong>g group.In the multivariate regression model, neithermixed-feed<strong>in</strong>g nor predom<strong>in</strong>ant bottlefeed<strong>in</strong>gwas significantly associated withpostpartum weight change (breast-feed<strong>in</strong>ggroup was the reference).Quality <strong>and</strong>limitationsBB
118Table 27. cont<strong>in</strong>uedAuthor YearCountry(N basel<strong>in</strong>e/followup)Brewer 1989US70/56BMI, body mass <strong>in</strong>dex.Studyfollowupperiod(s)3 <strong>and</strong> 6 mopostpartum<strong>Breastfeed<strong>in</strong>g</strong>exposureExclusivebreastfeed<strong>in</strong>gComparativefeed<strong>in</strong>g groupsExclusive formulafeed<strong>in</strong>g; mixedbreast <strong>and</strong>formula feed<strong>in</strong>gPrepregnancyweight (kg) /BMI (kg/m 2 )NDConfounders adjustedforAge, parity, pre-pregnancyweight, socioeconomic data,energy <strong>in</strong>take, energyexpenditure exclusive oflactation (physical activity)<strong>Outcomes</strong>Weight loss averaged 1.6, 2.1, <strong>and</strong> 1.5 kg/mofor exclusive breastfeed, exclusiveformula feed, <strong>and</strong> mixed feed, respectivelydur<strong>in</strong>g the first 3 mo corrected for an <strong>in</strong>itialfluid loss of 2 kg. Exclusive breastfeedresulted <strong>in</strong> an additional 0.43 kg/mo lossover the second 3 mo (P
Relationship between <strong>Maternal</strong> Type 2 Diabetes <strong>and</strong><strong>Breastfeed<strong>in</strong>g</strong>BackgroundStudies have shown that lactation has a beneficial effect on glucose <strong>and</strong> lipid metabolism;<strong>and</strong> improved pancreatic beta-cell function <strong>in</strong> women with gestational diabetes. 159,160 Thus, it isplausible that lactation could reduce the risk of the development of type 2 diabetes.Commonly considered confounders <strong>in</strong> the studies of relationship between maternal type 2diabetes <strong>and</strong> breastfeed<strong>in</strong>g were parity, body mass <strong>in</strong>dex (BMI), diet, physical activity, familyhistory of diabetes, <strong>and</strong> smok<strong>in</strong>g status.Published Systematic Review/Meta-Analysis (Table 28)One systematic review exam<strong>in</strong>ed the effect of breastfeed<strong>in</strong>g on maternal risk of subsequentdiabetes. 98 The authors identified three studies that evaluated the effects of breastfeed<strong>in</strong>g onglucose tolerance <strong>and</strong> <strong>in</strong>sul<strong>in</strong> levels; one study that evaluated the risk factors for recurrentgestational diabetes (GDM); <strong>and</strong> one study that exam<strong>in</strong>ed the relationship between lactation <strong>and</strong>the risk of develop<strong>in</strong>g type 2 diabetes <strong>in</strong> women who had GDM. For this report, we focused onlyon the one study that exam<strong>in</strong>ed the relationship between breastfeed<strong>in</strong>g <strong>and</strong> the risk of develop<strong>in</strong>gtype 2 diabetes <strong>in</strong> women with GDM.Kjos 1998 conducted a retrospective cohort study of 904 Hispanic American women withGDM. 161 Kjos 1998 found that the use of progest<strong>in</strong>-only oral contraceptives was associated withan almost three-fold risk of develop<strong>in</strong>g type 2 diabetes compared with the use of comb<strong>in</strong>ationestrogen-progest<strong>in</strong> oral contraceptives for breastfeed<strong>in</strong>g Lat<strong>in</strong>a women with recent GDM. S<strong>in</strong>ceprogest<strong>in</strong>-only oral contraceptive use was <strong>in</strong>variably associated with breastfeed<strong>in</strong>g <strong>in</strong> this cohort,the authors then looked for an <strong>in</strong>dependent effect of breastfeed<strong>in</strong>g on the risk of develop<strong>in</strong>gdiabetes among women who <strong>in</strong>itially elected nonhormonal forms of contraception <strong>and</strong> who werebreastfeed<strong>in</strong>g at the time of their <strong>in</strong>itial postpartum exam<strong>in</strong>ation. The results showed that the riskof develop<strong>in</strong>g diabetes <strong>in</strong> these women was not significantly different from the risk <strong>in</strong> womenwho elected nonhormonal contraception but did not breastfeed (unadjusted RR 0.90, 95%CI 0.56- 1.46; adjusted RR 1.16, 95%CI 0.70 - 1.92). The authors of the systematic review did notassess the quality of this study.The authors of the systematic review concluded that although no study has ever reported an<strong>in</strong>creased risk of develop<strong>in</strong>g diabetes from breastfeed<strong>in</strong>g, a s<strong>in</strong>gle study did show a potentialharm from the use of progest<strong>in</strong>-only oral contraceptive among breastfeed<strong>in</strong>g Lat<strong>in</strong>o women withrecent GDM.Studies Identified after the Published Systematic Review/Meta-Analysis (Table 29)One prospective, longitud<strong>in</strong>al cohort study on the association between the duration oflactation <strong>and</strong> the <strong>in</strong>cidence of type 2 diabetes was identified. 162 The study consisted of two largecohorts <strong>in</strong> the United States, <strong>in</strong>clud<strong>in</strong>g participants from the Nurses’ <strong>Health</strong> Study (NHS) <strong>and</strong>Nurses’ <strong>Health</strong> Study II (NHS II). The Nurses’ <strong>Health</strong> Study (NHS) was <strong>in</strong>itiated <strong>in</strong> 1976 <strong>and</strong>119
enrolled 121,700 women from 11 states. Participants were between 30 <strong>and</strong> 55 years of age atbasel<strong>in</strong>e, <strong>and</strong> each woman completed a detailed basel<strong>in</strong>e questionnaire regard<strong>in</strong>g diseases <strong>and</strong>health related topics. The Nurses’ <strong>Health</strong> Study II (NHS II), begun <strong>in</strong> 1989, enrolled 116,671women from 14 states. Participants were between 25 <strong>and</strong> 42 years of age <strong>and</strong> completed a similarbasel<strong>in</strong>e questionnaire as well as biennial followup questionnaires. This study was graded as highmethodological quality (grade A).The assessments of lactation history <strong>and</strong> type 2 diabetes were performed longitud<strong>in</strong>ally.Women <strong>in</strong> the NHS II were also asked to report the diagnosis of GDM on each biennialquestionnaire. Cox proportional hazards model was used to calculate the hazard ratio (HR) fortype 2 diabetes by lactation history. All models were age-adjusted. Potential confounders<strong>in</strong>clud<strong>in</strong>g parity, BMI at age 18 years, diet, physical activity, family history of diabetes, <strong>and</strong>smok<strong>in</strong>g status were <strong>in</strong>cluded <strong>in</strong> the multivariate model a priori. Lifetime lactation history amongparous women was stratified <strong>in</strong>to six groups: none (reference group), 0 to 3 months, more than 3to 6 months, more than 6 to 11 months, more than 11 to 23 months, <strong>and</strong> more than 23 months.Lifetime duration was updated every 2 years. L<strong>in</strong>ear trend was assessed us<strong>in</strong>g midpo<strong>in</strong>ts oflactation categories. In the analysis of HR per year of lactation, the midpo<strong>in</strong>ts of report<strong>in</strong>gcategories to calculate total lifetime lactation were used because this was the closestapproximation of the orig<strong>in</strong>al reported duration.In the NHS, women who had ever breastfed had a covariate-adjusted HR for type 2 diabetesof 0.97 (95%CI 0.91 - 1.02) compared with women who never breastfed. There was a modest butstatistically significant <strong>in</strong>verse association between duration of lactation <strong>and</strong> the risk of type 2diabetes. In the multivariate-adjusted model <strong>in</strong>clud<strong>in</strong>g current BMI, each additional year oflactation was associated with an HR of 0.96 (95%CI 0.92 - 0.99) for type 2 diabetes.Among women who had ever breastfed <strong>in</strong> the NHS II, the covariate-adjusted HR for type 2diabetes was 0.90 (95%CI 0.77 - 1.04). Each year of lactation was associated with a covariateadjustedHR of 0.84 (95%CI 0.78 - 0.89). When BMI was added to this model, the HR was 0.88(95%CI 0.82 - 0.94) for each additional year of lactation.Women with a history of GDM had a markedly <strong>in</strong>creased risk of type 2 diabetes <strong>in</strong> the NHSII cohort, with 624 cases per 100,000 person years compared with 118 cases per 100,000 personyearsamong those without such a history. Lactation had no effect on diabetes risk <strong>in</strong> the GDMgroup, with a covariate-adjusted HR of 0.96 (95% CI 0.84 - 1.09) per additional year of lactation.The effects of exclusive versus total breastfeed<strong>in</strong>g could be compared <strong>in</strong> the NHS II cohortdata. In models controll<strong>in</strong>g for age <strong>and</strong> parity, each year of lifetime exclusive breastfeed<strong>in</strong>g wasassociated with an HR for type 2 diabetes of 0.63 (95%CI 0.54 - 0.73), while each year of totalbreastfeed<strong>in</strong>g was associated with an HR of 0.76 (95%CI 0.71 - 0.81).ConclusionBased on the longitud<strong>in</strong>al study of two large cohorts <strong>in</strong> the United States with over 150,000parous women, we conclude that a longer duration of lifetime breastfeed<strong>in</strong>g is associated with areduced risk of develop<strong>in</strong>g type 2 diabetes among parous women who did not have a history ofGDM. There was a difference <strong>in</strong> the risk of develop<strong>in</strong>g type 2 diabetes between women with <strong>and</strong>without GDM <strong>in</strong> relation to lactation. Compared with women who did not have a history ofGDM, women with a history of GDM had a markedly <strong>in</strong>creased risk of type 2 diabetes; <strong>and</strong>lactation showed no significant relationship with diabetes risk among this group of women. One120
must be cautious <strong>in</strong> <strong>in</strong>terpret<strong>in</strong>g these f<strong>in</strong>d<strong>in</strong>gs, as they are only generalizable to population withcharacteristics similar to that of the Nurses’ <strong>Health</strong> cohort.121
122Table 28. Summary of systematic review/meta-analysis on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> maternal type 2 diabetesAuthor yearConfoundersPopulation Study description Intervention /ComparatorResultsconsideredTaylor 2005Kjos et al. (1998):A retrospective cohort study of904 Lat<strong>in</strong>as liv<strong>in</strong>g <strong>in</strong> US withGDM (based on NationalDiabetes Data Group Criteria)who gave birth betweenJanuary 1987 <strong>and</strong> March 1994,<strong>in</strong> whom postpartum diabeteswas excluded at 4 to 16 weekspost partum.SR of 1 retrospectivecohort study on theassociation betweenbreast milk feed<strong>in</strong>g(or lactation) <strong>and</strong>maternal type 2diabetesAt their basel<strong>in</strong>e postpartum visits,461 of the study subjects chose touse an oral contraceptive (OC)<strong>and</strong> 443 chose a nonhormonalmethod of contraception.Of those elect<strong>in</strong>g to use an OC, 78were given the progest<strong>in</strong>-only OCs<strong>in</strong>ce they were breast-feed<strong>in</strong>g attheir basel<strong>in</strong>e postpartum visits<strong>and</strong> planned to cont<strong>in</strong>ue breastfeed<strong>in</strong>g.S<strong>in</strong>ce progest<strong>in</strong>-only OC use was<strong>in</strong>variably associated with breastfeed<strong>in</strong>g<strong>in</strong> this cohort, the authorthen looked for an <strong>in</strong>dependenteffect of breast-feed<strong>in</strong>g on the riskof develop<strong>in</strong>g type 2 diabetesamong women who <strong>in</strong>itiallyelected nonhormonal forms ofcontraception (n=443).Gestational age atdiagnosis of GDM,highest fast<strong>in</strong>g glucoselevel dur<strong>in</strong>g the <strong>in</strong>dexpregnancy, <strong>and</strong> glucosearea under the curvefrom the diagnosticOGTTThe risk of develop<strong>in</strong>g type 2diabetes was not significantlydifferent betweenbreastfeed<strong>in</strong>g women <strong>and</strong>bottle feed<strong>in</strong>g women whochose non-hormonal forms ofcontraception (adjusted RR:1.16; 95%CI 0.70-1.92)Quality ofSR/MA <strong>and</strong>limitationsC aNo synthesis ofresults <strong>and</strong>unclear how theconclusionswere reachedGDM, gestational diabetes; RR, relative riska We did not grade the methodological quality for Kjos 1998 <strong>in</strong> the systematic review. Taylor 2005 review is also summarized <strong>in</strong> <strong>in</strong>fant outcome - type 2 DMsection.
123Table 29. Summary of studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> maternal type 2 diabetes (NIDDM)MeanAuthorBreast milk feed<strong>in</strong>gNumber of age atyear Study designDef<strong>in</strong>itions of type 2 diabetes duration (months),subjects followupCountryparous women only(year)Stuebe2005USProspective longitud<strong>in</strong>alcohorts (NHS <strong>and</strong> NHSII studies)NHS: prospectiveanalysis us<strong>in</strong>g casesfrom 1986 to 2002NHS II, retrospectiveanalysis us<strong>in</strong>g lactationdata from 1997 <strong>and</strong>2003, cases from 1989to 2001, parous womenonlyNurses’<strong>Health</strong> Study(NHS):121,700(83,585parouswomen)NHS II:116,671(73,418parouswomen)NHS:~52NHS II:~35(1) 1 or more classic symptoms (i.e.,excessive thirst, polyuria, weight loss,or hunger) plus either a fast<strong>in</strong>g glucoselevel of 140 mg/dL (7.8 mmol/L) ormore or r<strong>and</strong>om plasma glucose levelof 200 mg/dL (11.1 mmol/L) or more;(2) at least 2 <strong>in</strong>stances of elevatedplasma glucose concentration (fast<strong>in</strong>gglucose ≥140 mg/dL, r<strong>and</strong>om plasmaglucose ≥200 mg/dL, or oral glucosetolerance test ≥200 mg/dL after 2hours) on different occasions <strong>in</strong> theabsence of symptoms; or(3) treatment with <strong>in</strong>sul<strong>in</strong> or an oralhypoglycemic medication.The criteria for diagnosis of diabeteschanged <strong>in</strong> 1997, when a fast<strong>in</strong>gglucose level of 126 mg/dL (7.0mmol/L) or higher was made thediagnostic threshold.Adjusted aHazard Ratio(95%CI)NHS –NoneReference>0 to 3 0.98 (0.91-1.05)>3 to 6 1.03 (0.94-1.13)>6 to 11 0.96 (0.87-1.06)>11 to 23 0.92 (0.84-1.02)>23 0.88 (0.78-1.00)Per year of lactation 0.96 (0.92-0.99)NHS II –NoneReference>0 to 3 1.04 (0.86-1.26)>3 to 6 0.91 (0.73-1.14)>6 to 11 0.87 (0.72-1.06)>11 to 23 0.88 (0.74-1.06)>23 0.67 (0.54-0.84)Per year of lactation 0.88 (0.82-0.94)NHS II, never had GDM –NoneReference>0 to 3 1.00 (0.81-1.24)>3 to 6 0.80 (0.62-1.04)>6 to 11 0.86 (0.70-1.07)>11 to 23 0.77 (0.62-0.95)>23 0.58 (0.45-0.75)Per year of lactation 0.84 (0.78-0.91)NHS II, ever had GDM –NoneReference>0 to 3 1.18 (0.72-1.93)>3 to 6 1.30 (0.75-2.25)>6 to 11 0.89 (0.53-1.49)>11 to 23 1.19 (0.76-1.87)>23 0.97 (0.58-1.61)Per year of lactation 0.96 (0.84-1.09)GDM, gestational diabetesaConfounders adjusted <strong>in</strong> the model <strong>in</strong>clude parity, BMI, diet, physical activity, family history of diabetes, <strong>and</strong> smok<strong>in</strong>g status.Pvaluefortrend.02
Relationship between Osteoporosis <strong>and</strong> <strong>Breastfeed<strong>in</strong>g</strong>BackgroundOsteoporosis is a condition of decreased bone mass. This leads to fragile bones that are at an<strong>in</strong>creased risk for fractures. The World <strong>Health</strong> Organization (WHO) has established criteria formak<strong>in</strong>g the diagnosis of osteoporosis, <strong>and</strong> for determ<strong>in</strong><strong>in</strong>g levels that predict higher chances offractures. These criteria are based on compar<strong>in</strong>g bone m<strong>in</strong>eral density (BMD) <strong>in</strong> a particularpatient with those of a healthy 25-year-old female (T-scores). BMD values (T-scores) which fallwell below the average for the 25-year-old female (stated statistically as 2.5 st<strong>and</strong>ard deviationsbelow the average) are diagnosed as osteoporosis. Although BMD T-scores were basedorig<strong>in</strong>ally on assessment of BMD at the hip by dual-energy X-ray absorptiometry (DXA), theyhave been applied to def<strong>in</strong>e diagnostic thresholds at other skeletal sites <strong>and</strong> for other techniques.Experts have expressed concern that this approach may not produce comparable data betweensites <strong>and</strong> techniques. Of the various sampl<strong>in</strong>g sites, measurements of BMD made at the hippredict hip fracture better than measurements made at other sites, while BMD measurement atthe sp<strong>in</strong>e predicts sp<strong>in</strong>e fracture better than measurements at other sites(consensus.nih.gov/2000/2000Osteoporosis111html.htm).Calcium <strong>and</strong> bone metabolism is substantially altered dur<strong>in</strong>g pregnancy <strong>and</strong> lactation. Thetypical daily loss of calcium <strong>in</strong> breast milk has been estimated to range from 280 to 400 mg,although daily losses as great as 1000 mg calcium have been reported. 163 Physiologically, dur<strong>in</strong>gnurs<strong>in</strong>g, the body could theoretically meet this dem<strong>and</strong> by <strong>in</strong>creas<strong>in</strong>g the <strong>in</strong>test<strong>in</strong>al absorption ofcalcium, decreas<strong>in</strong>g renal calcium losses, <strong>and</strong> <strong>in</strong>creas<strong>in</strong>g the resorption of calcium from thematernal skeleton. Bone densities can decrease <strong>and</strong> <strong>in</strong>crease 3 to 10 percent <strong>in</strong> the span of a fewmonths <strong>in</strong> healthy mothers. 164 Prospective cohort studies have reported that lactation isassociated with bone m<strong>in</strong>eral loss <strong>in</strong> the first 6 months to 1 year postpartum, but such lossrebounds overtime. 165-169Confounders commonly considered <strong>in</strong> the studies of relationship between fracture risk <strong>and</strong>breastfeed<strong>in</strong>g were age, hormone replacement therapy, parity <strong>and</strong> BMI.Inclusion <strong>and</strong> Exclusion CriteriaTo evaluate the relationship between breastfeed<strong>in</strong>g <strong>and</strong> the development of osteoporosis, we<strong>in</strong>cluded all studies that exam<strong>in</strong>ed the l<strong>in</strong>k between breastfeed<strong>in</strong>g <strong>and</strong> fracture. We also <strong>in</strong>cludedlong-term prospective cohort studies (greater than 1 year of followup duration) that exam<strong>in</strong>ed therelationship between the duration of breastfeed<strong>in</strong>g <strong>and</strong> changes <strong>in</strong> bone m<strong>in</strong>eral densities or bonem<strong>in</strong>eral contents. Articles were excluded if they only used surrogate measures of fracture (e.g.,fracture risk score or <strong>in</strong>dex) or bone turnover markers.Results (Tables 30-31)A total of 44 potential relevant articles were retrieved for full-text screen<strong>in</strong>g. Thirty-fourarticles were excluded due to various reasons (e.g., cross-sectional design, relatively shortduration of follow up (< 2 years), studies done <strong>in</strong> develop<strong>in</strong>g countries). We <strong>in</strong>cluded a total ofsix case-control studies that exam<strong>in</strong>ed the risk of fractures <strong>in</strong> relation to a history of124
eastfeed<strong>in</strong>g, 170-175 <strong>and</strong> four long-term prospective cohort studies that exam<strong>in</strong>ed the changes ofbone m<strong>in</strong>eral densities or bone m<strong>in</strong>eral contents <strong>in</strong> relation to the duration of breastfeed<strong>in</strong>g. 176-179Risk of fractures <strong>in</strong> relation to a history of breastfeed<strong>in</strong>g (Table 30). A total of six casecontrolstudies were identified. There were a total of 1,594 subjects with hip, forearm, orvertebral fractures <strong>and</strong> 3,523 controls. All subjects were post-menopausal women with an agethat ranged from 45 to 103 years old. Three studies were conducted <strong>in</strong> the United States; onestudy each was conducted <strong>in</strong> Australia, Hong Kong, <strong>and</strong> Sweden. Four studies were ratedmethodological quality grade B; two was rated grade C.Incident cases of hip <strong>and</strong> forearm fractures were identified from hospital or cl<strong>in</strong>ical records(with or without radiography confirmations) <strong>in</strong> five studies. Matched or unmatched generalpopulation controls liv<strong>in</strong>g <strong>in</strong> the same area were used <strong>in</strong> three studies, while hospital controlswere used <strong>in</strong> the other two studies. In the rema<strong>in</strong><strong>in</strong>g one study, all women who were liv<strong>in</strong>g <strong>in</strong>three hous<strong>in</strong>g blocks were enrolled. Cases of def<strong>in</strong>ite vertebral fractures were classifiedaccord<strong>in</strong>g to the radiological diagnoses <strong>and</strong> the rema<strong>in</strong><strong>in</strong>g enrolled subjects without fractureswere classified as control subjects. Assessments of breastfeed<strong>in</strong>g history were based on subjects’long-term recalls <strong>in</strong> all studies. Only one study reported bl<strong>in</strong>ded <strong>in</strong>terviewers.Overall, there was no significant association between a history of breastfeed<strong>in</strong>g <strong>and</strong> the riskof hip, forearm, or vertebral fractures after adjustment for potential confounders. In four of sixstudies, parity was considered a potential effect modifier or confounder. Other confoundersexam<strong>in</strong>ed <strong>in</strong>cluded age, body mass <strong>in</strong>dex or weight, hormone replacement therapies, <strong>and</strong>bilateral oophorectomy. None of the studies provided data on the exclusivity of breastfeed<strong>in</strong>g.Long-term changes <strong>in</strong> bone m<strong>in</strong>eral densities or bone m<strong>in</strong>eral contents <strong>in</strong> relation to theduration of lactation (Table 31). A total of four prospective cohort studies were identified.Followup durations ranged from 2.5 to 12 years. Studies were done <strong>in</strong> different countries: onestudied 113 pre-menopausal parous women <strong>in</strong> Japan, one studied 169 pre- <strong>and</strong> peri-menopausalparous women with European heritage liv<strong>in</strong>g <strong>in</strong> the United States, one studied 92 premenopausalwomen <strong>in</strong> F<strong>in</strong>l<strong>and</strong>, <strong>and</strong> one studied 121 post-menopausal women <strong>in</strong> Denmark. Onestudy was of methodological quality grade A, two were of grade B, <strong>and</strong> one was of grade C,respectively.Matsushita 2002 exam<strong>in</strong>ed the effects of multiple pregnancies on BMD of lumbar sp<strong>in</strong>e (L2-L4) <strong>in</strong> 110 parous Japanese women. The outcome was the percent change <strong>in</strong> BMD, calculated bysubtract<strong>in</strong>g the value at the time of the <strong>in</strong>itial pregnancy from the value at the time of the secondpregnancy. The results showed that the BMD after the subsequent delivery was significantlyhigher than the BMD after the <strong>in</strong>itial delivery (P = 0.001), with a percent change <strong>in</strong> BMD of 1.4percent. Independent determ<strong>in</strong>ants of the percent change <strong>in</strong> BMD were explored by multipleregression analysis. The length of lactation between the deliveries showed no correlation with thepercent change <strong>in</strong> BMD (correlation coefficient = -0.06, P = 0.702). Age was the most significantpredictor for the percent change <strong>in</strong> BMD <strong>in</strong> the model.Sowers 1992 exam<strong>in</strong>ed various risk factors for 5-year radial BMD changes <strong>in</strong> 169 pre- <strong>and</strong>post-menopausal parous women with European heritage liv<strong>in</strong>g <strong>in</strong> the United States. The authorsreported that “a recalled history of breastfeed<strong>in</strong>g <strong>in</strong> parous women did not predict significantdifferences <strong>in</strong> BMD level or amount of BMD change”.Uusi-Rasi 2002 exam<strong>in</strong>ed the relationship between physical activity, calcium <strong>in</strong>take, <strong>and</strong> thema<strong>in</strong>tenance of bone mass <strong>in</strong> 92 non-smok<strong>in</strong>g premenopausal women liv<strong>in</strong>g <strong>in</strong> F<strong>in</strong>l<strong>and</strong>. Theeffects of total breastfeed<strong>in</strong>g duration on changes <strong>in</strong> bone m<strong>in</strong>eral contents (BMC) were also125
analyzed. Accord<strong>in</strong>g to the multiple stepwise regression analyses, the statistically significant<strong>in</strong>dependent predictors for site-specific bone loss were low calcium <strong>in</strong>take at the basel<strong>in</strong>e <strong>and</strong>change <strong>in</strong> body weight both at the proximal femur <strong>and</strong> at the distal radius sites. In addition,breastfeed<strong>in</strong>g was associated with radial bone loss; the longer the duration of breastfeed<strong>in</strong>g thegreater the bone loss (correlation coefficient = -0.34, P = 0.015).Hansen 1991 exam<strong>in</strong>ed the risk factors for the development of postmenopausal osteoporosisover a 12-year period <strong>in</strong> 121 postmenopausal women liv<strong>in</strong>g <strong>in</strong> Denmark. One hundred eleven ofthem (92 percent) had one or more pregnancies (mean 2.6) <strong>and</strong> breastfed their <strong>in</strong>fants for a meantotal breastfeed<strong>in</strong>g duration of 13 months. Compar<strong>in</strong>g postmenopausal women who neverbreastfed their <strong>in</strong>fants with those who did, there was no significant difference <strong>in</strong> lumbar sp<strong>in</strong>eBMD between groups. In addition, there was no significant difference <strong>in</strong> the annual rate ofpostmenopausal bone loss between these two groups.ConclusionThere is no evidence of an association between lifetime breastfeed<strong>in</strong>g duration <strong>and</strong>osteoporosis. In six case-control studies, there was no significant relationship between a historyof lactation <strong>and</strong> the risk of fractures <strong>in</strong> postmenopausal women. In two of three moderate or goodquality prospective cohort studies us<strong>in</strong>g bone m<strong>in</strong>eral density as a surrogate for osteoporosis,lactation does not appear to have an effect on long-term changes <strong>in</strong> bone m<strong>in</strong>eral densities. Thethird study found a small decrease <strong>in</strong> the bone m<strong>in</strong>eral contents <strong>in</strong> the distal radius with <strong>in</strong>creasedduration of breastfeed<strong>in</strong>g, but no significant changes <strong>in</strong> bone m<strong>in</strong>eral contents <strong>in</strong> the femoralneck or the trochanter. However, these f<strong>in</strong>d<strong>in</strong>gs should be <strong>in</strong>terpreted with caution because thefeed<strong>in</strong>g history was obta<strong>in</strong>ed by maternal recall <strong>and</strong> data on exclusivity of breastfeed<strong>in</strong>g were notprovided. Further <strong>in</strong>vestigation with accurate breastfeed<strong>in</strong>g data is warranted.126
127Table 30. Summary of case-control studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> risk of fracture <strong>in</strong> post-menopausal womenAuthorMean AgeOR (95% CI)PotentialCases Controls Def<strong>in</strong>ition ofyearat Dx of Lactation Comparatorconfounders(N) (N) fractureCountryfracture group group Age-adjusted Full adjusted*adjusted(year)All post-menopausal womenAlderman1986USACumm<strong>in</strong>g1993AustraliaHoffman1993USAChan 1996Hong Kong164180318174 137170 173144 163Hip fracturesbased oncl<strong>in</strong>ical recordsForearmfractures basedon cl<strong>in</strong>icalrecordsHip fracturespresent<strong>in</strong>g tothe hospitalsFirst hipfractureconfirmed byradiographyidentified fromhospitalrecordsDef<strong>in</strong>itevertebralfractures byradiography50-74BF 1-12 mo 1.60 (0.91-2.96)BF 13-24 mo Never BF0.40 (0.17-1.10)BF > 24 mo0.50 (0.21-1.44)BF 1-12 mo 0.80 (0.45-1.58)BF 13-24 mo Never BF0.80 (0.40-1.79)BF > 24 mo0.80 (0.38-1.87)65-100 Ever BF Never BF 0.72 (0.43-1.20) 0.64 (0.30-1.38)50-10375Ever BF Never BF 0.66 (0.41-1.05)BF ≤ 12 mo 0.67 (0.39-1.13)Never BFBF > 12 mo0.64 (0.32-1.29)BF < 24 mo 0.70 (0.40-1.30)BF ≥ 24 moNever BF0.60 (0.30-1.00)Age, naturallogarithm of theduration ofestrogen use, <strong>and</strong>relative weightAge, BMI, historyof HRT, currentuse ofpsychotropicmedications,current smok<strong>in</strong>gstatus, currentdairy productconsumption,score on mentalstate, current PA<strong>and</strong> health statusAgeAgeQuality<strong>and</strong>limitationsBBBCParouswomenwere notseparated
128Table 30. Cont<strong>in</strong>uedAuthoryearCountryCases(N)Controls(N)Def<strong>in</strong>ition offractureMean Ageat Dx offracture(year)LactationgroupOR (95% CI)Comparatorgroup Age-adjusted Full adjusted*Kreiger83 b First hipfractureconfirmed by0.50 (0.20-0.90) b198298radiography 45-74 BF (12-month <strong>in</strong>crease)USAidentified801 cfrom hospitalrecords0.60 (0.30, 1.0) cParous post-menopausal womenHip fracturesBF 6-10 mo 0.83 (0.66-1.05) 0.87 (0.68-1.11)Michaelssonbased onBF 11-162001 664 1,848 cl<strong>in</strong>ical or 71 moBF 1-5 mo 0.84 (0.65-1.08) 0.86 (0.66-1.12)SwedenregisterBF > 16 mo0.76 (0.60-0.98) 0.86 (0.67-1.12)recordsBF (3-month <strong>in</strong>crease) 0.96 (0.94-0.99) 0.98 (0.95-1.01)BF 1-12 mo 1.20 (0.73-1.95)BF 13-24mo0.70 (0.34-1.29)Alderman1986USACumm<strong>in</strong>g1993AustraliaHoffman1993USA268 211131 107103 125Hip orforearmfracturesbased oncl<strong>in</strong>icalrecordsHip fracturespresent<strong>in</strong>g tothe hospitalsFirst hipfractureconfirmed byradiographyidentifiedfrom hospitalrecords50-7465-10050-103BF > 24 moNever BF0.80 (0.38-1.51)Ever BF Never BF 0.47 (0.22-0.99) 0.55 (0.10-2.90)BF 0.5-3mo a0.56 (0.19-1.68) 0.64 (0.13-3.06)BF 3-6 mo a Never BF 0.41 (0.15-1.13) 0.79 (0.18-3.51)BF 6-9 mo a 0.47 (0.19-1.19) 0.41 (0.09-1.82)BF >9 mo a0.28 (0.07-1.18) 0.24 (0.04-1.53)Ever BF Never BF 0.87 (0.47-1.61)BF ≤ 12moBF > 12 moNever BFDx, diagnosis; BF, breastfeed<strong>in</strong>g; HRT, hormone replacement therapy; PA, physical activity* Adjusted for potential confounders, <strong>in</strong>clud<strong>in</strong>g agea Average breastfeed<strong>in</strong>g duration per child; b trauma controls ; c non-trauma controls0.80 (0.42-1.55)1.08 (0.45-2.60)PotentialconfoundersadjustedAge <strong>and</strong> BMI,bilateralovariectomy,<strong>and</strong> HRTAge, HRT, oralcontraceptiveuse, <strong>and</strong> BMISame as aboveSame as aboveAge, <strong>and</strong>number of livebirthsQuality <strong>and</strong>limitationsCSample size <strong>in</strong>BF analysis wasnot described;hospital controlsBBBB
129Table 31. Summary of prospective cohort studies on the relationship between duration of breastfeed<strong>in</strong>g <strong>and</strong> the long-term changes of bone m<strong>in</strong>eraldensity (BMD) or bone m<strong>in</strong>eral content (BMC)Author,YearCountryMatsushita,2001JapanSowers,1992USAUusi-Rasi,2002F<strong>in</strong>l<strong>and</strong>Hansen,1991DenmarkPopulationPre-menopausal,parous womenMixed pre- & perimenopausal,parouswomenPre-menopausalwomenPost-menopausalwomenMeanbasel<strong>in</strong>e age(yr)Mean durationof followup (yr)30 2.5 113N Duration of lactation ∆BMD (g/cm 2 ) or ∆BMC p Quality <strong>and</strong> limitationsLength of lactationbetween 1 st <strong>and</strong> 2 nddelivery (mo)22-54 5 169 Lactation vs. no lactation28(25-30)4.2(3.2-5.4)9251 12 121Total duration ofbreastfeed<strong>in</strong>g bLactation (87%): mean13 mo vs.no lactation b∆BMDsp<strong>in</strong>e:-0.06% a“No significant differences<strong>in</strong> BMD level or change”%∆BMCfemoral neck c%∆BMCtrochanter c%∆BMCdistal radius:β=-0.34 c∆BMDsp<strong>in</strong>e: 0.04∆BMCarm:0.1% per yearNSNSNSNS0.01NSNSABBCNo confounders adjusted;unclear if nonporous womenwere <strong>in</strong>cludedNS, not statistically significant; BMD sp<strong>in</strong>e , lumbar sp<strong>in</strong>e bone m<strong>in</strong>eral density; BMC arm , forearm bone m<strong>in</strong>eral contenta Variables <strong>in</strong> the multiple regression model: <strong>in</strong>terval between the scans (yr), lumbar sp<strong>in</strong>e BMD after the <strong>in</strong>itial delivery (g/cm 2 ), bone area (BA) after the <strong>in</strong>itialdelivery (cm 2 ), body weight after the <strong>in</strong>itial delivery (kg), age at <strong>in</strong>itial delivery (yr), ∆BA (cm 2 ), body weight changes between the scans (kg) length of lactationbetween the scans (mo), <strong>in</strong>terval between the time at which breast-feed<strong>in</strong>g was stopped <strong>and</strong> the next conception (mo); age at next delivery (yr). Dependentvariable, ∆BMD%, r 2 =0.174, p=0.037. The percent change <strong>in</strong> BMD (∆BMD%) was calculated by subtract<strong>in</strong>g the value at the time of the first pregnancy from thevalue at the time of the second pregnancyb Not clear whether nulliparous women were <strong>in</strong>cluded <strong>in</strong> the analysesc Multivariate stepwise regression for percent bone loss <strong>in</strong>cluded the follow<strong>in</strong>g variables: age, body weight, muscle strength, estimated maximal oxygen uptake <strong>and</strong>calcium <strong>in</strong>take, the absolute changes <strong>in</strong> body weight, muscle strength, estimated maximal oxygen uptake, calcium <strong>in</strong>take, physical, activity, duration ofbreastfeed<strong>in</strong>g <strong>and</strong> time from wean<strong>in</strong>g. Only statistical significant variables were kept <strong>in</strong> the f<strong>in</strong>al model.
Relation between Postpartum Depression <strong>and</strong> <strong>Breastfeed<strong>in</strong>g</strong>BackgroundPostpartum depression is a serious health problem. The prevalence has been estimated ataround 13%. 180 It not only affects mother’s health, it also affects her ability to care for her <strong>in</strong>fant.<strong>Breastfeed<strong>in</strong>g</strong> plays a role <strong>in</strong> affect<strong>in</strong>g an <strong>in</strong>fant’s health <strong>and</strong> <strong>in</strong> maternal-<strong>in</strong>fant bond<strong>in</strong>g. It isimportant to underst<strong>and</strong> the nature of the relationship between postpartum depression <strong>and</strong> thedecision to <strong>in</strong>itiate <strong>and</strong> cont<strong>in</strong>ue breastfeed<strong>in</strong>g.Many studies have exam<strong>in</strong>ed the relationship between breastfeed<strong>in</strong>g <strong>and</strong> the development ofpostpartum depression. The results have been quite variable. This may be expla<strong>in</strong>ed by the lackof a uniform st<strong>and</strong>ard <strong>in</strong> arriv<strong>in</strong>g at a diagnosis of postpartum depression. Some studies usedquestionnaires <strong>and</strong> some used cl<strong>in</strong>ical <strong>in</strong>terviews <strong>and</strong> different criteria of depression. Many of thestudies had relatively small number of subjects. Furthermore, the items commonly used to assesscl<strong>in</strong>ical depression like fatigue <strong>and</strong> sleep problems are to be expected <strong>in</strong> car<strong>in</strong>g for a newborn.Some of the potential confounders thought to be important <strong>in</strong> studies of depressive symptoms<strong>and</strong> feed<strong>in</strong>g practices were marital status, employment status, <strong>and</strong> whether or not the pregnancywas planned. 181Additional Methodological CommentsWe screened the abstracts identified from the MEDLINE general search on breastfeed<strong>in</strong>g <strong>in</strong>November 2005. Abstracts qualify<strong>in</strong>g for full text retrieval <strong>in</strong>cluded studies on the relationshipbetween breastfeed<strong>in</strong>g <strong>and</strong> postpartum depression, psychological disorders, psychiatric illnesses,or mental health issues. We also identified additional articles based on reviews of thebibliographies cited <strong>in</strong> the relevant retrieved studies from the search. We only <strong>in</strong>cluded studiesthat had at least 100 nurs<strong>in</strong>g mothers. Qualify<strong>in</strong>g study designs <strong>in</strong>cluded prospective cohortstudies <strong>and</strong> case-control studies. All methods of assessment of depression were <strong>in</strong>cluded. Onlydata perta<strong>in</strong><strong>in</strong>g to the relationship of breastfeed<strong>in</strong>g <strong>and</strong> postpartum depression were extractedfrom the studies.Results (Table 32)Prospective cohort. A total of six prospective cohort studies qualified for <strong>in</strong>clusion. 181-186There were no case-control studies. The number of women <strong>in</strong> each study ranged from 113 to2,375. Three of six studies were rated methodological quality grade B with<strong>in</strong> their respectivestudy design hierarchy <strong>and</strong> with respect to only the data on the relationship of breastfeed<strong>in</strong>g <strong>and</strong>postpartum depression. Studies of methodological quality grade C suffered from a comb<strong>in</strong>ationof <strong>in</strong>complete report<strong>in</strong>g of relevant data, <strong>in</strong>adequate bl<strong>in</strong>d<strong>in</strong>g, lack of or suboptimal adjustmentfor confound<strong>in</strong>g factors.Four of six studies did not have specific <strong>in</strong>clusion criteria based on basel<strong>in</strong>e mental healthstatus. Four studies screened for depression us<strong>in</strong>g the Ed<strong>in</strong>burgh Postnatal Depression Scale(EPDS), but the cut off po<strong>in</strong>t ranged from 9 to 13 (lowest severity score was zero, highestseverity score was 30). Four studies established the diagnosis of depression after cl<strong>in</strong>ical<strong>in</strong>terviews. None of the studies provided a clear def<strong>in</strong>ition of breastfeed<strong>in</strong>g.130
Four prospective cohort studies of moderate methodological quality total<strong>in</strong>g 4,941 subjectsreported postpartum depression rates of 6% to 18%. 181-183,185 In addition to a history ofbreastfeed<strong>in</strong>g, all of the studies also considered socio-demographic <strong>and</strong> obstetric variables as<strong>in</strong>dependent predictors of postpartum depression. Assessment of depression by self-reportedquestionnaires or <strong>in</strong>terviews took place from 1 to 12 months after birth. Except for one study, 182all of them reported that not breastfeed<strong>in</strong>g or early cessation of breastfeed<strong>in</strong>g was associated withpostpartum depression. One study reported that onset of postpartum depression occurred beforecessation of breastfeed<strong>in</strong>g <strong>in</strong> most cases. 185 One study reported that depressed mothers were lesslikely to cont<strong>in</strong>ue breastfeed<strong>in</strong>g beyond 2 to 4 months compared with mothers who were notdepressed. 183 In the one study that reported no significant difference <strong>in</strong> the development ofdepression <strong>in</strong> mothers who breastfed versus those who did not breastfeed, women who werebreastfeed<strong>in</strong>g at 1 month <strong>and</strong> were worried about breastfeed<strong>in</strong>g were significantly more likely tobecome depressed than those who did not worry (RR 3.0, 95%CI 1.041 - 9.216). 182Despite the poor methodological quality of the rema<strong>in</strong><strong>in</strong>g studies, their f<strong>in</strong>d<strong>in</strong>gs were alsoconsistent with those from studies of moderate quality. One study reported that high EPDSscorers experienced breastfeed<strong>in</strong>g more negatively than the low EPDS scorers (51% versus 16%,P < 0.0001). 186 One study reported that mothers who were depressed were less likely to <strong>in</strong>itiatebreastfeed<strong>in</strong>g. 184ConclusionStudies of moderate quality reported an association between not breastfeed<strong>in</strong>g or shortduration of breastfeed<strong>in</strong>g <strong>and</strong> postpartum depression. More <strong>in</strong>vestigation will be needed todeterm<strong>in</strong>e the nature of this association. It is plausible that postpartum depression led to earlycessation of breastfeed<strong>in</strong>g, as opposed to breastfeed<strong>in</strong>g alter<strong>in</strong>g the risk of depression. Botheffects might occur concurrently. Additional factors that may have a bear<strong>in</strong>g on both postpartumdepression <strong>and</strong> the decision to <strong>in</strong>itiate or term<strong>in</strong>ate breastfeed<strong>in</strong>g should also be sought.Moreover, documentation of basel<strong>in</strong>e mental health status before the <strong>in</strong>itiation of breastfeed<strong>in</strong>g<strong>and</strong> detailed record<strong>in</strong>g of breastfeed<strong>in</strong>g data will improve the quality of the studies <strong>and</strong> helpunderst<strong>and</strong> the nature of the association.131
132Table 32.Summary of the studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> postpartum depressionAuthor YearDef<strong>in</strong>ition of ConfoundersCountryStudy descriptionComparatorsdepression adjusted forPopulationProspective CohortWarner 1996UK2,375Subjects recruitedfrom postnatalwards prior todischargeHenderson 2003Australia1,745Subjects recruitedfrom postnatalwards; not underpsychologicalcare at the time ofrecruitmentHome <strong>in</strong>terview 6-8 wkafter delivery; Ed<strong>in</strong>burghPostnatal DepressionScale (EPDS) wascompleted at the<strong>in</strong>terviewSelf-reportedquestionnaires werecompleted at 2, 6, <strong>and</strong> 12mo after birth; subjectswith high EPDS scorewere offered a diagnostic<strong>in</strong>terviewScreen<strong>in</strong>g: high<strong>and</strong> low scoresus<strong>in</strong>g an EPDSthreshold of12/13Screen<strong>in</strong>g:EPDS >12.Diagnosis: DSMIVSociodemographic<strong>and</strong>obstetric variablesDemographic,per<strong>in</strong>atal, <strong>and</strong>postnatal factorsExam<strong>in</strong>ed“notbreastfeed<strong>in</strong>g”as one of thefactors <strong>in</strong>logisticanalysisExam<strong>in</strong>ed“earlycessation ofbreastfeed<strong>in</strong>g”<strong>in</strong> adjustedhazard ratioResults280/2,375 scored >12 onEPDS; not breastfeed<strong>in</strong>gat 6 wk (OR 1.52, 95%CI1.12-2.06), unplannedpregnancy (OR 1.44),unemployment <strong>in</strong> mother(OR 1.56) or <strong>in</strong> head ofhousehold (OR 1.50)were associated with anEPDS >12 <strong>in</strong> a stepwiselogistic analysis.18% developeddepression <strong>in</strong> the 12 moafter birth.Early cessation ofbreastfeed<strong>in</strong>g was foundto be associated withpostpartum depression(adjusted hazard ratio1.25, 95% CI 1.03 to1.52). Onset ofpostpartum depressionoccurred beforecessation ofbreastfeed<strong>in</strong>g <strong>in</strong> mostcases.Quality <strong>and</strong>limitationsBNo detailed<strong>in</strong>formation onbreastfeed<strong>in</strong>gBNo detailed<strong>in</strong>formation onbreastfeed<strong>in</strong>g
Table 32. Cont<strong>in</strong>uedAuthor YearCountryPopulationChaudron 2001US465Subjects notdepressed at 1month postpartumStudy descriptionSubjects participated <strong>in</strong>an <strong>in</strong>terview dur<strong>in</strong>g the2 nd trimester, <strong>and</strong> at 1<strong>and</strong> 4 mo after delivery;both the DiagnosticInterview Schedule (DIS)<strong>and</strong> Center forEpidemiologic StudiesDepression Scale (CES-D) were adm<strong>in</strong>istered ateach <strong>in</strong>terviewDef<strong>in</strong>ition ofdepressionDSM-III-Rcriteria; ≥16 onthe CES-D;<strong>and</strong>/or receiv<strong>in</strong>gantidepressantsConfoundersadjusted forAge, depressiondur<strong>in</strong>g pregnancy,postpartumthoughts of death<strong>and</strong> dy<strong>in</strong>g, difficultyfall<strong>in</strong>g asleepComparators<strong>Breastfeed<strong>in</strong>g</strong>vs. notbreastfeed<strong>in</strong>gResults6% became depressedbetween 1 <strong>and</strong> 4 mo;Women who breastfedtheir <strong>in</strong>fants were notsignificantly different <strong>in</strong>their development ofdepression from womenwho did not breastfeed.Of those women whowere breastfeed<strong>in</strong>g at 1mo, women who worriedabout breastfeed<strong>in</strong>g weresignificantly more likely tobecome depressed thanthose who did not worry(P=0.04)Quality <strong>and</strong>limitationsBNo detailed<strong>in</strong>formation onbreastfeed<strong>in</strong>g133
134Table 32. Cont<strong>in</strong>uedAuthor YearCountryCooper 1993UK243 at Oxford;113 atCambridgeNo restriction onmental healthstatus prior toenrollment notedSeimyr 2004Sweden352All Swedishspeak<strong>in</strong>gpregnant womenfrom sixantenatal cl<strong>in</strong>ics,with theirpartners or aloneStudy description2 separate cohortstudies (Oxford <strong>and</strong>Cambridge)At Cambridge,prospective subjectswere screened at 6 wkpostpartum us<strong>in</strong>g theEPDS. All high scorers(≥13) <strong>and</strong> otherselected participantsreceived full psychiatricassessment between 2<strong>and</strong> 3 mo postpartum.Adm<strong>in</strong>istered EPDS at2 mo before childbirth(I), 2 mo (II) <strong>and</strong> 12 mo(III) after child birthDef<strong>in</strong>ition ofdepressionResearchDiagnosticCriteria (RDC)Cut-off po<strong>in</strong>t of9/10 on EPDSis used to setthe thresholdfor vulnerabilityto depressionConfounders adjustedforSocial class, age, <strong>and</strong>educationDid not report actualadjustment, butreported that therewas no difference withregards to age,education, parity, <strong>and</strong>length of maritalrelationship betweenlow <strong>and</strong> high-scor<strong>in</strong>gwomenComparatorsReported onlyon “ceasedbreastfeed<strong>in</strong>g”Breastfed vs.not breastfedResultsAt Oxford, 56% of subjects withpsychiatric symptoms versus23% of subjects withoutpsychiatric symptoms hadceased breastfeed<strong>in</strong>g by 8 wkpostpartum (P
Table 32. Cont<strong>in</strong>uedAuthor YearCountryHannah 1992UK231Women who haddelivered a livebabyStudy descriptionQuestionnaires (generalquestionnaire <strong>and</strong>EPDS) on 5 th daypostpartum <strong>and</strong> repeatEPDS at 6 weekspostpartumDef<strong>in</strong>ition ofdepressionPostpartumdepressiondef<strong>in</strong>ed byEPDS ≥ 13 at6 weeksConfoundersadjusted forDid not reportadjustment forbreastfeed<strong>in</strong>g, but didreport that low moodafter a previousdelivery was apredictor of post-nataldepressionComparatorsEver breastfedvs. neverbreastfedResultsAt 6 wk, 18/26 (69%) womenwith EPDS ≥ 13 vs. 175/200(88%) women with EPDS < 13had ever breastfed.Quality <strong>and</strong>limitationsCNo adjustmentfor confounderswith respect tobreastfeed<strong>in</strong>gCES-D, Center for Epidemiological Studies Depression Scale; DIS, Diagnostic Interview Schedule; DSM IV, Diagnostic Statistical Manual; EPDS, Ed<strong>in</strong>burghPostnatal Depression Scale; RDC, Research Diagnostic Criteria135
Relationship between <strong>Maternal</strong> Breast Cancer <strong>and</strong> OvarianCancer <strong>and</strong> <strong>Breastfeed<strong>in</strong>g</strong>BackgroundBreast cancer is the second most frequently diagnosed <strong>and</strong> second most deadly cancer amongwomen. 187 Risk factors associated with <strong>in</strong>creased risk of breast cancer <strong>in</strong>clude: family history,nulliparity, early menarche, hormone replacement therapy, obesity, <strong>and</strong> advanced age. Ovariancancer ranks seventh <strong>in</strong> the most frequently diagnosed <strong>and</strong> fourth <strong>in</strong> the most deadly canceramong women. 187 Risk factors for ovarian cancers are similar to those of breast cancer. Whilebreast <strong>and</strong> ovarian cancers are closely associated with parity, women with <strong>in</strong>creased parity alsohave <strong>in</strong>creased lifetime duration of breastfeed<strong>in</strong>g. Therefore, it would be <strong>in</strong>structive to exam<strong>in</strong>ethe relationship of breastfeed<strong>in</strong>g <strong>and</strong> the risk of develop<strong>in</strong>g breast or ovarian cancer.MethodsBreast CancerWe identified two meta-analyses <strong>and</strong> one systematic review that evaluated the relationshipbetween breastfeed<strong>in</strong>g <strong>and</strong> maternal breast cancer. 188-190 We also identified 23 primary studiespublished s<strong>in</strong>ce 2001, the cut-off date for literature search used <strong>in</strong> the latest meta-analysis.Primary studies were screened based on the same <strong>in</strong>clusion criteria described <strong>in</strong> the latest metaanalysis.In addition, we elected to <strong>in</strong>clude only primary studies conducted <strong>in</strong> developedcountries. Twenty of the 23 primary studies were excluded for the follow<strong>in</strong>g reasons: studiespublished <strong>in</strong> develop<strong>in</strong>g countries (5); studies that did not meet the eligibility criteria (e.g.,studies that did not provide data on the follow<strong>in</strong>g: <strong>in</strong>cident <strong>in</strong>vasive breast cancers, reproductivefactors, <strong>and</strong> use of hormonal preparation) (13); duplicate study (1); <strong>and</strong> review that was notsystematically conducted (1). A total of three studies from developed countries publishedsubsequent to the latest meta-analysis were <strong>in</strong>cluded <strong>in</strong> the update. 191-193Published Systematic Reviews <strong>and</strong>/or Meta-Analyses (Table 33)The most recent meta-analysis published by the Collaborative Group on Hormonal Factors <strong>in</strong>breast cancer comb<strong>in</strong>ed 45 studies published through 2001 <strong>and</strong> two unpublished studies. 189 Themeta-analysis evaluated a total of 50,302 parous women with <strong>in</strong>cident <strong>in</strong>vasive breast cancer <strong>and</strong>96,973 controls. Included <strong>in</strong> the meta-analysis were primary studies that analyzed at least 100cases of <strong>in</strong>cident <strong>in</strong>vasive breast cancers per study regardless of the menopausal status withadditional <strong>in</strong>formation on reproductive factors <strong>and</strong> use of hormonal preparations. Both cohort<strong>and</strong> case-control studies from developed <strong>and</strong> develop<strong>in</strong>g countries were <strong>in</strong>cluded. Individualsubject data from the primary studies were analyzed for homogeneity across study def<strong>in</strong>itions.The majority of the primary studies did not differentiate between exclusive <strong>and</strong> partialbreastfeed<strong>in</strong>g, <strong>and</strong> some studies varied <strong>in</strong> the def<strong>in</strong>ition of “ever breastfeed<strong>in</strong>g”. The average ageat diagnosis of breast cancer <strong>in</strong> the studies was 50 years. There was a higher proportion ofwomen with either nulliparity or low parity <strong>in</strong> the breast cancer group compared with the controlgroup. In addition, lower number of the parous women <strong>in</strong> the breast cancer group had ever136
eastfed their <strong>in</strong>fants compared with the control group. There was a statistically significantreduction <strong>in</strong> risk of breast cancer by 4.3% (95% CI 2.9-5.8) for each year of breastfeed<strong>in</strong>g. Thereduction <strong>in</strong> the risk of breast cancer with breastfeed<strong>in</strong>g rema<strong>in</strong>ed unaltered even afterstratification for potential confounders such as parity, number of children breastfed, menopausalstatus, <strong>and</strong> lifetime duration of breastfeed<strong>in</strong>g. The results were also adjusted for ethnic orig<strong>in</strong>,education, family history of breast cancer, age at menarche, height, weight, body mass <strong>in</strong>dex, <strong>and</strong>use of hormonal contraceptives, alcohol, <strong>and</strong> tobacco. Decrease <strong>in</strong> the relative risk of breastcancer associated with each year of breastfeed<strong>in</strong>g rema<strong>in</strong>ed homogeneous across the studies withregards to developed versus develop<strong>in</strong>g countries, age at diagnosis, menopausal status, familyhistory of breast cancer, <strong>and</strong> study designs. In addition, the decrease <strong>in</strong> relative risk of breastcancer <strong>in</strong> parous women, accord<strong>in</strong>g to breastfeed<strong>in</strong>g history (ever versus never) <strong>and</strong> number ofbirths, was more pronounced after four or more births. The methodological quality of the metaanalysiswas rated grade A.In the meta-analysis by Bernier 2000 evaluated the relationship of breastfeed<strong>in</strong>g withhistologically diagnosed breast cancer <strong>in</strong> parous women. 188 The meta-analysis comb<strong>in</strong>ed 25,871cases <strong>and</strong> 44,910 controls from 23 primary case-control studies. Criteria for <strong>in</strong>clusion are studiesfrom developed <strong>and</strong> develop<strong>in</strong>g countries published <strong>in</strong> English or French languages between1980 <strong>and</strong> 1998 that provided usable data for the calculation of odds ratio of breastfeed<strong>in</strong>g <strong>and</strong>breast cancer risk. The meta-analysis used both fixed <strong>and</strong> r<strong>and</strong>om effects model. There was asmall, but statistically significant decreased risk of breast cancer <strong>in</strong> women who had breastfedtheir <strong>in</strong>fants compared with women who had not. The decreased risk was further explored byexam<strong>in</strong><strong>in</strong>g the menopausal status at the time of diagnosis of breast cancer <strong>and</strong> the duration ofbreastfeed<strong>in</strong>g. Women who were pre-menopausal at the time of diagnosis of breast cancer had asmall but statistically significant decreased risk of breast cancer compared with menopausalwomen. The duration of breastfeed<strong>in</strong>g was divided <strong>in</strong>to categories of 1 to 6 months, 7 to 12months, <strong>and</strong> more than 12 months. When these categories of breastfeed<strong>in</strong>g were compared withnon-breastfeed<strong>in</strong>g, only those whose lifetime duration of breastfeed<strong>in</strong>g was longer than 12months (compared to never) had a small but statistically significant reduction <strong>in</strong> the risk of breastcancer <strong>in</strong> subgroup analysis. The authors reported that there was no “publication bias”. Themethodological quality of the meta-analysis was rated grade B.Another systematic review <strong>in</strong>cluded all English language studies published through 1998 <strong>and</strong>enrolled at least 200 women with breast cancer. 190 In addition, only studies that explicitlyadjusted for the number of full-term pregnancies <strong>and</strong> age at first birth were <strong>in</strong>cluded. The data<strong>in</strong>cluded 19,482 cases <strong>and</strong> 37,627 controls from 24 case-control studies, <strong>and</strong> 3,857 casesidentified from three longitud<strong>in</strong>al followup studies that comprised of 229,574 subjects. The casecontrolstudies were conducted <strong>in</strong> hospital- or population-based sett<strong>in</strong>gs. Studies conducted <strong>in</strong>developed <strong>and</strong> develop<strong>in</strong>g countries were <strong>in</strong>cluded. Based on qualitative appraisal, the authorsconcluded that either there was no relationship between breastfeed<strong>in</strong>g <strong>and</strong> the risk ofdevelopment of breast cancer or there was a weak protective effect of ever breastfeed<strong>in</strong>g aga<strong>in</strong>stthe development of breast cancer. The authors did report some reduction <strong>in</strong> the risk ofdevelopment of breast cancer <strong>in</strong> premenopausal women who had breastfed their <strong>in</strong>fants for longduration. The methodological quality of the systematic review was rated grade B.137
Studies Published after the Systematic Reviews/Meta-Analyses(Table 34)We identified three eligible studies from developed countries that were published subsequentto the latest meta-analysis. 191-193 One study was multi-center; 192 the rema<strong>in</strong>ders were s<strong>in</strong>glecenter. 191,193 One study was a prospective cohort of Korean women <strong>and</strong> evaluated onlypremenopausal women. 193 The other two were case-control studies; one evaluated therelationship between breast cancer <strong>and</strong> breastfeed<strong>in</strong>g among carriers of deleterious BRCA1 <strong>and</strong>BRCA2 mutations, 192 the other evaluated <strong>in</strong>cident <strong>in</strong>vasive breast cancer patients. 191 Two studies<strong>in</strong>cluded only women whose mean age at diagnosis of breast cancer was <strong>in</strong> the premenopausalrange. 192,193 All studies reported a statistically significant reduced risk or odds of breast cancerwith <strong>in</strong>creased duration of breastfeed<strong>in</strong>g, which varied across the studies. The duration ofbreastfeed<strong>in</strong>g ranged from 12 to 24 or more months. The methodological quality of the studiesranged from grade B to C.ConclusionResults from both meta-analyses concluded that there was a reduction <strong>in</strong> the risk of breastcancer <strong>in</strong> women who breastfed their <strong>in</strong>fants. No studies evaluated exclusive breastfeed<strong>in</strong>g.Studies also reported decreased risk or odds of breast cancer <strong>in</strong> women with a lifetimebreastfeed<strong>in</strong>g of more than 12 months. Neither one of the meta-analyses detected any publicationbias. In addition, one of the meta-analyses <strong>and</strong> the systematic review reported decreased odds ofbreast cancer primarily <strong>in</strong> premenopausal women. F<strong>in</strong>d<strong>in</strong>gs from primary studies publishedsubsequent to the meta-analyses concurred with the f<strong>in</strong>d<strong>in</strong>gs from the meta-analyses. Inconclusion, there is evidence to support the observation that breastfeed<strong>in</strong>g is associated with areduction <strong>in</strong> the risk of breast cancer.138
139Table 33. Summary of systematic reviews/meta-analyses on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> the risk of breast cancerAuthor YearNumberConfounders consideredStudyInterventionofPopulationdescription/ComparatorsubjectsResultsIncident <strong>in</strong>vasivePer 12 mo ofbreast cancerbreastfeed<strong>in</strong>gCollaborativeGroup onHormonal Factors<strong>in</strong> Breast Cancer200250,302cases96,973controlsBernier 2000 25,871cases44,910controlsLipworth 2000 19,482cases37,627controlsMA of cohort<strong>and</strong> casecontrolstudiesMA of casecontrolstudiesSR of casecontrolstudiesParous women withhistologicallydiagnosed breastcancerPremenopausalwomen with breastcancerEthnic orig<strong>in</strong>, education, familyhistory of breast cancer, age atmenarche, height, weight, bodymass <strong>in</strong>dex, <strong>and</strong> use ofhormonal contraceptives,alcohol, <strong>and</strong> tobaccoAge at diagnosis or at full termpregnancy, parity, ethnicity,age at menarche, family historyof breast cancer, parityYes, descriptive summary <strong>Breastfeed<strong>in</strong>g</strong> ever /neverMA, meta-analyses; SR, systematic review; RR, relative risk; OR, odds ratio; SE, st<strong>and</strong>ard error; NA, not applicableRR reduction of breastcancer 4.3% (99% SE0.8)<strong>Breastfeed<strong>in</strong>g</strong> ever / Adjusted RR 0.96 (99% SEnever0.2, p=.04)Increas<strong>in</strong>g duration of Adjusted RR 0.38 (99% SEbreastfeed<strong>in</strong>g0.01, p
Table 34. Summary of case-control studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> breast cancer140Author, yearCountryCases(N)Controls(N)Def<strong>in</strong>ition ofdiseaseAge at diagnosis ofdisease(year)<strong>Breastfeed<strong>in</strong>g</strong>groupComparatorgroupConfoundersadjustedAdjusted oddsratio (95% CI)Age, oral 0.8 (0.7, 1.0)149 1-12 mocontraceptives, NSLee 2003 aNever parity, smok<strong>in</strong>g, 0.7 (0.5, 1.1)Korea32 Incident 33-4413-24 mo(N=161) exercise <strong>and</strong>NSobesity 0.6 (0.3, 1.0)18>24 moP=.04Oral 0.89 (0.68, 1.17)≤1 yrcontraceptive NS685 685 Invasive BRCA1 39Neveruse <strong>and</strong> parity 0.55 (0.38, 0.80)Jernstrom>1 yrP=.00120041.12 (0.73, 1.71)Multi-center≤1 yrNS280 280 Invasive BRCA2 39Never0.95 (0.56, 1.59)>1 yrNS
Ovarian CancerMethodsNo meta-analysis was identified on this topic. Eligible designs <strong>in</strong>cluded prospective cohorts,case-cohort studies or nested case-control studies. Cross-sectional studies were excluded, asdescribed <strong>in</strong> the Methods section. Eligible studies were conducted <strong>in</strong> developed countries. Wequantified the association between breastfeed<strong>in</strong>g <strong>and</strong> any type of histopathologically def<strong>in</strong>edmaternal ovarian cancer. No specific exclusion criteria were used for the participants <strong>in</strong> theprimary studies.We recorded or estimated odds ratios for the association between breastfeed<strong>in</strong>g <strong>and</strong> ovariancancer for the follow<strong>in</strong>g comparisons: women who ever breastfed versus never breastfed; womenwho breastfed less than 12 months (cumulative duration) versus those who never breastfed; <strong>and</strong>women who breastfed at least 12 months (cumulative duration) versus never. The 12-monthscutoff was arbitrary, <strong>and</strong> was chosen for symmetry with analyses on maternal breast canceroutcomes. At a m<strong>in</strong>imum, studies that were <strong>in</strong>cluded <strong>in</strong> the meta-analyses must have beenadjusted for parity (or used match<strong>in</strong>g for parity). Adjustment for the use of oral contraceptives(or appropriate match<strong>in</strong>g) was desirable but not m<strong>and</strong>atory. Studies that reported unadjustedeffects only were not <strong>in</strong>cluded <strong>in</strong> the meta-analyses, but are reported <strong>in</strong> the tables <strong>and</strong> text.For each study, we estimated the odds ratios for the comparisons of <strong>in</strong>terest when they werenot directly reported. This was done for studies that analyzed breastfeed<strong>in</strong>g as an ord<strong>in</strong>alcategorical predictor us<strong>in</strong>g cutoffs other than 12 months, provided that mothers who neverbreastfed were the reference category. In such studies, the odds ratios for the comparisons of<strong>in</strong>terest were estimated by comb<strong>in</strong><strong>in</strong>g odds ratios for different durations of breastfeed<strong>in</strong>g us<strong>in</strong>g ar<strong>and</strong>om effects model. For example, Riman 2002 194 did not report the odds ratio of ever versusnever breastfeed<strong>in</strong>g, but reported odds ratios for specific durations of breastfeed<strong>in</strong>g versus neverbreastfeed<strong>in</strong>g. Compared with women who never breastfed, the adjusted odds ratio <strong>in</strong> the Rimanstudy for 1 to 5 months of cumulative breastfeed<strong>in</strong>g was 0.99 (95%CI 0.64 -1.52); for 6 to 11months, it was 0.77 (95%CI 0.50 - 1.19) <strong>and</strong> for at least 12 months of cumulative breastfeed<strong>in</strong>g,it was 0.87 (95%CI 0.56 - 1.35). We can estimate the odds ratio of ever versus neverbreastfeed<strong>in</strong>g <strong>in</strong> the Riman 2002 study with a r<strong>and</strong>om effects meta-analysis of theaforementioned duration-specific odds ratios (estimated adjusted odds ratio was 0.87, 95%CI0.68 - 1.12).Results (Tables 35-38)We did not identify any prospective studies. We found 15 eligible case-control studies thatexam<strong>in</strong>ed the relationship between breastfeed<strong>in</strong>g <strong>and</strong> maternal ovarian cancer. 194-210 In addition,we identified three studies that conducted secondary analyses on population subgroups <strong>in</strong>clud<strong>in</strong>gwhite, black, <strong>and</strong> Jewish women by pool<strong>in</strong>g data from case-control studies. 211-213 Populationbasedcontrols were used <strong>in</strong> n<strong>in</strong>e of the 15 studies <strong>and</strong> hospital-based controls were used <strong>in</strong> therema<strong>in</strong><strong>in</strong>g six. A total of 6,006 subjects with ovarian cancer were studied. The smallest sample<strong>in</strong>cluded 76 subjects with ovarian cancer matched with 76 hospital-based controls, 208 <strong>and</strong> thelargest <strong>in</strong>cluded 1,028 subjects matched with 2,390 hospital-based controls. 195141
Data were gathered from <strong>in</strong>terviewers us<strong>in</strong>g structured questionnaires, <strong>and</strong> therefore outcomeassessment was not bl<strong>in</strong>ded. Participant’s age ranged from 17 to 79 years. The report<strong>in</strong>g of<strong>in</strong>formation on breastfeed<strong>in</strong>g duration generally did not dist<strong>in</strong>guish between exclusive or partialbreastfeed<strong>in</strong>g. Terms commonly used were breastfeed<strong>in</strong>g, lactation, <strong>and</strong> <strong>in</strong> one <strong>in</strong>stance, nurs<strong>in</strong>g.In 13 out of 15 case-control studies the outcome was histologically confirmed epithelial ovariancancer. All protocols <strong>in</strong>cluded women regardless of menopausal status, except for one study thatexam<strong>in</strong>ed peri- <strong>and</strong> postmenopausal women, <strong>and</strong> another restricted to women under age 55years. 194,198 One primary study <strong>in</strong>cluded white women only. 202 None of the studies verifieddetails of the breastfeed<strong>in</strong>g history by objective data such as hospital or cl<strong>in</strong>ic records. F<strong>in</strong>ally,there was wide variability <strong>in</strong> how breastfeed<strong>in</strong>g duration was categorized <strong>in</strong> the various studies(Table 35). Because of potential recall bias of breastfeed<strong>in</strong>g history, lack of data verification, <strong>and</strong>lack of bl<strong>in</strong>d<strong>in</strong>g, the majority of the case control studies (n=11) was rated methodological gradeB. The rema<strong>in</strong><strong>in</strong>g four case-control studies were rated grade C. All studies adjusted for parity,<strong>and</strong> all but one study also adjusted for oral contraceptive use.Meta-analysesEver breastfed versus never breastfed. N<strong>in</strong>e studies with a total of 4,387 cases <strong>and</strong> 10,574controls were <strong>in</strong>cluded <strong>in</strong> the comparison of ever versus never breastfeed<strong>in</strong>g (Figure 12). Ther<strong>and</strong>om effects meta-analysis found an association between breastfeed<strong>in</strong>g <strong>and</strong> reduced ovariancancer risk (OR adj 0.79, 95%CI 0.68 – 0.91). 194,195,197,199-201,204-206,210 There was a statisticallysignificant between-study heterogeneity (P=0.02), which was ma<strong>in</strong>ly due to the outly<strong>in</strong>g study ofChiaffar<strong>in</strong>o 2005. Exclud<strong>in</strong>g the study yielded very similar estimates without a statisticallysignificant heterogeneity.For five of the n<strong>in</strong>e studies we, estimated the odds ratio of ever versus neverbreastfeed<strong>in</strong>g. 194,197,199-201,210 If we exclude these five studies from the meta-analysis, a total of2,582 cases <strong>and</strong> 4,138 controls rema<strong>in</strong>ed; <strong>and</strong> the association between breastfeed<strong>in</strong>g <strong>and</strong> reducedovarian cancer risk was no longer statistically significant (OR adj 0.80, 95%CI 0.59 – 1.09) 195,204-206 Aga<strong>in</strong>, there was a statistically significant heterogeneity among the four rema<strong>in</strong><strong>in</strong>g studies(p
Figure 12. Meta-Analysis of case-control studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> maternalovarian cancer risk: ever breastfed versus never breastfed.Less than 12 months of cumulative breastfeed<strong>in</strong>g versus never breastfed. Cumulativebreastfeed<strong>in</strong>g for less than 12 months was not statistically significantly associated with adecreased risk of ovarian cancer <strong>in</strong> a meta-analysis of six studies, <strong>in</strong>clud<strong>in</strong>g 1,911 cases <strong>and</strong>5,007 controls <strong>in</strong> total (OR adj 0.95; 95%CI: 0.80 – 1.12). (Figure 13) The odds ratios for thiscomparison were estimated for three of the six studies. 194,195,200,201 There was no statisticallysignificant heterogeneity between the six studies. Two studies (Chiaffar<strong>in</strong>o 2005 195 <strong>and</strong> Hartge1989 199 ) were <strong>in</strong>cluded <strong>in</strong> this meta-analysis despite the fact that they used as cutoffs shortercumulative duration of breastfeed<strong>in</strong>g (10 <strong>and</strong> 9 months, respectively). Exclud<strong>in</strong>g them, thesummary of the adjusted odds ratio rema<strong>in</strong>ed statistically non-significant (0.87, 95%CI 0.74 -1.02).143
Figure 13. Meta-Analysis of case-control studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> maternalovarian cancer risk: breastfed less than 12 months (cumulative duration) versus never breastfedTwo studies (Chiaffar<strong>in</strong>o 2005 195 <strong>and</strong> Hartge 1989 199 ) were <strong>in</strong>cluded <strong>in</strong> this meta-analysis despite the fact that theyused as cutoffs shorter cumulative different than 12 months (10 <strong>and</strong> 9 months, respectively). A sensitivity analysisthat excluded them yielded similar <strong>in</strong>ferences (summary of adjusted odds ratios 0.87 [95%CI 0.74, 1.02]).At least 12 months of cumulative breastfeed<strong>in</strong>g versus never breastfed. Six studies <strong>in</strong>clud<strong>in</strong>g1,650 cases <strong>and</strong> 4,575 controls provided adjusted odds ratios for this comparison, 194,197,210 orallowed an approximation. 195,199-201 (Figure 14) <strong>Breastfeed<strong>in</strong>g</strong> of at least 12 months cumulativeduration was associated with 28% lower odds for ovarian cancer (OR adj 0.72, 95%CI 0.54 –0.97). There was a statistically significant heterogeneity across the six studies. Two studies(Chiaffar<strong>in</strong>o 2005 195 <strong>and</strong> Hartge 1989 199 ) were <strong>in</strong>cluded <strong>in</strong> this meta-analysis despite the fact thatthey used as cutoffs shorter cumulative duration of breastfeed<strong>in</strong>g (10 <strong>and</strong> 9 months,respectively). Exclud<strong>in</strong>g them, the summary adjusted odds ratio was even more suggestive of aprotective association (0.63 [95%CI 0.50, 0.79]).144
Figure 14. Meta-Analysis of case-control studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> maternalovarian cancer risk: breastfed at least 12 months (cumulative duration) versus never breastfed.Two studies (Chiaffar<strong>in</strong>o 2005 195 <strong>and</strong> Hartge 1989 199 ) were <strong>in</strong>cluded <strong>in</strong> this meta-analysis despite the fact that theyused as cutoffs shorter cumulative different than 12 months (10 <strong>and</strong> 9 months, respectively). A sensitivity analysisthat excluded them yielded similar <strong>in</strong>ferences (summary of adjusted odds ratios 0.63 [95%CI 0.50, 0.79]).Subgroup analyses <strong>and</strong> additional resultsPre- versus post-menopausal women (Table 36). Three studies reported on the risk of ovariancancer stratified by menopausal status. There were sporadic statistically significant associationsbetween specific categories of breastfeed<strong>in</strong>g duration <strong>and</strong> reduced risk for ovarian cancer <strong>in</strong>Sik<strong>in</strong>d 1997 204 <strong>and</strong> Tung 2005. 207 Tung 2005 reported a significant dose-response trend between<strong>in</strong>creas<strong>in</strong>g breastfeed<strong>in</strong>g duration <strong>and</strong> reduction <strong>in</strong> maternal ovarian cancer risk for postmenopausalwomen (P value for trend = 0.003). No statistically significant dose-response trendswere found <strong>in</strong> the postmenopausal stratum of Tung 2005 <strong>and</strong> <strong>in</strong> both strata <strong>in</strong> the other twostudies. Wynder 1969 reported that <strong>in</strong> premenopausal women, 10 percent of the cases versusseven percent of the controls breastfed for 12 months or more; 209 for postmenopausal women, 24percent of the cases versus 21 percent of the controls breastfed for 12 months or more. Nostatistical comparison was reported.Risk by histologic type (Table 37). Five studies reported the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> the risk of ovarian cancer subgrouped by tumor histology. 194,195,201,205-207Comparisons between tumor types <strong>in</strong>cluded muc<strong>in</strong>ous versus nonmuc<strong>in</strong>ous, <strong>and</strong> <strong>in</strong>vasive versusborderl<strong>in</strong>e tumors. Data were limited to allow robust conclusions per histologic type. Moreover,these analyses were subgroup analyses, <strong>and</strong> therefore, should be viewed as hypothesis form<strong>in</strong>gobservations <strong>and</strong> be <strong>in</strong>terpreted conservatively.Sporadic associations between specific durations or breastfeed<strong>in</strong>g <strong>and</strong> reduced risk forhistological subtypes were reported <strong>in</strong> all studies except for Chiaffar<strong>in</strong>o 2005. <strong>Breastfeed<strong>in</strong>g</strong> wasnot protective for muc<strong>in</strong>ous or serous cancers consistently across the five studies. Increasedduration of breastfeed<strong>in</strong>g was associated with reduced risk for non-muc<strong>in</strong>ous cancers <strong>in</strong> Tung2003 (P for trend < 0.001). Titus-Ernstoff 2001 reported an association of breastfeed<strong>in</strong>g withreduced risk for comb<strong>in</strong>ed endometrioid <strong>and</strong> clear cell carc<strong>in</strong>omas, <strong>and</strong> Riman 2002 reported an145
association with reduced risk for clear cell ovarian cancer for a specific duration of cumulativebreastfeed<strong>in</strong>g (5 months).Pooled analysis of subgroups (Table 38). Secondary subgroup analyses were conducted ondifferent racial groups <strong>in</strong> three studies. John 1993 studied 53 cases of ovarian cancer <strong>in</strong> blackwomen us<strong>in</strong>g data from seven case-control studies, 211 whereas Whittemore 1992 exam<strong>in</strong>ed dataof white women from the same studies <strong>and</strong> added the cases from five additional studies for acomb<strong>in</strong>ed population of 1,071 cases. Ever hav<strong>in</strong>g breastfed was not associated with the risk ofdevelopment of ovarian cancer <strong>in</strong> black women but was reported to reduce the risk for whitewomen. Whittemore 1992 divided the sample <strong>in</strong>to hospital <strong>and</strong> population subjects, the oddsratio for those who breastfed their <strong>in</strong>fants compared with those who did not <strong>in</strong> the developmentof ovarian cancer were 0.73 (95%CI 0.51-1.0) <strong>and</strong> 0.81 (95%CI 0.68-0.95), respectively. 212Modugno 2003 analyzed 242 Jewish women from five studies conducted <strong>in</strong> Israel <strong>and</strong> the UnitedStates. 213 This was a cohort study compar<strong>in</strong>g carriers <strong>and</strong> noncarriers of BRCA1 or BRCA2. Thestudy did not f<strong>in</strong>d a difference between carriers <strong>and</strong> noncarriers of BRCA1 or BRCA2 mutation<strong>in</strong> the breastfeed<strong>in</strong>g status or breastfeed<strong>in</strong>g duration <strong>and</strong> the risk of ovarian cancer.ConclusionWe reviewed 15 case-control studies that exam<strong>in</strong>ed the relationship between breastfeed<strong>in</strong>g<strong>and</strong> the risk of ovarian cancer, <strong>and</strong> performed quantitative syntheses us<strong>in</strong>g data from n<strong>in</strong>e studiesthat adjusted for potential confounders. The overall result from the n<strong>in</strong>e studies suggests anassociation between breastfeed<strong>in</strong>g <strong>and</strong> a reduction <strong>in</strong> the risk of ovarian cancer. Because thereport<strong>in</strong>g <strong>in</strong> these studies was <strong>in</strong>consistent, we needed to estimate the odds ratios <strong>in</strong> five of n<strong>in</strong>estudies for the meta-analysis. Exclud<strong>in</strong>g these five studies results <strong>in</strong> loss of statisticalsignificance for this association.There was <strong>in</strong>direct evidence for a dose-response relationship between breastfeed<strong>in</strong>g <strong>and</strong> areduction <strong>in</strong> the risk of ovarian cancer. <strong>Breastfeed<strong>in</strong>g</strong> of less than 12 months (cumulativeduration) was not statistically significantly associated with a reduction <strong>in</strong> the risk of ovariancancer <strong>in</strong> a meta-analysis of six studies. However, breastfeed<strong>in</strong>g of more than 12 months(cumulative duration) was associated with a reduction <strong>in</strong> the risk of ovarian cancer, comparedwith never breastfeed<strong>in</strong>g. We caution that the cutoff of 12 months was arbitrary, <strong>and</strong> the oddsratios were estimated <strong>in</strong> half of these studies. Therefore, the <strong>in</strong>terpretation of the postulated doseresponserelationship should be done with caution.F<strong>in</strong>ally, several studies assessed subgroups of pre- <strong>and</strong> post-menopausal women <strong>and</strong> ovariancancer histology. Overall, few sporadic statistically significant associations were identified <strong>in</strong>some subgroups <strong>and</strong> for some specific durations of breastfeed<strong>in</strong>g. These f<strong>in</strong>d<strong>in</strong>gs do notconstitute robust evidence.We conclude that there is some evidence to suggest an association between breastfeed<strong>in</strong>g <strong>and</strong>a reduction <strong>in</strong> the risk of maternal ovarian cancer. However, one must be cautious <strong>in</strong> <strong>in</strong>terpret<strong>in</strong>gthis association because it was largely based on estimations of the odds ratios from retrospectivestudies.146
147Table 35. Summary of case-control studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> maternal ovarian cancerAuthorYearCountryChiaffar<strong>in</strong>o2005ItalyRiman2002SwedenSisk<strong>in</strong>d1997AustraliaCases(N)Controls(N)1,028 2,390655 3899618 724Def<strong>in</strong>ition ofdiseaseEpithelial ovariancancer based onhistologyEpithelial ovariancancer based onhistologyEpithelial ovariancancer based onhistologyMean / medianage at dx ofdisease(year)Cases 62Controls 63Cases 57Controls 56<strong>Breastfeed<strong>in</strong>g</strong>groupEver BFBF 1-4 mo56 a BF 5-8 moBF 9-16 moBF ≥17 moBF 1-5 moBF 6-11 moBF ≥12 moEver BFBF 1-6 moBF 7-12 moBF 13-24 moBF 25-36 mo> 36 moComparatorgroup Confounders adjustedNever BFNever BFBF
Table 35. Cont<strong>in</strong>uedAuthorYearCountryCases(N)Controls(N)Def<strong>in</strong>ition ofdiseaseMean / medianage at dx ofdisease(year)<strong>Breastfeed<strong>in</strong>g</strong>groupComparatorgroup Confounders adjustedAdjustedodds ratio(95% CI)Quality148Tung2003;2005USANess2000Modugno2001USARisch1994Canada558 607531 1190450 564Epithelial ovariancancer based onhistologyEpithelial ovariancancer based onhistologyEpithelial ovariancancer based onhistologyCasesMuc<strong>in</strong>ous 50Nonmuc<strong>in</strong>ous 55Controls 56CasesInvasive 53Borderl<strong>in</strong>e 45Controls 49Cases 57Controls 58Ever BFBF ≤5 moBF 6-16 moBF >16 moBF 1-5 moBF 6-11 moBF 12-23 moBF ≥24 moTotal durationBF of cases(0.51 yr)BF duration/pregnancy ofcases (2.24mo)Never BFNever BFTotalduration ofcontrols(0.65 yr)BF duration/pregnancyof controls(2.72 mo)Age, ethnicity, study site,education, oralcontraceptive use, tuballigationAge, number ofpregnancies, familyhistory of ovarian cancer,race, oral contraceptiveuse, tubal ligation,hysterectomy,breastfeed<strong>in</strong>gRegression adjusted for3 age groups, cont<strong>in</strong>uousvariables age, totalduration of oralcontraceptive use0.6(0.4-0.7)0.6(0.4-0.9)0.6(0.4-0.9)0.6(0.4-0.8)0.9(0.7-1.2)0.9(0.6-1.3)0.7(0.5-1.1)0.6(0.4-1.0)0.89(0.75-1.05)0.87(0.76-0.99BBB
149Table 35. Cont<strong>in</strong>uedAuthorYearCountryGw<strong>in</strong>n1990USATitus-Ernstoff2001USAGreggi2000ItalyHartge1989USACases(N)Controls(N)436 3833378 417330 721203 257Def<strong>in</strong>ition ofdiseaseEpithelial ovariancancer based onhistologyEpithelial ovariancancer based onpathology or slidesOvarian cancerbased on histologyEpithelial ovariancancer based onhistologyMean or medianage at dx ofdisease(year)20-54Cases 20-74Controls matchedwith<strong>in</strong> 4 years54Cases 54Controls 55<strong>Breastfeed<strong>in</strong>g</strong>groupEver BFComparatorgroupConfoundersadjustedAdjusted oddsratio (95% CI)Relative risk0.6(0.5-0.8)0.6(0.5-0.9)Pregnancy, oralcontraceptiveBF 1-2 moNever BF use, age, <strong>and</strong>BF 3-5 mo age-pregnancy 0.8BF 6-11 mo <strong>in</strong>teraction0.8BF 12-23 mo 0.7BF ≥24 mo0.30.7Ever BF(0.5-1.0)0.9BF 6 mo0.7(0.4-1.0)2.4% Reduction risk per month BFBF ≤12 mo Age, education,parity, oral0.8 (1.0-1.1)BF >12 mocontraceptiveNever BFuse, family 0.5history of (0.4-0.8)ovarian cancerBF 1-9 moBF 10-18 moBF 19-110 moNever BFAge, race,parity, difficultyconceiv<strong>in</strong>g, oralcontraceptives,surgicalmenopause,HRT, or familyhistory ofovarian canceras neededRate ratio0.8(0.5-1.2)0.5(0.2-0.9)1.1(0.5-2.6)QualityBBBB
150Table 35. Cont<strong>in</strong>uedAuthorYearCountryYen2003TaiwanRisch1983USACramer1983USAWynder1969USAWest1966USACases(N)Controls(N)86 369H284 705P215 215P158 300H76 76HDef<strong>in</strong>ition ofdiseaseEpithelial ovariancancer based onhistologyMalignant &borderl<strong>in</strong>emalignant epithelialovarian cancerEpithelial ovariancancerEpithelial ovariancancer based onhistologyMalignant ovariancancer based onpathologyMean ormedian ageat dx ofdisease(year)Cases 47Controls 44Cases 20-74Controls 21-75Cases 52Control NDCases 53Controls 50Dx, diagnosis; BF, breastfeed<strong>in</strong>g; Mo, month(s); Yr, year(s)<strong>Breastfeed<strong>in</strong>g</strong>groupBF ≤1 yrBF >1 yrBF ≥3 moComparatorgroupNever BFBF 0.3Adjustedodds ratio(95% CI)0.82(0.35-1.9)0.55(0.29-1.01)Relative risk0.69(0.50-0.96)Cruderelative risk1.11(0.70-1.76)Quality--- ND --- C--- None --- CBCCa Chiaffar<strong>in</strong>o -dx with<strong>in</strong> past year, Risch –dx with<strong>in</strong> past 18 monthsb Nulliparous <strong>and</strong> parous women
151Table 36. Summary of case-control studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> maternal ovarian cancer by menopausal statusMean orAuthormedian ageCases Controls Def<strong>in</strong>ition of<strong>Breastfeed<strong>in</strong>g</strong> Comparator Confoundersp forYearat dx ofORadj (95% CI)(N)(N)diseasegroup group adjustedtrendCountrydisease(year)Tung2003;2005USASisk<strong>in</strong>d1997AustraliaWynder1969USAPremenopausal217Postmenopausal341Premenopausal215Postmenopausal403Premenopausal55Postmenopausal95PremenopausalBF 6-12 mo Never BF Age, ethnicity, 0.81 (0.43-1.54)BF ≤6 mo 0.96 (0.49-1.85)256 Epithelial ovarian Cases 55BF >12 mostudy site,0.46 (0.22-0.97)cancer based on Controls 55education, tubalPostmenopausalBF 6-12 mo Never BF ovulationBF ≤6 mo 0.64 (0.41-1.02)histologyligation, HRT,0.60 (0.36-1.00)351BF >12 mo0.69 (0.43-1.12)BF 1-6 mo 0.75 (0.46-1.21)PremenopausalNever BFBF 7-12 mo 0.53 (0.31-0.94)264BF 13-24 mo Age, parity, age at 1.03 (0.54-1.95)BF >24 mo1Epithelial ovarianbirth, education,0.29 (0.08-1.04)Cases 58oral contraceptivecancer based onBF 1-6 mo 0.98 (0.65-1.47)Controls 57use, smok<strong>in</strong>gPostmenopausalBF 13-24 mo Never BF menopausal statushistologyBF 7-12 mohistory,0.83 (0.54-1.26)0.88 (0.56-1.38)460BF 25-36 mo 0.93 (0.46-1.88)BF >36 mo1.27 (0.50-3.2)PremenopausalBF >12 mo9% Cases957% ControlsPostmenopausal205Epithelial ovariancancer based onhistologyCases 52Control NDDx, diagnosis; BF, breastfeed<strong>in</strong>g; Mo, month(s); Yr, year(s)BF >12 mo24% Cases21% Controls0.0030.08NDNDQuality--- ND --- --- CBB
152Table 37. Summary of case-control studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> maternal ovarian cancer by histologic typeAuthorMean age at dxAdjustedCases Controls<strong>Breastfeed<strong>in</strong>g</strong> Comparato ConfoundersYearof disease Histologic type (n)odds ratio(N) (N)group r group adjustedCountry(year)(95% CI)Chiaffar<strong>in</strong>o2005ItalyTitus-Ernstoff2001USATung2003USANess2000Modugno2001USA1028 2390528 523558 607531 1,190Cases 56Controls 57Cases 20-74Controlsmatched with<strong>in</strong> 4yearsCasesMuc<strong>in</strong>ous 50Nonmuc<strong>in</strong>ous55Controls 56CasesInvasive 53Borderl<strong>in</strong>e 45Controls 49Serous (492)Muc<strong>in</strong>ous (81)Ever BFNever BFAge, center,education, parity,oral contraceptiveuse, family hx ofovarian/ breastcancer <strong>in</strong> 1 ºrelatives1.1(0.85-1.48)1.59(0.82-3.07)p fortrendSerous borderl<strong>in</strong>e (86) 0.8 (0.4-1.6) 0.61Serous <strong>in</strong>vasive (229) 1.0 (0.6-1.4) 0.34Muc<strong>in</strong>ous (83) Ever BF Never BF Age, state, parity 0.6 (0.3-1.2) 0.88Endometrioid/clear cell(130)Muc<strong>in</strong>ous (109)Nonmuc<strong>in</strong>ous (449)Borderl<strong>in</strong>eSerous (79)Muc<strong>in</strong>ous (60)InvasiveSerous (278)Muc<strong>in</strong>ous (52)Endometrioid (136)Other (150)Ever BFBF ≤5 moBF 6-16 moBF >16 moEver BFBF ≤5 moBF 6-16 moBF >16 moMonths BFMonths BFNever BFNever BFAge, ethnicity, studysite, education, oralcontraceptive use,tubal ligationAge, number of livebirths, years of oralcontraceptive use,years of noncontraceptiveestrogen use <strong>and</strong>months breastfed,tubal ligation,hysterectomy,family history ofovarian <strong>and</strong> breastcancer, ethnicity0.71ND0.4 (0.2-0.7) 0.040.8 (0.5-1.4)0.6 (0.4-1.4)0.7 (0.3-1.3)0.9 (0.8-1.8)0.8 (0.5-1.4)0.7 (0.4-0.9)0.5 (0.3-0.7)0.4 (0.3-0.7)0.95*(0.92-1.00)0.99(0.96-1.02)1.00(0.99-1.01)1.01(0.98-1.03)0.98(0.95-1.00)0.97*(0.94-1.00)0.990.0005NDNDQualityBBBB
153Table 37. Cont<strong>in</strong>uedAuthorCases ControlsYear(N) (N)CountryRiman2002Sweden* p
154Table 38. Summary of pooled-analysis of case-control studies on the relationship between breastfeed<strong>in</strong>g <strong>and</strong> ovarian cancer by population subgroupsMean age atAuthorAdjustedPopulation Cases Controls Def<strong>in</strong>ition of dx of <strong>Breastfeed<strong>in</strong>g</strong> Comparator ConfoundersYearodds ratiocharacteristic (N)(N)disease disease group group adjustedCountry(95% CI)(year)QualityEver BF 0.73 (0.51-1.0)BF 1-5 mo 0.95 (0.62-1.5)201 1,081BF 6-11 mo Never BF0.40 (0.20-0.78)BF 12-23 mo 0.70 (0.36-1.4)Whittemore a1992USAJohn b1993USAWhite870 4,624Black 53 259Epithelialovarian cancerEpithelialovarian cancerNDCasesInvasive 53Borderl<strong>in</strong>e 37Controls NDBF ≥24 moAge, study, 0.59 (0.22-1.6)Ever BFparity, oral 0.81 (0.68-contraceptive 0.95)BF 1-5 mo use 0.87 (0.72-1.1)BF 6-11 mo Never BF0.74 (0.57-0.96)BF 12-23 mo0.69 (0.51-0.94)BF ≥24 mo0.74 (0.49-1.1)Ever BF 0.90 (0.42-1.9)Study, birthBF 1-5 mo Never BF year, reference 1.0 (0.39-2.6)≥6 moage, parity0.85 (0.36-2.0)BBModugno c2003USA, IsraelJewish 95 147Epithelialovarian cancerCasesBRCA1 51BRCA2 61ControlsBRCA- 58BRCA1Ever BFDuration BFBRCA2Ever BFDuration BFBRCA1/2Ever BFDuration BFBRCA-BRCA-BRCA-Age atdiagnosis, yearof birth,number of livebirths, oralcontraceptiveuse, history oftubal ligationH-hospital or cl<strong>in</strong>ic controls; P, population controlsa Sample also <strong>in</strong>cluded Cramer 1983 <strong>and</strong> Hartge 1989; b Sample also <strong>in</strong>cluded Ness 2000.c Cases def<strong>in</strong>ed as Jewish women with ovarian cancer <strong>and</strong> BRCA1 or BRCA2 mutation, controls def<strong>in</strong>ed as ovarian cancer cases only.1.36(0.68-2.73)1.01(0.98-1.04)0.70(0.28-1.72)1.02(0.99-1.05)1.09(0.61-1.97)1.02(0.99-1.04)B
Other ResearchAn important area of research that is not systematically reviewed <strong>in</strong> this report is the use ofbreastfeed<strong>in</strong>g promotion <strong>in</strong>tervention trial to measure health effects (this topic will be covered <strong>in</strong>a separate report). The best known of these types of studies is the Promotion of <strong>Breastfeed<strong>in</strong>g</strong>Intervention Trial (PROBIT) conducted <strong>in</strong> the Republic of Belarus. 17 This was a clusterr<strong>and</strong>omized controlled trial of 34 maternal hospitals <strong>and</strong> associated polycl<strong>in</strong>ics with a total of17,046 mother-<strong>in</strong>fant pairs consist<strong>in</strong>g of full term <strong>in</strong>fants <strong>and</strong> their healthy mothers who <strong>in</strong>tendedto breastfeed. The experimental <strong>in</strong>tervention was modeled on the Baby-Friendly Initiative of theWorld <strong>Health</strong> Organization <strong>and</strong> United Nations Children’s Fund, which emphasizes assistancewith <strong>in</strong>itiat<strong>in</strong>g <strong>and</strong> ma<strong>in</strong>ta<strong>in</strong><strong>in</strong>g breastfeed<strong>in</strong>g <strong>and</strong> lactation <strong>and</strong> postnatal breastfeed<strong>in</strong>g support.The control <strong>in</strong>tervention was cont<strong>in</strong>uation of the usual <strong>in</strong>fant feed<strong>in</strong>g practices. Results from thestudy showed that <strong>in</strong>fants <strong>in</strong> the <strong>in</strong>tervention arm were more likely to be exclusively breastfed at3 months (43.3% vs. 6.4%; P
Chapter 4. DiscussionTwenty-three outcomes were analyzed <strong>in</strong> this report. Approximately 400 articles wouldneeded to be reviewed if only articles with primary data were <strong>in</strong>cluded; this is a much largervolume of literature than can be feasibly reviewed with<strong>in</strong> the time period of this report. With theavailability of many published systematic reviews on breastfeed<strong>in</strong>g, we used this literature as theevidence for a large number of outcomes, supplemented by updates of these systematic reviewswith new primary studies. We performed several new systematic reviews on outcomes notpreviously reported. The exist<strong>in</strong>g systematic reviews were conducted over a wide span of time<strong>and</strong> by diverse groups of <strong>in</strong>vestigators; there were large variations <strong>in</strong> the approach <strong>and</strong> quality ofthese reviews.Even though we have assessed the report<strong>in</strong>g quality of these systematic reviews (us<strong>in</strong>gst<strong>and</strong>ards of report<strong>in</strong>g of systematic reviews of observational studies – MOOSE statement 22 <strong>and</strong>additional parameters that we devised), we cannot reliably know the validity of the reportedsummary data without know<strong>in</strong>g the details of the primary studies. A number of systematicreviews reported that <strong>in</strong>clusion <strong>and</strong> exclusion of some primary studies were reached byconsensus between at least two <strong>in</strong>vestigators. Without know<strong>in</strong>g the details of how thoseconsensuses were reached, it would be difficult to replicate the f<strong>in</strong>d<strong>in</strong>gs <strong>in</strong> those reviews as it isquite plausible that someone who is not familiar with the details of the consensus might havecome up with a different set of studies for <strong>in</strong>clusion <strong>in</strong> the review. It should also be stressed thata well-performed systematic review does not necessarily imply that the body of evidence for aparticular outcome of <strong>in</strong>terest is of high quality. While some systematic reviews assessed thequality of the <strong>in</strong>dividual studies, the methods used varied. Any systematic review is limited bythe quality of the primary studies <strong>in</strong>cluded <strong>in</strong> the review. Unless the method used to assess thequality of the primary studies is transparent <strong>and</strong> the details made available for exam<strong>in</strong>ation, itwould be difficult to reliably determ<strong>in</strong>e the validity of the conclusions.In most circumstances, it would be unethical to r<strong>and</strong>omize mother-<strong>in</strong>fant pair <strong>in</strong>tobreastfeed<strong>in</strong>g (or breast milk feed<strong>in</strong>g) or not breastfeed<strong>in</strong>g arm <strong>in</strong> a trial. Therefore, thebreastfeed<strong>in</strong>g literature is primarily comprised of observational studies, either cohort or casecontrolstudies. There are a number of potential deficiencies related to the study designs thatcould limit the <strong>in</strong>ternal validity <strong>and</strong> the generalizability of the f<strong>in</strong>d<strong>in</strong>gs. Some of these potentialdeficiencies <strong>in</strong>clude (1) misclassification of exposure; (2) confound<strong>in</strong>g from the process of selfselection;(3) residual confound<strong>in</strong>g; <strong>and</strong> (4) <strong>in</strong>sufficient statistical power.Misclassification of exposure (breastfeed<strong>in</strong>g status/duration) is likely <strong>in</strong> the studies reviewed<strong>in</strong> this report. Most studies relied on mothers’ recall for the data on breastfeed<strong>in</strong>g. Recall is proneto error. One study from South Africa reported that at 6 to 9 months post-delivery, 13 percent ofmothers could not remember the specific tim<strong>in</strong>g when they gave someth<strong>in</strong>g other than breastmilk to their <strong>in</strong>fant. In those mothers who could remember, 57 percent of them overestimated theduration of exclusive breastfeed<strong>in</strong>g by about 8 weeks, <strong>and</strong> 15 percent underestimated theduration by about 3 weeks. 215 Misclassification, may bias the effect estimate; particularly if therecall error is nonr<strong>and</strong>om, such as <strong>in</strong> studies where cases are more likely to underestimate theamount of breastfeed<strong>in</strong>g than controls (for an example, see Norris <strong>and</strong> Scott 1996 90 ).In studies where subjects were self-selected, there could be confound<strong>in</strong>g from the process ofself-selection (e.g., if subjects who perceive their diseases are due to a lack of breastfeed<strong>in</strong>g weremore likely to participate <strong>in</strong> the study).157
Residual confound<strong>in</strong>g is a possibility for all observational studies, because it is difficult (ifnot impossible) to control for all potential confound<strong>in</strong>g variables <strong>in</strong> these studies. Although it ispossible to control for differences <strong>in</strong> demographic factors, it may not be possible to control forbehavioral factors <strong>in</strong>tr<strong>in</strong>sic <strong>in</strong> the desire to breastfeed.Large sample size is often needed to exam<strong>in</strong>e the relationship between breastfeed<strong>in</strong>g <strong>and</strong>various diseases <strong>and</strong> health conditions because of the need to adjust for numerous confounders tom<strong>in</strong>imize all the potential biases described earlier. It is impossible to predict how these differentlimitations may <strong>in</strong>teract to <strong>in</strong>crease or decrease the effect estimate.Compound<strong>in</strong>g the issue of less-than-ideal study design are the heterogeneity of the breastmilk itself <strong>and</strong> differences <strong>in</strong> how the feed<strong>in</strong>gs of breast milk were def<strong>in</strong>ed across differentstudies. The composition of breast milk varies both with<strong>in</strong> <strong>and</strong> between <strong>in</strong>dividuals. 216,217 Thecomposition could vary depend<strong>in</strong>g on preterm versus term delivery, the maternal diet, maternalbody weight, time of day, beg<strong>in</strong>n<strong>in</strong>g versus near the end of feed, first few months of lactationversus later lactation, milk volume, <strong>and</strong> numerous other factors. On the other h<strong>and</strong>, thecomposition of formulas has also changed significantly over the last twenty years. For example,contemporary formulas have added <strong>in</strong>gredients like nucleotides <strong>and</strong> long-cha<strong>in</strong> polyunsaturatedfatty acids that were absent from older formulations. How the heterogeneity both with<strong>in</strong> <strong>and</strong>between comparators would affect the effect estimate is unclear. Also, studies def<strong>in</strong>edbreastfeed<strong>in</strong>g differently. Many studies did not have a category of “exclusive breastfeed<strong>in</strong>g”. Inthe ones that did have this category, “exclusive” could mean no supplement of any k<strong>in</strong>d<strong>in</strong>clud<strong>in</strong>g water or it could mean occasional formula supplement is permissible. This mix<strong>in</strong>g <strong>in</strong>of formula <strong>in</strong> the “exclusive” breastfeed<strong>in</strong>g group may potentially dilute the true effect of breastmilk <strong>and</strong> bias the results toward the null f<strong>in</strong>d<strong>in</strong>g. In addition, no study <strong>in</strong> this review exam<strong>in</strong>edthe differences between actually breastfeed<strong>in</strong>g an <strong>in</strong>fant <strong>and</strong> bottle or gavage feed<strong>in</strong>g an <strong>in</strong>fantwith breast milk. How the act of breastfeed<strong>in</strong>g itself plays a role <strong>in</strong> the different effects measuredis unknown.We have summarized the effects of breastfeed<strong>in</strong>g (or breast milk feed<strong>in</strong>g) on a large numberof <strong>in</strong>fant <strong>and</strong> maternal outcomes. Some of the outcomes are well def<strong>in</strong>ed <strong>and</strong> specific (e.g.,childhood acute lymphocytic leukemia, breast cancer); <strong>and</strong> some are not so well def<strong>in</strong>ed <strong>and</strong>non-specific (e.g., asthma, gastro<strong>in</strong>test<strong>in</strong>al <strong>in</strong>fections). When the reported outcome is welldef<strong>in</strong>ed <strong>and</strong> specific, it lends confidence that the effect reported is valid for that outcome. Whenthe reported outcome is not well def<strong>in</strong>ed, one might have some reservation regard<strong>in</strong>g the validityof the measured effect for that outcome.For all the above reasons, we f<strong>in</strong>d that there is a wide range of quality of evidence for thedifferent outcomes exam<strong>in</strong>ed <strong>in</strong> this review.For severe lower respiratory tract diseases, good quality studies did f<strong>in</strong>d a relationshipbetween breastfeed<strong>in</strong>g <strong>and</strong> a reduction <strong>in</strong> the risk of hospitalization secondary to lowerrespiratory tract diseases.For acute otitis media, the results from our meta-analyses of cohort studies of good <strong>and</strong>moderate methodological quality showed that breastfeed<strong>in</strong>g was associated with a significantreduction <strong>in</strong> the risk of acute otitis media. Compar<strong>in</strong>g ever breastfeed<strong>in</strong>g with exclusive bottlefeed<strong>in</strong>g,the pooled adjusted odds ratio of acute otitis media was 0.77 (95%CI 0.64 - 0.91). Whencompar<strong>in</strong>g exclusive breastfeed<strong>in</strong>g with exclusive bottle-feed<strong>in</strong>g, either for more than 3 or 6months duration, the pooled odds ratio was 0.50 (95%CI 0.36 - 0.70).For non-specific gastroenteritis, one systematic review identified three primary studies thatcontrolled for potential confounders. These studies reported that there was a reduction <strong>in</strong> the risk158
of non-specific gastro<strong>in</strong>test<strong>in</strong>al <strong>in</strong>fections dur<strong>in</strong>g the first year of life <strong>in</strong> breastfed <strong>in</strong>fants fromdeveloped countries, although the observed range of risk reduction was wide. However, onerecent case-control study of 304 <strong>in</strong>fants (167 cases <strong>and</strong> 137 controls) from Engl<strong>and</strong> showed thatthe <strong>in</strong>fants who were breastfeed<strong>in</strong>g had a reduced risk of diarrhea compared to <strong>in</strong>fants who werenot breastfeed<strong>in</strong>g (adjusted OR 0.36, 95% CI 0.18 to 0.74, P=0.005). The result was adjusted forage, sex, social class, contact with person <strong>in</strong> <strong>and</strong> outside household, <strong>and</strong> other factors. Also,analysis of nested observational cohorts from the Belarus trial showed that the group of <strong>in</strong>fantswho were exclusively breastfed for at least 6 months compared to the group of <strong>in</strong>fants who werebreastfed for 3 to 6 months had a statistically significant reduced risk of one or more episodes ofgastro<strong>in</strong>test<strong>in</strong>al <strong>in</strong>fection <strong>in</strong> the first 12 months of life (adjusted OR = 0.61; 95%CI 0.41-0.93). 214The result was adjusted for geographic orig<strong>in</strong>, urban versus rural location, maternal education,<strong>and</strong> number of sibl<strong>in</strong>gs <strong>in</strong> the household.For necrotiz<strong>in</strong>g enterocolitis (NEC) <strong>in</strong> preterm <strong>in</strong>fants, our meta-analysis of four RCTs founda marg<strong>in</strong>ally statistically significant reduction (5% risk difference) of the NEC risk with breastmilk feed<strong>in</strong>g. Tak<strong>in</strong>g <strong>in</strong>to account the high case-fatality rate of NEC, we consider this estimate isof mean<strong>in</strong>gful cl<strong>in</strong>ical difference. However, One must be cognizant of the cl<strong>in</strong>ical heterogeneityunderly<strong>in</strong>g these RCTs <strong>in</strong> <strong>in</strong>terpret<strong>in</strong>g the f<strong>in</strong>d<strong>in</strong>gs of the meta-analysis. Three of the four RCTswere published <strong>in</strong> the 1980’s. Whether <strong>in</strong>fants born <strong>in</strong> the early 1980’s should be comb<strong>in</strong>ed with<strong>in</strong>fants born <strong>in</strong> the late 1990’s <strong>in</strong>to a meta-analysis is debatable. Neonatal care has madetremendous strides <strong>in</strong> the last 20 years. Present day preterm formula milk is vastly different frompreterm formula milk 20 years ago. All the studies had patient populations that were quiteheterogeneous, gestational age ranged from 23 weeks to more than 33 weeks <strong>and</strong> birth weightranged from less than 1000 g to more than 1,600 g. One study <strong>in</strong>cluded only “healthy” <strong>in</strong>fants,another <strong>in</strong>cluded both “healthy” <strong>and</strong> “ill” <strong>in</strong>fants. In addition, the types of breast milk, themethods of feed<strong>in</strong>gs, <strong>and</strong> the times of enrollments <strong>in</strong>to the trials were all different. How theheterogeneity <strong>in</strong> the studies affected the f<strong>in</strong>d<strong>in</strong>gs is not clear. In addition, studies exam<strong>in</strong><strong>in</strong>g theissue of NEC were frequently also exam<strong>in</strong><strong>in</strong>g the issue of neonatal sepsis, as it is not possible tohave NEC without concomitant sepsis. In future studies, it would be worthwhile to exam<strong>in</strong>e therelationship of breast milk exposure <strong>and</strong> sepsis <strong>in</strong> preterm <strong>in</strong>fants.For asthma, our subgroup analysis showed that breastfeed<strong>in</strong>g was associated with a reducedrisk <strong>in</strong> children under 10 years of age with a positive family history. However, this associationdoes not hold true for older children as one publication reported a very large adjusted odds ratio(OR 8.7, 95%CI 3.4 – 22.2) for develop<strong>in</strong>g asthma <strong>in</strong> children 6 to 13 years of age who wereexclusively breastfed for at least 4 months <strong>and</strong> had a positive history of maternal asthma. 56 Therelationship of breastfeed<strong>in</strong>g, maternal history, <strong>and</strong> long-term outcome of asthma bears further<strong>in</strong>vestigation.For atopic dermatitis, available evidence from one well-performed systematic review on fullterm <strong>in</strong>fants <strong>in</strong> developed countries suggest that exclusive breastfeed<strong>in</strong>g for at least 3 monthsconfer a protective advantage <strong>in</strong> the development of atopic dermatitis <strong>in</strong> those subjects with afamily history of atopy. The systematic review did not make a dist<strong>in</strong>ction between atopicdermatitis of <strong>in</strong>fancy (under 2 years of age) <strong>and</strong> persistent or new atopic dermatitis at older ages.This is important because the diagnosis of atopic dermatitis <strong>in</strong> patients younger than 2 years ofage are sometimes attributed to symptoms of <strong>in</strong>fectious orig<strong>in</strong> <strong>and</strong> breastfeed<strong>in</strong>g may have aprotective effect aga<strong>in</strong>st <strong>in</strong>fections. But a stratified analysis by different durations of followupshowed that the risk reduction was similar <strong>in</strong> those with less than 2 years compared with morethan 2 years of followup.159
For cognitive outcome <strong>in</strong> term <strong>in</strong>fants from developed countries, sibl<strong>in</strong>g analysis <strong>and</strong>prospective studies that controlled specifically for maternal <strong>in</strong>telligence found little or noevidence to support an association between breastfeed<strong>in</strong>g <strong>and</strong> cognitive performance <strong>in</strong> children.Most of the published studies adjusted their analyses for socioeconomic status <strong>and</strong> maternaleducation but not specifically for maternal <strong>in</strong>telligence. For those studies that still reported asignificant effect after specific adjustment for maternal <strong>in</strong>telligence, residual confound<strong>in</strong>g fromother factors like different home environments cannot be ruled out.No def<strong>in</strong>itive conclusion regard<strong>in</strong>g the relationship of breast milk exposure <strong>and</strong> cognitivedevelopment <strong>in</strong> preterm <strong>in</strong>fants can be drawn at this time. Studies that controlled for maternal<strong>in</strong>telligence reported conflict<strong>in</strong>g results. In addition to maternal <strong>in</strong>telligence, comorbidities (e.g.,neurological impairment, extremely low birth weight, other neonatal illnesses), early<strong>in</strong>tervention, environmental, <strong>and</strong> socioeconomic factors should also be controlled for <strong>in</strong> future<strong>in</strong>vestigation of this relationship.For adult blood pressure, evidence suggests that there is an association between a history ofbreastfeed<strong>in</strong>g dur<strong>in</strong>g pregnancy <strong>and</strong> a small reduction <strong>in</strong> adult blood pressure, but the cl<strong>in</strong>ical orpublic health implication of this f<strong>in</strong>d<strong>in</strong>g is unclear. Furthermore, The association weakened afterstratification by study size, suggest<strong>in</strong>g the possibility of bias.For adult cholesterol, a lack of explicit analysis of potential confounders <strong>in</strong> the meta-analysishampered the conclusion drawn from the study. Therefore, the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> adult cholesterol levels cannot be adequately addressed at this time.For cardiovascular mortality <strong>in</strong> adults, the meta-analysis was limited by the statisticalheterogeneity across studies, apparent outcome modification by differences <strong>in</strong> gender (<strong>and</strong>therefore, calls <strong>in</strong>to question the appropriateness of comb<strong>in</strong><strong>in</strong>g outcomes from men <strong>and</strong> women<strong>in</strong>to a s<strong>in</strong>gle analysis), <strong>and</strong> more than 30% of the subjects dropped out <strong>in</strong> the studies. Because ofthese reasons, no def<strong>in</strong>itive conclusions can be drawn regard<strong>in</strong>g the relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> cardiovascular mortality. Further <strong>in</strong>vestigation is warranted.For Sudden <strong>Infant</strong> Death Syndrome (SIDS), our meta-analysis <strong>in</strong>cluded only studies thatreported clear def<strong>in</strong>itions of exposure, outcomes, <strong>and</strong> results adjusted for well-knownconfounders or risk factors for SIDS. The summary estimate found a statistically significantadjusted odds ratio for an association between breastfeed<strong>in</strong>g <strong>and</strong> a reduced risk of SIDS(adjusted OR 0.64, 95%CI 0.51 - 0.81). We conclude that there is a relationship betweenbreastfeed<strong>in</strong>g <strong>and</strong> a reduced risk of SIDS. One must be cautious <strong>in</strong> <strong>in</strong>terpret<strong>in</strong>g this relationship,however. As this f<strong>in</strong>d<strong>in</strong>g stems from analysis of observational studies, this f<strong>in</strong>d<strong>in</strong>g cannot provecausality. It is plausible that <strong>in</strong>fants who breastfed <strong>and</strong> breastfed well are less prone to SIDSbecause of some yet unclarified neurophysiological reasons, <strong>and</strong> not because breastfeed<strong>in</strong>g itselfdirectly confers a protective effect. Further <strong>in</strong>vestigation is warranted.For post-neonatal mortality (exclud<strong>in</strong>g SIDS), there are <strong>in</strong>sufficient data to characterize therelationship between breastfeed<strong>in</strong>g <strong>and</strong> post-neonatal <strong>in</strong>fant mortality adequately. Further<strong>in</strong>vestigation is warranted.For childhood leukemia, available evidence suggests that there is an association betweenbreastfeed<strong>in</strong>g <strong>and</strong> a reduced risk of acute lymphocytic leukemia <strong>and</strong> acute myelogenousleukemia. Our f<strong>in</strong>d<strong>in</strong>gs from the meta-analyses of the three case-controlled studies that weregraded good or fair quality by one systematic review were consistent with the results from theother meta-analysis, but with smaller effect size <strong>and</strong> smaller statistical significance. Furtherevaluation of the biological mechanisms underp<strong>in</strong>n<strong>in</strong>g this relationship while tak<strong>in</strong>g <strong>in</strong>to160
consideration potential biases can be achieved with more large-scale case-controlled studiesutiliz<strong>in</strong>g population-based <strong>and</strong> socioeconomic status-matched controls.For obesity, evidence from three systematic reviews <strong>and</strong> meta-analyses suggests that ahistory of breastfeed<strong>in</strong>g is associated with a reduction <strong>in</strong> the risk of obesity <strong>in</strong> later life.However, one must be aware of the possibility of residual confound<strong>in</strong>g <strong>in</strong> <strong>in</strong>terpret<strong>in</strong>g thisassociation. The pooled adjusted odds ratio of obesity compar<strong>in</strong>g ever breastfed to neverbreastfed was 0.76 (95%CI 0.67-0.86) <strong>in</strong> one meta-analysis <strong>and</strong> 0.93 (95%CI: 0.88–0.99) <strong>in</strong> theother. The magnitude of effects was reduced when more confounders were adjusted <strong>in</strong> theseanalyses.For type 2 diabetes, based on f<strong>in</strong>d<strong>in</strong>gs from a high-quality systematic review <strong>and</strong> metaanalysesof seven studies, early breastfeed<strong>in</strong>g was associated with a lower risk of type 2 diabetes<strong>in</strong> later life compared with those <strong>in</strong>itially formula-fed. However, only three studies appropriatelyadjusted for all the important confounders, <strong>in</strong>clud<strong>in</strong>g birth weight, parental diabetes,socioeconomic status, <strong>and</strong> <strong>in</strong>dividual or maternal body size. Even though these three studiesfound that adjustment did not alter the crude estimate, we cannot be completely confident thatpotential confound<strong>in</strong>g by birth weight <strong>and</strong> maternal factors has been ruled out for the overallpooled estimate. This potentially could exaggerate the magnitude of the association.For type 1 diabetes, even though there are some data to support that breastfeed<strong>in</strong>g for morethan 3 months is associated with a reduced risk of type 1 diabetes, this f<strong>in</strong>d<strong>in</strong>g must be<strong>in</strong>terpreted with caution because of the likelihood of recall biases <strong>and</strong> suboptimal adjustments forpotential confounders <strong>in</strong> the primary studies.For postpartum depression, studies of moderate quality reported an association between notbreastfeed<strong>in</strong>g or short duration of breastfeed<strong>in</strong>g <strong>and</strong> postpartum depression. It is plausible thatpostpartum depression led to early cessation of breastfeed<strong>in</strong>g, as opposed to breastfeed<strong>in</strong>galter<strong>in</strong>g the risk of depression. Both effects might occur concurrently. Additional factors thatmay have a bear<strong>in</strong>g on both postpartum depression <strong>and</strong> the decision to <strong>in</strong>itiate or term<strong>in</strong>atebreastfeed<strong>in</strong>g should be sought. Documentation of basel<strong>in</strong>e mental health status before the<strong>in</strong>itiation of breastfeed<strong>in</strong>g <strong>and</strong> detailed record<strong>in</strong>g of breastfeed<strong>in</strong>g data will improve the qualityof the studies <strong>and</strong> help underst<strong>and</strong> the nature of the association.There is no evidence of an association between lifetime breastfeed<strong>in</strong>g duration <strong>and</strong> maternalosteoporosis. Lactation does not appear to have an effect on long-term changes <strong>in</strong> bone m<strong>in</strong>eraldensities. However, this conclusion is limited by the fact that the feed<strong>in</strong>g history <strong>in</strong> the studieswas obta<strong>in</strong>ed by maternal recall <strong>and</strong> no data on exclusivity of breastfeed<strong>in</strong>g were available.Further <strong>in</strong>vestigation with accurate breastfeed<strong>in</strong>g data is warranted.For breast cancer, there is good evidence to support the observation that breastfeed<strong>in</strong>g isassociated with a reduction <strong>in</strong> the risk of breast cancer. This association is more likely <strong>in</strong> thosewomen with <strong>in</strong>creased lifetime months of breastfeed<strong>in</strong>g their <strong>in</strong>fants.For ovarian cancer, there is some evidence to suggest an association between breastfeed<strong>in</strong>g<strong>and</strong> a reduction <strong>in</strong> the risk of maternal ovarian cancer. However, one must be cautious <strong>in</strong><strong>in</strong>terpret<strong>in</strong>g this association because it was largely based on estimations of the odds ratios fromretrospective studies.For postpartum weight change, we found that the overall effect of breastfeed<strong>in</strong>g on return-topre-pregnancyweight (weight change from pre-pregnancy or first trimester to 1 to 2 yearpostpartum) was negligible (less than 1 kg), <strong>and</strong> the effect of breastfeed<strong>in</strong>g on postpartum weightchange was unclear. Results from the studies also suggest that many other factors have largereffects on weight retention or postpartum weight loss than breastfeed<strong>in</strong>g. Methodological161
challenges <strong>in</strong> these studies <strong>in</strong>clude the accurate measurement of energy balance, adequate controlfor numerous covariables, <strong>and</strong> quantify<strong>in</strong>g accurately the exclusivity <strong>and</strong> the duration ofbreastfeed<strong>in</strong>g. None of the <strong>in</strong>cluded studies tackled all of these challenges.Concern<strong>in</strong>g the risk of maternal type 2 diabetes, a longer duration of lifetime breastfeed<strong>in</strong>g isassociated with a reduced risk of develop<strong>in</strong>g type 2 diabetes among parous women who did nothave a history of gestational diabetes (GDM). There was a difference <strong>in</strong> the risk of develop<strong>in</strong>gtype 2 diabetes between women with <strong>and</strong> without GDM <strong>in</strong> relation to lactation. Compared withwomen who did not have a history of GDM, women with a history of GDM had a markedly<strong>in</strong>creased risk of type 2 diabetes; <strong>and</strong> lactation showed no significant relationship with diabetesrisk among this group of women. One must be cautious <strong>in</strong> <strong>in</strong>terpret<strong>in</strong>g these f<strong>in</strong>d<strong>in</strong>gs, as they areonly generalizable to population with characteristics similar to that of the Nurses’ <strong>Health</strong> cohort.An important area of research that is not systematically reviewed <strong>in</strong> this report is the use ofbreastfeed<strong>in</strong>g promotion <strong>in</strong>tervention trial to measure health effects (this topic is not part of thescope of this report <strong>and</strong> it will be covered <strong>in</strong> a separate report). The best known of these types ofstudies is the previously described Promotion of <strong>Breastfeed<strong>in</strong>g</strong> Intervention Trial (PROBIT)conducted <strong>in</strong> the Republic of Belarus. 17 Data from this study provided good evidence thatbreastfeed<strong>in</strong>g is associated with a reduction <strong>in</strong> the risk of gastro<strong>in</strong>test<strong>in</strong>al <strong>in</strong>fection <strong>and</strong> atopicdermatitis. Whether results from studies conducted <strong>in</strong> other countries are applicable to the UnitedStates is unclear. In Belarus, mothers often stay <strong>in</strong> the hospital close to one week post delivery,<strong>in</strong>fant formulas can cost as much as 20% of an average salary, <strong>and</strong> there is an obligatoryprolonged maternity leave (approximately 3 years <strong>in</strong> most cases). In contrast, <strong>in</strong> the UnitedStates, mothers are often discharged with<strong>in</strong> 48 hours post delivery <strong>and</strong> formula manufacturersprovide rebates to the Special Supplemental Nutrition Program for Women, <strong>Infant</strong>s, <strong>and</strong> Children(www.wicprogram.org). The factors <strong>in</strong> Belarus could work <strong>in</strong> conjunction with the <strong>in</strong>terventionto help promote the <strong>in</strong>crease <strong>in</strong> the rate of exclusive breastfeed<strong>in</strong>g. On the other h<strong>and</strong>, one mayargue that the results reported <strong>in</strong> the Belarus study could serve as a best-case scenario <strong>in</strong> terms ofthe potential benefits of breastfeed<strong>in</strong>g when optimal promotion <strong>and</strong> support of breastfeed<strong>in</strong>g are<strong>in</strong> place. More research <strong>in</strong> this country along the l<strong>in</strong>e of the Belarus study should be considered.Of note, there were a few <strong>in</strong>dividual primary studies on asthma, cardiovascular mortality, <strong>and</strong>type 1 diabetes that reported <strong>in</strong>crease <strong>in</strong> risk of those diseases <strong>in</strong> subjects who had beenbreastfed. Even though those studies were few <strong>in</strong> numbers, those f<strong>in</strong>d<strong>in</strong>gs should not be ignored<strong>and</strong> further <strong>in</strong>vestigation should be done.Lastly, the outcomes analyzed <strong>in</strong> this review represent only a portion of all possible healthoutcomes related to breastfeed<strong>in</strong>g reported by <strong>in</strong>vestigators worldwide. To work with<strong>in</strong> theconstra<strong>in</strong>ts of resources, we relied on the advice from our panel of technical experts <strong>in</strong> f<strong>in</strong>aliz<strong>in</strong>gthe list of outcomes <strong>in</strong>cluded <strong>in</strong> this review. Thus, some important outcomes (e.g., growth <strong>and</strong>nutrition) have, by necessity, not been <strong>in</strong>cluded <strong>in</strong> this review. Additional systematic reviewsgermane to those important outcomes would be of value.Future ResearchAssessment of the association between breastfeed<strong>in</strong>g <strong>and</strong> health outcomesObservational studies will rema<strong>in</strong> the major source of <strong>in</strong>formation <strong>in</strong> this field. Clear subjectselection criteria, adopt<strong>in</strong>g a common def<strong>in</strong>ition of “exclusive breastfeed<strong>in</strong>g”, reliable collectionof feed<strong>in</strong>g data, specific <strong>and</strong> properly quantifiable outcomes of <strong>in</strong>terest, controll<strong>in</strong>g for importantpotential confounders <strong>in</strong>clud<strong>in</strong>g child-specific factors, <strong>and</strong> bl<strong>in</strong>ded assessment of the outcomemeasures will help immeasurably to improve the quality of these studies. Traditional162
etrospective case-control studies, usually used when the disease is rare, are less desirablebecause of the many caveats noted earlier. Prospective nested case-control studies with bl<strong>in</strong>dedassessment of the outcome measures would provide more reliable results.As have been mentioned previously, it is not possible to elim<strong>in</strong>ate self-selection bias <strong>in</strong>observational studies because of behavioral or attitud<strong>in</strong>al factors <strong>in</strong>tr<strong>in</strong>sic <strong>in</strong> the desire tobreastfeed. Thus, it is worthwhile to study these factors to further underst<strong>and</strong> the reasons for thedecision to breastfeed.Sibl<strong>in</strong>g analysis provides a method to control for hereditary <strong>and</strong> household factors that areimportant <strong>in</strong> certa<strong>in</strong> outcomes, provided that those factors are similar for the sibl<strong>in</strong>gs of <strong>in</strong>terest.Although such analysis may be less susceptible to confounders <strong>and</strong> effect modifiers that areshared by sibl<strong>in</strong>gs, one must remember that it is not immune to biases. This method should beused when the appropriate data are available.There is a large degree of heterogeneity across studies among many of the outcomes. Theheterogeneity persisted after adjust<strong>in</strong>g for potential confounders. It might be helpful to studybreast milk composition (e.g., oligosaccharides, nucleotides, <strong>and</strong> others) with respect to theresidual heterogeneity. In addition, maternal genetic variations <strong>in</strong> the production of those factorsof <strong>in</strong>terest from breast milk can be studied (for an example, see the discussion by Newburg2005 218 concern<strong>in</strong>g the variability of antidiarrheal effect of breastfeed<strong>in</strong>g accord<strong>in</strong>g to theprevalence of the secretor gene (fucosyltransferase 2) <strong>and</strong> the Lewis gene (fucosyltransferase 3)<strong>in</strong> the study population).Assessment of the efficacy/effectiveness of breastfeed<strong>in</strong>g promotion <strong>in</strong>terventionsCluster r<strong>and</strong>omized controlled studies similar to the Belarus trial will provide underst<strong>and</strong><strong>in</strong>gof the effectiveness of various breastfeed<strong>in</strong>g promotion <strong>in</strong>terventions. Any substantialdifferences <strong>in</strong> the degree of breastfeed<strong>in</strong>g between the two groups as a result of the <strong>in</strong>terventionwill provide further opportunity to <strong>in</strong>vestigate any disparity <strong>in</strong> health outcomes between the twogroups.163
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List of Acronyms <strong>and</strong> AbbreviationsAbbreviationAdjAHRQALLAMLAOMBayley MDIBFBMC armBMD sp<strong>in</strong>eBMIBWCDCCES-DCIC-sectionCVDDBPDISDMDSM IVDxEPDSExcluFHGAGDMHHospHRTHtIHDIOMIQLDLLRTILTCDescriptionAdjustedAgency for <strong>Health</strong>care Research <strong>and</strong> QualityAcute Lymphocytic LeukemiaAcute myeloid leukemiaAcute Otitis MediaBayley Mental Development Index<strong>Breastfeed<strong>in</strong>g</strong>Forearm bone m<strong>in</strong>eral contentLumbar sp<strong>in</strong>e bone m<strong>in</strong>eral densityBody mass <strong>in</strong>dexBirth weightCenters for Disease Control <strong>and</strong> PreventionCenter for Epidemiological Studies Depression ScaleConfidence <strong>in</strong>tervalDelivery by cesarean sectionCardiovascular diseaseDiastolic blood pressureDiagnostic Interview ScheduleDonor milkDiagnostic Statistical ManualDiagnosisEd<strong>in</strong>burgh Postnatal Depression ScaleExclusiveFamily historyGestational ageGestational diabetesHospital or cl<strong>in</strong>ic controlsHospitalizationHormone replacement therapyHeightIschemic heart diseaseInstitute of Medic<strong>in</strong>eIntelligence quotientLow-density lipoprote<strong>in</strong>Lower respiratory track <strong>in</strong>fectionLong-term recalls185
AbbreviationDescriptionMAMeta-analysisMANCOVA Multivariate analysis of varianceMDIBayley Mental Development IndexMMExclusive mother’s milkMoMonthsNANot applicableNDNo data/not documentedNECNecrotiz<strong>in</strong>g EntercolitisNLSY79 National longitud<strong>in</strong>al survey of youth 1979NSNon-significantOCOvarian cancerOGTTOral glucose tolerance testOROdds RatioPPopulation controlsPAPhysical activityPIATPeabody <strong>in</strong>dividual achievement testPIARPoverty <strong>in</strong>dex ratioPPVT-RPeabody Picture Vocabulary TestROMRecurrent Otitis MediaPFPreterm formulaRDCResearch Diagnostic CriteriaRRRelative riskRTIRespiratory <strong>in</strong>fectionSBPSystolic blood pressureSDSSt<strong>and</strong>ard deviation scoreSESt<strong>and</strong>ard errorSESSocioeconomic statusSRSystematic reviewSUDAANSoftware adjusted sampleTEPTechnical Expert PanelVit D suppl Vitam<strong>in</strong> D supplementationWISC-RWeschler Intelligence Scale for ChildrenwkWeekWPPSI-RWechsler Preschool <strong>and</strong> Primary Scales of IntelligenceWtWeightYrYear186
Appendix A. MEDLINE ® Search StrategyMEDLINE 1966-April 2006# Search History Results1 exp <strong>in</strong>fant nutrition/ 286202 exp Milk, Human/ 109003 human milk.mp. 52314 (human adj2 milk).tw. 60405 breast milk.mp. 49946 breastmilk.mp. 3157 breast feed<strong>in</strong>g.mp. 189058 breastfeed$.mp. 50999 breast fed.mp. 343410 breastfed.mp. 133911 (breast adj2 fed).tw. 370512 exp lactation/ 2405913 (lactat<strong>in</strong>g or lactation).mp. 3336114 or/1-13 6855415 exp HIV Infections/ 15035616 HIV.mp. 15136817 *fatty acids/ 2100818 *am<strong>in</strong>o acids/ 3248119 or/15-18 24366420 14 not 19 6601821 limit 20 to animals 3219622 20 not 21 3382223 limit 22 to english language 2705424 follow-up studies/ 30881825 (follow-up or followup).tw. 34003926 exp Case-Control Studies/ 29728327 (case adj20 control).tw. 4495428 exp Longitud<strong>in</strong>al Studies/ 50827529 longitud<strong>in</strong>al.tw. 6265230 exp Cohort Studies/ 54801131 cohort.tw. 7350532 (r<strong>and</strong>om$ or rct).tw. 32416333 exp R<strong>and</strong>omized Controlled Trials/ 3996634 exp r<strong>and</strong>om allocation/ 54141A-1
35 exp Double-Bl<strong>in</strong>d Method/ 8406136 exp S<strong>in</strong>gle-Bl<strong>in</strong>d Method/ 944637 r<strong>and</strong>omized controlled trial.pt. 20898838 cl<strong>in</strong>ical trial.pt. 42041039 controlled cl<strong>in</strong>ical trials/ 300540 (cl<strong>in</strong>$ adj trial$).tw. 9086041 ((s<strong>in</strong>gl$ or doubl$ or trebl$ or tripl$) adj (bl<strong>in</strong>d$ or mask$)).tw. 8058642 exp PLACEBOS/ 2421243 placebo$.tw. 9187844 exp Research Design/ 19796145 exp Evaluation Studies/ 53913946 exp Prospective Studies/ 19511147 exp Comparative Study/ 123379048 or/24-47 280365149 23 <strong>and</strong> 48 8238limit 49 to (addresses or bibliography or biography or case reports or congressesor consensus development conference or consensus development conference,50nih or dictionary or directory or editorial or festschrift or governmentpublications or <strong>in</strong>terview or lectures or legal cases or legislation or letter or360news or newspaper article or overall or patient education h<strong>and</strong>out or periodical<strong>in</strong>dex)51 49 not 50 7878A-2
Appendix B. Sample Data Abstraction FormsEvidence table for Systematic ReviewsAuthor,TopicYear[UI]Systematic reviews/Meta-analyses/BothDatabases searched (Dates of literature search)Countries where primary studies conducted(Developed countries only or mixed)Study design [No. of studies]No. of subjectsStudy population <strong>and</strong> sampl<strong>in</strong>gIntervention/ExposureComparator<strong>Outcomes</strong>Methods used for meta-analysesHeterogeneity assessmentsResultsAuthors’ conclusionsQuality of the systematic reviewCommentsB-1
Author, yr:Topic of the systematic review*/MA:Report<strong>in</strong>g of Background1 Description of study outcomes2 Types of exposure or <strong>in</strong>tervention used3 Types of study designs used4 Study populationReport<strong>in</strong>g of Search strategy5 Search strategy, <strong>in</strong>clud<strong>in</strong>g time period <strong>and</strong> key words6 Effort to <strong>in</strong>clude all available studies (contact with authors)7 Databases <strong>and</strong> registries searched8 Method of address<strong>in</strong>g published articles other than English9 Method of h<strong>and</strong>l<strong>in</strong>g abstracts <strong>and</strong> unpublished studiesReport<strong>in</strong>g of Methods10 Rationale for selection <strong>and</strong>/or cod<strong>in</strong>g of data11 Assessment of confound<strong>in</strong>g12 Assessment of quality13 Assessment of heterogeneity14 Description of statistical methods sufficient to replicate15 Provision of appropriate tables <strong>and</strong> graphsReport<strong>in</strong>g of Results16 Graphic summariz<strong>in</strong>g of <strong>in</strong>dividual study estimates <strong>and</strong> overall17 Tables giv<strong>in</strong>g descriptive <strong>in</strong>formation of each study <strong>in</strong>cluded18 Results of sensitivity test<strong>in</strong>g (subgroup analysis)19 Indication of statistical uncerta<strong>in</strong>ty of f<strong>in</strong>d<strong>in</strong>gs20 Quantitative assessment of bias (eg. publication bias)Overall quality*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyReport<strong>in</strong>g yes/noEvaluation of quality of a systematic review or meta-analysis1 Is search strategy appropriate/relevant to the key question(s)?2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to the studies of<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> StudyDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g therelevant data, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, variousbiases <strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or notadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the useof a particular analytic method or model appropriate?8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity,did the authors look at the actual differences <strong>in</strong> PICOS, for example?)?8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)?9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis?Yes /No/PartiallyB-2
Author, Year, UI #Study characteristicsMean age (range):Pre-pregnancy BW (range):Pre-pregnancy BMI (range):Race:Enrolled/Evaluate:Location:Sites:Fund<strong>in</strong>g:Subjects’healthconditionsStudy design <strong>and</strong>follow-up durationEligibility criteria<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsControl Exposuresor InterventionsB-3Outcome Def<strong>in</strong>ition Statistical analyses <strong>and</strong> confounders adjusted ResultsBias/confounders/limitationsCommentsA: strong, B: A B Cmoderate, C: weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>gData collection xWithdraw <strong>and</strong>xdropoutAnalyses xIntervention<strong>in</strong>tegrityOverall:
B-4Doma<strong>in</strong>/questionSelection BiasAre <strong>in</strong>dividuals selected to participate likely to be representative of target population?Place an “X” <strong>in</strong> oneVerylikelySomewhat likely NotlikelyWhat % of selected <strong>in</strong>dividuals agreed to participate? 80-100 60-79
Appendix C. Evidence TablesPart I. Term <strong>Infant</strong> <strong>Outcomes</strong>Acute Otitis MediaAlho 1996Duffy 1997Sassen 1994Stenstrom 1997Uhari 1994 SRMA*Vernacchio 2004* Systematic Review/Meta-AnalysisC-1
Alho, 1996[ 8633605]Study design <strong>and</strong>Study characteristicsfollow-up durationMean GA (range): ND RetrospectiveMean BW (range): ND Mean follow-up = 22% Male: NDmoRace: NDEnrolled/Evaluate:2512/ 825Location: NorthernF<strong>in</strong>l<strong>and</strong>Sites: S<strong>in</strong>gleFund<strong>in</strong>g:Eligibility criteriaAll pregnant women <strong>in</strong> the twonorthernmost prov<strong>in</strong>ces ofF<strong>in</strong>l<strong>and</strong> with estimated dates ofdelivery between July1, 1985 <strong>and</strong>June30, 1986 were enrolled.The research program<strong>in</strong>vestigated the fetal period <strong>and</strong>the later development <strong>and</strong>illnesses of the children.<strong>Breastfeed<strong>in</strong>g</strong> Exposures orInterventions<strong>Breastfeed<strong>in</strong>g</strong> among children older than 3mo of ageControl Exposures or InterventionsBottle feed<strong>in</strong>g among children older than3 mo of ageAlho, 1996[ 8633605]Outcome Def<strong>in</strong>ition Statistical analyses <strong>and</strong> confounders adjusted ResultsDiagnostic criteria for AOM:At least one acute Symptom-Earache, fever, irritability, respiratory symptoms,Restless sleep, etc.<strong>and</strong>one pneumo-otoscopic f<strong>in</strong>d<strong>in</strong>gdist<strong>in</strong>ctredness <strong>and</strong> outward bulg<strong>in</strong>g or reduced mobilityof the eardrumAdjusted ORConfounders:Day careParental smok<strong>in</strong>gOR=0.9CI: 0.8 - 1.0Bias/limitationsCommentsA: strong, B: moderate, C: weak A B CSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>gData collection xWithdraw <strong>and</strong> dropout xAnalyses xIntervention <strong>in</strong>tegrity xOverall: CHigh dropout rateC-2
Duffy, 1997 [9310540]Study characteristicsMean GA (range):Mean BW (range):% Male: 52Race: 99% CaucasianEnrolled/Evaluate:306/238Location: USASites: MultiFund<strong>in</strong>g: National InstituteOf Child <strong>Health</strong> <strong>and</strong> HumanDevelopment Grant 19679Study design <strong>and</strong>follow-up durationProspectiveFollow-up duration:24 moEligibility criteriaConsecutive <strong>in</strong>fants at wellbaby visits shortly after birth.<strong>Infant</strong>s with craniofacialabnormalities, geneticdisorders, immunedeficiencies were excluded<strong>Breastfeed<strong>in</strong>g</strong> Exposures or InterventionsChanges <strong>in</strong> feed<strong>in</strong>g modes were assessed atscheduled office visits• Exclusive milk breastfeed<strong>in</strong>g• Comb<strong>in</strong>ed breast- <strong>and</strong> formulafeed<strong>in</strong>g<strong>Maternal</strong> guardians completed a questionnaireat 24months to determ<strong>in</strong>e the reliability ofvarious postnatal parameters.K statistics: r>0.9 for classification <strong>and</strong> durationof feed<strong>in</strong>g modes (birth, 3, 6, <strong>and</strong> 12 mo ofage)Control Exposures orInterventionsChanges <strong>in</strong> feed<strong>in</strong>g modeswere assessed at scheduledoffice visits• Formula feed<strong>in</strong>gDuffy, 1997 [9310540]Outcome Def<strong>in</strong>itionAOM def<strong>in</strong>ed by presence of one or more ofFever, irritability, ear pa<strong>in</strong>, pull<strong>in</strong>g at the ears,AndTympanic membrane changes <strong>in</strong>clud<strong>in</strong>gIncreased thickness, bulg<strong>in</strong>g, loss of l<strong>and</strong>marks,Decreased mobilityStatistical analyses <strong>and</strong> confoundersadjustedRRConfounder: age of colonizationResultsExclusive BF at 3mo was associatedwith RR= 0.62;95%CI: 0.43-.89;At 6 mo, RR=0.46;95%CI: 0.29-0.74Bias/limitationsCommentsA: strong, B: moderate, C: weak A B CSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>gData collection xWithdraw <strong>and</strong> dropout xAnalyses xIntervention <strong>in</strong>tegrity xOverall: BC-3
Sassen, 1994 [7978038]Study characteristicsMean GA (range): NDMean BW (range): ND% Male: 53Race: 96.6% DutchEnrolled/Evaluate:289/232Location: Netherl<strong>and</strong>sSites: Multi; 1 urban <strong>and</strong>2 ruralFund<strong>in</strong>g: NDStudy design <strong>and</strong>follow-up durationProspectiveMean follow-up= 23.6 moEligibility criteriaChildren born between July 1987<strong>and</strong> October 1988<strong>Breastfeed<strong>in</strong>g</strong> Exposures orInterventionsBefore breastfeed<strong>in</strong>g was stopped(or per month)Control Exposures orInterventionsUp to 4 mo after stopp<strong>in</strong>gSassen, 1994 [7978038]Outcome Def<strong>in</strong>ition Statistical analyses <strong>and</strong> confounders adjusted ResultsAOM diagnosis by physician;If purulent otorrhea; orif treatment for AOM givenCriteria for AOM consisted of:Acute symptomsearache, fever, irritability, restless sleep, etc.Otoscopic signsdist<strong>in</strong>ctredness <strong>and</strong>/orOutward bulg<strong>in</strong>g of the tympanic membraneTympanometry results not usedAdjusted for 1. Number of sibl<strong>in</strong>gs2. Socio-economic status3. Duration of breastfeed<strong>in</strong>gOR= 0.92 95%CI: 0.76-1.07Bias/limitationsCommentsA: strong, B: moderate, C: weak A B CSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>gData collection xWithdraw <strong>and</strong> dropout xAnalyses xIntervention <strong>in</strong>tegrity xOverall: BParents who are not Dutch could notEnroll their <strong>in</strong>fants because theQuestionnaire was not translatedC-4
Stenstrom, 1997 [9039487]StudycharacteristicsStudy design <strong>and</strong> followupdurationMean GA (range): Case-controlMean BW (range): At exam<strong>in</strong>ation children% Male: 61 were between 3 <strong>and</strong> 7Race:years oldEnrolled/Evaluate: Controls were between 4Location: Sweden <strong>and</strong> 6 yearsSites: S<strong>in</strong>gle/MultiFund<strong>in</strong>g:Eligibility criteriaAll children born <strong>in</strong> the period 1978-81 registered to havehad five or more episodes of AOM before age 30mo wereselected <strong>and</strong> classified as cases (otitis-prone)From the official computerized population register <strong>in</strong> Malmo,412 children with less than 5 episodes of AOMWere selected at r<strong>and</strong>om as a control group, <strong>and</strong> matchedwith otitis-prone children for age <strong>and</strong> sex so that each otitispronechild had two matched controls<strong>Breastfeed<strong>in</strong>g</strong> Exposures orInterventionsEver breastfeed<strong>in</strong>gControl Exposuresor InterventionsNever breastfeed<strong>in</strong>gStenstrom, 1997 [9039487]Outcome Def<strong>in</strong>itionAOM diagnosed otoscopically by an ENTphysician,Pediatrician or general practitionerStatistical analyses <strong>and</strong> confoundersadjustedEstimates not reportedNo adjustment for confoundersResultsNo differences between the groupsfoundBias/limitationsCommentsA: strong, B: moderate, C: A B CweakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>gData collection xWithdraw <strong>and</strong> dropout xAnalyses xIntervention <strong>in</strong>tegrity xOverall: CNo confounders adjustedC-5
Evidence table for Systematic Reviews of <strong>Breastfeed<strong>in</strong>g</strong> <strong>and</strong> Acute otitis mediaAuthor, Topic Uhari, 1996 Acute otitis mediaYear[UI]Literature search (Dates) Medl<strong>in</strong>e (1966-1994); Other databases searched? (yes); unpublished data used? (no)Countries where primary F<strong>in</strong>l<strong>and</strong>, USA, Scotl<strong>and</strong>studies conductedStudy eligibility / <strong>in</strong>clusioncriteriaSearch was limited to the English language <strong>and</strong> to human subjects. Only orig<strong>in</strong>al studies ofrisk factors with adequate control groups <strong>and</strong> that reported actual numbers of patients were<strong>in</strong>cludedStudy design [No. Of 2Case-control [12,17] 8Observational [[13,15,16,20,22,23,25,27]studies]No. of subjects Case control: 671 Observational: 4455Study population(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Intervention/Exposure(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Comparator (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)<strong>Outcomes</strong> (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)Heterogeneityassessments<strong>Breastfeed<strong>in</strong>g</strong> > 3 months 2,548<strong>Breastfeed<strong>in</strong>g</strong> > 6 months 3,384<strong>Breastfeed<strong>in</strong>g</strong> (yes/no) 2, 193Studies of association between breastfeed<strong>in</strong>g <strong>and</strong> acute otitis media <strong>and</strong> recurrence of AOM• Specific age groups of children <strong>in</strong> the cohorts are not specifiedThe studies reviewed reported breastfeed<strong>in</strong>g as yes/no or breastfeed<strong>in</strong>g > 3months vs < 3months or breastfeed<strong>in</strong>g > 6 months vs < 6 monthsDuration of breastfeed<strong>in</strong>g10 studies evaluated the risk of Acute otitis media <strong>and</strong> recurrence of Acute otitis associatedwith breast milk feed<strong>in</strong>g. The diagnosis of AOM varied, but pneumatic otoscopy was used <strong>in</strong>the diagnosis. There was no restriction on study <strong>in</strong>clusion accord<strong>in</strong>g to the diagnostic criteriaused. Twenty-two studies evaluat<strong>in</strong>g an array of risk factors for development <strong>and</strong> recurrenceof AOM were <strong>in</strong>cluded <strong>in</strong> the Meta-analysis. Seven of the twenty-two studies explicitlyevaluated the association between breast milk feed<strong>in</strong>g <strong>and</strong> AOM, while another 3/22 studies<strong>in</strong>cluded breast milk feed<strong>in</strong>g among other risk factors that were evaluated. All the studiesagreed on the protective effect of breast milk feed<strong>in</strong>g aga<strong>in</strong>st AOM.Pooled estimate of the relative risk <strong>and</strong> the 95% CI were calculated from data from studiesthat were sufficiently homogeneous. Pooled estimates of risks were derived with the r<strong>and</strong>omeffects model.Details of cl<strong>in</strong>ical <strong>and</strong> statistical heterogeneity assessment is published elsewhereQuality assessments Not donePublication biasNot doneassessmentsStatistical Analysis or R<strong>and</strong>om effects model used for the pooled estimates of risksmeta-analytic methodsResults • breastfeed<strong>in</strong>g for at least 3 months <strong>and</strong> AOM ;RR=0.87; 95% CI: 0.79 – 0.95; p = 0.003• breastfeed<strong>in</strong>g yes/no <strong>and</strong> recurrent AOM: RR=0.48; 95% CI: 0.32-0.72; p=0.0004• breastfeed<strong>in</strong>g > 3 mo vs < 3 mo <strong>and</strong> recurrent AOM: RR= 0.69; 95% CI: 0.46-1.03;p=0.07• breastfeed<strong>in</strong>g > 6 mo vs < 6 mo <strong>and</strong> recurrent AOM: RR= 0.69; 95% CI: 0.49-0.97;p=0.03Quality of the systematicreviewAuthor’s <strong>in</strong>terpretations ofthe resultsNot done• In the meta-analysis, breastfeed<strong>in</strong>g was beneficial <strong>and</strong> breastfeed<strong>in</strong>g even for only 3months decreased the risk of AOMC-6
Author,Year[UI]Topic Uhari, 1996 Acute otitis media• <strong>Breastfeed<strong>in</strong>g</strong> for 6 months or more decreased the recurrence of AOM• <strong>Breastfeed<strong>in</strong>g</strong> should be promoted to protect aga<strong>in</strong>st acute otitis media.Comments / LimitationsThere was no restriction on <strong>in</strong>clusion accord<strong>in</strong>g to the diagnostic criteria used for AOM.There are no details on how breastfeed<strong>in</strong>g data was collected or duration of follow-up.Meta-analyses comb<strong>in</strong>ed both case-control <strong>and</strong> cohort studies <strong>and</strong> did not address thepotential biases <strong>in</strong> the <strong>in</strong>dividual studies.Author, yr: Uhari, 1994Topic of the systematic review*/MA: Acute otitis mediaReport<strong>in</strong>g yes/noReport<strong>in</strong>g of Background1 Description of study outcomes Yes2 Types of exposure or <strong>in</strong>tervention used Yes3 Types of study designs used Yes4 Study population YesReport<strong>in</strong>g of Search strategy5 Search strategy, <strong>in</strong>clud<strong>in</strong>g time period <strong>and</strong> key words Yes6 Effort to <strong>in</strong>clude all available studies (contact with authors) No (Medl<strong>in</strong>e only)7 Databases <strong>and</strong> registries searched Yes8 Method of address<strong>in</strong>g published articles other than English No9 Method of h<strong>and</strong>l<strong>in</strong>g abstracts <strong>and</strong> unpublished studies NoReport<strong>in</strong>g of Methods10 Rationale for selection <strong>and</strong>/or cod<strong>in</strong>g of data No11 Assessment of confound<strong>in</strong>g No12 Assessment of quality No13 Assessment of heterogeneity Yes14 Description of statistical methods sufficient to replicate Yes15 Provision of appropriate tables <strong>and</strong> graphs YesReport<strong>in</strong>g of Results16 Graphic summariz<strong>in</strong>g of <strong>in</strong>dividual study estimates <strong>and</strong> overall Yes17 Tables giv<strong>in</strong>g descriptive <strong>in</strong>formation of each study <strong>in</strong>cluded Partially18 Results of sensitivity test<strong>in</strong>g (subgroup analysis) No19 Indication of statistical uncerta<strong>in</strong>ty of f<strong>in</strong>d<strong>in</strong>gs Yes20 Quantitative assessment of bias (eg. publication bias) NoOverall qualityC*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyEvaluation of quality of a systematic review or meta-analysisYes /No/Partially1 Is search strategy appropriate/relevant to the key question(s)? Partially2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to the studies of Yes<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> Study YesDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g the Yesrelevant data, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, various NoC-7
Evaluation of quality of a systematic review or meta-analysisYes /No/Partiallybiases <strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or not Noadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the use Yesof a particular analytic method or model appropriate?8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity, Yesdid the authors look at the actual differences <strong>in</strong> PICOS, for example?)?8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)? N/A9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis? YesC-8
Vernacchio, 2004 [15126021]Study characteristicsMean GA (range):Mean BW (range): 3,400,median% Male: 50.8Race: 68.4% both parents whiteEnrolled/Evaluate: 15,113/11,349Location: USASites: MultiFund<strong>in</strong>g: Contract no. 1-HD-4-3221 NationalInstitute of Child <strong>and</strong> Human Development<strong>and</strong> the National Institute on Deafness <strong>and</strong>other Communication DisordersStudy design <strong>and</strong>follow-up durationProspectiveFollowup- 6 moEligibility criteria6 mo old <strong>in</strong>fants who participated<strong>in</strong> the <strong>in</strong>fant care practices study<strong>Breastfeed<strong>in</strong>g</strong> Exposures orInterventions<strong>Breastfeed<strong>in</strong>g</strong>A child was considered to bebreastfed at 6 mo if he or she wasbreastfeed<strong>in</strong>g at the time of the 6mo questionnaire, whether or notsupplemental formula or solid foodswere usedControl Exposures orInterventionsNo breastfeed<strong>in</strong>gA child was considered notto be breastfed at 6 mo if heor she was notbreastfeed<strong>in</strong>g at the time ofthe 6 mo questionnaireVernacchio,2004 [15126021]Outcome Def<strong>in</strong>ition Statistical analyses <strong>and</strong> confounders adjusted ResultsAs part of the 6 mo questionnaire, each mother wasasked health care provider <strong>in</strong> the month prior to date ofcomplet<strong>in</strong>g the questionnaire. I so, they were asked toselect a diagnosis from a menu of options that <strong>in</strong>cluded“ear <strong>in</strong>fection”ORConfoundersGenderDaycare attendanceMother’s marital statusMother’s ageMother’s parityNumber of children <strong>in</strong> the homeUnadjustedOR=0.6695%CI:0.59-0.74AdjustedOR=0.6995%CI:0.61-0.78Bias/limitationsCommentsA: strong, B: moderate, C: A B CweakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>gData collection xWithdraw <strong>and</strong> dropout xAnalyses xIntervention <strong>in</strong>tegrity xOverall: BC-9
Appendix C. Evidence TablesPart I. Term <strong>Infant</strong> <strong>Outcomes</strong>AsthmaBurgess 2006Gdalevich 2001 SRMA*Kull 2004Sears 2002Wright 2001* Systematic Review/Meta-AnalysisC-10
Burgess, 2006 [16585289]StudycharacteristicsMean GA (range):185Mean BW (range):3402% Male: 52Race: NDEnrolled/Evaluate:7223/4964Location: AustraliaSites: S<strong>in</strong>gleFund<strong>in</strong>g: NDStudy design <strong>and</strong> follow-up durationProspective cohort with questionnaires at birth, 6 months, 5 <strong>and</strong> 14years. <strong>Breastfeed<strong>in</strong>g</strong> data collected at 6 monthsEligibility criteriaMothers <strong>and</strong> terms<strong>in</strong>gletons<strong>Breastfeed<strong>in</strong>g</strong> Exposures orInterventionsCategories:Never breastfed< 3 weeks3 – 6 weeks7 weeks – 3 months≥ 4 monthsControl Exposures orInterventionsNABurgess, 2006 [16585289]Outcome Def<strong>in</strong>itionAt 14 years, mother reportedasthma, qualitative answers toepisodes of asthma past <strong>in</strong> 6months.Supplemental questionnaire at14 year follow-up request<strong>in</strong>gdata on frequency of asthmameds, asthma-related sick daysfrom school, asthma-relatedhospital admissions, parentalhistory of asthmaStatistical analyses <strong>and</strong>confounders adjustedChi-square for categoricalvariablesLogistic regression adjust<strong>in</strong>g forbreastfeed<strong>in</strong>g, maternalasthma, paternal asthma,smok<strong>in</strong>g early <strong>and</strong> latepregnancy, frequency of coughs<strong>and</strong> cold first 6 months, annualfamily <strong>in</strong>comeOutcomeAsthmaORunadj (95% CI)Results<strong>Breastfeed<strong>in</strong>g</strong> durationNo BF 3 wk-3 ≥4 momo1.0 1.03 1.03 (0.9-(0.9- 1.2)1.2)Of 4,964 subjects with breastfeed<strong>in</strong>g <strong>and</strong> asthma data,1408 (28%) mother-reported cases of adolescentasthma3,720 returned 14 year follow-up questionnaireNonsignificant relationship between duration ofbreastfeed<strong>in</strong>g <strong>and</strong> asthma. Stratification for parentalasthma or child’s sex had no effect. No association forbreastfeed<strong>in</strong>g duration <strong>and</strong> asthma meds, asthmarelatedsick days from school or hospitalizationBias/limitationsCommentsA: strong, B: moderate, C: A B CweakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdraw <strong>and</strong> dropout xAnalyses xIntervention <strong>in</strong>tegrity NANo report<strong>in</strong>g of adjusted OR, discrepancy for %males <strong>in</strong> table, dropout/withdraw > 30%,significant differences between completers <strong>and</strong>noncompleters, no def<strong>in</strong>ition or description ofbreastfeed<strong>in</strong>g.Overall CC-11
Evidence table for Systematic Reviews of <strong>Breastfeed<strong>in</strong>g</strong>Author, Year[UI] Topic Gdalevich, 2001 AsthmaLiterature search (Dates) Medl<strong>in</strong>e (1966 to 1999); Other databases searched? (no); unpublished data used? (no)Countries where primary Developed only: USA, Canada, UK, Italy, Australia <strong>and</strong> New Zeal<strong>and</strong>studies conductedStudy eligibility / <strong>in</strong>clusioncriteriaProspective studies; maternal recall of the child’s feed<strong>in</strong>g history of not more than 12 months;duration of BF for 3 months or more.Study design [No. Of Prospective study design [12]studies]No. of subjects 8,183Study populationChildren (with <strong>and</strong> without family h/o atopy <strong>and</strong> asthma <strong>and</strong> comb<strong>in</strong>ed population)(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Intervention/Exposure(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedExclusive breastfeed<strong>in</strong>g (3 mo or more with no substitutes or supplements to mother’s milk orsolids)studies)Comparator (def<strong>in</strong>ition <strong>in</strong> without ≥ 3 mo of exclusive breastfeed<strong>in</strong>g<strong>in</strong>cluded studies)<strong>Outcomes</strong> (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)HeterogeneityassessmentsQuality assessmentsPublication biasassessmentsStatistical Analysis ormeta-analytic methodsResultsQuality of the systematicreviewAuthor’s <strong>in</strong>terpretations ofthe resultsComments / LimitationsAsthma (Diagnosed by physician, consecutive report<strong>in</strong>g of wheez<strong>in</strong>g beyond the age of 1year, <strong>and</strong> treatment for lower respiratory tract allergy were def<strong>in</strong>ed as study outcomes)Yes by graphical presentation <strong>and</strong> application of heterogeneity testUnclear; studies critically appraised on 8 items (maternal recall; bl<strong>in</strong>ded to exposure; durationof bf; exclusivity of bf; diagnostic criteria; bl<strong>in</strong>ded ascerta<strong>in</strong>ment of outcome; age; control forconfound<strong>in</strong>g)Yes; calculation of the fail-safe NFixed effect model ; was also compared to r<strong>and</strong>om effects modelMetric used odds ratioThe summary OR was 0.47 (95% CI, 0.34-0.66) <strong>in</strong> the 5 studies (1788 subjects) with less than 2 yearsof follow-up, <strong>and</strong> 0.72 (95% CI, 0.62-0.84) <strong>in</strong> the 12 studies with 2 or more years of follow-up.The protective effect estimate of BF was more pronounced <strong>in</strong> the children with a family history of atopy<strong>in</strong> the subset of studies that assessed this population separately, OR= 0.52 (95% CI, 0.35-0.79), than <strong>in</strong>the studies <strong>in</strong> which both unstratified population data <strong>and</strong> children without atopic first-degree relativeswere <strong>in</strong>cluded, OR = 0.73 (95% CI, 0.62-0.86). When we further restricted the analysis to studies<strong>in</strong>volv<strong>in</strong>g only children without a family history of atopy, the OR was 0.99 (95% CI, 0.48-2.03).Exclusion from the analysis of the studies with borderl<strong>in</strong>e bl<strong>in</strong>d<strong>in</strong>g of diagnos<strong>in</strong>g physicians10,15,19 orthose lack<strong>in</strong>g a statement of BF exclusivity20 yielded respective ORs of 0.71 (95% CI, 0.61-0.84) <strong>and</strong>0.72 (95% CI, 0.61-0.85).AThe summary analysis of the 12 prospective studies supports the role of exclusive BF <strong>in</strong> theprevention of childhood asthma. The protective effect was higher <strong>in</strong> the subgroup of childrenwith a positive family history of asthma or atopy.Children age range not mentioned; <strong>in</strong>cluded studies that did not adjust for confound<strong>in</strong>g;C-12
Author, yr: Gdalevich, 2001Topic of the systematic review*/MA: AsthmaReport<strong>in</strong>g yes/noReport<strong>in</strong>g of Background1 Description of study outcomes Y2 Types of exposure or <strong>in</strong>tervention used Y3 Types of study designs used Y4 Study population YReport<strong>in</strong>g of Search strategy5 Search strategy, <strong>in</strong>clud<strong>in</strong>g time period <strong>and</strong> key words Y6 Effort to <strong>in</strong>clude all available studies (contact with authors) Y7 Databases <strong>and</strong> registries searched Y8 Method of address<strong>in</strong>g published articles other than English N9 Method of h<strong>and</strong>l<strong>in</strong>g abstracts <strong>and</strong> unpublished studies YReport<strong>in</strong>g of Methods10 Rationale for selection <strong>and</strong>/or cod<strong>in</strong>g of data Y11 Assessment of confound<strong>in</strong>g Y12 Assessment of quality Y13 Assessment of heterogeneity Y14 Description of statistical methods sufficient to replicate Y15 Provision of appropriate tables <strong>and</strong> graphs YReport<strong>in</strong>g of Results16 Graphic summariz<strong>in</strong>g of <strong>in</strong>dividual study estimates <strong>and</strong> overall Y17 Tables giv<strong>in</strong>g descriptive <strong>in</strong>formation of each study <strong>in</strong>cluded Y18 Results of sensitivity test<strong>in</strong>g (subgroup analysis) Y19 Indication of statistical uncerta<strong>in</strong>ty of f<strong>in</strong>d<strong>in</strong>gs Y20 Quantitative assessment of bias (eg. publication bias) NOverall qualityA*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyEvaluation of quality of a systematic review or meta-analysisYes /No/Partially1 Is search strategy appropriate/relevant to the key question(s)? Y2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to the studies of Y<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> Study YDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g theYrelevant data, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, variousYbiases <strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or notYadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the use Yof a particular analytic method or model appropriate?8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity, Ydid the authors look at the actual differences <strong>in</strong> PICOS, for example?)?8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)? Y9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis? YC-13
Kull, 2004; Kull, 2002Wickman 2003StudycharacteristicsMean GA (range):NDMean BW (range):ND% Male: 50.5Race: NDEnrolled/Evaluate:4089/3601Location: SwedenSites: MultipleFund<strong>in</strong>g: Nonprofit;governmentStudy design <strong>and</strong>follow-up durationProspective,longitud<strong>in</strong>al cohortwith f<strong>in</strong>al datacollection at 4 yearfollow-upEligibility criteriaAll newborns from February 1994through November 1996 <strong>in</strong> a predef<strong>in</strong>edarea of Stockholm, Sweden were <strong>in</strong>vitedto the study. 4089 (75%) of all <strong>in</strong>fantswere <strong>in</strong>cluded.Data from all 4 questionnaires (at 2months, 1, 2, <strong>and</strong> 4 years of age) wereavailable for 3619 (88%) children.Complete answers on the subjects ofbreast-feed<strong>in</strong>g, potential confounders,<strong>and</strong> outcome were required to be<strong>in</strong>cluded <strong>in</strong> the analyses, leav<strong>in</strong>g 3601children (88% of the orig<strong>in</strong>al study base)for analyses.<strong>Breastfeed<strong>in</strong>g</strong> Exposures or InterventionsThe <strong>in</strong>dependent variable of breast-feed<strong>in</strong>g was categorizedas follows: exclusive breast-feed<strong>in</strong>g was dichotomized with the25 th percentile as the cutoff po<strong>in</strong>t (
Kull, 2004; Kull, 2002Outcome Def<strong>in</strong>itionAsthma: At 4 years of age,asthma was def<strong>in</strong>ed as at least4 episodes of wheez<strong>in</strong>g dur<strong>in</strong>gthe last 12 months or at least 1episode of wheez<strong>in</strong>g dur<strong>in</strong>g thesame period if the child wasreceiv<strong>in</strong>g <strong>in</strong>haled steroids.Early-onset persistentasthma implies that the childfulfilled the asthma criteria notonly at 4 years but also dur<strong>in</strong>gthe first 2 years of life.Early-onset transient asthmadenotes that the child wasfulfill<strong>in</strong>g asthma criteria dur<strong>in</strong>gthe first 2 years of life but not at4 years of age.Late onset of asthma impliesthat the child was not classifiedas hav<strong>in</strong>g asthma dur<strong>in</strong>g thefirst 2 years of life but fulfilledthe asthma criteria at 4 years.Statistical analyses <strong>and</strong>confounders adjustedThe relationship betweenbreast-feed<strong>in</strong>g <strong>and</strong> healthoutcomes was analyzed withlogistic regression, adjusted formaternal age, maternal smok<strong>in</strong>gdur<strong>in</strong>g pregnancy or at 2months of age, <strong>and</strong> heredity.Heredity: Heredity forallergic diseases was def<strong>in</strong>ed asphysician diagnosed asthma,hay fever, or both <strong>in</strong>comb<strong>in</strong>ation with allergy to afurred pet, pollen, or both <strong>in</strong> 1(s<strong>in</strong>gle heredity) or 2 (doubleheredity) parents.ResultsOutcomeExclusive BF0-2 mo 3-4 mo ≥5 moAsthma n/N 48/541 41/701 111/2142ORadj (95% CI) 1.0 0.67 (0.43-1.03)0.61 (0.42-0.86)Asthma & No n/N 30/383 24/502 55/1500heredityORadj (95% CI) 1.0 0.61 (0.36-1.06)0.48 (0.30-0.77)Asthma & Heredity n/N 18/158 17/199 56/642ORadj (95% CI) 1.0 0.76 (0.37-1.54)0.81 (0.46-1.44)Early-onset & n/N 25/532 19/687 36/2118persistent asthmaORadj (95% CI) 1.0 0.56 (0.30-1.04)0.35 (0.21-0.60)Early-onset n/N 36/532 19/687 73/2118transient asthmaORadj (95% CI) 1.0 0.39 (0.22- 0.51 (0.30-0.69) 0.77)n/N 22/532 21/687 73/2118Late onset ofasthmaORadj (95% CI) 1.0 0.71 (0.38-0.82 (0.50-1.35)1.31)Note: The <strong>in</strong>teraction between asthma <strong>and</strong> heredity was not statisticallysignificant.The prevalence of asthma among children exclusively breastfed forless than 4 months was 9.1% compared with 6.4% among childrenbreast-fed for 4 months or more (ORadj, 0.72; 95% CI, 0.53-0.97). TheORadj for asthma related to breast-feed<strong>in</strong>g for 4 months or more was0.58 (95% CI, 0.38-0.88) <strong>in</strong> children without heredity for allergic diseases<strong>and</strong> 0.73 (95% CI, 0.43-1.20) <strong>in</strong> children with heredity.Bias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdraw <strong>and</strong> xdropoutAnalyses xIntervention N/A<strong>in</strong>tegrityOverall: AC-15
Sears, 2002 [16585289]StudycharacteristicsMean GA (range):NDMean BW(range):ND% Male: NDRace: NDEnrolled/Evaluate:1037/1037Location: NewZeal<strong>and</strong>Sites: S<strong>in</strong>gleFund<strong>in</strong>g:GovernmentStudy design <strong>and</strong> follow-up durationAmbidirectional cohort study - enrolled at age 3 <strong>and</strong>followed prospectively up to 21 years. Accompanied<strong>and</strong> unaccompanied assessments at 3, 5, 7, 9, 11,13, 15, 18, 21, <strong>and</strong> 26 years.EligibilitycriteriaPopulationstudy of livebornchildren<strong>Breastfeed<strong>in</strong>g</strong> Exposures or InterventionsCategories:Not breastfedBreastfed > 4 weeksBreastfed def<strong>in</strong>ition <strong>in</strong>cludes some formula feed<strong>in</strong>gdur<strong>in</strong>g birth<strong>in</strong>g stay at hospital. Feed<strong>in</strong>g history<strong>in</strong>clud<strong>in</strong>g duration of breastfeed<strong>in</strong>g from regular,<strong>in</strong>itially weekly, home & cl<strong>in</strong>ic visits dur<strong>in</strong>g first 2-3yearsControlExposures orInterventionsNAC-16
Sears, 2002 [16585289]Outcome Def<strong>in</strong>itionAt age 9 years, ever hav<strong>in</strong>g asthma fromcomprehensive questionnaires by<strong>in</strong>terviewers with data on frequency ofwheez<strong>in</strong>g, asthma diagnosis, drugs, cl<strong>in</strong>icalcharacteristics, admissions; current asthmadef<strong>in</strong>ed as positive response as reported bychild or parent with accompanied symptomsof last 12 months; some verification byairway hyper-responsivenessStatistical analyses<strong>and</strong> confoundersadjustedChi-square forcategorical variablesMultivariate regressioncontroll<strong>in</strong>g for SES, birthorder, sheepsk<strong>in</strong> use <strong>in</strong><strong>in</strong>fancy, maternalsmok<strong>in</strong>gResultsOutcomeBF statusNo BF(n=504)>4 weeksn=(533)Asthma ever n/N 27/417 47/398at 9 years(6%) (12%)ORadj (95% CI) 1.0 1.93(1.18-3.17)Current n/N 74/496 113/484asthma at 26 (15%) (23%)yearsORadj (95% CI) 1.0 1.74(1.26-2.40)Currentasthma withn/N 11/409(3%)28/385(7%)AHR at 9yearsORadj (95% CI) 1.0 2.83Asthma everat 9 yearsFamily historynegativeORadj (95% CI)Asthma everat 9 yearsFamily historypositiveORadj (95% CI)(1.39-5.78)n/N 10/229 23/216(4%) (11%)2.61(1.21-5.62)n/N 16/174 23/174(9%) (13%)P value0.00810.00080.00280.2911.50(0.77-2.96)AHR, airway hyper-responsiveness to methachol<strong>in</strong>e or salbutamolMultivariate analysis of current asthma at 9 years with breastfeed<strong>in</strong>g >4 weeks with adjusted OR 2.40 (1.36-4.26), p = 0.0027Analysis for different duration of BF showed similar results of greaterrisk of asthma at 9 years for moreBias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdraw <strong>and</strong> xdropoutAnalyses xIntervention<strong>in</strong>tegrityN/AOverall: AC-17
Wright, 2000 [11065066]Wright, 2001 [11182011]StudyStudy design <strong>and</strong> follow-up durationcharacteristicsMean GA (range):NDMean BW (range):ND% Male: NDRace: NDEnrolled/Evaluate:1,246/926Location: USASites: MultipleFund<strong>in</strong>g:GovernmentWright, 2000 [11065066]Wright, 2001 [11182011]Prospective, longitud<strong>in</strong>al newborn cohort withquestionnaires ascerta<strong>in</strong><strong>in</strong>g respiratory health at2, 3, 6, 9, 11, 13 yearsAdditional data collection by health surveillancevisit to MDEligibilitycriteria<strong>Health</strong>ynewborn<strong>in</strong>fantsOutcome Def<strong>in</strong>ition Statistical analyses <strong>and</strong> confounders adjusted ResultsPhysician diagnosedasthma, wheez<strong>in</strong>g orasthma symptoms reported≥ 2 questionnaires fromages 6 to 13 yearsBivariate analyses between feed<strong>in</strong>g history <strong>and</strong>asthma, <strong>and</strong> stratified by maternal asthma statusLogistic regression to assess odds of asthma,recurrent wheeze were related to breast feed<strong>in</strong>g<strong>and</strong> maternal asthma adjust<strong>in</strong>g for confounders:maternal education, smok<strong>in</strong>g status <strong>in</strong> 1 st year,sex, ethnicity, 2 or more sibl<strong>in</strong>gs at home or daycare use versus neither first 6 months, paternalasthma<strong>Breastfeed<strong>in</strong>g</strong> Exposures or InterventionsChildren classified by duration of exclusive breast feed<strong>in</strong>g:never breast fed, breast fed exclusively 4 monthsAge 6-13:Nonsignificant for breastfeed<strong>in</strong>g duration <strong>and</strong> asthmaNonsignificant for breastfeed<strong>in</strong>g duration <strong>and</strong> asthmafor children with non-asthmatic mothers ORadj 2.1 (0.9-5.1)Significant for maternal asthmatics ORadj 8.7 (3.4-22.2)BF status<strong>Maternal</strong> asthma Never
Appendix C. Evidence TablesPart I. Term <strong>Infant</strong> <strong>Outcomes</strong>Atopic DermatitisGdalevich 2001 SRMA** Systematic Review/Meta-AnalysisC-19
Evidence table for Systematic Reviews of <strong>Breastfeed<strong>in</strong>g</strong>Author, Year[UI] Topic Gdalevich 2001 (UI 11568741) Atopic dermatitisLiterature search (Dates) Medl<strong>in</strong>e (1966 to 5/2000); Other databases searched? No; unpublished data used? NoCountries where primary Not reported; but all studies were performed <strong>in</strong> developed countriesstudies conductedStudy eligibility / <strong>in</strong>clusioncriteriaProspective studies of full-term <strong>in</strong>fants <strong>in</strong> whom the ORs of atopic dermatitis associatedwith breastfeed<strong>in</strong>g were reported or could be calculated. Exclusion: breastfeed<strong>in</strong>gduration of
Author, yr: Gdalevich 2001Topic of the systematic review*/MA: Atopic dermatitisReport<strong>in</strong>g yes/noReport<strong>in</strong>g of Background1 Description of study outcomes Y2 Types of exposure or <strong>in</strong>tervention used Y3 Types of study designs used Y4 Study population YReport<strong>in</strong>g of Search strategy5 Search strategy, <strong>in</strong>clud<strong>in</strong>g time period <strong>and</strong> key words Y6 Effort to <strong>in</strong>clude all available studies (contact with authors) Y7 Databases <strong>and</strong> registries searched Y8 Method of address<strong>in</strong>g published articles other than English N9 Method of h<strong>and</strong>l<strong>in</strong>g abstracts <strong>and</strong> unpublished studies NReport<strong>in</strong>g of Methods10 Rationale for selection <strong>and</strong>/or cod<strong>in</strong>g of data Y11 Assessment of confound<strong>in</strong>g Y12 Assessment of quality Y13 Assessment of heterogeneity Y14 Description of statistical methods sufficient to replicate Y15 Provision of appropriate tables <strong>and</strong> graphs YReport<strong>in</strong>g of Results16 Graphic summariz<strong>in</strong>g of <strong>in</strong>dividual study estimates <strong>and</strong> overall Y17 Tables giv<strong>in</strong>g descriptive <strong>in</strong>formation of each study <strong>in</strong>cluded N18 Results of sensitivity test<strong>in</strong>g (subgroup analysis) Y19 Indication of statistical uncerta<strong>in</strong>ty of f<strong>in</strong>d<strong>in</strong>gs Y20 Quantitative assessment of bias (eg. publication bias) NOverall quality*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyEvaluation of quality of a systematic review or meta-analysisYes /No/Partially1 Is search strategy appropriate/relevant to the key question(s)? Y2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to the studies of Y<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> Study YDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g theYrelevant data, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, variousYbiases <strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or notYadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the use Yof a particular analytic method or model appropriate?8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity, Y/Ndid the authors look at the actual differences <strong>in</strong> PICOS, for example?)?8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)? Y9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis? YC-21
Appendix C. Evidence TablesPart I. Term <strong>Infant</strong> <strong>Outcomes</strong>CVD MortalityMart<strong>in</strong> 2004 SRMA** Systematic Review/Meta-AnalysisC-22
Evidence table for Systematic Reviews of <strong>Breastfeed<strong>in</strong>g</strong>Author,Year[UI] Topic Mart<strong>in</strong>, 2004 Cardiovascular MortalityLiterature search (Dates) Medl<strong>in</strong>e (up to April 2003); Other databases searched? (yes); unpublished data used? (yes)Countries where primary Developed countries: US <strong>and</strong> UKstudies conductedStudy eligibility / <strong>in</strong>clusioncriteriaArticles were considered eligible for <strong>in</strong>clusion <strong>in</strong> the current review if <strong>in</strong>fants who had beenbreastfed were compared with those who had been bottle (artificially) fed, if the outcomewas cardiovascular disease or ischemic heart disease mortality, <strong>and</strong> if estimates of theassociation between hav<strong>in</strong>g been breastfed <strong>in</strong> <strong>in</strong>fancy <strong>and</strong> cardiovascular disease orischemic heart disease mortality could be obta<strong>in</strong>ed from the paper or after correspondencewith the authors.Study design [No. Of Historical cohort studies [4]studies]No. of subjects25,166 at basel<strong>in</strong>e; 10,785 at follow-upStudy population (def<strong>in</strong>ition<strong>in</strong> <strong>in</strong>cluded studies)Intervention/Exposure(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Comparator (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)<strong>Outcomes</strong> (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)Heterogeneity assessmentsQuality assessmentsW<strong>in</strong>gard, 1994: 1373 birth children <strong>in</strong> CaliforniaHertfordshire cohort: 5908 women <strong>and</strong> 10374 men born <strong>in</strong> 11 of 12 districts <strong>in</strong> HertfordshireBoyd Orr: 4999 men <strong>and</strong> women from a survey of diet <strong>and</strong> health <strong>in</strong> pre-war Brita<strong>in</strong>Caerphilly, 2003: 2512 meddle-aged men liv<strong>in</strong>g <strong>in</strong> Caerphilly, South Wales• Any or exclusive breastfeed<strong>in</strong>g. If results for both any or exclusive breastfeed<strong>in</strong>g werepresented <strong>in</strong> the paper, the exclusive breastfeed<strong>in</strong>g association was used <strong>in</strong> the metaanalysis.• Prolonged breastfeed<strong>in</strong>g: any or exclusive breastfeed<strong>in</strong>g >1 year.Exclusive bottle-feed<strong>in</strong>gCardiovascular disease or ischemic heart disease mortalityCochran’s Q statisticI 2 testNo quality score was used, although specific aspects of the quality of each study, <strong>in</strong>clud<strong>in</strong>gcontrol of confound<strong>in</strong>g, loss to follow-up, recall bias, def<strong>in</strong>ition of breastfeed<strong>in</strong>g, <strong>and</strong> samplesize, were discussedNot done, although there was a discussion on publication bias as one of the potentiallimitations of the meta-analyses.R<strong>and</strong>om effect modelPublication biasassessmentsStatistical Analysis or metaanalyticmethodsResults • All four studies were historical cohorts born between 1904 <strong>and</strong> 1939.• R<strong>and</strong>om-effect models showed little difference <strong>in</strong> all cause mortality between breast<strong>and</strong> bottle-fed subjects (pooled rate ratio: 1.01; 95% CI: 0.91-1.13, p=0.8), <strong>and</strong> therewas little evidence of heterogeneity.• Five observations from three studies suggested little or no association betweenbreastfeed<strong>in</strong>g <strong>and</strong> cardiovascular disease mortality <strong>in</strong> both males <strong>and</strong> females, <strong>and</strong> onesuggested a possible adverse effect (Caerphilly cohort). In r<strong>and</strong>om effects metaanalysis,cardiovascular disease mortality was similar <strong>in</strong> breastfed versus bottlefedsubjects (pooled rate ratio: 1.06; 95% CI: 0.94–1.20). There was no statistical evidenceof between-study heterogeneity.• Ischemic heart disease mortality was 6% lower amongst males who had been breastfed<strong>in</strong> the Hertfordshire cohort, but 56% higher amongst breastfed females. This result is <strong>in</strong>l<strong>in</strong>e with po<strong>in</strong>t estimates from the Boyd Orr cohort suggest<strong>in</strong>g that ischemic heartdisease mortality was 10% lower amongst males who had been breastfed, but 40%higher amongst breastfed females (although there was little statistical evidence of<strong>in</strong>teraction: p=0.2). In Caerphilly, however, ischemic heart disease mortality was 73%higher amongst breastfed males. In a r<strong>and</strong>om effects meta-analysis, there wasevidence of heterogeneity.C-23
Author,Year[UI] Topic Mart<strong>in</strong>, 2004 Cardiovascular Mortality• There was little evidence that prolonged breastfeed<strong>in</strong>g was associated with all-causemortality (pooled rate ratio: 0.94; 95% CI: 0.71–1.24), although there was moderatestatistical evidence of heterogeneity.• There was weak evidence that prolonged breastfeed<strong>in</strong>g was associated with a 16%<strong>in</strong>crease (95% CI: 0.99–1.36; p=0.06) <strong>in</strong> cardiovascular disease mortality, <strong>and</strong> noevidence of <strong>in</strong>consistency <strong>in</strong> estimates.• There was little evidence that prolonged breastfeed<strong>in</strong>g was associated with ischemicheart disease mortality (rate ratio: 1.08; 95% CI: 0.88–1.31; p=0.5) <strong>and</strong> there was noheterogeneity.Quality of the systematic BreviewAuthor’s <strong>in</strong>terpretations ofthe resultsComments / Limitations• There are at least three possible sources of bias <strong>in</strong> the studies reviewed: selection bias,<strong>in</strong>formation bias or recall bias (except for one study) <strong>and</strong> publication bias. Only 2 of the4 studies had at least 70% of the target population <strong>in</strong> the follow-up. Recall bias isunlikely <strong>in</strong> only Hertfordshire cohort as breastfeed<strong>in</strong>g was prospectively ascerta<strong>in</strong>ed.Publication bias is possible but the studies were relatively large <strong>and</strong> unpublishedestimates were obta<strong>in</strong>ed.• As confound<strong>in</strong>g <strong>and</strong> bias may have distorted results from <strong>in</strong>dividual studies, thestatistical comb<strong>in</strong>ation of estimates <strong>in</strong>to a comb<strong>in</strong>ed rate ratio needs to be <strong>in</strong>terpretedwith caution. Our new analysis, together with evidence from published <strong>and</strong> unpublishedliterature, does not provide strong evidence that breastfeed<strong>in</strong>g is related to all-cause orcardiovascular disease mortality. The confidence limits around our po<strong>in</strong>t estimates <strong>and</strong>the observed between-study heterogeneity for associations between breastfeed<strong>in</strong>g <strong>and</strong>ischemic heart disease, however, do not rule out important beneficial or adversecardiovascular effects of breastfeed<strong>in</strong>g.• Although we found little evidence to support a cardioprotective effect of breastfeed<strong>in</strong>gextend<strong>in</strong>g <strong>in</strong>to old age, its beneficial <strong>in</strong>fluence on <strong>in</strong>fant <strong>and</strong> child health <strong>and</strong> cognitivedevelopment supports the idea that it should be promoted as the <strong>in</strong>fant feed<strong>in</strong>g methodof choice.We agree with authors’ conclusion <strong>and</strong> discussion on the limitations of the meta-analyses.However, given large heterogeneity across studies (especially for IHD mortality), metaanalysesmight not be appropriate. At least for the outcome of IHD mortality, men <strong>and</strong>women should be comb<strong>in</strong>ed separately because of apparent effect modification by gender.Results from Hertford cohort were only adjusted for age.C-24
Author, yr: Mart<strong>in</strong>, 2004Topic of the systematic review*/MA: CVD mortalityReport<strong>in</strong>g yes/noReport<strong>in</strong>g of Background1 Description of study outcomes Yes2 Types of exposure or <strong>in</strong>tervention used Yes3 Types of study designs used Yes4 Study population YesReport<strong>in</strong>g of Search strategy5 Search strategy, <strong>in</strong>clud<strong>in</strong>g time period <strong>and</strong> key words Yes6 Effort to <strong>in</strong>clude all available studies (contact with authors) Yes7 Databases <strong>and</strong> registries searched Yes8 Method of address<strong>in</strong>g published articles other than English No9 Method of h<strong>and</strong>l<strong>in</strong>g abstracts <strong>and</strong> unpublished studies YesReport<strong>in</strong>g of Methods10 Rationale for selection <strong>and</strong>/or cod<strong>in</strong>g of data No11 Assessment of confound<strong>in</strong>g Yes12 Assessment of quality Yes13 Assessment of heterogeneity Partially14 Description of statistical methods sufficient to replicate Yes15 Provision of appropriate tables <strong>and</strong> graphs YesReport<strong>in</strong>g of Results16 Graphic summariz<strong>in</strong>g of <strong>in</strong>dividual study estimates <strong>and</strong> overall Yes17 Tables giv<strong>in</strong>g descriptive <strong>in</strong>formation of each study <strong>in</strong>cluded Yes18 Results of sensitivity test<strong>in</strong>g (subgroup analysis) No19 Indication of statistical uncerta<strong>in</strong>ty of f<strong>in</strong>d<strong>in</strong>gs Yes20 Quantitative assessment of bias (eg. publication bias) NoOverall qualityB*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyEvaluation of quality of a systematic review or meta-analysisYes /No/Partially1 Is search strategy appropriate/relevant to the key question(s)? Yes2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to the studies of Yes<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> Study YesDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g the Norelevant data, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, various Yesbiases <strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or not Partiallyadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the use Noof a particular analytic method or model appropriate?8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity, Partiallydid the authors look at the actual differences <strong>in</strong> PICOS, for example?)?8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)? Yes9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis? YesC-25
Appendix C. Evidence TablesPart I. Term <strong>Infant</strong> <strong>Outcomes</strong>LeukemiaBeral 2001 SRMA*Davis 1998 SRMA*Guise 2005 SRMA*Kwan 2004 SRMA** Systematic Review/Meta-AnalysisC-26
Evidence table for Systematic Reviews of <strong>Breastfeed<strong>in</strong>g</strong>Author, Year[UI] Topic Beral (or USCCS Investigators), 2000; 2001 LeukemiaLiterature search (Dates) NDCountries where primary Mixed developed <strong>and</strong> develop<strong>in</strong>g countriesstudies conductedStudy eligibility / <strong>in</strong>clusioncriteriaNot described. Meta-analyses were performed for the associations between breastfeed<strong>in</strong>g<strong>and</strong> leukemia, Hodgk<strong>in</strong>’s disease, non-Hodgk<strong>in</strong>’s lymphoma, other childhood cancers <strong>and</strong> allchildhood cancers comb<strong>in</strong>ed. For the purpose of our review, we focus on childhood leukemiaonly.Study design [No. Of Case-control studies [15]studies]No. of subjects Cases: 7,401 Controls: 14,587Study population(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Intervention/Exposure(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Comparator (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)<strong>Outcomes</strong> (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)HeterogeneityassessmentsQuality assessmentsPublication biasassessmentsStatistical Analysis ormeta-analytic methodsResultsQuality of the systematicreviewAuthor’s <strong>in</strong>terpretations ofthe resultsComments / LimitationsCases: Children with all leukemia, <strong>in</strong>clud<strong>in</strong>g ALLControls: NDEver breastfeed<strong>in</strong>g<strong>Breastfeed<strong>in</strong>g</strong> duration ≤ 6 months<strong>Breastfeed<strong>in</strong>g</strong> duration > 6 monthsnever breast fedAll leukemia, <strong>in</strong>clud<strong>in</strong>g ALLNDNDNDThis is a primary study (UKCCS study) plus meta-analyses.No methods of meta-analyses were described.The UKCCS results did not differ significantly from those of previous studies. Results fromprevious studies were comb<strong>in</strong>ed with UKCCS results. For childhood leukemia, there isevidence of a statistically significant reduction <strong>in</strong> the OR associated with ever hav<strong>in</strong>g beenbreastfed (OR=0.86, 95%CI 0.81-0.92) <strong>and</strong> hav<strong>in</strong>g been breastfed for more than 6 months(OR=0.78, 95% CI 0.71-0.85).CIt is unclear whether the apparent small reduction <strong>in</strong> the risk of each type of childhood cancerreported here is a non-specific effect of breastfeed<strong>in</strong>g on childhood cancer or whether itreflects some systematic bias shared by the majority of the case-control studies that have<strong>in</strong>vestigated etiological factors <strong>in</strong> childhood cancer. We are unable to decide which of thesepossibilities is the more likely.This is a primary study (UKCCS study) plus meta-analyses. Authors focused on their resultsregard<strong>in</strong>g the association between breastfeed<strong>in</strong>g <strong>and</strong> childhood cancer <strong>in</strong> UKCCS study. Nomethods for the meta-analyses were described. They did not report the st<strong>and</strong>ard stepsrequired for a systematic review, <strong>in</strong>clud<strong>in</strong>g explicit search criteria, <strong>in</strong>clusion <strong>and</strong> exclusioncriteria, <strong>and</strong> quality assessment.However, we agree with the author’s <strong>in</strong>terpretations of the results.C-27
Author, yr: Beral 2000; 2001Topic of the systematic review*/MA: LeukemiaReport<strong>in</strong>g yes/noReport<strong>in</strong>g of Background1 Description of study outcomes Yes2 Types of exposure or <strong>in</strong>tervention used Yes3 Types of study designs used Yes4 Study population NoReport<strong>in</strong>g of Search strategy5 Search strategy, <strong>in</strong>clud<strong>in</strong>g time period <strong>and</strong> key words No6 Effort to <strong>in</strong>clude all available studies (contact with authors) No7 Databases <strong>and</strong> registries searched No8 Method of address<strong>in</strong>g published articles other than English No9 Method of h<strong>and</strong>l<strong>in</strong>g abstracts <strong>and</strong> unpublished studies NoReport<strong>in</strong>g of Methods10 Rationale for selection <strong>and</strong>/or cod<strong>in</strong>g of data No11 Assessment of confound<strong>in</strong>g No12 Assessment of quality No13 Assessment of heterogeneity Yes14 Description of statistical methods sufficient to replicate Yes15 Provision of appropriate tables <strong>and</strong> graphs YesReport<strong>in</strong>g of Results16 Graphic summariz<strong>in</strong>g of <strong>in</strong>dividual study estimates <strong>and</strong> overall Yes17 Tables giv<strong>in</strong>g descriptive <strong>in</strong>formation of each study <strong>in</strong>cluded No18 Results of sensitivity test<strong>in</strong>g (subgroup analysis) No19 Indication of statistical uncerta<strong>in</strong>ty of f<strong>in</strong>d<strong>in</strong>gs Yes20 Quantitative assessment of bias (eg. publication bias) NoOverall qualityC*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyEvaluation of quality of a systematic review or meta-analysisYes /No/Partially1 Is search strategy appropriate/relevant to the key question(s)? Unclear2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to the studies of No<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> Study YesDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g the Norelevant data, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, various Nobiases <strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or not Noadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the use Noof a particular analytic method or model appropriate?8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity, Nodid the authors look at the actual differences <strong>in</strong> PICOS, for example?)?8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)? Yes9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis? YesC-28
Evidence table for Systematic Reviews of <strong>Breastfeed<strong>in</strong>g</strong>Author, Year[UI] Topic Davis, 1998 LeukemiaLiterature search (Dates) Medl<strong>in</strong>e (“over the past 10 to 15 years”); Other databases searched? (no); unpublisheddata used? (no)Countries where primarystudies conductedPrimarily developed countries: UK, USA, ItalyIncluded one develop<strong>in</strong>g country: Ch<strong>in</strong>aStudy eligibility / <strong>in</strong>clusioncriteriaFor the purpose of our review, we excluded the study from Ch<strong>in</strong>aNot described, except the author stated that hypothesis of the study was that artificial<strong>in</strong>fant feed<strong>in</strong>g (or never breast fed) <strong>in</strong>creases the risk for cancer <strong>in</strong> childhood. For thepurpose of our review, we focus on childhood leukemia only.Study design [No. OfCase-control studies [5]studies]No. of subjects All leukemia [reported <strong>in</strong> 1 study]- Cases: 171 Controls: 342Acute lymphoblastic leukemia (ALL) [reported <strong>in</strong> all 5 studies]- Cases:1,356 Controls:1,336Acute non-lymphoblastic leukemia (ANLL) [reported <strong>in</strong> 2 studies]- Cases: 129 Controls:379Study population (def<strong>in</strong>ition<strong>in</strong> <strong>in</strong>cluded studies)Intervention/Exposure(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Comparator (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)<strong>Outcomes</strong> (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)Heterogeneity assessmentsQuality assessmentsPublication biasassessmentsStatistical Analysis or metaanalyticmethodsResultsQuality of the systematicreviewAuthor’s <strong>in</strong>terpretations ofthe resultsComments / LimitationsCases: Children with all leukemia, ALL or ANLLControls: Children with no cancers, except for one study used children withrhabdomyosarcoma as controlsAny breastfeed<strong>in</strong>gLong-term breastfeed<strong>in</strong>g: more than 6 to 8 monthsArtificial <strong>in</strong>fant feed<strong>in</strong>g (or never breast fed)“All leukemia, ALL, <strong>and</strong> ANLL”NDNDNDNo meta-analysis was performed.The odds ratio <strong>and</strong> 95% CI or p values for the relationship between <strong>in</strong>fant feed<strong>in</strong>g <strong>and</strong>cancer <strong>in</strong> childhood were provided <strong>in</strong> the papers; <strong>in</strong> other cases where the number ofexposed <strong>and</strong> unexposed cases <strong>and</strong> controls were provided, additional effect estimateswere calculated <strong>in</strong> order to compare studies.None of the <strong>in</strong>cluded studies reported a significant association between all leukemia, ALLor ANLL <strong>and</strong> <strong>in</strong>fant feed<strong>in</strong>g.CNo evidence of an association between <strong>in</strong>fant feed<strong>in</strong>g <strong>and</strong> any childhood cancer except forHodgk<strong>in</strong>’s disease.The ma<strong>in</strong> purpose of this review was to exam<strong>in</strong>e the association between <strong>in</strong>fant feed<strong>in</strong>g<strong>and</strong> childhood cancer. Due to non-significant f<strong>in</strong>d<strong>in</strong>gs for leukemia, the author did not focuson the results on leukemia. Inclusion or exclusion criteria were not described, noassessments of study heterogeneity or methodology quality.C-29
Author, yr: Davis, 1998Topic of the systematic review*/MA: LeukemiaReport<strong>in</strong>g yes/noReport<strong>in</strong>g of Background1 Description of study outcomes Yes2 Types of exposure or <strong>in</strong>tervention used Yes3 Types of study designs used Yes4 Study population YesReport<strong>in</strong>g of Search strategy5 Search strategy, <strong>in</strong>clud<strong>in</strong>g time period <strong>and</strong> key words No6 Effort to <strong>in</strong>clude all available studies (contact with authors) No7 Databases <strong>and</strong> registries searched Yes8 Method of address<strong>in</strong>g published articles other than English No9 Method of h<strong>and</strong>l<strong>in</strong>g abstracts <strong>and</strong> unpublished studies NoReport<strong>in</strong>g of Methods10 Rationale for selection <strong>and</strong>/or cod<strong>in</strong>g of data Yes11 Assessment of confound<strong>in</strong>g No12 Assessment of quality No13 Assessment of heterogeneity No14 Description of statistical methods sufficient to replicate N/A15 Provision of appropriate tables <strong>and</strong> graphs YesReport<strong>in</strong>g of Results16 Graphic summariz<strong>in</strong>g of <strong>in</strong>dividual study estimates <strong>and</strong> overall No17 Tables giv<strong>in</strong>g descriptive <strong>in</strong>formation of each study <strong>in</strong>cluded Yes18 Results of sensitivity test<strong>in</strong>g (subgroup analysis) N/A19 Indication of statistical uncerta<strong>in</strong>ty of f<strong>in</strong>d<strong>in</strong>gs N/A20 Quantitative assessment of bias (eg. publication bias) N/AOverall qualityC*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyEvaluation of quality of a systematic review or meta-analysisYes /No/Partially1 Is search strategy appropriate/relevant to the key question(s)? No2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to the studies of Yes<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> Study YesDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g the Norelevant data, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, various Nobiases <strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or not Noadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the use N/Aof a particular analytic method or model appropriate?8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity, Nodid the authors look at the actual differences <strong>in</strong> PICOS, for example?)?8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)? Yes9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis? PartiallyC-30
Evidence table for Systematic Reviews of <strong>Breastfeed<strong>in</strong>g</strong>Author,Year[UI] Topic Guise, 2005 LeukemiaLiterature search (Dates) Medl<strong>in</strong>e (1990-March 2004); Other databases searched? (no); unpublished data used? (no)Countries where primarystudies conductedDeveloped countries only: Netherl<strong>and</strong>s, Italy, US, Germany, Australia, New Zeal<strong>and</strong>,Canada, Engl<strong>and</strong>, Wales, Scotl<strong>and</strong>, Sweden, FranceStudy eligibility / <strong>in</strong>clusioncriteriaStudies provid<strong>in</strong>g data regard<strong>in</strong>g the association of breastfeed<strong>in</strong>g <strong>and</strong> occurrence ofchildhood leukemia. A study must have been <strong>in</strong> full text, been published after 1990,conta<strong>in</strong>ed more than 100 participants, had concurrent comparison groups, been conducted<strong>in</strong> a developed country, <strong>and</strong> been published <strong>in</strong> the English language.Study design [No. OfCase-control studies [10]studies]No. of subjects9,653 leukemia casesStudy population (def<strong>in</strong>ition<strong>in</strong> <strong>in</strong>cluded studies)Cases: Childhood ALL or all childhood leukemiasControls: Matched or unmatched population (majority) <strong>and</strong> hospital controlsIntervention/Exposure Any measures of breastfeed<strong>in</strong>g(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Comparator (def<strong>in</strong>ition <strong>in</strong> Any<strong>in</strong>cluded studies)<strong>Outcomes</strong> (def<strong>in</strong>ition <strong>in</strong> Childhood ALL or all childhood leukemias def<strong>in</strong>ed <strong>in</strong> the orig<strong>in</strong>al studies<strong>in</strong>cluded studies)Heterogeneity assessments NDQuality assessments 2 <strong>in</strong>dependent <strong>in</strong>vestigators rated study quality by us<strong>in</strong>g criteria from the US PreventiveServices Task Force <strong>and</strong> the National <strong>Health</strong> Service Center for Reviews <strong>and</strong>Dissem<strong>in</strong>ation. Three levels of grade: good, fair <strong>and</strong> poor quality. Studies received a poorrat<strong>in</strong>g if the cases were not assessed reliably, if the groups assembled were notcomparable, if there was considerable attrition or differences <strong>in</strong> nonrespondents betweencases <strong>and</strong> controls, or if there was not adequate consideration given to confound<strong>in</strong>g.Publication biasNDassessmentsStatistical Analysis or metaanalyticNo meta-analysis or statistical analysis was performed.methodsResults Ten studies met all <strong>in</strong>clusion criteria <strong>and</strong> were reviewed for study quality to identify 2good-quality case-control studies, 2 fair-quality studies, <strong>and</strong> 6 poor-quality studies. Of the10 studies, 6 were conducted <strong>in</strong> European countries. All studies but 1 focused solely onchildhood leukemia. The majority <strong>in</strong>cluded
Author,Year[UI] Topic Guise, 2005 Leukemia<strong>in</strong>clusion <strong>in</strong> analysis.The primary f<strong>in</strong>d<strong>in</strong>gs of our review <strong>in</strong>dicate that there are few high-quality studies. Thestudies frequently failed to measure important factors such as breastfeed<strong>in</strong>g exclusivity(report<strong>in</strong>g ever breastfed rather than quantify<strong>in</strong>g breastfeed<strong>in</strong>g by exclusivity comb<strong>in</strong>ed withduration) <strong>and</strong> consideration of other important confounders such as SES <strong>and</strong> other<strong>in</strong>fectious exposures (such as household or school contacts). None of the studies <strong>in</strong>cluded<strong>in</strong> this systematic review ere without flaw. An optimal study might be conducted with<strong>in</strong> theframework of a large population-based registry or cohort with full access to medical records,pathology, <strong>and</strong> demographic data that would be able to accurately identify all cases of ALLdiagnosed (with pathologic confirmation) at >1 year of age with<strong>in</strong> a def<strong>in</strong>ed time period.Comments / Limitations A meta-analysis by Beral, 2001 (or UKCCS <strong>in</strong>vestigators) seemed to have performed acomprehensive search, but they did not report the st<strong>and</strong>ard steps required for a systematicreview, <strong>in</strong>clud<strong>in</strong>g explicit search criteria, <strong>in</strong>clusion <strong>and</strong> exclusion criteria, <strong>and</strong> qualityassessment. This meta-analysis <strong>in</strong>cluded 15 studies. Of these 15 studies, 8 were also<strong>in</strong>cluded <strong>in</strong> Guise, 2005. Four were excluded because they were published before 1990,<strong>and</strong> 3 were conducted <strong>in</strong> develop<strong>in</strong>g countries.Guise, 2005 (10 studies <strong>in</strong>cluded) <strong>and</strong> Kwan, 2004 (14 studies <strong>in</strong>cluded) had same set ofstudies, except that Guise excluded studies published before1990, <strong>and</strong> <strong>in</strong> develop<strong>in</strong>gcountries. Guise, 2005 did not <strong>in</strong>clude non-peer-reviewed studies.Guise et al. discussed the differences between their review <strong>and</strong> previous meta-analyses byUKCCS <strong>in</strong>vestigators <strong>and</strong> Guise, 2005 <strong>in</strong> details. We thought their comments were fair.It would have been preferable if meta-analyses by tak<strong>in</strong>g <strong>in</strong>to account study quality grad<strong>in</strong>gwere also performed.C-32
Author, yr: Guise, 2005Topic of the systematic review*/MA: LeukemiaReport<strong>in</strong>g yes/noReport<strong>in</strong>g of Background1 Description of study outcomes Yes2 Types of exposure or <strong>in</strong>tervention used Yes3 Types of study designs used Yes4 Study population YesReport<strong>in</strong>g of Search strategy5 Search strategy, <strong>in</strong>clud<strong>in</strong>g time period <strong>and</strong> key words Yes6 Effort to <strong>in</strong>clude all available studies (contact with authors) No7 Databases <strong>and</strong> registries searched Yes8 Method of address<strong>in</strong>g published articles other than English No9 Method of h<strong>and</strong>l<strong>in</strong>g abstracts <strong>and</strong> unpublished studies NoReport<strong>in</strong>g of Methods10 Rationale for selection <strong>and</strong>/or cod<strong>in</strong>g of data Yes11 Assessment of confound<strong>in</strong>g Yes12 Assessment of quality Yes13 Assessment of heterogeneity N/A14 Description of statistical methods sufficient to replicate N/A15 Provision of appropriate tables <strong>and</strong> graphs YesReport<strong>in</strong>g of Results16 Graphic summariz<strong>in</strong>g of <strong>in</strong>dividual study estimates <strong>and</strong> overall No17 Tables giv<strong>in</strong>g descriptive <strong>in</strong>formation of each study <strong>in</strong>cluded Yes18 Results of sensitivity test<strong>in</strong>g (subgroup analysis) N/A19 Indication of statistical uncerta<strong>in</strong>ty of f<strong>in</strong>d<strong>in</strong>gs N/A20 Quantitative assessment of bias (eg. publication bias) N/AOverall qualityA*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyEvaluation of quality of a systematic review or meta-analysisYes /No/Partially1 Is search strategy appropriate/relevant to the key question(s)? Yes2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to the studies of Yes<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> Study YesDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g the Yesrelevant data, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, various Yesbiases <strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or not Yesadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the use Noof a particular analytic method or model appropriate?8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity, Yesdid the authors look at the actual differences <strong>in</strong> PICOS, for example?)?8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)? Yes9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis? PartiallyC-33
Evidence table for Systematic Reviews of <strong>Breastfeed<strong>in</strong>g</strong>Author, Topic Kwan, 2004 LeukemiaYear[UI]Literature search (Dates) Medl<strong>in</strong>e (up to 2003); Other databases searched? (yes); unpublished data used? (yes)Countries where primarystudies conductedMostly developed countries: Netherl<strong>and</strong>s, Italy, US, Germany, Australia, New Zeal<strong>and</strong>,Canada, Engl<strong>and</strong>, Wales, Scotl<strong>and</strong>, Sweden, FranceStudy eligibility / <strong>in</strong>clusioncriteriaStudy design [No. Ofstudies]No. of subjectsStudy population(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Intervention/Exposure(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Comparator (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)<strong>Outcomes</strong> (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)HeterogeneityassessmentsQuality assessmentsPublication biasassessmentsStatistical Analysis ormeta-analytic methods2 develop<strong>in</strong>g countries: Ch<strong>in</strong>a, Russia,Studies that presented data on any type of leukemia on children 15 years or younger <strong>in</strong> termsof an odds ratio <strong>and</strong> confidence <strong>in</strong>terval <strong>and</strong> analyzed duration of breastfeed<strong>in</strong>g <strong>in</strong> monthswere selected for the analysis.Case-control studies [n=14]*Note 12 studies <strong>in</strong> developed countries. S<strong>in</strong>ce this is a meta-analysis article, we could notseparate these 12 studies. Three of the 14 studies were not peer-reviewed.6,835 ALL cases <strong>and</strong> 1,216 acute myeloid leukemia (AML), which <strong>in</strong>cluded ANLLEight of the 14 studies excluded cases of leukemia <strong>in</strong> <strong>in</strong>fants (usually children younger than 1year of age) to avoid possible biases associated with premature cessation of breastfeed<strong>in</strong>g <strong>in</strong>children with cancer <strong>and</strong> also because most leukemias occurr<strong>in</strong>g dur<strong>in</strong>g <strong>in</strong>fancy are know tohave different etiologies from childhood leukemias.Short-term breastfeed<strong>in</strong>g, def<strong>in</strong>ed as breastfeed<strong>in</strong>g for six months or lessLong-term breastfeed<strong>in</strong>g, def<strong>in</strong>ed as breastfeed<strong>in</strong>g for more than six monthsNo breastfeed<strong>in</strong>g or never been breast-fedThe ALL classification was generally straightforward, with only one study specify<strong>in</strong>g “leukemia”<strong>in</strong>stead of “ALL”.Four studies used the classifications “other leukemias” or ANLL <strong>in</strong>stead of AML. Nevertheless,they were <strong>in</strong>cluded <strong>in</strong> the AML group s<strong>in</strong>ce the majority of such cases are AML cases.Chi-square statisticND, although there are comments on the potential biases for each <strong>in</strong>cluded study <strong>in</strong> thesummary tablesFunnel plotFixed- <strong>and</strong> r<strong>and</strong>om-effect models.For each of the 14 articles reviewed, <strong>and</strong> R <strong>and</strong> its 95% CI were extracted. When available,ORs adjusted for SES were selected s<strong>in</strong>ce SES was the most widely used potentialconfounder <strong>in</strong> these studies.Results • No evidence of publication bias was apparent for studies report<strong>in</strong>g results on theassociation between long-term breastfeed<strong>in</strong>g <strong>and</strong> risk of ALL (p=0.58) or AML (p=0.46).• A significant negative association was observed between short-term breastfeed<strong>in</strong>g <strong>and</strong>ALL (OR=0.88, 95%CI 0.80-0.96), but the AML results (OR=0.90, 95%CI 0.80-1.02) werenot significant.• A significant negative association was observed between long-term breastfeed<strong>in</strong>g <strong>and</strong>ALL (OR=0.76, 95%CI 0.68-0.84), <strong>and</strong> AML (OR=0.85, 95%CI 0.73-0.98).• Heterogeneity statistics for leukemia types <strong>and</strong> duration of breastfeed<strong>in</strong>g were notsignificant except for the ALL analysis address<strong>in</strong>g short-term breastfeed<strong>in</strong>g (p=0.03).However, the results from fixed- <strong>and</strong> r<strong>and</strong>om-effect models were almost exactly thesame.• The follow<strong>in</strong>g table (modified from table 4 <strong>in</strong> the orig<strong>in</strong>al table) shows the ORs for SESadjusteddata from the meta-analysis , as well as separately from the United K<strong>in</strong>gdomChildhood Cancer study (UKCCS) <strong>and</strong> the Children’s Cancer Group (CCG) study.Overall, SES as a potential confounder appeared to play no substantial role <strong>in</strong> thef<strong>in</strong>d<strong>in</strong>gs of either the short-term or long-term breastfeed<strong>in</strong>g studies.C-34
Author,Year[UI]Topic Kwan, 2004 LeukemiaQuality of the systematicreviewAuthor’s <strong>in</strong>terpretations ofthe resultsComments / LimitationsDuration of breastfeed<strong>in</strong>gOR (95% CI)ALLAMLMeta-analysis N=6470 (85%) N=1179 (15%)≤6 months 0.90 (0.82, 0.99) 0.91 (0.80, 1.04)>6 months 0.75 (0.67, 0.85) 0.85 (0.73, 0.98)UKCCS 2001 N=1401 (87%) N=214 (13%)≤6 months 0.90 (0.77, 1.04) 0.85 (0.60, 1.20)>6 months 0.89 (0.75, 1.05) 0.65 (0.43, 1.00)CCG study 1999 N=1744 (79%) N=456 (21%)≤6 months 0.86 (0.73, 1.01) 0.95 (0.68, 1.33)>6 months 0.72 (0.60, 0.87) 0.57 (0.39, 0.84)AThis meta-analysis demonstrated protective association between breastfeed<strong>in</strong>g <strong>and</strong> risk ofchildhood ALL <strong>and</strong> possibly AML. However, three alternative explanations must be consideredFirst, a systematic bias may be present <strong>in</strong> case-control studies of childhood leukemia aris<strong>in</strong>gfrom differential participation rates for case <strong>and</strong> control samples that differed <strong>in</strong> SES. In thecurrent meta-analysis, participation rates could be calculated for only six of the 14 <strong>in</strong>cludedstudies. For five of these six studies, the participation rates for cases were higher than thosefor controls, <strong>and</strong> <strong>in</strong> most of these studies, the controls were higher SES than the cases.Therefore the association of breastfeed<strong>in</strong>g with SES <strong>in</strong> comb<strong>in</strong>ation with differentialparticipation rates by SES could have biased the OR toward a protective effect. Second, theeffect on ALL risk may be spurious, as suggested by the results of the two cohort studies(Ref#22 <strong>and</strong> 23), unfortunately, these studies provided no <strong>in</strong>formation regard<strong>in</strong>g AML. Third,the protective effect of breastfeed<strong>in</strong>g may not be limited to ALL. Further evaluation of thebiological mechanisms while tak<strong>in</strong>g <strong>in</strong>to consideration potential biases can be feasiblyachieved with more large-scale case-control studies utiliz<strong>in</strong>g population-based, SES-matchedcontrols.In conclusion, the potential protective effect of breastfeed<strong>in</strong>g on risk of childhood ALL may bemore complicated than the current literature suggests. Nevertheless, the available evidencesuggests that such a protective effect exists for both ALL <strong>and</strong> AML, with the caveats noted.We agree with authors’ concerns regard<strong>in</strong>g potential biases <strong>in</strong> the <strong>in</strong>cluded studies. Theirconclusion was appropriately cautious. However, the review still comb<strong>in</strong>ed all studiesregardless of these potential biases, <strong>and</strong> over-emphasized the importance of the results fromthe meta-analysis. We could not determ<strong>in</strong>e whether specific study should be <strong>in</strong>cluded <strong>in</strong> theanalyses. Perhaps comb<strong>in</strong><strong>in</strong>g results from only high-quality studies would be preferable, butunfortunately the review did not appraise the methodological quality of the primary studies.C-35
Author, yr: Kwan, 2004Topic of the systematic review*/MA: LeukemiaReport<strong>in</strong>g yes/noReport<strong>in</strong>g of Background1 Description of study outcomes Yes2 Types of exposure or <strong>in</strong>tervention used Yes3 Types of study designs used Yes4 Study population YesReport<strong>in</strong>g of Search strategy5 Search strategy, <strong>in</strong>clud<strong>in</strong>g time period <strong>and</strong> key words Yes6 Effort to <strong>in</strong>clude all available studies (contact with authors) Yes7 Databases <strong>and</strong> registries searched Yes8 Method of address<strong>in</strong>g published articles other than English No9 Method of h<strong>and</strong>l<strong>in</strong>g abstracts <strong>and</strong> unpublished studies YesReport<strong>in</strong>g of Methods10 Rationale for selection <strong>and</strong>/or cod<strong>in</strong>g of data Yes11 Assessment of confound<strong>in</strong>g Yes12 Assessment of quality Yes13 Assessment of heterogeneity Yes14 Description of statistical methods sufficient to replicate Yes15 Provision of appropriate tables <strong>and</strong> graphs YesReport<strong>in</strong>g of Results16 Graphic summariz<strong>in</strong>g of <strong>in</strong>dividual study estimates <strong>and</strong> overall Yes17 Tables giv<strong>in</strong>g descriptive <strong>in</strong>formation of each study <strong>in</strong>cluded Yes18 Results of sensitivity test<strong>in</strong>g (subgroup analysis) Yes19 Indication of statistical uncerta<strong>in</strong>ty of f<strong>in</strong>d<strong>in</strong>gs Yes20 Quantitative assessment of bias (eg. publication bias) YesOverall qualityA*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyEvaluation of quality of a systematic review or meta-analysisYes /No/Partially1 Is search strategy appropriate/relevant to the key question(s)? Yes2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to the studies of Yes<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> Study YesDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g the Norelevant data, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, various Yesbiases <strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or not Yesadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the use Yesof a particular analytic method or model appropriate?8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity, Yesdid the authors look at the actual differences <strong>in</strong> PICOS, for example?)?8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)? Yes9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis? YesC-36
Appendix C. Evidence TablesPart I. Term <strong>Infant</strong> <strong>Outcomes</strong>CognitiveAgostoni 2001Anderson 1999 SRMA*Angelsen 2001Der 2006Drane 2000 SRMA*GomezSanchiz 2003 2004Ja<strong>in</strong> 2002 SRMA*Lawlor 2006Mortensen 2002Oddy 2003 2004Qu<strong>in</strong>n 2001* Systematic Review/Meta-AnalysisC-37
Agostoni, 2001 [11787675]StudyStudy design <strong>and</strong> follow-up durationcharacteristicsMean GA (range): Prospective cohort; Bayley results at 1 y/o weretermcompared <strong>in</strong> breastfeed<strong>in</strong>g ≥6 mo with 3-6 moMean BW (range):% Male: 55%Race:Enrolled/Evaluate:44/44Location: ItalySites: S<strong>in</strong>gle/MultiFund<strong>in</strong>g:Eligibility criteriaTerm <strong>in</strong>fants; exclusivelybreastfed ≥3 mo<strong>Breastfeed<strong>in</strong>g</strong> Exposures orInterventionsControl Exposures orInterventionsAgostoni, 2001 [11787675]Outcome Def<strong>in</strong>itionCognitive outcome of <strong>in</strong>terest:Bayley Mental Development Index(MDI)Statistical analyses <strong>and</strong>confounders adjustedAdjustment for parity, maternaleducation, age, <strong>and</strong> smok<strong>in</strong>ghabitsResultsAfter adjustment, Bayley MDI <strong>in</strong> 29 subjects breastfed >6 mocompared to 15 subjects breastfed 3-6 mo showed a 2.0 po<strong>in</strong>tadvantage (95% CI –3.2, 7.3).Bias/limitationsCommentsA: strong, B: A B Cmoderate, C: weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collectionWithdrawal <strong>and</strong>dropoutAnalyses xIntervention<strong>in</strong>tegrityOverall: CSmall sample size, Bayley at youngagexC-38
Evidence table for Systematic ReviewsAuthor, Year[UI] Topic Anderson, 1999 [UI] Cognitive DevelopmentSystematic reviews/Metaanalyses/BothMeta-analysisDatabases searched (Dates of Medl<strong>in</strong>e (1966-1996); references identified <strong>in</strong> bibliographies.literature search)Countries where primary studies Developed countries only: UK, US, Australia, Germany, New Zeal<strong>and</strong>, <strong>and</strong> Spa<strong>in</strong>conducted (Developed countriesonly or mixed)Study design [No. of studies] Observational (n=11)No. of subjects 7,081Study population <strong>and</strong> sampl<strong>in</strong>g • Studies of association between breastfeed<strong>in</strong>g <strong>and</strong> cognitive development <strong>in</strong>full-term <strong>and</strong> low-birth weight <strong>in</strong>fants (?premature)Intervention/ExposureComparatorMany of the studies that were reviewed only reported breastfeed<strong>in</strong>g versus bottlefeed<strong>in</strong>g, without more detailed <strong>in</strong>formation on exclusivity, frequency, or duration.Information on tim<strong>in</strong>g <strong>and</strong> duration of breastfeed<strong>in</strong>g were <strong>in</strong>cluded where available.•Both fixed effects <strong>and</strong> r<strong>and</strong>om effects were calculatedSee below<strong>Outcomes</strong>Methods used for meta-analysesHeterogeneity assessmentsResults • Unadjusted (fixed effects) pooled mean difference for the 11 observations was5.32 (95% CI, 4.51, 6.14); heterogeneous across studies• Adjusted (fixed effects) pooled mean difference was 3.16 (95% CI, 2.35, 3.98);homogeneous across studies• An average adjusted benefit of 5.18 po<strong>in</strong>ts was obta<strong>in</strong>ed for low-birth weightchildren across 6 available observationsAuthors’ conclusionsQuality of the systematic reviewCommentsAfter adjustment for key cofactors, breast-feed<strong>in</strong>g was associated with significantlyhigher scores for cognitive development than was formula feed<strong>in</strong>gBNo appraisals of study quality (other than confound<strong>in</strong>g); effect score is ast<strong>and</strong>ardized mean difference score of different cognitive measurementsC-39
Author, yr: Anderson, 1999Topic of the systematic review*/MA: Cognitive SRReport<strong>in</strong>g yes/noReport<strong>in</strong>g of Background1 Description of study outcomes Y2 Types of exposure or <strong>in</strong>tervention used Y3 Types of study designs used Y4 Study population YReport<strong>in</strong>g of Search strategy5 Search strategy, <strong>in</strong>clud<strong>in</strong>g time period <strong>and</strong> key words Y/N6 Effort to <strong>in</strong>clude all available studies (contact with authors) N7 Databases <strong>and</strong> registries searched Y8 Method of address<strong>in</strong>g published articles other than English N9 Method of h<strong>and</strong>l<strong>in</strong>g abstracts <strong>and</strong> unpublished studies NReport<strong>in</strong>g of Methods10 Rationale for selection <strong>and</strong>/or cod<strong>in</strong>g of data Y11 Assessment of confound<strong>in</strong>g Y12 Assessment of quality (<strong>in</strong> addition to confound<strong>in</strong>g) N13 Assessment of heterogeneity Y14 Description of statistical methods sufficient to replicate Y15 Provision of appropriate tables <strong>and</strong> graphs YReport<strong>in</strong>g of Results16 Graphic summariz<strong>in</strong>g of <strong>in</strong>dividual study estimates <strong>and</strong> overall Y17 Tables giv<strong>in</strong>g descriptive <strong>in</strong>formation of each study <strong>in</strong>cluded Y18 Results of sensitivity test<strong>in</strong>g (subgroup analysis) Y19 Indication of statistical uncerta<strong>in</strong>ty of f<strong>in</strong>d<strong>in</strong>gs Y20 Quantitative assessment of bias (eg. publication bias) NOverall quality*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyEvaluation of quality of a systematic review or meta-analysisYes /No/Partially1 Is search strategy appropriate/relevant to the key question(s)? Y2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to the studies of Y<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> Study Y/NDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g the Nrelevant data, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, various Nbiases <strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or not Y/Nadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the use Yof a particular analytic method or model appropriate?8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity, Ydid the authors look at the actual differences <strong>in</strong> PICOS, for example?)?8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)? Y9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis? YC-40
Angelsen, 2001 [11517096]Study characteristics Study design <strong>and</strong> follow-up duration Eligibility criteriaMean GA (range): 39.6 wkMean BW (range): 3656 g% Male:Race: whiteEnrolled/Evaluate:521/345/291 (5 yr)Location: Norway &SwedenSites: MultiFund<strong>in</strong>g:Prospective cohort; 10% r<strong>and</strong>omlyselected from eligible population;Duration of breastfeed<strong>in</strong>g: retrospectivelyrecordedWhite, parity 1 or 2, s<strong>in</strong>gleton,registered prior to 20 th wk gestationExcluded:
Der, 2006 UI 17020911Study characteristicsMean GA (range): termMean BW (range):% Male:Race:Enrolled/Evaluate: 3161mothers <strong>and</strong> 5475childrenLocation: USSites: MultiFund<strong>in</strong>g:Study design <strong>and</strong> follow-up durationDatabase analysis of a prospective study; sibl<strong>in</strong>g pairs analysis, <strong>and</strong> metaanalysis;Database from the US national longitud<strong>in</strong>al survey of youth 1979 (NLSY79) <strong>and</strong>children of the women <strong>in</strong> the survey, Peabody <strong>in</strong>dividual achievement test (PIAT)was adm<strong>in</strong>istered to children between the ages of 5 <strong>and</strong> 14 biennially from 1986to 2002, all outcomes st<strong>and</strong>ardized to a mean of 100 <strong>and</strong> SD of 15; maternalcognitive ability was measured with the Armed Forces Qualification Test (AFQT);For meta-analysis, only <strong>in</strong>cluded studies that quantified the effect of breastfeed<strong>in</strong>gstatus on cognitive ability after controll<strong>in</strong>g for parental <strong>in</strong>telligence among full term<strong>in</strong>fants (Medl<strong>in</strong>e 1966 to 1/2006 <strong>and</strong> other sources)EligibilitycriteriaExcluded
Doma<strong>in</strong>/questionSelection BiasAre <strong>in</strong>dividuals selected to participate likely to be representative of target population?Place an “X” <strong>in</strong> oneVerylikelySomewhat likely NotlikelyWhat % of selected <strong>in</strong>dividuals agreed to participate? 80-100 60-79
Evidence table for Systematic Reviews of <strong>Breastfeed<strong>in</strong>g</strong>Author,Year[UI] Topic Drane 2000 Cognitive DevelopmentLiterature search (Dates) Database not specified; literature search from 1966-98Countries where primarystudies conductedStudy eligibility / <strong>in</strong>clusioncriteriaStudy design [No. Ofstudies]No. of subjectsStudy population (def<strong>in</strong>ition<strong>in</strong> <strong>in</strong>cluded studies)Intervention/Exposure(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Comparator (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)<strong>Outcomes</strong> (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)Heterogeneity assessmentsQuality assessmentsPublication biasassessmentsStatistical Analysis or metaanalyticmethodsResultsQuality of the systematicreviewAuthor’s <strong>in</strong>terpretations ofthe resultsComments / LimitationsSubjects born between 1960 <strong>and</strong> 1998, English language, studies exam<strong>in</strong>ed some aspectof cognitive developmentStudies were assessed to determ<strong>in</strong>e if they met 3 methodological st<strong>and</strong>ards: def<strong>in</strong>ition ofoutcome: operational def<strong>in</strong>ition of cognitive outcome <strong>and</strong> outcome measure us<strong>in</strong>gst<strong>and</strong>ardized tests; correct classification of type of feed<strong>in</strong>g: measure breast feed<strong>in</strong>g as acont<strong>in</strong>uous variable (duration of exclusive breast feed<strong>in</strong>g or proportion of diet as breast milk)or at least as a 3-level categorical variable (exclusive breast or formula fed; partial breastfed); <strong>and</strong> control for potential confound<strong>in</strong>g variables: socio-economic status, maternaleducation, birth weight, gestational age, birth order, gender <strong>in</strong> studies measur<strong>in</strong>g verbalabilityTerm <strong>and</strong> preterm <strong>in</strong>fants24/30 studies met entry criteria. 5 studies met the 3 methodological st<strong>and</strong>ards.Lucas 1992, Lucas 1994, Horwood 1998, Malloy 1998; Rogan 1993 (considered to havemet 2.5 st<strong>and</strong>ards because the duration that a baby was mostly breast fed was measured)Lucas 1994 was a RCT, the rema<strong>in</strong><strong>in</strong>g 5 studies were cohorts.Advantages <strong>in</strong> IQ as measured by the WISC-R, Bayley <strong>and</strong> McCarthy Scales wereobserved <strong>in</strong> Lucas 1992, Rogan 1993, Pollock 1994, <strong>and</strong> Horwood 1998.In term <strong>in</strong>fants, effects on IQ <strong>in</strong> the range of 2-5 po<strong>in</strong>ts (0.2-0.3 SD) were found.In low birth weight <strong>in</strong>fants who received breast milk, Lucas 1992 reported an 8 IQ po<strong>in</strong>tadvantage.Lucas 1994 did not f<strong>in</strong>d statistical significant difference <strong>in</strong> Bayley Mental Development Scalescores <strong>in</strong> <strong>in</strong>fants fed solely on a diet of donor breast milk compared with <strong>in</strong>fants fed solelyon a diet of term formula. Malloy 1998 did not f<strong>in</strong>d an effect of <strong>in</strong>fant feed<strong>in</strong>g on WISC-Rscores at 9-10 years of age <strong>in</strong> term <strong>in</strong>fants.B“The question of whether breast feed<strong>in</strong>g <strong>and</strong> formula feed<strong>in</strong>g have differential effects oncognitive development has not been comprehensively answered. A m<strong>in</strong>ority of the studiesreviewed met acceptable st<strong>and</strong>ards for validity <strong>and</strong>, thus, are likely to provide <strong>in</strong>accurateestimates of the association between <strong>in</strong>fant feed<strong>in</strong>g <strong>and</strong> cognitive development.”The methodological st<strong>and</strong>ards proposed may not be universally accepted. Study designswere not taken <strong>in</strong>to consideration. Conclusions are also limited by the fact that almost all thestudies were cohorts.C-44
Author, yr: Drane, 2000Topic of the systematic review*/MA: cognitiveReport<strong>in</strong>g yes/noReport<strong>in</strong>g of Background1 Description of study outcomes Y2 Types of exposure or <strong>in</strong>tervention used Y3 Types of study designs used Y4 Study population YReport<strong>in</strong>g of Search strategy5 Search strategy, <strong>in</strong>clud<strong>in</strong>g time period <strong>and</strong> key words Y6 Effort to <strong>in</strong>clude all available studies (contact with authors) N7 Databases <strong>and</strong> registries searched N8 Method of address<strong>in</strong>g published articles other than English N9 Method of h<strong>and</strong>l<strong>in</strong>g abstracts <strong>and</strong> unpublished studies NReport<strong>in</strong>g of Methods10 Rationale for selection <strong>and</strong>/or cod<strong>in</strong>g of data Y11 Assessment of confound<strong>in</strong>g Y12 Assessment of quality Y13 Assessment of heterogeneity Y/N14 Description of statistical methods sufficient to replicate N/A15 Provision of appropriate tables <strong>and</strong> graphs YReport<strong>in</strong>g of Results16 Graphic summariz<strong>in</strong>g of <strong>in</strong>dividual study estimates <strong>and</strong> overall Y17 Tables giv<strong>in</strong>g descriptive <strong>in</strong>formation of each study <strong>in</strong>cluded Y/N18 Results of sensitivity test<strong>in</strong>g (subgroup analysis) N/A19 Indication of statistical uncerta<strong>in</strong>ty of f<strong>in</strong>d<strong>in</strong>gs N/A20 Quantitative assessment of bias (eg. publication bias) N/AOverall quality*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyEvaluation of quality of a systematic review or meta-analysisYes /No/Partially1 Is search strategy appropriate/relevant to the key question(s)? Y/N2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to the studies of Y<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> Study YDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g the Nrelevant data, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, various Y/Nbiases <strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or not Yadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the use Yof a particular analytic method or model appropriate?8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity, Y/Ndid the authors look at the actual differences <strong>in</strong> PICOS, for example?)?8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)? Y9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis? YC-45
GomezSanchiz, 2003 [12635980]GomezSanchiz, 2004 [15494884]StudycharacteristicsStudy design <strong>and</strong> follow-up durationMean GA (range): Prospective cohort from 1 rural (born 10/1995-39.6 wk9/1997) <strong>and</strong> 1 urban (born 3/1996-2/1998)Mean BW (range): sites, compar<strong>in</strong>g breastfed > 4 mo,
Doma<strong>in</strong>/questionSelection BiasAre <strong>in</strong>dividuals selected to participate likely to be representative of target population?Place an “X” <strong>in</strong> oneVerylikelySomewhat likely NotlikelyWhat % of selected <strong>in</strong>dividuals agreed to participate? 80-100 60-79
Evidence table for Systematic Reviews of <strong>Breastfeed<strong>in</strong>g</strong>Author, Topic Ja<strong>in</strong>, 2002 Cognitive DevelopmentYear[UI]Literature search (Dates) Medl<strong>in</strong>e (1996-2/2001); Other databases searched? (no); unpublished data used? (no)Countries where primarystudies conductedStudy eligibility / <strong>in</strong>clusioncriteriaEnglish language studies; <strong>in</strong>dependently assessed the relationship between breastfeed<strong>in</strong>g<strong>and</strong> a cognitive outcome; tests of motor ability alone were not <strong>in</strong>cludedStudy design [No. Of 30 birth cohorts; 2 RCTs; 5 school registry cohorts; 3 case-control studiesstudies]No. of subjects Ranged from 50 to >11,000Study populationTerm <strong>and</strong> pre-term children(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Intervention/Exposure <strong>Breastfeed<strong>in</strong>g</strong>, breast milk, or choice to breast feed(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Comparator (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)<strong>Outcomes</strong> (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)HeterogeneityassessmentsQuality assessmentsPublication biasassessmentsStatistical Analysis ormeta-analytic methodsResultsAppropriate outcome: st<strong>and</strong>ardized <strong>in</strong>dividual measure of general <strong>in</strong>telligence <strong>and</strong> that theassessment be done when the child was at least 2 years of ageFollow<strong>in</strong>g were exam<strong>in</strong>ed for each article: overall design of the study, sample size, targetpopulation, quality of feed<strong>in</strong>g data, control of susceptibility bias, bl<strong>in</strong>d<strong>in</strong>g, outcome measures,<strong>and</strong> format of results40 studies from 1929 to 2/2001 were <strong>in</strong>cluded <strong>in</strong> this review1. 40 separate papers were published. Because some of these papers <strong>in</strong>vestigatedthe same sample, there were only studies of 33 different groups of children.2. 30 cohorts (27 with full-term children), 2 RCTs <strong>in</strong> preterm children, 5 school registrycohorts, <strong>and</strong> 3 case-control studies.3. 35 articles either studied mixed full-term <strong>and</strong> preterm <strong>in</strong>fants, only full-term <strong>in</strong>fants,or did not specify the gestational age or birth weight. 5 articles studied exclusivelylow birth weight <strong>in</strong>fants.4. Sample size ranged from 50 to >11,0005. Quality of feed<strong>in</strong>g data (exclusive breastfeed<strong>in</strong>g or not, tim<strong>in</strong>g of feed<strong>in</strong>g datacollection, source of feed<strong>in</strong>g data, duration of breastfeed<strong>in</strong>g): 9 articles met all 4criteria (8 full-term cohorts); 15 articles did not adequately def<strong>in</strong>e breastfeed<strong>in</strong>g byfail<strong>in</strong>g to report whether <strong>in</strong>fants only received breast milk or were supplementedwith formula or food. 2 preterm observational birth cohorts did not meet st<strong>and</strong>ard forappropriate def<strong>in</strong>ition of breastfeed<strong>in</strong>g, it was def<strong>in</strong>ed as the “<strong>in</strong>tent to breastfeed.”21 studies did not meet the st<strong>and</strong>ard for tim<strong>in</strong>g of data collection because the<strong>in</strong>formation was obta<strong>in</strong>ed either too late or too early. 27 <strong>in</strong>cluded a feed<strong>in</strong>g group forwhom breastfeed<strong>in</strong>g duration was at least 1 month.6. 9 studies controlled adequately for both socioeconomic status <strong>and</strong> level ofstimulation of the child; 31 studies controlled for socioeconomic status.7. 15 studies stated that observers of the outcome were bl<strong>in</strong>d to feed<strong>in</strong>g status.8. 22 studies used an appropriate measure of cognition. Of the rema<strong>in</strong><strong>in</strong>g studies, 8measured outcomes <strong>in</strong> children
Author,Year[UI]Quality of the systematicreviewAuthor’s <strong>in</strong>terpretations ofthe resultsComments / LimitationsTopic Ja<strong>in</strong>, 2002 Cognitive DevelopmentAassess cognition, 1 case control study used the presence of a learn<strong>in</strong>g disorder asits outcome measure, the other 2 case control studies used the diagnoses ofpervasive developmental disorder <strong>and</strong> <strong>in</strong>fantile autism, respectively, as outcomemeasures.9. 33 studies reported some way to <strong>in</strong>terpret the cl<strong>in</strong>ical significance of results, <strong>and</strong> 21allowed calculation of an effect size.10. 7 studies that found that the effects of breastfeed<strong>in</strong>g statistically significant <strong>in</strong> theunadjusted analysis, became <strong>in</strong>significant when controll<strong>in</strong>g for socioeconomicstatus, stimulation, or other factors.11. Only 2 studies met all the methodological st<strong>and</strong>ards. One study concluded that “anybeneficial effect of breastfeed<strong>in</strong>g on cognitive development is quite small <strong>in</strong>magnitude”, another study found that children who were breastfed had mean IQscores 4.6 po<strong>in</strong>ts higher than those never breastfed after controll<strong>in</strong>g forsocioeconomic status <strong>and</strong> other factors. Among the studies that controlled forsocioeconomic status <strong>and</strong> stimulation/<strong>in</strong>teraction of the child (not <strong>in</strong>clud<strong>in</strong>g theprevious 2), 3 concluded that breastfeed<strong>in</strong>g promotes cognitive development, <strong>and</strong> 4did not.“No conv<strong>in</strong>c<strong>in</strong>g evidence exists regard<strong>in</strong>g he comparative effects of breastfeed<strong>in</strong>g <strong>and</strong>artificial feed<strong>in</strong>g on <strong>in</strong>telligence.”Selection of methodological st<strong>and</strong>ards may not be acceptable to all <strong>in</strong>vestigators.Author, yr: Ja<strong>in</strong>, 2002Topic of the systematic review*/MA: cognitiveReport<strong>in</strong>g yes/noReport<strong>in</strong>g of Background1 Description of study outcomes Y2 Types of exposure or <strong>in</strong>tervention used Y3 Types of study designs used Y4 Study population YReport<strong>in</strong>g of Search strategy5 Search strategy, <strong>in</strong>clud<strong>in</strong>g time period <strong>and</strong> key words Y6 Effort to <strong>in</strong>clude all available studies (contact with authors) N7 Databases <strong>and</strong> registries searched Y8 Method of address<strong>in</strong>g published articles other than English Y9 Method of h<strong>and</strong>l<strong>in</strong>g abstracts <strong>and</strong> unpublished studies NReport<strong>in</strong>g of Methods10 Rationale for selection <strong>and</strong>/or cod<strong>in</strong>g of data Y11 Assessment of confound<strong>in</strong>g Y12 Assessment of quality Y13 Assessment of heterogeneity Y/N14 Description of statistical methods sufficient to replicate Y15 Provision of appropriate tables <strong>and</strong> graphs YReport<strong>in</strong>g of Results16 Graphic summariz<strong>in</strong>g of <strong>in</strong>dividual study estimates <strong>and</strong> overall N/A17 Tables giv<strong>in</strong>g descriptive <strong>in</strong>formation of each study <strong>in</strong>cluded Y18 Results of sensitivity test<strong>in</strong>g (subgroup analysis) N19 Indication of statistical uncerta<strong>in</strong>ty of f<strong>in</strong>d<strong>in</strong>gs Y/NC-49
Report<strong>in</strong>g yes/no20 Quantitative assessment of bias (eg. publication bias) NOverall quality*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyEvaluation of quality of a systematic review or meta-analysisYes /No/Partially1 Is search strategy appropriate/relevant to the key question(s)? Y2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to the studies of Y<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> Study YDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g the Yrelevant data, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, various Ybiases <strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or not Yadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the use Yof a particular analytic method or model appropriate?8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity, Y/Ndid the authors look at the actual differences <strong>in</strong> PICOS, for example?)?8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)? Y9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis? YC-50
Lawlor 2006 [16466433]Study characteristics Study design <strong>and</strong> follow-up duration Eligibility criteriaMean GA (range): term <strong>and</strong>preterm (>98% term <strong>in</strong> followupN=3794)Mean BW (range): 3794 (% Male: 52%Race:Enrolled/Evaluate: 7223/3999 (5yrs)/3794 (14 yrs)Location: AustraliaSites: S<strong>in</strong>gleFund<strong>in</strong>g:Prospective cohort; Peabody PictureVocabulary test at 5 years <strong>and</strong> Raven’sst<strong>and</strong>ard progressive matrices at 14 yearsLive birth who did notdie before dischargefrom hospital<strong>Breastfeed<strong>in</strong>g</strong> Exposures orInterventionsDuration of breastfeed<strong>in</strong>g (never,
Lawlor 2006 [16466433]Outcome Def<strong>in</strong>itionCognitive outcome of<strong>in</strong>terest: Raven’sst<strong>and</strong>ard progressivematrices at 14 yearsStatistical analyses <strong>and</strong>confounders adjustedAdjustment for sex, parentalcharacteristics (maternal age,ethnicity, education, paternaleducation, family <strong>in</strong>come, gravidity,maternal smok<strong>in</strong>g), labor, Apgarscores, birthweight, height, BMIResultsAt age 14 years, Never breastfed = 694,
Doma<strong>in</strong>/questionSelection BiasAre <strong>in</strong>dividuals selected to participate likely to be representative of target population?Place an “X” <strong>in</strong> oneVerylikelySomewhat likely NotlikelyWhat % of selected <strong>in</strong>dividuals agreed to participate? 80-100 60-79
Mortensen 2002 [11988057]Study characteristicsMean GA (range):Mean BW (range):% Male: 490/973 (50% <strong>in</strong>cohort 1); 2280 (100% <strong>in</strong>cohort 2)Race:Enrolled/Evaluate: 973 hadWAIS, 2280 had BPP testLocation: DenmarkSites: S<strong>in</strong>gle/MultiFund<strong>in</strong>g:Study design <strong>and</strong> follow-up durationProspective cohort but the breastfeed<strong>in</strong>g <strong>in</strong>formation was collected retrospectivelyat the 1-year exam<strong>in</strong>ation.There were 2 sub-cohorts; one participated <strong>in</strong> an ongo<strong>in</strong>g developmental researchprogram between 1982-1994 <strong>and</strong> took the WAIS at 27.2 years old; the other onetook the draft board <strong>in</strong>telligence test: Borge Priens Prove (BPP) at 18.7 years; theBPP has a correlation of 0.82 with the full scale WAIS IQ.EligibilitycriteriaExcludedtw<strong>in</strong>s<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsControlExposures orInterventionsMortensen 2002 [11988057]Outcome Def<strong>in</strong>itionRelationship of WAIS score <strong>and</strong>BPP score to duration ofbreastfeed<strong>in</strong>gStatistical analyses <strong>and</strong>confounders adjustedAdjusted for parental socialstatus <strong>and</strong> education, s<strong>in</strong>glemother status, mother’s height,age, <strong>and</strong> weight ga<strong>in</strong> dur<strong>in</strong>gpregnancy, cigarette dur<strong>in</strong>g 3 rdtrimester, number ofpregnancies, estimatedgestational age, birthweight,birth length, <strong>and</strong> <strong>in</strong>dices ofpregnancy <strong>and</strong> deliverycomplicationsResults<strong>Breastfeed<strong>in</strong>g</strong> duration9 moWAIS 99.4 101.7 102.3 106.0 104.0Adjusted P=0.003 for overall F testBPP 38.0 39.2 39.9 40.1 40.1Adjusted P=0.01 for overall F testBias/limitationsCommentsA: strong, B: moderate, C: A B CweakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdrawal <strong>and</strong> dropout xAnalyses xIntervention <strong>in</strong>tegrityOverall: BC-54
Doma<strong>in</strong>/questionSelection BiasAre <strong>in</strong>dividuals selected to participate likely to be representative of target population?Place an “X” <strong>in</strong> oneVerylikelySomewhat likely NotlikelyWhat % of selected <strong>in</strong>dividuals agreed to participate? 80-100 60-79
Oddy, 2003 [12562475] conta<strong>in</strong>s the same data as <strong>in</strong> Oddy, 2004 [15384602]Study characteristics Study design <strong>and</strong> follow-up duration Eligibility criteriaMean GA (range): 37-39 wkMean BW (range):% Male:Race:Enrolled/Evaluate: 2393 term atbirth, 1444 at 6 years, 1371 at 8yearsLocation: AustraliaSites: S<strong>in</strong>gle/MultiFund<strong>in</strong>g:Prospective cohort compar<strong>in</strong>g no breastfeed<strong>in</strong>g, 4 mo of breastfeed<strong>in</strong>g;Peabody Picture Vocabulary Test (PPVT-R) wasadm<strong>in</strong>istered at 6 y/o <strong>and</strong> a Performance subtest(Perceptual organization WISC- Block Design) at 8y/oChildren with non-Englishspeak<strong>in</strong>g parents were excluded;preterm <strong>in</strong>fants were alsoexcluded<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsControl Exposuresor InterventionsOddy, 2003 [12562475] conta<strong>in</strong>s the same data as <strong>in</strong> Oddy, 2004 [15384602]OutcomeDef<strong>in</strong>itionScore of PPV-Rat 6 y/o <strong>and</strong> BlockDesign score at 8y/oStatistical analyses <strong>and</strong> confoundersadjustedAssociation between breastfeed<strong>in</strong>g duration <strong>and</strong>PPVT-R at 6 years <strong>and</strong> Block Design at 8 yearswere adjusted for gender, gestational age,maternal age <strong>and</strong> education, parental smok<strong>in</strong>g,<strong>and</strong> the presence of older sibl<strong>in</strong>gs.Results90% of children were breastfed at some po<strong>in</strong>t, 28% were breastfedfor >6 mo, solid foods were <strong>in</strong>troduced at ≤6 mo <strong>in</strong> 88% of <strong>in</strong>fantsBoth verbal IQ <strong>and</strong> performance scores <strong>in</strong>crease with <strong>in</strong>creas<strong>in</strong>gmaternal education comb<strong>in</strong>ed with a longer duration of breastfeed<strong>in</strong>g,with the most profound effect of breastfeed<strong>in</strong>g occurr<strong>in</strong>g <strong>in</strong> thehighest education groups (P6 mo compared with children never breastfed(F=8.59, P=0.003). The adjusted association of full breastfeed<strong>in</strong>g withthe Performance subtest was not significant (F=1.49, P=0.223).Bias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdrawal<strong>and</strong> dropoutAnalyses xIntervention<strong>in</strong>tegrityOverall: BxC-56
Doma<strong>in</strong>/questionSelection BiasAre <strong>in</strong>dividuals selected to participate likely to be representative of target population?Place an “X” <strong>in</strong> oneVerylikelySomewhat likely NotlikelyWhat % of selected <strong>in</strong>dividuals agreed to participate? 80-100 60-79
Qu<strong>in</strong>n 2001 [11885710]StudycharacteristicsMean GA (range):Mean BW (range):% Male: 53%Race:Enrolled/Evaluate:4049/3880Location: AustraliaSites: S<strong>in</strong>gleFund<strong>in</strong>g:Study design <strong>and</strong> follow-up durationProspective cohort; data were collected atenrollment, shortly after birth, at 6 months <strong>and</strong> at 5years.Peabody Picture Vocabulary Test (PPVT-R) wasadm<strong>in</strong>istered at 5 years. Results were analyzed <strong>in</strong>relation to breastfeed<strong>in</strong>g duration.Eligibility criteriaS<strong>in</strong>gleton;At 5 years, children with major neurologicalabnormalities <strong>and</strong> those for whom the datawere <strong>in</strong>complete were excluded<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsControl Exposuresor InterventionsQu<strong>in</strong>n 2001 [11885710]OutcomeStatistical analyses <strong>and</strong> confounders adjustedDef<strong>in</strong>itionScore onPPVT-RAdjusted for birthweight, poverty, maternaleducation, maternal age, time <strong>in</strong> daycare orpreschool, number of children <strong>in</strong> the household at 5yearsResults<strong>Breastfeed<strong>in</strong>g</strong> ≥6 mo 103.6 (SD 13.1)No breastfeed<strong>in</strong>g 94.2 (SD 14.1)There was a significant trend towards <strong>in</strong>creas<strong>in</strong>g PPVT-R with<strong>in</strong>creased duration of breastfeed<strong>in</strong>g (P=0.0000)After adjustment, the mean for those breastfed ≥6 mo was 8.2po<strong>in</strong>ts (95%CI 6.5, 9.9) higher for females <strong>and</strong> 5.8 po<strong>in</strong>ts (95%CI4.1, 7.5) higher for males when compared to those never breastfed.Bias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdrawal <strong>and</strong> xdropoutAnalyses xIntervention<strong>in</strong>tegrityOverall: BC-58
Doma<strong>in</strong>/questionSelection BiasAre <strong>in</strong>dividuals selected to participate likely to be representative of target population?Place an “X” <strong>in</strong> oneVerylikelySomewhat likely NotlikelyWhat % of selected <strong>in</strong>dividuals agreed to participate? 80-100 60-79
Appendix C. Evidence TablesPart I. Term <strong>Infant</strong> <strong>Outcomes</strong>Gastro<strong>in</strong>test<strong>in</strong>al InfectionsChien 2001 SRMA*Quigley 2006* Systematic Review/Meta-AnalysisC-60
Evidence table for Systematic Reviews of <strong>Breastfeed<strong>in</strong>g</strong>Author, Topic Chien, 2001 UI 11795054 Gastro<strong>in</strong>test<strong>in</strong>al (GI) InfectionYear[UI]Literature search(Dates)Medl<strong>in</strong>e (1996 to 1/1998); Other databases searched? (Yes) Science Citation Index was used toidentify frequently cited articles <strong>in</strong> the reference lists of studies from MEDLINE; unpublished dataCountries whereprimary studiesconductedStudy eligibility /<strong>in</strong>clusion criteriaStudy design [No. Ofstudies]No. of subjectsStudy population(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Intervention/Exposure(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Comparator(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)<strong>Outcomes</strong> (def<strong>in</strong>ition<strong>in</strong> <strong>in</strong>cluded studies)HeterogeneityassessmentsQuality assessmentsPublication biasassessmentsStatistical Analysis ormeta-analyticmethodsResultsQuality of thesystematic reviewAuthor’s<strong>in</strong>terpretations of theresultsComments /Limitationsused? NoIndustrialized countries (UK, New Zeal<strong>and</strong>, US, Australia, Scotl<strong>and</strong>)GI <strong>in</strong>fection was def<strong>in</strong>ed to be any illness associated with vomit<strong>in</strong>g, change <strong>in</strong> consistency orfrequency of stools, or isolation of a known enteropathogenic bacterial or viral agent; GI outcomerestricted to first year of life; excluded studies <strong>in</strong> which mortality was employed as a comb<strong>in</strong>edoutcome event; excluded studies <strong>in</strong> which all the various types of <strong>in</strong>fections were comb<strong>in</strong>ed as anoutcome measureProspective (12 studies, 5473 subjects) <strong>and</strong> retrospective (2 studies, 504 subjects) cohort studies;case-control studies (2 studies, 331 pairs);See above<strong>Infant</strong> feed<strong>in</strong>g practices grouped <strong>in</strong>to either exclusive breastfeed<strong>in</strong>g <strong>and</strong> partial/mixed feed<strong>in</strong>g orexclusive artificial feed<strong>in</strong>gYesFixed effect model; pooled results weighted accord<strong>in</strong>g to sample sizeConflict<strong>in</strong>g results on the effect of breastfeed<strong>in</strong>g on GI <strong>in</strong>fection: 9/16 studies (56%) yielded astatistically significant protective effect of breastfeed<strong>in</strong>g on GI <strong>in</strong>fections;Majority of studies suffered from methodological deficiencies; 4 studies fulfilled criteria of controll<strong>in</strong>gfor detection bias, analyses of confounders, hav<strong>in</strong>g a clear def<strong>in</strong>ition of <strong>in</strong>fant feed<strong>in</strong>g practices <strong>and</strong><strong>in</strong>fectious outcomes; 3 of these studies reported breastfeed<strong>in</strong>g was protective aga<strong>in</strong>st GI <strong>in</strong>fection;Pooled estimate of the cohort studies: OR 0.36 (95% CI 0.32, 0.41; heterogeneity P
Author, yr: Chien, 2001Topic of the systematic review*/MA:Report<strong>in</strong>g yes/noReport<strong>in</strong>g of Background1 Description of study outcomes Y2 Types of exposure or <strong>in</strong>tervention used Y3 Types of study designs used Y4 Study population YReport<strong>in</strong>g of Search strategy5 Search strategy, <strong>in</strong>clud<strong>in</strong>g time period <strong>and</strong> key words Y/N6 Effort to <strong>in</strong>clude all available studies (contact with authors) N7 Databases <strong>and</strong> registries searched Y8 Method of address<strong>in</strong>g published articles other than English N9 Method of h<strong>and</strong>l<strong>in</strong>g abstracts <strong>and</strong> unpublished studies NReport<strong>in</strong>g of Methods10 Rationale for selection <strong>and</strong>/or cod<strong>in</strong>g of data Y11 Assessment of confound<strong>in</strong>g Y/N12 Assessment of quality Y13 Assessment of heterogeneity Y14 Description of statistical methods sufficient to replicate Y15 Provision of appropriate tables <strong>and</strong> graphs YReport<strong>in</strong>g of Results16 Graphic summariz<strong>in</strong>g of <strong>in</strong>dividual study estimates <strong>and</strong> overall Y17 Tables giv<strong>in</strong>g descriptive <strong>in</strong>formation of each study <strong>in</strong>cluded Y18 Results of sensitivity test<strong>in</strong>g (subgroup analysis) N19 Indication of statistical uncerta<strong>in</strong>ty of f<strong>in</strong>d<strong>in</strong>gs Y20 Quantitative assessment of bias (eg. publication bias) NOverall quality*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyEvaluation of quality of a systematic review or meta-analysisYes /No/Partially1 Is search strategy appropriate/relevant to the key question(s)? Y/N2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to the studies of Y<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> Study YDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g theNrelevant data, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, variousY/Nbiases <strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or notYadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the use Y/Nof a particular analytic method or model appropriate?8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity, Y/Ndid the authors look at the actual differences <strong>in</strong> PICOS, for example?)?8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)? Y9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis? YC-62
Quigley, 2006 [16308409]Study characteristicsStudy design <strong>and</strong>follow-up durationMean GA (range): Case-control study;Mean BW (range): stratified by age% Male: 58group (0-3 mo, 3-5.9Race:mo, 6-8.9 mo, ≥ 9Enrolled/Evaluate: mo), social167 cases/ 137 controls deprivation score,Location: UKlocation of practiceSites: Multi(London, notFund<strong>in</strong>g:London);questionnaire oncurrent milk feed<strong>in</strong>gEligibility criteria< 1 yr old <strong>and</strong> had data on<strong>in</strong>fant feed<strong>in</strong>g<strong>Breastfeed<strong>in</strong>g</strong> Exposures or InterventionsCurrent exclusive breast milk (only milkreceived was breast milk, but many had beenweaned on to solids), mixed feed<strong>in</strong>gControl Exposures orInterventionsCurrent formulaQuigley, 2006 [16308409]Statistical analyses <strong>and</strong> confoundersOutcome Def<strong>in</strong>itionadjustedA diarrheal case wasdef<strong>in</strong>ed as “someonewho presented to theGeneral Practitioner withloose stools orsignificant vomit<strong>in</strong>g < 2weeks, <strong>in</strong> the absence ofa known non-<strong>in</strong>fectiouscause <strong>and</strong> preceded bya symptom-free periodof 3 weeks.”age, sex, wean<strong>in</strong>g, social class, travel,no access to food mixer, contact withperson with diarrhea/vomit<strong>in</strong>g <strong>in</strong> <strong>and</strong>outside householdMultivariate analysisResultsCompleted questionnaire: 190 cases (60%);161 controls (90%); excluded 23 cases <strong>and</strong>24 controls (no feed<strong>in</strong>g data, no match,“other” feed<strong>in</strong>g)Analyzed: 167 cases/ 137 controlsAdjusted OR of diarrheaCurrent BF 0.36 (95% CI 0.18, 0.74)Current not BF 1P=0.005“Little evidence of the protection ofbreastfeed<strong>in</strong>g persist<strong>in</strong>g beyond 2 monthsfollow<strong>in</strong>g breastfeed<strong>in</strong>g cessation.”Bias/limitationsCommentsA: strong, A B CB: moderate,C: weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>gData collection xWithdraw <strong>and</strong>xdropoutAnalyses xIntervention<strong>in</strong>tegrityCannot rule out recall or response biasesC-63
Appendix C. Evidence TablesPart I. Term <strong>Infant</strong> <strong>Outcomes</strong><strong>Infant</strong> MortalityChen 2004C-64
Chen 2004 [15121986]Study characteristicsMean GA (range): NDMean BW (range):
Appendix C. Evidence TablesPart I. Term <strong>Infant</strong> <strong>Outcomes</strong>Respiratory Tract DiseasesBachrach 2003 SRMA** Systematic Review/Meta-AnalysisC-66
Evidence table for Systematic Reviews of <strong>Breastfeed<strong>in</strong>g</strong>Author, Year[UI] Topic Bachrach, 2003 [12622672] Respiratory IllnessLiterature search (Dates)Medl<strong>in</strong>e (1966-2002); Other databases searched? (yes); unpublished data used?(yes)Countries where primary studies Developed countries (US, Canada, New Zeal<strong>and</strong>, Australia, Scotl<strong>and</strong>, Norway)conductedStudy eligibility / <strong>in</strong>clusion criteria Included studies from developed countries; healthy full-term <strong>in</strong>fants; <strong>and</strong> provideddata on exclusive breast feed<strong>in</strong>gExcluded studies on cystic fibrosis <strong>and</strong> allergic conditions; sick, premature, <strong>and</strong>/orlow birth weight <strong>in</strong>fantsStudy design [No. Of studies] Prospective cohort [5]; retrospective cohort [2]; ecological study [1]; cross-sectional[1]. Only cohort studies were comb<strong>in</strong>ed.No. of subjects3201 exposed / 1324 unexposedStudy population (def<strong>in</strong>ition <strong>in</strong> <strong>Health</strong>y full term <strong>in</strong>fants<strong>in</strong>cluded studies)Intervention/Exposure (def<strong>in</strong>ition Exclusive breastfeed<strong>in</strong>g at least of 2 months or 9 months of total (any) breastfeed<strong>in</strong>g<strong>in</strong> <strong>in</strong>cluded studies)Comparator (def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cluded None breastfeed<strong>in</strong>gstudies)<strong>Outcomes</strong> (def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Hospitalization due to lower respiratory tract disease (LRTD) <strong>in</strong> <strong>in</strong>fancy: bronchiolitis,asthma, pneumonia, empyema, <strong>and</strong> <strong>in</strong>fections due to specific agents (eg, RSV)Heterogeneity assessments Yes; No statistical heterogeneity. Used sensitivity analysis to test appropriateness ofcomb<strong>in</strong><strong>in</strong>g studies.Quality assessmentsNonePublication bias assessments None (but the authors exam<strong>in</strong>ed unpublished data)Statistical Analysis or metaanalyticR<strong>and</strong>om effects model; subgroup analyses for two covariates – smok<strong>in</strong>g <strong>and</strong> SESmethodsResults Summary relative risk from 7 cohort studies: 0.28 (0.14 - 0.54)Quality of the systematic review AAuthor’s <strong>in</strong>terpretations of theresultsConsistent effect was found among all primary studies that <strong>in</strong>dicated a protectiverole of breastfeed<strong>in</strong>g <strong>in</strong> LRTDComments / LimitationsIncluded studies that had precise def<strong>in</strong>ition of breastfeed<strong>in</strong>gC-67
Author, yr: Bachrach, 2003Topic of the systematic review*/MA: <strong>Breastfeed<strong>in</strong>g</strong> <strong>and</strong> LRTIReport<strong>in</strong>g yes/noReport<strong>in</strong>g of Background1 Description of study outcomes Y2 Types of exposure or <strong>in</strong>tervention used Y3 Types of study designs used Y4 Study population YReport<strong>in</strong>g of Search strategy5 Search strategy, <strong>in</strong>clud<strong>in</strong>g time period <strong>and</strong> key words Y6 Effort to <strong>in</strong>clude all available studies (contact with authors) Y7 Databases <strong>and</strong> registries searched Y8 Method of address<strong>in</strong>g published articles other than English Y9 Method of h<strong>and</strong>l<strong>in</strong>g abstracts <strong>and</strong> unpublished studies YReport<strong>in</strong>g of Methods10 Rationale for selection <strong>and</strong>/or cod<strong>in</strong>g of data Y11 Assessment of confound<strong>in</strong>g Y12 Assessment of quality N13 Assessment of heterogeneity Y14 Description of statistical methods sufficient to replicate Y15 Provision of appropriate tables <strong>and</strong> graphs YReport<strong>in</strong>g of Results16 Graphic summariz<strong>in</strong>g of <strong>in</strong>dividual study estimates <strong>and</strong> overall Y17 Tables giv<strong>in</strong>g descriptive <strong>in</strong>formation of each study <strong>in</strong>cluded Y18 Results of sensitivity test<strong>in</strong>g (subgroup analysis) Y19 Indication of statistical uncerta<strong>in</strong>ty of f<strong>in</strong>d<strong>in</strong>gs N20 Quantitative assessment of bias (eg. publication bias) NOverall qualityA*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyEvaluation of quality of a systematic review or meta-analysis1 Is search strategy appropriate/relevant to the key question(s)?2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to the studies of<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> StudyDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g therelevant data, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, variousbiases <strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or notadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the useof a particular analytic method or model appropriate?8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity,did the authors look at the actual differences <strong>in</strong> PICOS, for example?)?8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)? yes9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis? yesYes /No/PartiallyyesyespartiallynoyesyesyesC-68
Appendix C. Evidence TablesPart I. Term <strong>Infant</strong> <strong>Outcomes</strong>ObesityArenz 2004 SRMA*Harder 2005 SRMA*Owen 2005 SRMA** Systematic Review/Meta-AnalysisC-69
Evidence table for Systematic Reviews of <strong>Breastfeed<strong>in</strong>g</strong>Author,Year[UI] Topic Arenz, 2004 [15314625] ObesityLiterature search (Dates) Medl<strong>in</strong>e (1966-Dec 2003); Other databases searched? (yes); unpublished data used? (no)Countries where primary Developed countries: Germany, USA, Brita<strong>in</strong>, Australia, New Zeal<strong>and</strong>, Czech Republicstudies conductedStudy eligibility / <strong>in</strong>clusioncriteria• Population-based cohort, cross-sectional or case–control studies with children older than1 y at the last follow-up stage, published <strong>in</strong> English, French, Italian, Spanish or German.• Only studies with adjustment for at least three of the follow<strong>in</strong>g relevant confound<strong>in</strong>g or<strong>in</strong>teract<strong>in</strong>g factors birth weight, parental overweight, parental smok<strong>in</strong>g, dietary factors,physical activity <strong>and</strong> socioeconomic status were <strong>in</strong>cluded <strong>in</strong> this meta-analysis.• Odds ratio or relative risk had to be reported <strong>and</strong> age at the last follow-up had to bebetween 5 <strong>and</strong> 18 y; feed<strong>in</strong>g-mode had to be assessed <strong>and</strong> reported <strong>and</strong> obesity asoutcome had to be def<strong>in</strong>ed by body mass <strong>in</strong>dex (BMI) percentiles >90, 95 or 97 kg/m2. Ifrisk estimates were calculated for different percentile values <strong>in</strong> a particular study, theStudy design [No. Ofstudies]estimate for the highest percentile-value was <strong>in</strong>cluded <strong>in</strong> the meta-analysis.Studies did not meet <strong>in</strong>clusion criteria for meta-analyses: prospective cohort study [11];retrospective cohort [1]; cross-sectional study [4]; case-control study [2]Studies met <strong>in</strong>clusion criteria for meta-analyses: prospective cohort study [2]; crosssectionalstudy [7]No. of subjects For studies met <strong>in</strong>clusion criteria for meta-analyses only: 69,000Study population (def<strong>in</strong>ition<strong>in</strong> <strong>in</strong>cluded studies)Intervention/Exposure(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Comparator (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)<strong>Outcomes</strong> (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)Heterogeneity assessmentsQuality assessmentsPublication biasassessmentsStatistical Analysis or metaanalyticmethodsResultsChildren <strong>and</strong> adolescents. One study <strong>in</strong>cluded some adult subjects but the various oddsratios were reported depend<strong>in</strong>g on age <strong>and</strong> not clear which odds ratio was used <strong>in</strong> themeta-analyses.Def<strong>in</strong>ition of feed<strong>in</strong>g mode varied across studies:Never BF or partly BF < 3 months vs. BF ≥ 3 month; mostly or only BF vs. mostly or onlyformula feed<strong>in</strong>g <strong>in</strong> the first 6 months; BF never vs. ever; BF never vs. > 6 months, BFgroups: 9 months(exclusivity of BF not reported)Def<strong>in</strong>ition of childhood obesity varied across studies:BMI ≥97 th percentile, >95 th percentile, def<strong>in</strong>ition accord<strong>in</strong>g to Cole et al.Sensitivity analyses by test<strong>in</strong>g the stability of the f<strong>in</strong>d<strong>in</strong>gs across different approaches <strong>in</strong>study design, exposure ascerta<strong>in</strong>ment <strong>and</strong> selection of study participants.NDFunnel plotFixed-effect <strong>and</strong> r<strong>and</strong>om-effect model: both crude <strong>and</strong> adjusted odds ratios (AOR) of thestudies were used.• In total, 28 studies met the <strong>in</strong>clusion criteria for the systematic review, 19 of them werenot eligible for the meta-analysis.• The pooled crude OR for breast-feed<strong>in</strong>g <strong>and</strong> obesity def<strong>in</strong>ed as BMI >90th, 95th or 97thpercentile could be calculated for six studies. In the fixed-effects model, the OR was 0.67,95% CI (0.62, 0.73). In the r<strong>and</strong>om effects model an almost identical OR was found (datanot shown).• The AOR calculated for n<strong>in</strong>e studies was 0.78, 95% CI (0.71, 0.85) for both fixed <strong>and</strong>r<strong>and</strong>om-effects model.• Sensitivity analyses were performed, compar<strong>in</strong>g the studies accord<strong>in</strong>g to the follow<strong>in</strong>gcriteria: cohort study or cross-sectional study, different def<strong>in</strong>itions of breast-feed<strong>in</strong>g,different def<strong>in</strong>itions of obesity, different age-groups <strong>and</strong> number of potential confoundersconsidered for adjustment. The protective effect of breast-feed<strong>in</strong>g was more pronounced<strong>in</strong> studies with adjustment for less than seven potential confound<strong>in</strong>g factors compared toadjustment for seven or more potential confound<strong>in</strong>g factors.• The funnel plot showed an asymmetric pattern, which was due to a particular study. Thefunnel plot regression analysis did not reject the null hypothesis of symmetry (df=8,C-70
Author,Year[UI] Topic Arenz, 2004 [15314625] ObesityP=0.71), suggest<strong>in</strong>g that there was no publication bias.Quality of the systematic AreviewAuthor’s <strong>in</strong>terpretations ofthe results“The results from meta-analysis <strong>in</strong>dicate that breast-feed<strong>in</strong>g is associated with a small butconsistent protective effect aga<strong>in</strong>st obesity risk <strong>in</strong> later childhood.”Comments / Limitations Highly heterogeneous def<strong>in</strong>itions of breastfeed<strong>in</strong>g across studies overall meta-analysis was<strong>in</strong>appropriate, but sensitivity analyses were performed to reduce heterogeneity. Sensitivityanalyses are very important but very few studies <strong>in</strong> each stratum due to small number ofstudies met the criteria for meta-analyses.C-71
Author, yr: Arenz, 2004Topic of the systematic review*/MA:Report<strong>in</strong>g yes/noReport<strong>in</strong>g of Background1 Description of study outcomes Yes2 Types of exposure or <strong>in</strong>tervention used Yes3 Types of study designs used Yes4 Study population YesReport<strong>in</strong>g of Search strategy5 Search strategy, <strong>in</strong>clud<strong>in</strong>g time period <strong>and</strong> key words Yes6 Effort to <strong>in</strong>clude all available studies (contact with authors) Yes7 Databases <strong>and</strong> registries searched Yes8 Method of address<strong>in</strong>g published articles other than English No9 Method of h<strong>and</strong>l<strong>in</strong>g abstracts <strong>and</strong> unpublished studies NoReport<strong>in</strong>g of Methods10 Rationale for selection <strong>and</strong>/or cod<strong>in</strong>g of data Yes11 Assessment of confound<strong>in</strong>g Yes12 Assessment of quality Yes13 Assessment of heterogeneity Yes14 Description of statistical methods sufficient to replicate Yes15 Provision of appropriate tables <strong>and</strong> graphs YesReport<strong>in</strong>g of Results16 Graphic summariz<strong>in</strong>g of <strong>in</strong>dividual study estimates <strong>and</strong> overall Yes17 Tables giv<strong>in</strong>g descriptive <strong>in</strong>formation of each study <strong>in</strong>cluded Yes18 Results of sensitivity test<strong>in</strong>g (subgroup analysis) Yes19 Indication of statistical uncerta<strong>in</strong>ty of f<strong>in</strong>d<strong>in</strong>gs Yes20 Quantitative assessment of bias (eg. publication bias) YesOverall qualityA*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyEvaluation of quality of a systematic review or meta-analysisYes /No/Partially1 Is search strategy appropriate/relevant to the key question(s)? Yes2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to the studies of Yes<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> Study YesDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g theNDrelevant data, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, variousYesbiases <strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or notYesadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the use Yesof a particular analytic method or model appropriate?8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity, Yesdid the authors look at the actual differences <strong>in</strong> PICOS, for example?)?8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)? Partially9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis? YesC-72
Evidence table for Systematic Reviews of <strong>Breastfeed<strong>in</strong>g</strong>Author, Topic Harder, 2005 [16076830] ObesityYear[UI]Literature search (Dates) Medl<strong>in</strong>e (1966-December 2003); Other databases searched? (yes); unpublished data used?(no)Countries where primary Developed countries: UK, US, Canada, Germany, Australia, New Zeal<strong>and</strong>, Czechoslovakiastudies conductedStudy eligibility /<strong>in</strong>clusion criteria1) an orig<strong>in</strong>al report compar<strong>in</strong>g breastfed subjects with exclusively formula-fed subjects(referent group) of any given age, 2) report the odds ratio <strong>and</strong> 95% CI (or data to calculatethem) of overweight or obesity associated with breastfeed<strong>in</strong>g, <strong>and</strong> 3) report the duration ofbreastfeed<strong>in</strong>g for at least one exposure group.Study design [No. Of Cohort (<strong>in</strong>clud<strong>in</strong>g cross-sectional design) [16]; case-control study [1]studies]No. of subjects Ranged 66 to 32,200 total 120,831Study populationPrimarily children. Two studies <strong>in</strong>cluded adults.(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Intervention/Exposure(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Comparator (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)<strong>Outcomes</strong> (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)HeterogeneityassessmentsQuality assessmentsPublication biasassessmentsStatistical Analysis ormeta-analytic methodsResultsMedian duration of breastfeed<strong>in</strong>g categories: < 1 month (reference), 1-3 month, 4-6 months, 7-9 months, > 9monthEach month <strong>in</strong>crease <strong>in</strong> the duration of breastfeed<strong>in</strong>g: We calculated a study specificregression coefficient <strong>and</strong> correspond<strong>in</strong>g 95% CI for each study by use of a log-l<strong>in</strong>ear model.The result<strong>in</strong>g odds ratio <strong>and</strong> 95% CI for change <strong>in</strong> risk for each month of breastfeed<strong>in</strong>g werepooled with a r<strong>and</strong>om-effect modelAny def<strong>in</strong>ition of overweight or obesity, varied across studiesNDNDFunnel plot with Begg test <strong>and</strong> Egger testUnadjusted odds ratios <strong>and</strong> 95% CI were calculated directly from the data given <strong>in</strong> the articles,where possible. Otherwise, the published odds ratio <strong>and</strong> 95% CI were used. Three approacheswere taken: First, duration of breastfeed<strong>in</strong>g as the <strong>in</strong>dependent variable <strong>and</strong> the weighted oddsratio for overweight <strong>in</strong> breastfed prob<strong>and</strong>s, compared with formula-fed subjects, as thedependent variable (for meta-regression). Second, the r<strong>and</strong>om-effect model pooled odds ratiofor overweight <strong>in</strong> breastfed subjects was calculated separately for five predef<strong>in</strong>ed categories ofduration of breastfeed<strong>in</strong>g. Third, the pool-first method was used to comb<strong>in</strong>e the regressioncoefficients obta<strong>in</strong>ed from the studies (for trend estimation).For meta-regression analysis, all duration-specific odds ratios had to be related to therespective duration of breastfeed<strong>in</strong>g. The median of the upper <strong>and</strong> lower limits of each categoryof duration of breastfeed<strong>in</strong>g was assigned to the particular estimate <strong>in</strong> each study. Estimateswere plotted aga<strong>in</strong>st the respective duration of breastfeed<strong>in</strong>g as <strong>in</strong>dependent variable. Aweighted meta-regression with duration of breastfeed<strong>in</strong>g as the covariate was perform(r<strong>and</strong>om-effects model).For studies that provided data for more than two categories of duration of breastfeed<strong>in</strong>g, weapplied the “pool-first method” to quantify the dose-response relation. This was possible for 11studies. We calculated a study specific regression coefficient <strong>and</strong> correspond<strong>in</strong>g 95% CI foreach study by use of a log-l<strong>in</strong>ear model. The result<strong>in</strong>g odds ratio <strong>and</strong> 95% CI for change <strong>in</strong> riskfor each month of breastfeed<strong>in</strong>g were pooled with a r<strong>and</strong>om-effect model.• From the 17 studies that reported duration of breastfeed<strong>in</strong>g, 14 gave data for more than onecategory of duration of breastfeed<strong>in</strong>g, lead<strong>in</strong>g to 52 estimates <strong>in</strong>cluded <strong>in</strong> the meta-regressionanalysis. In the weighted meta-regression, duration of breastfeed<strong>in</strong>g was significantlynegatively related to risk of overweight (regression coefficient: 0.94, 95%CI 0.89-0.98).C-73
Author,Year[UI]Topic Harder, 2005 [16076830] Obesity• From 1 month of breastfeed<strong>in</strong>g onward, the risk of subsequent overweight cont<strong>in</strong>uouslydecreased up to a reduction of more than 30%, reach<strong>in</strong>g a plateau at 9 months ofbreastfeed<strong>in</strong>g.No. of durationspecificstudyestimatesDuration of breastfeed<strong>in</strong>g9 mo5 14 15 11 7OR for overweight 1.0 0.81 0.76 0.67 0.6895% CI 0.65, 1.55 0.74, 0.88 0.67, 0.86 0.55, 0.82 0.50, 0.91Quality of the systematicreviewAuthor’s <strong>in</strong>terpretationsof the resultsComments / Limitations• Each month of breastfeed<strong>in</strong>g was found to be associated with a 4% decrease <strong>in</strong> risk (OR:0.96/month of breastfeed<strong>in</strong>g, 95%CI 0.94-0.98). A fixed-effects model revealed a similarpooled OR <strong>and</strong> a nearly identical 95% CI (OR: 0.96/month of breastfeed<strong>in</strong>g, 95%CI 0.95-0.98)• In only two of these studies was the <strong>in</strong>fluence of the duration of exclusive breastfeed<strong>in</strong>ganalyzed. The pooled OR for risk of overweight per month of exclusive breastfeed<strong>in</strong>g was0.94 (95%CI 0.89-0.99, r<strong>and</strong>om-effect model)• Subgroup analyses revealed that the def<strong>in</strong>ition of overweight <strong>in</strong>fluenced the estimate onlyslightly. In studies that used BMI to def<strong>in</strong>e overweight, the pooled OR was 0.96 (95%CI 0.94-0.98) for 8 studies, while the OR was 0.93 (95%CI 0.87-0.99) for the 3 studies that usedanother measure to def<strong>in</strong>e overweight or obesity.• The age at exam<strong>in</strong>ation had only a marg<strong>in</strong>al <strong>in</strong>fluence on the magnitude of the effect ofduration of breastfeed<strong>in</strong>g on risk of overweight. The pooled OR from all 5 studies<strong>in</strong>vestigat<strong>in</strong>g prob<strong>and</strong>s up to or <strong>in</strong>clud<strong>in</strong>g 5 years of age was 0.97 (95%CI 0.94-0.99), while <strong>in</strong>older subjects aged 6 or more years, it was 0.96 (95%CI 0.93-0.99) for 6 studies.• No evidence of publication bias was observed, as <strong>in</strong>dicated by a symmetric funnel plot <strong>and</strong> anonsignificant Begg test <strong>and</strong> Egger test.B“Us<strong>in</strong>g three different techniques, we show that a longer duration of breastfeed<strong>in</strong>g is associatedwith a larger decrease <strong>in</strong> risk of overweight. Each of the three methods used <strong>in</strong> our study has itsown advantages <strong>and</strong> limitations.”“In summary, we found that the duration of breastfeed<strong>in</strong>g is <strong>in</strong>versely <strong>and</strong> l<strong>in</strong>early associatedwith the risk of overweight. The risk of overweight was reduced by 4% for each month ofbreastfeed<strong>in</strong>g. This effect lasted up to a duration of breastfeed<strong>in</strong>g of 9 months <strong>and</strong> was<strong>in</strong>dependent of the def<strong>in</strong>ition of overweight <strong>and</strong> age at follow-up. Even if <strong>in</strong>terpreted as be<strong>in</strong>g ofrelatively small size, this association, if causal, might be of importance for the generalpopulation. S<strong>in</strong>ce the majority of studies analyzed here used partially breastfed subjects, itmight be concluded that, beyond exclusive breastfeed<strong>in</strong>g, also longer partial breastfeed<strong>in</strong>g upto 9 months leads to a greater decrease <strong>in</strong> risk of overweight <strong>in</strong> later life, which might beconsidered <strong>in</strong> future cl<strong>in</strong>ical recommendation.”The meta-analyses address<strong>in</strong>g the relationship between duration of breastfeed<strong>in</strong>g <strong>and</strong> the riskof overweight was well-performed. However, the authors’ conclusion implied a causalrelationship, which is not appropriate because most of the “cohort” studies <strong>in</strong>cluded <strong>in</strong> theanalyses were <strong>in</strong> fact cross-sectional studies because the breastfeed<strong>in</strong>g exposure wasascerta<strong>in</strong>ed retrospectively at the time of the assessment of obesity. Causality cannot beascerta<strong>in</strong>ed <strong>in</strong> cross-sectional design. Most importantly, crude OR was used <strong>in</strong> the metaanalyses,which is the major limitation.C-74
Author, yr: Harder, 2005Topic of the systematic review*/MA: ObesityReport<strong>in</strong>g yes/noReport<strong>in</strong>g of Background1 Description of study outcomes Yes2 Types of exposure or <strong>in</strong>tervention used Yes3 Types of study designs used Yes4 Study population YesReport<strong>in</strong>g of Search strategy5 Search strategy, <strong>in</strong>clud<strong>in</strong>g time period <strong>and</strong> key words Yes6 Effort to <strong>in</strong>clude all available studies (contact with authors) Yes7 Databases <strong>and</strong> registries searched Yes8 Method of address<strong>in</strong>g published articles other than English No9 Method of h<strong>and</strong>l<strong>in</strong>g abstracts <strong>and</strong> unpublished studies NoReport<strong>in</strong>g of Methods10 Rationale for selection <strong>and</strong>/or cod<strong>in</strong>g of data Yes11 Assessment of confound<strong>in</strong>g Partially12 Assessment of quality Partially13 Assessment of heterogeneity No14 Description of statistical methods sufficient to replicate Yes15 Provision of appropriate tables <strong>and</strong> graphs YesReport<strong>in</strong>g of Results16 Graphic summariz<strong>in</strong>g of <strong>in</strong>dividual study estimates <strong>and</strong> overall Yes17 Tables giv<strong>in</strong>g descriptive <strong>in</strong>formation of each study <strong>in</strong>cluded Yes18 Results of sensitivity test<strong>in</strong>g (subgroup analysis) Yes19 Indication of statistical uncerta<strong>in</strong>ty of f<strong>in</strong>d<strong>in</strong>gs Yes20 Quantitative assessment of bias (eg. publication bias) YesOverall qualityB*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyEvaluation of quality of a systematic review or meta-analysisYes /No/Partially1 Is search strategy appropriate/relevant to the key question(s)? Yes2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to the studies of Yes<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> Study YesDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g the NDrelevant data, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, various Partiallybiases <strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or not Yesadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the use Yesof a particular analytic method or model appropriate?8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity, Partiallydid the authors look at the actual differences <strong>in</strong> PICOS, for example?)?8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)? Yes9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis? YesC-75
Evidence table for Systematic Reviews of <strong>Breastfeed<strong>in</strong>g</strong>Author, Year[UI] Topic Owen, 2005 ObesityLiterature search (Dates) Medl<strong>in</strong>e (completed <strong>in</strong> September 2003); Other databases searched? (yes); unpublisheddata used? (no)Countries where primarystudies conductedDeveloped <strong>and</strong> develop<strong>in</strong>g countries: UK, Germany, USA, Canada, Italy, Turkey, Australia,New Zeal<strong>and</strong>, Slovak Republic, Ch<strong>in</strong>a, Czech Republic, SwedenStudy eligibility / <strong>in</strong>clusioncriteria61 studies that compared a measure of obesity (quantitatively or narratively) amongbreastfed <strong>and</strong> formula-fed subjects were considered. Studies that def<strong>in</strong>ed the odds of obesityor be<strong>in</strong>g overweight for breastfed <strong>and</strong> formula-fed subjects were reported more often <strong>and</strong>were <strong>in</strong>cluded <strong>in</strong> a meta-analysis; 28 studies with 29 estimates (1 study reported results for 2Study design [No. Ofstudies]No. of subjectsStudy population(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Intervention/Exposure(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Comparator (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)<strong>Outcomes</strong> (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)HeterogeneityassessmentsQuality assessmentsPublication biasassessmentsStatistical Analysis ormeta-analytic methodsResultspopulations) met this <strong>in</strong>clusion criterion.Historical cohort, prospective cohort, cross-sectional studies: total 61 studies, <strong>and</strong> 28 studies<strong>in</strong>cluded <strong>in</strong> the meta-analysesN=298,900 <strong>in</strong> the overall meta-analysis28 studies (298,900 subjects) provided 29 unadjusted odds ratios relat<strong>in</strong>g the <strong>in</strong>itial <strong>in</strong>fantfeed<strong>in</strong>g method <strong>and</strong> obesity. Four observations were for <strong>in</strong>fants, 23 for children, <strong>and</strong> 2 foradults.Breastfed vs. formula-fed.The exclusiveness of <strong>in</strong>fant feed<strong>in</strong>g was based on the classification given <strong>in</strong> each article. Thefeed<strong>in</strong>g groups were def<strong>in</strong>ed as be<strong>in</strong>g mutually exclusive <strong>in</strong> 4 studies, the breastfed group<strong>in</strong>cluded mixed feeders <strong>in</strong> 7 studies <strong>and</strong> the formula-fed group <strong>in</strong>cluded mixed feeders <strong>in</strong> 7studies. In 2 studies <strong>in</strong> which <strong>in</strong>fants were breastfed exclusively, the exclusivity of formulafeed<strong>in</strong>g could not be determ<strong>in</strong>ed.Any measures of obesity or adiposity.Most studies used a percentile cutoff based on BMI, describ<strong>in</strong>g subjects at the tail of thedistribution. The 95th or 97th percentile was used most often, although some studies usedcutoff values as low as the 85th percentile. A smaller number of studies used absolute BMIvalues or cutoff values based on st<strong>and</strong>ardized weight or weight for height. Studies <strong>in</strong>volv<strong>in</strong>g<strong>in</strong>fants used def<strong>in</strong>itions based on percentiles of weight for length or percentiles of weightonly.Q test with chi-square statisticsNDBegg funnel plot. Report<strong>in</strong>g bias was also assessed.Results from fixed-effects models are reported throughout, because these reflect only ther<strong>and</strong>om error with<strong>in</strong> each study, are more conservative because they are less affected byresults of smaller studies that show stronger associations, <strong>and</strong> make no assumptions aboutthe representativeness of the available studies.Meta-regression was used to exam<strong>in</strong>e the <strong>in</strong>fluence of the follow<strong>in</strong>g factors (def<strong>in</strong>ed a priori)with a test for trend: study size (2500 subjects), age group at outcomemeasurement (<strong>in</strong>fants 1 to 9 years of age, older children 10to =16 years of age), year of birth, <strong>and</strong> response rates(analyzed as a cont<strong>in</strong>uous variable). The effects of adjustment for factors such as parentalbody size (mostly BMI), socioeconomic status, <strong>and</strong> maternal smok<strong>in</strong>g were exam<strong>in</strong>ed <strong>in</strong> 6studies that provided data before <strong>and</strong> after adjustment for all 3 of these factors. The effectsof study methods, particularly the method of ascerta<strong>in</strong>ment of <strong>in</strong>fant feed<strong>in</strong>g status (whethercontemporary or recalled over a period of >=3 years), study response rate, <strong>and</strong> def<strong>in</strong>ition ofobesity (equivalent to
Author, Year[UI] Topic Owen, 2005 Obesity• In a fixed-effects model <strong>in</strong>clud<strong>in</strong>g all studies, breastfed subjects were less likely to bedef<strong>in</strong>ed as obese than were formula-fed subjects (OR: 0.87; 95% CI: 0.85–0.89). Therewas evidence of marked heterogeneity among studies (p=2 months (OR: 0.81; 95% CI:0.77– 0.84), compared with those breastfed for any duration (OR: 0.89; 95% CI: 0.86–0.91)<strong>in</strong> the same studies.• Studies that did not provide odds ratios were much less likely to report that breastfeed<strong>in</strong>gwas associated with a reduced risk of obesity, compared with studies that did provide oddsratios (1 of 35 studies <strong>and</strong> 18 of 29 studies, respectively; P
Author, yr: Owen, 2005Topic of the systematic review*/MA:Report<strong>in</strong>g yes/noReport<strong>in</strong>g of Background1 Description of study outcomes Yes2 Types of exposure or <strong>in</strong>tervention used Yes3 Types of study designs used Yes4 Study population YesReport<strong>in</strong>g of Search strategy5 Search strategy, <strong>in</strong>clud<strong>in</strong>g time period <strong>and</strong> key words Yes6 Effort to <strong>in</strong>clude all available studies (contact with authors) Yes7 Databases <strong>and</strong> registries searched Yes8 Method of address<strong>in</strong>g published articles other than English No9 Method of h<strong>and</strong>l<strong>in</strong>g abstracts <strong>and</strong> unpublished studies NoReport<strong>in</strong>g of Methods10 Rationale for selection <strong>and</strong>/or cod<strong>in</strong>g of data Yes11 Assessment of confound<strong>in</strong>g Partially12 Assessment of quality Yes13 Assessment of heterogeneity Yes14 Description of statistical methods sufficient to replicate Yes15 Provision of appropriate tables <strong>and</strong> graphs YesReport<strong>in</strong>g of Results16 Graphic summariz<strong>in</strong>g of <strong>in</strong>dividual study estimates <strong>and</strong> overall Yes17 Tables giv<strong>in</strong>g descriptive <strong>in</strong>formation of each study <strong>in</strong>cluded Yes18 Results of sensitivity test<strong>in</strong>g (subgroup analysis) Yes19 Indication of statistical uncerta<strong>in</strong>ty of f<strong>in</strong>d<strong>in</strong>gs Yes20 Quantitative assessment of bias (eg. publication bias) YesOverall qualityB*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyEvaluation of quality of a systematic review or meta-analysisYes /No/Partially1 Is search strategy appropriate/relevant to the key question(s)? Yes2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to the studies of Yes<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> Study YesDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g the Yesrelevant data, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, various Yesbiases <strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or not Partiallyadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the use Yesof a particular analytic method or model appropriate?8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity, Yesdid the authors look at the actual differences <strong>in</strong> PICOS, for example?)?8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)? Yes9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis? YesC-78
Appendix C. Evidence TablesPart I. Term <strong>Infant</strong> <strong>Outcomes</strong>Sudden <strong>Infant</strong> Death SyndromeHauck 2003McVea 2000 SRMA*Mitchell 1997Schellscheidt 1997Venneman 2005* Systematic Review/Meta-AnalysisC-79
Hauck, 2003 [UI# 12728140]Study designStudy characteristics <strong>and</strong> follow-updurationMean GA (range): 89 days for Case-controlcases <strong>and</strong> 85 days for controls studyMean BW (range): 2813 g Follow-up NAcases <strong>and</strong> 2915g for controls% Male: ndRace: 75% black; 13.1%Hispanic white; 11.9% non-Hispanic whiteEnrolled/Evaluate: 260 SIDS<strong>and</strong> 260 matched controlsLocation: communityEligibility criteriaCases: Included Chicago resident <strong>in</strong>fants whose death between Nov 1993<strong>and</strong> April 1996 was determ<strong>in</strong>ed by the office of medical exam<strong>in</strong>er of CookCounty, Ill<strong>in</strong>ois to be caused by SIDSTwo weeks after caregivers were asked 235 questionsControls: One liv<strong>in</strong>g control <strong>in</strong>fant was matched to each case <strong>in</strong>fant onmaternal race/ethnicity, age at death/<strong>in</strong>terview; <strong>and</strong> birth weight. They werer<strong>and</strong>omly selected <strong>in</strong> groups of 20 for white <strong>in</strong>fants <strong>and</strong> <strong>in</strong> groups of 40 forHispanic <strong>and</strong> black <strong>in</strong>fants<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventions<strong>Breastfeed<strong>in</strong>g</strong> currentyes <strong>and</strong> ever yesControl Exposuresor Interventions<strong>Breastfeed<strong>in</strong>g</strong>current no <strong>and</strong> evernoSites: S<strong>in</strong>gle/Multi PopulationbasedFund<strong>in</strong>g: GovHauck, 2003 [UI# 12728140]Outcome Def<strong>in</strong>itionSIDS: The sudden death of an <strong>in</strong>fant under 1 yr of age, which rema<strong>in</strong>sunexpla<strong>in</strong>ed after a thorough case <strong>in</strong>vestigation, <strong>in</strong>clud<strong>in</strong>g performanceof a complete autopsy, exam<strong>in</strong>ation of the death scene, <strong>and</strong> review ofthe cl<strong>in</strong>ical history.Statistical analyses <strong>and</strong>confounders adjustedUnivariate <strong>and</strong> multivariatemodelsAdjusted for maternal age,marital status, education, <strong>and</strong><strong>in</strong>dex of prenatal careResultsBreast feed<strong>in</strong>g No wasreferenceBreast feed<strong>in</strong>g ever No (cases vcontrols)/Yes (cases v controls)N=205 v 130 / 55 v 130OR=0.2 (0.1-0.3)Adj OR=0.4 (0.2-0.7)<strong>Breastfeed<strong>in</strong>g</strong> current No (casesv controls)/Yes (cases v controls)N=243 v 199 / 17 v 61OR=0.2 (0.1-0.4)Adj OR=0.3 (0.2-0.7)Bias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>gData collectionWithdraw <strong>and</strong>dropoutAnalysesIntervention<strong>in</strong>tegrityxC-80
Evidence table for Systematic Reviews of <strong>Breastfeed<strong>in</strong>g</strong>Author, Year[UI] McVea 2000 [11138219] SIDSTopicThe role of breastfeed<strong>in</strong>g <strong>in</strong> sudden <strong>in</strong>fant death syndrome (SIDS)Key questions addressedQuestion 1 – <strong>Infant</strong> mortalityDates of literature search – 1966-1997Databases searchedMEDLINE-all English language literature searchDissertation Abstracts Onl<strong>in</strong>eBibliography of all relevant articlesCountries where primary studies Developed (Regions - North America, Europe, <strong>and</strong> Australia)conducted(Developed v develop<strong>in</strong>g)Study eligibility / <strong>in</strong>clusion criteria M<strong>in</strong>imal def<strong>in</strong>ition of SIDS was met (sudden unexpla<strong>in</strong>ed death of an <strong>in</strong>fant or youngchild)Orig<strong>in</strong>al data presented that allowed calculation of an odds ratio for bottle feed<strong>in</strong>gStudy design [No. Of studies] Total = 23Case control [18]Nested case control [4]Cohort [1]No. of subjects Cases (n=99) Controls (n=47 413)Study population (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)Children (Age range birth to 2 years when outcome occurred – 17 studies; 8 studiesnd on age range)Intervention (def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Breast feed<strong>in</strong>g (No st<strong>and</strong>ard method of measur<strong>in</strong>g breast feed<strong>in</strong>g was used <strong>in</strong> thestudies - breastfed at birth, breastfed at the time of death, “breast fed”, “partiallybreast fed”)Comparator (def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cluded Bottle fed (nd)studies)<strong>Outcomes</strong> (def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)HeterogeneityQuality of Individual studiesSIDS (autopsy proven <strong>in</strong> majority – 14 studies, death certificates or coroner’s reports– 4 studies, unclear – 6 studies)Not explored although studies were heterogeneous with respect to a variety offactorsYes. Quality scores of studies ranged from 11 to 36 po<strong>in</strong>ts (on a 42 po<strong>in</strong>t max score)Better quality studies reported slightly higher risks of bottle feed<strong>in</strong>gYes. “The shape of the funnel graph endorsed the absence of publication bias ofPublication biasonly positive studies”Statistical AnalysisR<strong>and</strong>om Effects modelUsed unadjusted odds ratio for the meta-analysisSeparate meta-analysis was performed us<strong>in</strong>g only those studies with “good” qualityscores <strong>and</strong> after 1988Dose-response relationship exploredResults The pooled OR for the 23 studies us<strong>in</strong>g r<strong>and</strong>om effects model resulted <strong>in</strong> an OR =2.11 (95% CI 1.66-2.68) i.e. the overall risk of SIDS was twice as great for bottle-fed<strong>in</strong>fants compared to breastfed <strong>in</strong>fants.The pooled OR from the higher quality studies also demonstrated a two fold<strong>in</strong>crease <strong>in</strong> risk among bottle fed <strong>in</strong>fants OR = 2.24The pooled OR from studies after 1988 OR = 2.32Confounders: Individual studies adjusted for potential confounders; 6 studiesreported adjusted OR; 4 studies reported no protective effect of breastfeed<strong>in</strong>g, while2 reported adj OR that rema<strong>in</strong>ed significant.Dose Response relationship: 4 out of 9 studies showed a dose response trendwith the risk of SIDS <strong>in</strong>creas<strong>in</strong>g with <strong>in</strong>creas<strong>in</strong>g formula feed<strong>in</strong>g. None of the studieshad sufficient power to demonstrate a statistically significant difference betweenpartial v no breastfeed<strong>in</strong>g.Quality of the systematic review C (see limitations)C-81
Author, Year[UI] McVea 2000 [11138219] SIDSComments / LimitationsMisclassification of SIDS <strong>and</strong> breastfeed<strong>in</strong>gUnadjusted odds ratio for pooled analysisHeterogeneity not exploredUnable to comb<strong>in</strong>e studies with adjusted OR <strong>in</strong> the pooled analysis because ofdifferences <strong>in</strong> case match<strong>in</strong>gC-82
Author, yr: McVea, 2000Topic of the systematic review*/MA: The role of breastfeed<strong>in</strong>g <strong>in</strong> SIDSReport<strong>in</strong>g yes/noReport<strong>in</strong>g of Background1 Description of study outcomes Y2 Types of exposure or <strong>in</strong>tervention used Y3 Types of study designs used Y4 Study population YReport<strong>in</strong>g of Search strategy5 Search strategy, <strong>in</strong>clud<strong>in</strong>g time period <strong>and</strong> key words Y6 Effort to <strong>in</strong>clude all available studies (contact with authors) N7 Databases <strong>and</strong> registries searched Y8 Method of address<strong>in</strong>g published articles other than English N9 Method of h<strong>and</strong>l<strong>in</strong>g abstracts <strong>and</strong> unpublished studies YReport<strong>in</strong>g of Methods10 Rationale for selection <strong>and</strong>/or cod<strong>in</strong>g of data Y11 Assessment of confound<strong>in</strong>g N12 Assessment of quality Y13 Assessment of heterogeneity N14 Description of statistical methods sufficient to replicate Y15 Provision of appropriate tables <strong>and</strong> graphs YReport<strong>in</strong>g of Results16 Graphic summariz<strong>in</strong>g of <strong>in</strong>dividual study estimates <strong>and</strong> overall Y17 Tables giv<strong>in</strong>g descriptive <strong>in</strong>formation of each study <strong>in</strong>cluded Y18 Results of sensitivity test<strong>in</strong>g (subgroup analysis) N19 Indication of statistical uncerta<strong>in</strong>ty of f<strong>in</strong>d<strong>in</strong>gs Y20 Quantitative assessment of bias (eg. publication bias) NOverall QualityC*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyEvaluation of quality of a systematic review or meta-analysisYes /No/Partially1 Is search strategy appropriate/relevant to the key question(s)? partially2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to the studies of partially<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> Study yesDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g the norelevant data, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, various yesbiases <strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or not yesadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the use yesof a particular analytic method or model appropriate?8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity, nodid the authors look at the actual differences <strong>in</strong> PICOS, for example?)?8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)? yes9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis? partiallyC-83
Mitchell 1997 [UI# 9346984]Studydesign <strong>and</strong>Study characteristicsfollow-updurationMean GA (range): 2.6- Case-cohort9.1 wk for cases; 2.4-9.2 study designwk for controls2 yr cohort;Mean BW (range): follow-up
Schellscheidt J 1997 [UI# 9266202]Study characteristicsMean GA (range): 8days to one yrMean BW (range): nd% Male: ndRace: ndEnrolled/Evaluate: 59Location: communitySites: S<strong>in</strong>gle/MultiPopulation based studyFund<strong>in</strong>g: ndStudy design <strong>and</strong>follow-up durationCase-control studyFollow-up NotapplicableIncidence of SIDSdur<strong>in</strong>g the 2 yrsEligibility criteriaFor cases: No positive autopsy f<strong>in</strong>d<strong>in</strong>gs; m<strong>in</strong>imal f<strong>in</strong>d<strong>in</strong>gs without anyrelationship to death; f<strong>in</strong>d<strong>in</strong>gs possibly related to death (but notexpla<strong>in</strong><strong>in</strong>g it) <strong>and</strong> autopsy f<strong>in</strong>d<strong>in</strong>gs expla<strong>in</strong><strong>in</strong>g death.For controls: Two controls were selected for each case of the same age±4 weeks <strong>and</strong> sex r<strong>and</strong>omly by the pediatrician or a general practitioner<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventions<strong>Breastfeed<strong>in</strong>g</strong> <strong>in</strong> weeks>12 wks (ref)Control Exposuresor Interventions<strong>Breastfeed<strong>in</strong>g</strong> <strong>in</strong>weeks1-6 wks7-12 wksNoneSchellscheidt J 1997 [UI# 9266202]Outcome Def<strong>in</strong>ition Statistical analyses <strong>and</strong> confounders adjusted ResultsSame as eligibility criteriaVariables were entered as dichotomous <strong>in</strong>dicatorsAnalyses were univariate. No confounders were adjustedBreast feed<strong>in</strong>g cases versus controlsNone (N=29 vs 27)OR=7.7 (2.7, 22.3)1-6 wk (N=12 vs 40)OR=2.1 (0.7, 6.7)7-12 wk (N=10 vs 39)OR=1.8 (0.6, 6.0)>12 wk (N=7 vs 50) REFBias/limitationsCommentsA: strong, B: moderate, C: weak A B CSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdraw <strong>and</strong> dropoutAnalyses xIntervention <strong>in</strong>tegrityC-85
Vennemann, 2005 [UI# 16188764]Study design <strong>and</strong>Study characteristicsfollow-up durationMean GA (range): ndMean BW (range): nd% Male: cases 60.4%Controls 60.3%Race: ndEnrolled/Evaluate: SIDScases 404/333Location: population basedCase-control studydesignDuration SIDS dur<strong>in</strong>g3 yr periodFollow-up durationNAEligibility criteriaCases: All reported cases of sudden <strong>and</strong> unexpected deaths <strong>in</strong>the first year of life after the first 7 d <strong>and</strong> all cases wereautopsied.Controls: Three controls with the best age match<strong>in</strong>g werechosen<strong>Breastfeed<strong>in</strong>g</strong> Exposuresor Interventions<strong>Breastfeed<strong>in</strong>g</strong> >2 wk yesControl Exposures orInterventions<strong>Breastfeed<strong>in</strong>g</strong> >2wk NoSites: S<strong>in</strong>gle/Multi 18centers <strong>in</strong>volvedFund<strong>in</strong>g: ndVennemann, 2005 [UI# 16188764]Outcome Def<strong>in</strong>ition Statistical analyses <strong>and</strong> confounders adjusted ResultsSudden <strong>and</strong> unexpected deaths <strong>in</strong>the first year of life after the first 7d <strong>and</strong> all cases were autopsied.Univariate <strong>and</strong> multivariate analysis were done us<strong>in</strong>g conditional logisticregression. The multivariate model <strong>in</strong>cludes all variables which were foundsignificant at the 5% level <strong>in</strong> the univariate analysis except gestational age, asthis was closely related to birthweight<strong>Breastfeed<strong>in</strong>g</strong> >2wkYes N=165/827(cases/controls)No N=168/171Univariate OR=5.36(3.97-7.23)MultivariateOR=1.71 (1.06-2.77)Bias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdraw <strong>and</strong> xdropoutAnalyses xInterventionx<strong>in</strong>tegrityOverall = BC-86
Appendix C. Evidence TablesPart I. Term <strong>Infant</strong> <strong>Outcomes</strong>Type 1 DMEURODIAS 2002Gerste<strong>in</strong> 1994 SRMA*Jones 1998McK<strong>in</strong>ney 1999Meloni 1997Norris 1996 SRMA*Tai 1998Visalli 2003* Systematic Review/Meta-AnalysisC-87
EURODIAS, 2002 [12351473]Studydesign <strong>and</strong>Study characteristicsfollow-updurationAge at Dx of IDDM: ND Case-controlMean GA (range): ND studyMean BW (range): ND% Male: NDRace: NDEnrolled/Evaluate:683/610 for cases;2167/1616 for controlsLocation: EuropeSites: MultiFund<strong>in</strong>g: GovernmentEligibility criteriaCases: cases were identified from a population-basedregister of childhood-onset diabetes operat<strong>in</strong>g <strong>in</strong> a substudyof EURODIAB (5 participat<strong>in</strong>g centers)Controls: a population-based sample of control children,matched to the patients <strong>in</strong> age distribution, was obta<strong>in</strong>ed<strong>in</strong> each center us<strong>in</strong>g sources that depended on localcircumstances as previously described (<strong>in</strong>clud<strong>in</strong>gschools, population register, polycl<strong>in</strong>ics, <strong>and</strong> generalpractitioner register)<strong>Breastfeed<strong>in</strong>g</strong> Exposures or InterventionsParents were <strong>in</strong>terviewed or filled <strong>in</strong> thequestionnaire regard<strong>in</strong>g <strong>in</strong>formation about <strong>in</strong>fantfeed<strong>in</strong>g (duration of breast-feed<strong>in</strong>g, age at<strong>in</strong>troduction of formula feed<strong>in</strong>g, dairy milk, foodconta<strong>in</strong><strong>in</strong>g fruit, vegetable, fish, meat, <strong>and</strong> egg).Breast-feed<strong>in</strong>g of any duration (or ever breastfeed<strong>in</strong>g)ControlExposures orInterventionsNever breastfeed<strong>in</strong>gEURODIAS, 2002 [12351473]OutcomeStatistical analyses <strong>and</strong> confounders adjustedDef<strong>in</strong>itionPooled ORs ofIDDM forexposuresobta<strong>in</strong>ed fromeach centerMantel Haenszel approach was used to pool odds ratio(ORs) for exposures (e.g. breastfeed<strong>in</strong>g, early<strong>in</strong>troduction of solid food) obta<strong>in</strong>ed from each center,to test the significance of the comb<strong>in</strong>ed OR, <strong>and</strong> totest for heterogeneity <strong>in</strong> the ORs between centers.To adjust for potential confounders, logistic regressionanalysis was used with terms <strong>in</strong>cluded <strong>in</strong> the modelto represent centers. Adjustments <strong>in</strong>cluded heightSDS, weight SDS, maternal age at delivery, neonataljaundice, neonatal respiratory <strong>in</strong>fection, vitam<strong>in</strong> Dsupplementation, <strong>and</strong> asthma.ResultsBreast-feed<strong>in</strong>g of any duration was associated with a reduction<strong>in</strong> risk, with a pooled OR of 0.75 (95% CI 0.58-0.96) <strong>and</strong> noevidence of heterogeneity between centers.The <strong>in</strong>troduction of cow’s milk before 3 months of age (OR 1.15,95%CI 0.74-1.81), cow’s milk or formula (OR 1.01, 95%CI0.81-1.25), or solid foods (OR 0.74, 95%CI 0.57-0.95) wasnot associated with any significant elevation <strong>in</strong> risk. Indeedthe f<strong>in</strong>d<strong>in</strong>g for solid foods suggested a reduced risk, althoughthere was significant heterogeneity between centers(p
Q1: Insul<strong>in</strong>-Dependent Diabetes MellitusAuthor, Year[UI] Gerste<strong>in</strong>, 1994 [8112184] Type 1 Diabetes MellitusLiterature search Medl<strong>in</strong>e (no data); Other databases searched? (no); unpublished data used? (yes)(Dates)Countries where Developed countries only: Norway, Denmark, Italy, US, Australia, Canada, Sweden, F<strong>in</strong>l<strong>and</strong>, UKprimary studiesconductedStudy eligibility /<strong>in</strong>clusion criteriaArticles or letters to the editor were eligible for <strong>in</strong>clusion if they reported orig<strong>in</strong>al research deal<strong>in</strong>gwith both type I diabetes <strong>and</strong> cow’s milk exposure or avoidance <strong>and</strong> were published <strong>in</strong> peerreviewedjournals. Articles were excluded if they exclusively used surrogate markers for either typeI diabetes or cow’s milk exposure.Study design [No. Of Ecological <strong>and</strong> time-series studies [3]; Case-control studies [13]; Cohort study [1]; case series [1]studies]No. of subjects Data available for case-control studies only:Study population(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Intervention/Exposure(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Comparator(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)<strong>Outcomes</strong> (def<strong>in</strong>ition<strong>in</strong> <strong>in</strong>cluded studies)HeterogeneityassessmentsQuality assessmentsPublication biasassessmentsStatistical Analysis ormeta-analyticmethodsCases: 3,708 Controls: 20,340• Ecological <strong>and</strong> time-series studies <strong>in</strong> which the prevalence of type I DM was comparedwith the rate of breast-feed<strong>in</strong>g or cow’s milk consumption <strong>in</strong> different populations or overa specified period of time.• Case-control studies <strong>in</strong> which the neonatal feed<strong>in</strong>g histories of patients with type I DM<strong>and</strong> <strong>in</strong>dividually matched non-DM control subjects were compared. Studies that usedpopulation breast-feed<strong>in</strong>g registries as control data also were <strong>in</strong>cluded, because the lowprevalence of type I DM <strong>in</strong> the general population ensures that population data isrepresentative of the breast-feed<strong>in</strong>g habits of non-DM <strong>in</strong>dividuals.• There was a letter to the editor report<strong>in</strong>g an analysis of two cohort studies <strong>and</strong> an articlethat described the neonatal feed<strong>in</strong>g history of a series of patients with DM.• There were no controlled trials of exposure to cow’s milk.Cow’s milk exposure (<strong>and</strong> therefore non-exclusive breastfeed<strong>in</strong>g)Cow’s milk avoidance (<strong>and</strong> therefore breastfeed<strong>in</strong>g)Type I DM.Surrogate markers of type I DM (such as the presence of islet cell antibodies) were excluded.Q statistics <strong>and</strong> chi-square distributionSix methodological criteria were assessed for case-control studies only. Each criterion was marked<strong>in</strong>dividually <strong>and</strong> listed <strong>in</strong> a summary table of all studies. There was no summary grad<strong>in</strong>g.Not doneMeta-analyses of ORs were done for case-control studies. Both adjusted (preferred) <strong>and</strong>unadjusted ORs were used. Fixed-effect model.C-89
Author, Year[UI] Gerste<strong>in</strong>, 1994 [8112184] Type 1 Diabetes MellitusResults • Time-series <strong>and</strong> ecological studies showed an association (geographically <strong>and</strong>temporally) between rate/prevalence of breastfeed<strong>in</strong>g <strong>and</strong> the <strong>in</strong>cidence of type I DM.• Results from the 13 case-control studies were mixed. Some of these studiesdemonstrated that patients with type I DM were more likely to have a history of neonatalcow’s milk exposure or a short/negative history of breast-feed<strong>in</strong>g than non-DM controlsubjects; other studies failed to demonstrate such a relationship. When these resultswere meta-analyzed, the OR for type I DM <strong>in</strong> patients exposed to
Report<strong>in</strong>g yes/no20 Quantitative assessment of bias (eg. publication bias) YesOverall qualityB*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyEvaluation of quality of a systematic review or meta-analysisYes /No/Partially1 Is search strategy appropriate/relevant to the key question(s)? Partially2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to the studies of Yes<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> Study YesDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g the Norelevant data, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, various Yesbiases <strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or not Partiallyadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the use Partiallyof a particular analytic method or model appropriate?8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity, Yesdid the authors look at the actual differences <strong>in</strong> PICOS, for example?)?8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)? Yes9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis? YesC-91
Jones, 1998 [9698133]Studydesign <strong>and</strong>Study characteristicsfollow-updurationAge at Dx of IDDM: ND Case-controlMean GA (range): ND studyMean BW (range): ND% Male: 53Race: NDEnrolled/Evaluate:
McK<strong>in</strong>ney, 1999 [10372244]Studydesign <strong>and</strong>Study characteristicsfollow-updurationAge at Dx of IDDM: 0-15 Case-controlMean GA (range): 11% ≤37 wks studyMean BW (range): 7%
Meloni, 1997 [9051384]StudycharacteristicsAge at Dx of IDDM:6 (1-15) yrMean GA (range):NDMean BW (range):ND% Male: 53Race: NDEnrolled/Evaluate:115/100 for casesLocation: ItalySites: S<strong>in</strong>gleFund<strong>in</strong>g: NDStudydesign <strong>and</strong>follow-updurationCase-controlstudyEligibility criteriaCases: All diabetic subjects followed up at the university hospital whomet the <strong>in</strong>clusion criteria: 1: age < 17 years at diagnosis of IDDM, 2)diagnosis of IDDM was achieved between 1983 <strong>and</strong>1994, <strong>and</strong> 3)patient’s mother was currently liv<strong>in</strong>g, which was considered necessaryto obta<strong>in</strong> accurate <strong>in</strong>fant diet <strong>in</strong>formation. Accord<strong>in</strong>g to these criteria,100 IDDM patients (of the 115 eligible) were <strong>in</strong>cluded.Controls: children admitted at the same university hospital, matched eachdiabetic case for sex <strong>and</strong> age. None of the control subjects had afamily history of IDDM.<strong>Breastfeed<strong>in</strong>g</strong> Exposuresor InterventionsLong-term maternal recall ofthe duration of complete orpartial breast-feed<strong>in</strong>g dur<strong>in</strong>g<strong>in</strong>fant’s 1 st year of life.Control Exposures orInterventionsLong-term maternal recall ofthe age at which dietaryproducts conta<strong>in</strong><strong>in</strong>g cow’smilk were <strong>in</strong>troduced <strong>in</strong>tothe diet dur<strong>in</strong>g <strong>in</strong>fant’s 1 styear of lifeMeloni, 1997 [9051384]Outcome Def<strong>in</strong>itionRisk of IDDM, comparedchildren who had beenbreast-fed to those who hadnot been breast fedRisk of IDDM, comparedchildren who had beenbreast-fed for 1-2 months, 3-5 months, or >6 months tothose who had not beenbreast-fed.Statistical analyses <strong>and</strong>confounders adjustedThe OR of diabetes accord<strong>in</strong>g tobreast-feed<strong>in</strong>g, the duration ofbreast-feed<strong>in</strong>g, the age at<strong>in</strong>troduction of dietary productsconta<strong>in</strong><strong>in</strong>g cow’s milk, <strong>and</strong> the age at<strong>in</strong>troduction of solid food wereestimated by means of conditionallogistic regression, where the stratawere def<strong>in</strong>ed by s<strong>in</strong>gle year of age at<strong>in</strong>terview <strong>and</strong> sex.Also <strong>in</strong>cluded <strong>in</strong> the models wereterms for mother’s education <strong>and</strong>number of sibl<strong>in</strong>gs.ResultsIDDM Controls OR (95% CI)casesBFYes 84 70 1*No 16 30 0.41 (0.19-0.91)Duration ofBF (mo)>6 25 19 1*3-5 41 25 1.18 (0.52-2.68)1-2 18 26 0.48 (0.19-1.24)0 16 30 0.36 (0.14-0.94)Cont<strong>in</strong>uous1.10 (0.99-1.22)coefficient***reference category**cont<strong>in</strong>uous per 1 month <strong>in</strong>creaseBias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdraw <strong>and</strong> xdropoutAnalyses xIntervention N/A<strong>in</strong>tegrityOverall: BLimitations: Long-term maternalrecalls. Hospital controlsC-94
Q1: Insul<strong>in</strong>-Dependent Diabetes MellitusAuthor, Year[UI] Norris, 1996 [8664407] Type 1 Diabetes MellitusLiterature search Medl<strong>in</strong>e (1966-1994); Other databases searched? (no); unpublished data used? (yes)(Dates)Countries whereprimary studiesDeveloped countries only: Norway, Denmark, Italy, US, Australia, Canada, Sweden, F<strong>in</strong>l<strong>and</strong>, BritishIsles, Irel<strong>and</strong>, UKconductedStudy eligibility /<strong>in</strong>clusion criteriaInclusion: all epidemiologic studies exam<strong>in</strong><strong>in</strong>g <strong>in</strong>fant diet <strong>and</strong> IDDM riskExclusion: studies with <strong>in</strong>sufficient data for meta-analysesStudy design [No. Of Case-control studies [17]studies]No. of subjects Cases: 4,656 Controls: 16,383Study population(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Intervention/Exposure(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Comparator(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)<strong>Outcomes</strong> (def<strong>in</strong>ition<strong>in</strong> <strong>in</strong>cluded studies)HeterogeneityassessmentsCases: IDDM patients identified from diabetes cl<strong>in</strong>ics, school surveys, registries, physician surveys,or pediatric departments.Controls: non-IDDM controls selected from sibl<strong>in</strong>gs, national population data, friends, classmates,physician referred samples, national population registry, r<strong>and</strong>om sample of household, child healthsystem, or schools <strong>and</strong> day careA=breastfeed<strong>in</strong>g status (ever/never)B=total breastfeed<strong>in</strong>g durationC=exposure to breast-milk substitutesD=exposure to cow’s milk-based substitutesOdds ratios for the risk of IDDM“The addition to the model of a variable for each study <strong>in</strong> the analyses resulted <strong>in</strong> an improvement<strong>in</strong> the overall fit of the model (as determ<strong>in</strong>ed by the log-likelihood statistic) compared with the modelconta<strong>in</strong><strong>in</strong>g only the exposure variable, <strong>in</strong>dicat<strong>in</strong>g heterogeneity of effect across studies. We alsoevaluated study heterogeneity by add<strong>in</strong>g to the model product terms obta<strong>in</strong>ed by multiply<strong>in</strong>g theexposure variable by each study variable.”Sensitivity analyses on various study characteristicsInclud<strong>in</strong>g unpublished dataQuality assessmentsPublication biasassessmentsStatistical Analysis or Stratified unconditional logistic regression was used to estimate OR <strong>and</strong> 95%CI. This methodmeta-analyticweights each study by its sample size. Variables for the <strong>in</strong>dividual studies <strong>and</strong> for the exposure ofmethods<strong>in</strong>terest were <strong>in</strong>cluded <strong>in</strong> the model. Both matched <strong>and</strong> unmatched ORs were used.Results • The summary odds ratio (OR) of the 18 studies that exam<strong>in</strong>ed the association between neverbe<strong>in</strong>g breast-fed <strong>and</strong> IDDM was 1.13 (95% CI = 1.04-123).• Meta-analyses of summary ORs were done <strong>in</strong> the 14 studies that exam<strong>in</strong>ed IDDM risk bymonths of breastfeed<strong>in</strong>g duration. The duration categories <strong>in</strong> the analyses were cumulative,rather than mutually exclusive. The summary OR for IDDM <strong>in</strong> subjects who were breast-fed forless than 3 months compared with those who were breast-fed for at least 3 months was 1.23(95%CI = 1.12-1.35).• When compar<strong>in</strong>g the ORs by whether or not the studies relied on long-term recall to assess<strong>in</strong>fant diet, studies us<strong>in</strong>g exist<strong>in</strong>g <strong>in</strong>fant records to determ<strong>in</strong>e breastfeed<strong>in</strong>g <strong>in</strong>itiation <strong>and</strong>duration failed to show the associations reported <strong>in</strong> the studies rely<strong>in</strong>g on long-term recall fortheir exposure data.Quality of thesystematic reviewAuthor’s<strong>in</strong>terpretations of theresultsBOur meta-analysis showed that the <strong>in</strong>creased risk of IDDM associated with any of the <strong>in</strong>fant dietexposures is small Interpretation of weak associations (that is, generally an OR
Author, Year[UI] Norris, 1996 [8664407] Type 1 Diabetes MellitusComments /LimitationsVery thoughtful analyses but the analysis cannot be replicated due to lack of <strong>in</strong>dividual study data.Only crude ORs were used <strong>in</strong> the meta-analyses due to limitation of meta-analytic technique.Conclusions were well justified.C-96
Author, yr: Norris, 1996Topic of the systematic review*/MA: Type 1 DMReport<strong>in</strong>g yes/noReport<strong>in</strong>g of Background1 Description of study outcomes yes2 Types of exposure or <strong>in</strong>tervention used yes3 Types of study designs used yes4 Study population yesReport<strong>in</strong>g of Search strategy5 Search strategy, <strong>in</strong>clud<strong>in</strong>g time period <strong>and</strong> key words no6 Effort to <strong>in</strong>clude all available studies (contact with authors) yes7 Databases <strong>and</strong> registries searched yes8 Method of address<strong>in</strong>g published articles other than English no9 Method of h<strong>and</strong>l<strong>in</strong>g abstracts <strong>and</strong> unpublished studies yesReport<strong>in</strong>g of Methods10 Rationale for selection <strong>and</strong>/or cod<strong>in</strong>g of data yes11 Assessment of confound<strong>in</strong>g yes/no12 Assessment of quality yes13 Assessment of heterogeneity yes14 Description of statistical methods sufficient to replicate yes15 Provision of appropriate tables <strong>and</strong> graphs yesReport<strong>in</strong>g of Results16 Graphic summariz<strong>in</strong>g of <strong>in</strong>dividual study estimates <strong>and</strong> overall no17 Tables giv<strong>in</strong>g descriptive <strong>in</strong>formation of each study <strong>in</strong>cluded yes18 Results of sensitivity test<strong>in</strong>g (subgroup analysis) yes19 Indication of statistical uncerta<strong>in</strong>ty of f<strong>in</strong>d<strong>in</strong>gs yes20 Quantitative assessment of bias (eg. publication bias) yesOverall qualityB*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyEvaluation of quality of a systematic review or meta-analysisYes /No/Partially1 Is search strategy appropriate/relevant to the key question(s)? Partially2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to the studies of Yes<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> Study YesDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g the Yesrelevant data, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, various Yesbiases <strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or not Partiallyadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the use Yesof a particular analytic method or model appropriate?8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity, Yesdid the authors look at the actual differences <strong>in</strong> PICOS, for example?)?8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)? Yes9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis? YesC-97
Tai, 1998 [9925351]Study characteristicsAge at Dx of IDDM: 8.3±3.3SDMean GA (range): 1% ≤36 wk;99% >36 wkMean BW (range): 21%
Tai, 1998 [9925351]OutcomeDef<strong>in</strong>itionOR ofdevelop<strong>in</strong>gIDDMStatistical analyses <strong>and</strong> confoundersadjustedAge <strong>and</strong> sex were adjusted us<strong>in</strong>g logisticregression analysis. The age-sexadjustedORs were estimated from theregression coefficient <strong>and</strong> its S.E. for therisk factor.Multiple logistic regression analysis wasthen carried out by <strong>in</strong>clud<strong>in</strong>g risk factorswhich were statistically significant <strong>in</strong>univariate analyses as well as thosereported <strong>in</strong> other studies <strong>in</strong> the model.ResultsI. Age-sex-adjusted ORs of develop<strong>in</strong>g IDDM (univariate):Risk factors Cases N Controls N OR (95% CI)Feed<strong>in</strong>g style dur<strong>in</strong>g <strong>in</strong>fancyBreast-feed<strong>in</strong>g 46 82 1.00Cow’s milk 70 109 1.43 (0.83-2.47)Duration of BF (months)Never 70 109 1.00
Visalli, 2003 [12876166]Study designStudy characteristics <strong>and</strong> follow-updurationAge at Dx of IDDM: ND Case-controlMean GA (range): ND studyMean BW (range): ND% Male: 50Race: NDEnrolled/Evaluate:330/150 for cases;1200/750 for controlsLocation: ItalySites: MultiFund<strong>in</strong>g:Eligibility criteriaCases: type 1 DM patients selected (330 cases) for this study were diagnosedwith<strong>in</strong> the EURODIAS ACE study, <strong>and</strong> were born between 1977 <strong>and</strong> 1989.Controls: population based control subjects born <strong>in</strong> the same period were chosenfrom primary <strong>and</strong> secondary school enrolment records <strong>in</strong> the region, <strong>and</strong> theselection process was designed <strong>in</strong> collaboration with EURODIAS Substudy 2group. Out of 1,100 controls replied to the questionnaires, 750 were r<strong>and</strong>omlyselected, match<strong>in</strong>g 1 case with 5 controls by age.<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsQuestionnaires weredistributed to all parentsof cases <strong>and</strong> controls.Duration of breastfeed<strong>in</strong>g ≥ 3 monthsEnd of breast feed<strong>in</strong>g ≥3 monthsControlExposures orInterventionsDuration of breastfeed<strong>in</strong>g < 3monthsEnd of breastfeed<strong>in</strong>g < 3monthsVisalli, 2003 [12876166]OutcomeDef<strong>in</strong>itionOR of IDDMStatistical analyses <strong>and</strong>confounders adjustedConditional logisticregression analysis wasperformed to adjust thepossible confounders(those significant <strong>in</strong>univariate analyses).ResultsI. Univariate analysis:Risk factors OR 95% CIFull term birth 1.44 0.81-2.56Duration of BF < 3 mo 2.12 1.38-3.26Beg<strong>in</strong>n<strong>in</strong>g of wean<strong>in</strong>g < 3 mo 1.81 1.06-3.07End of breast feed<strong>in</strong>g < 3 mo 2.03 1.24-3.33Cow’s milk before 23 mo 1.49 0.72-3.11II. Multivariate logistic regression analysis for risk factors which have beenfound to be significantRisk factors OR 95% CIDuration of BF < 3 mo 1.74 1.40-2.45Family history of type 1 DM 1.17 1.05-1.76Presence of <strong>in</strong>fectious disease dur<strong>in</strong>g 1.60 1.32-2.20mother’s pregnancyOccurrence of eczema 1.61 1.25-2.66Bias/limitationsCommentsA: strong, B: moderate, C: weak A B CSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdraw <strong>and</strong> dropout xAnalyses xIntervention <strong>in</strong>tegrityN/AOverall: COnly 45% of the eligible cases were able to becontacted.C-100
Appendix C. Evidence TablesPart I. Term <strong>Infant</strong> <strong>Outcomes</strong><strong>Infant</strong> Type 2 DMOwen 2006 SRMA*Taylor 2005 SRMA** Systematic Review/Meta-AnalysisC-101
Evidence table for Systematic Reviews of <strong>Breastfeed<strong>in</strong>g</strong>Author, Year[UI] Topic Owen, 2006 Type 2 diabetesLiterature search (Dates) Medl<strong>in</strong>e (1966-November 2004); Other databases searched? (yes); unpublished data used?(no)Countries where primary Developed countries: UK, US, Canada, Dutchstudies conductedStudy eligibility / <strong>in</strong>clusioncriteriaExclusion criteria: <strong>in</strong>fant feed<strong>in</strong>g status or measures of diabetes were not recorded. Studiesdid not compare diabetic outcomes among those formula <strong>and</strong> breastfed. Studies did notprovide the odds of type 2 diabetes, mean differences <strong>in</strong> blood glucose, or differences <strong>in</strong>plasma <strong>in</strong>sul<strong>in</strong> between those breastfed <strong>and</strong> formula fed.Note: For the purpose of this review, we only focus on those studies reported OR of type 2Study design [No. Ofstudies]No. of subjectsStudy population (def<strong>in</strong>ition<strong>in</strong> <strong>in</strong>cluded studies)Intervention/Exposure(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Comparator (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)<strong>Outcomes</strong> (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)Heterogeneity assessmentsQuality assessmentsPublication biasassessmentsStatistical Analysis or metaanalyticmethodsResultsQuality of the systematicreviewAuthor’s <strong>in</strong>terpretations ofthe resultsdiabetes as an outcomes.Historical cohort study [3]; Cross-sectional study [2]; Prospective cohort [1]; Case-controlstudy [1]Total of 76,744 subjects6 studies conducted <strong>in</strong> adults <strong>and</strong> 1 conducted <strong>in</strong> adolescentsEver breastfed vs. formula fed <strong>in</strong> all 7 studies.Feed<strong>in</strong>g status was reported as be<strong>in</strong>g exclusive <strong>in</strong> one of these studies.OR (95% CI) of type 2 diabetesChi-squared test.Meta-regression <strong>and</strong> sensitivity analysis were used to exam<strong>in</strong>e potential heterogeneityacross studies (see Quality assessment)The effect of study size, year of birth, the method of ascerta<strong>in</strong>ment of <strong>in</strong>fant feed<strong>in</strong>g status(whether contemporary or recalled up to 71 y after birth), type of formula fed, study responserate (analyzed as a cont<strong>in</strong>uous variable), study design (r<strong>and</strong>omized controlled trial, casecontrol,or cohort), <strong>and</strong> whether <strong>in</strong>fants were born pre- or full-term was exam<strong>in</strong>ed by us<strong>in</strong>gmeta-regression <strong>and</strong> sensitivity analysis.Sensitivity analyses were used to exam<strong>in</strong>e the effect of adjustment for importantconfounders <strong>and</strong> of fast<strong>in</strong>g status.Funnel plots with Begg <strong>and</strong> Egger testsFixed-effect model.• Six of the 7 studies related breastfeed<strong>in</strong>g to a lower risk of type 2 diabetes, <strong>and</strong> therewas no evidence of heterogeneity across studies.• Overall, the subjects who were breastfed showed a lower risk of type 2 diabetes than didthose who were formula fed (pooled OR: 0.61; 0.44-0.85; p=0.003).• Three studies had <strong>in</strong>formation on relevant confounders (birthweight, parental diabetes,socioeconomic status, <strong>and</strong> <strong>in</strong>dividual or maternal body size). However the OR relat<strong>in</strong>gbreastfeed<strong>in</strong>g <strong>and</strong> diabetes risk was similar before (0.55; 95% CI: 0.35-0.86; p=0.009)<strong>and</strong> after (0.55, 95% CI 0.34-0.90; p=0.017) adjustment.• The method for ascerta<strong>in</strong><strong>in</strong>g feed<strong>in</strong>g exposure was unrelated to the ORs.AIn the present overview of published studies relat<strong>in</strong>g <strong>in</strong>fant feed<strong>in</strong>g <strong>and</strong> risk of diabetes, thepooled estimate from 6 studies conducted <strong>in</strong> adults <strong>and</strong> 1 study conducted <strong>in</strong> adolescentsshowed that early breastfeed<strong>in</strong>g was consistently associated with a lower risk of type 2diabetes <strong>in</strong> later life compared with those <strong>in</strong>itially formula fed.C-102
Author, Year[UI] Topic Owen, 2006 Type 2 diabetesPublication bias is an important potential explanation for the consistent associationsobserved <strong>in</strong> these published studies. The results provide no evidence of marked publicationbias, although the statistical power of formal tests was limited by the small number of studiesavailable for analysis.It is possible that confound<strong>in</strong>g by birthweight <strong>and</strong> maternal factors could lead tooverestimation of the association between breastfeed<strong>in</strong>g <strong>and</strong> diabetes <strong>in</strong> later life.Comments / Limitations Pooled different study designsC-103
Author, yr: Owen, 2006Topic of the systematic review*/MA: Type 2 DMReport<strong>in</strong>g yes/noReport<strong>in</strong>g of Background1 Description of study outcomes yes2 Types of exposure or <strong>in</strong>tervention used yes3 Types of study designs used yes4 Study population yesReport<strong>in</strong>g of Search strategy5 Search strategy, <strong>in</strong>clud<strong>in</strong>g time period <strong>and</strong> key words yes6 Effort to <strong>in</strong>clude all available studies (contact with authors) no7 Databases <strong>and</strong> registries searched yes8 Method of address<strong>in</strong>g published articles other than English no9 Method of h<strong>and</strong>l<strong>in</strong>g abstracts <strong>and</strong> unpublished studies noReport<strong>in</strong>g of Methods10 Rationale for selection <strong>and</strong>/or cod<strong>in</strong>g of data yes11 Assessment of confound<strong>in</strong>g yes12 Assessment of quality yes13 Assessment of heterogeneity yes14 Description of statistical methods sufficient to replicate yes15 Provision of appropriate tables <strong>and</strong> graphs yesReport<strong>in</strong>g of Results16 Graphic summariz<strong>in</strong>g of <strong>in</strong>dividual study estimates <strong>and</strong> overall Yes17 Tables giv<strong>in</strong>g descriptive <strong>in</strong>formation of each study <strong>in</strong>cluded yes18 Results of sensitivity test<strong>in</strong>g (subgroup analysis) yes19 Indication of statistical uncerta<strong>in</strong>ty of f<strong>in</strong>d<strong>in</strong>gs yes20 Quantitative assessment of bias (eg. publication bias) yesOverall qualityA*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyEvaluation of quality of a systematic review or meta-analysisYes /No/Partially1 Is search strategy appropriate/relevant to the key question(s)? Yes2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to the studies of Yes<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> Study YesDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g the Partiallyrelevant data, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, various Yesbiases <strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or not Yesadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the use Yesof a particular analytic method or model appropriate?8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity, Yesdid the authors look at the actual differences <strong>in</strong> PICOS, for example?)?8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)? Yes9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis? YesC-104
Evidence table for Systematic Reviews of <strong>Breastfeed<strong>in</strong>g</strong>Author, Year[UI] Topic Taylor, 2005 [UI] Type 2 diabetesLiterature search (Dates) Medl<strong>in</strong>e (1966-2003); Other databases searched? (yes); unpublished data used? (no)Countries where primary Developed countries only: US, Canada, Germanystudies conductedStudy eligibility / <strong>in</strong>clusioncriteriaSearch was limited to the English language <strong>and</strong> to human subjects. All studies <strong>in</strong>volvedterm s<strong>in</strong>gleton <strong>in</strong>fants unless otherwise noted.Study design [No. Of studies] Cohort studies [2]; case-control study [1]No. of subjects 1,514Study population (def<strong>in</strong>ition <strong>in</strong> • Studies of association between breastfeed<strong>in</strong>g <strong>and</strong> type 2 diabetes<strong>in</strong>cluded studies)• Children of mothers with diabetesIntervention/Exposure(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cluded studies)Comparator (def<strong>in</strong>ition <strong>in</strong>Many of the studies that were reviewed only reported breastfeed<strong>in</strong>g versus bottlefeed<strong>in</strong>g, without more detailed <strong>in</strong>formation on exclusivity, frequency, or duration.Information on tim<strong>in</strong>g <strong>and</strong> duration of breastfeed<strong>in</strong>g were <strong>in</strong>cluded where available.<strong>in</strong>cluded studies)<strong>Outcomes</strong> (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)Heterogeneity assessmentsQuality assessmentsPublication bias assessmentsStatistical Analysis or metaanalyticmethodsResultsQuality of the systematicreviewAuthor’s <strong>in</strong>terpretations of theresultsComments / Limitations• Impaired glucose tolerance (IGT): fast<strong>in</strong>g glucose < 140 mg/dL <strong>and</strong> 2-hour glucose> 140 mg/dL (after 1.75 g/kg OGTT)• Type 2 diabetes (NIDDM): 2-hour glucose ≥ 200 mg/dL (after 75 g OGTT) or fast<strong>in</strong>gglucose ≥ 126 mg/dLN/AN/AN/AN/AAssociation between breastfeed<strong>in</strong>g <strong>and</strong> type 2 DM:• Consistently <strong>in</strong> 2 studies (1 retrospective cohort; 1 case-control study), exclusivebreastfeed<strong>in</strong>g is associated with lower risk of diabetes.Children of Mothers with DM:• One retrospective cohort study found that DM <strong>in</strong> the next generation was lesscommon among breastfed children than among bottle-fed children, of both motherswith DM <strong>and</strong> without DM.CBased on the literature reviewed, breastfeed<strong>in</strong>g should be strongly encouraged for allwomen, with or without diabetes.No synthesis of results or appraisals of study quality. Unclear how the conclusions werereached.C-105
Author, yr: Taylor, 2005Topic of the systematic review*/MA: Type 2 DMReport<strong>in</strong>g yes/noReport<strong>in</strong>g of Background1 Description of study outcomes yes2 Types of exposure or <strong>in</strong>tervention used yes3 Types of study designs used yes4 Study population yesReport<strong>in</strong>g of Search strategy5 Search strategy, <strong>in</strong>clud<strong>in</strong>g time period <strong>and</strong> key words yes6 Effort to <strong>in</strong>clude all available studies (contact with authors) no7 Databases <strong>and</strong> registries searched yes8 Method of address<strong>in</strong>g published articles other than English no9 Method of h<strong>and</strong>l<strong>in</strong>g abstracts <strong>and</strong> unpublished studies noReport<strong>in</strong>g of Methods10 Rationale for selection <strong>and</strong>/or cod<strong>in</strong>g of data yes11 Assessment of confound<strong>in</strong>g partially12 Assessment of quality no13 Assessment of heterogeneity N/A14 Description of statistical methods sufficient to replicate N/A15 Provision of appropriate tables <strong>and</strong> graphs noReport<strong>in</strong>g of Results16 Graphic summariz<strong>in</strong>g of <strong>in</strong>dividual study estimates <strong>and</strong> overall no17 Tables giv<strong>in</strong>g descriptive <strong>in</strong>formation of each study <strong>in</strong>cluded no18 Results of sensitivity test<strong>in</strong>g (subgroup analysis) N/A19 Indication of statistical uncerta<strong>in</strong>ty of f<strong>in</strong>d<strong>in</strong>gs yes20 Quantitative assessment of bias (eg. publication bias) noOverall qualityC*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyEvaluation of quality of a systematic review or meta-analysisYes /No/Partially1 Is search strategy appropriate/relevant to the key question(s)? Partially2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to the studies of Yes<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> Study YesDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g the Norelevant data, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, various Nobiases <strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or not Partiallyadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the use Noof a particular analytic method or model appropriate?8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity, Partiallydid the authors look at the actual differences <strong>in</strong> PICOS, for example?)?8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)? Unclear(no tables)9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis? NoC-106
Appendix C. Evidence TablesPart II. Preterm <strong>Infant</strong> <strong>Outcomes</strong>Cognitive Premature <strong>Infant</strong>sBier 2002Eidelman 2004Elgen 2002Feldman 2003Horwood 2001O’Connor 2003P<strong>in</strong>elli 2003Smith 2003Vohr 2006C-107
Bier 2002 [2003020034]Study characteristics Study design <strong>and</strong> follow-up duration Eligibility criteriaMean GA (range) breast milkgroup: 28.6 wk (23-34)Mean BW (range): 1174 g (600-1965)% Male: 45%Race:Enrolled/Evaluate: 29 <strong>in</strong> humanmilk group; 10 <strong>in</strong> formula groupLocation: USSites: MultiFund<strong>in</strong>g:Non-r<strong>and</strong>omized comparison of breast milkversus formula fed preterm <strong>in</strong>fants(convenience sample)Excluded <strong>in</strong>fants with mothers who usedillicit drugs, had mental illness, HIV<strong>in</strong>fection, <strong>and</strong> others.<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsControl Exposuresor InterventionsBier 2002 [2003020034]OutcomeDef<strong>in</strong>itionBayley MDI at7-month <strong>and</strong> at12-monthStatistical analyses <strong>and</strong>confounders adjustedAdjusted for maternal resultof Peabody PictureVocabulary Test (PPVT) <strong>and</strong>days of oxygenResultsMean Bayley MDI at 7 month, human milk group =94 ± 7, <strong>in</strong> formula group = 90 ± 9 (Difference NS)At 12 months, human milk group = 101 ± 11,formula group = 90 ± 9 (P
Eidelman 2004 [15384601]StudyStudy design <strong>and</strong> follow-up durationcharacteristicsMean GA (range): Prospective cohort separated <strong>in</strong>to 3 groups30.5 wk (26-33 wk) based on amount of human milk feed<strong>in</strong>g;Mean BW (range): Bayley scales assessed at 6 months corrected1298 g (640-1720 g) age% Male: 53%Race:Evaluated: 86Location: IsraelSites: S<strong>in</strong>gleFund<strong>in</strong>g:Eligibility criteria75% of nutrition ashuman milk; 25-75%; <strong>and</strong>
Elgen, 2003 [14580653]StudycharacteristicsMean GA (range):BW (range):
Feldman, 2003 [12918090]StudyStudy design <strong>and</strong>characteristics follow-up durationMean GA (range): 30 Prospective cohort;wk (26-33)consecutiveMean BW (range): enrollment (6 decl<strong>in</strong>ed)1298 (640-1720)% Male:Race:Enrolled/Evaluate: 86Location: IsraelSites: S<strong>in</strong>gle/MultiFund<strong>in</strong>g:Eligibility criteria
Horwood, 2001 [11124919]StudycharacteristicsMean GA (range):Mean BW (range):% Male:Race:Evaluated:298/280 analyzedLocation: NewZeal<strong>and</strong>Sites: S<strong>in</strong>gle/MultiFund<strong>in</strong>g:Study design <strong>and</strong> follow-up durationCross-sectional; all 413 very low birth birthweight <strong>in</strong>fants who were live born <strong>in</strong> 1986 whowere admitted to one neonatal unit; retrospective recall of breast milk feed<strong>in</strong>g <strong>and</strong> durationof feed<strong>in</strong>g; children were assessed by WISC-R (excluded 17 children who could not reliablybe assessed because of sensor<strong>in</strong>eural disability; 1 child was excluded because the data onbreastfeed<strong>in</strong>g were miss<strong>in</strong>g) at 7 yrEligibilitycriteriaLive born verylow birthweight<strong>in</strong>fants<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsNot breastfed (n=76)Breastfed < 4months (n=99)4-7 months (n=46)≥ 8 months (n=59)ControlExposures orInterventionsHorwood, 2001 [11124919]OutcomeStatistical analyses <strong>and</strong> confounders adjustedDef<strong>in</strong>itionWISC-R Controlled for per<strong>in</strong>atal, socio-demographic (family <strong>in</strong>come, s<strong>in</strong>gle/twoparent family, child ethnicity), <strong>and</strong> maternal factors (age, education,smok<strong>in</strong>g); the data were analyzed us<strong>in</strong>g multiple l<strong>in</strong>ear regressiontechniques <strong>in</strong> which the measures of verbal <strong>and</strong> performance IQ wereregressed on the four level measure of breastfeed<strong>in</strong>g treated as acont<strong>in</strong>uous variable <strong>and</strong> significant covariate factors.ResultsChildren who were breastfed ≥ 8 months hadmean verbal IQ 10.2 (SD 0.56) higher <strong>and</strong> meanperformance IQ 6.2 (SD 0.35) higher thanchildren who did not receive breast milk.After adjustment for covariates, there rema<strong>in</strong>ed asignificant association between duration of receiptof breast milk <strong>and</strong> verbal IQ, with a 6 po<strong>in</strong>tadvantage for <strong>in</strong>fants who received breast milk for≥ 8 months compared with no breastfeed<strong>in</strong>g(P
O’Connor, 2003 [14508214]Study Study design <strong>and</strong> followupdurationcharacteristicsGA ):
P<strong>in</strong>elli, 2003 [2003083348]StudycharacteristicsMean GA (range):80% breast milk vs80% breastmilk group: 93 (SD16); for 80% breastmilk group: 92 (SD15); for 0.05 for all comparisonsBias/limitationsCommentsA: strong, B: moderate, A B CC: weakSelection xStudy design xConfounder/bias xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdraw <strong>and</strong> dropout xAnalyses xIntervention <strong>in</strong>tegrityCognitive test at a young ageC-114
Smith, 2003 [14630603]Study characteristicsMedian GA (range):27.4 wkMedian BW (range):1014 g% Male:Race:Enrolled/Evaluate:439/420Location: USSites: MultiFund<strong>in</strong>g:Study design <strong>and</strong> follow-updurationCohort; subjects were fromDevelopmental Epidemiology Networkcohort (n=1442), 439 enrolled <strong>in</strong>follow up studies at 6 to 8 yrEligibility criteriaSurviv<strong>in</strong>g children with selected ultrasoundabnormalities were <strong>in</strong>cluded (n=119), <strong>and</strong> a r<strong>and</strong>omsample (1:4 ratio) of <strong>in</strong>fants frequency matched forgestation were <strong>in</strong>cluded; had undergoneneuropsychological assessment <strong>and</strong> for whom parentalquestionnaires were complete by 9/2002<strong>Breastfeed<strong>in</strong>g</strong> Exposuresor InterventionsReceived expressed milkwithout progress<strong>in</strong>g to directbreastfeed<strong>in</strong>g, receiveddirect breastfeed<strong>in</strong>gControlExposures orInterventionsNo human milkSmith, 2003 [14630603]Outcome Def<strong>in</strong>itionKaufman Assessment Battery forChildren (an estimate for overall<strong>in</strong>tellectual function); PeabodyPicture Vocabulary Test <strong>and</strong> Cl<strong>in</strong>icalEvaluation of LanguageFundamentals (verbal); CaliforniaChildren’s Verbal Learn<strong>in</strong>g Test(memory); Wide Range Assessmentof Visual Motor Abilities (visualspatialskill) These measures werest<strong>and</strong>ardized with a mean of 100po<strong>in</strong>ts <strong>and</strong> st<strong>and</strong>ard deviation of 15po<strong>in</strong>ts.Statistical analyses <strong>and</strong>confounders adjusted<strong>Maternal</strong> verbal ability, HomeObservation for Measurementof the Environment Inventory,SES, duration of hospitalizationResultsCompared with nonparticipat<strong>in</strong>g mothers, those whoparticipated were older, more educated, more likely to bemarried, be non-smokers, <strong>and</strong> have private medical<strong>in</strong>surance.153 subjects did not receive human milk; 142 receivedexpressed milk without progress<strong>in</strong>g to direct breastfeed<strong>in</strong>g;125 received direct breastfeed<strong>in</strong>g (the majority of them firstreceived expressed breast milk); 20% of <strong>in</strong>fants receivedbreast milk >6 mo.Breast milk feed<strong>in</strong>gs were associated with higherunadjusted test scores for each doma<strong>in</strong> of cognitive functionexcept memory.In the regression model that <strong>in</strong>cluded social advantage <strong>and</strong>neonatal morbidity, the adjusted score <strong>in</strong> overall <strong>in</strong>tellectualfunction associated with direct breastfeed<strong>in</strong>g was reducedto 3.6 po<strong>in</strong>ts (95% CI, -0.3, 7.5) from 10.7 (95%CI, 7.0,14.4). Breastfed children had an advantage <strong>in</strong> visual-motor<strong>in</strong>tegration measure (adjusted IQ 5.1, 95% CI, 1.0, 9.2)Bias/limitationsCommentsA: strong, B: moderate, A B CC: weakSelection xStudy design xConfounder/bias xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdraw <strong>and</strong> dropout xAnalyses xIntervention <strong>in</strong>tegrity27% of subjects with ultrasoundabnormalities; the tim<strong>in</strong>g of collection ofbreastfeed<strong>in</strong>g data was not reportedC-115
Vohr, 2006 [16818526]Study characteristics Study design <strong>and</strong> follow-up duration Eligibility criteria <strong>Breastfeed<strong>in</strong>g</strong> Exposures or InterventionsMean GA (range): 26.5wkMean BW (range): 785g (BM), 794 (no)% Male: 45%Race:Enrolled/Evaluate:1159/1035Location: USSites: MultiFund<strong>in</strong>g:Prospective cohort; Bayley results at 18to 22 mos corrected age; exam<strong>in</strong>erbl<strong>in</strong>ded to feed<strong>in</strong>g history, primarycaretaker stayed with the child dur<strong>in</strong>gthe Bayley exam<strong>in</strong>ationEnrolled prospectively <strong>in</strong> theGlutam<strong>in</strong>e Trial at 15 sites ofNeonatal Research Network;survivorsBreast milk – received some breast milk dur<strong>in</strong>ghospitalization; total volume received calculatedper day, values were <strong>in</strong>terpolated for days of theweek <strong>in</strong> which the data were not collectedControl Exposures orInterventionsC-116
Vohr, 2006 [16818526]Statistical analysesOutcome Def<strong>in</strong>ition <strong>and</strong> confoundersadjustedCognitive outcome of Adjustment for marital<strong>in</strong>terest: Bayley status, maternalMental Development education, age,Index (MDI)race/ethnicity, <strong>in</strong>fant’sgestational age, gender,culture positive sepsis,grade 3 to 4<strong>in</strong>traventricularhemorrhage, oxygen at36 wks gestational age,necrotiz<strong>in</strong>g enterocolitis,<strong>and</strong> weight
Appendix C. Evidence TablesPart II. Preterm <strong>Infant</strong> <strong>Outcomes</strong>Necrotiz<strong>in</strong>g EnterocolitisFurman 2003Gross 1983Lucas 1984 1990McGuire 2001 SRMA*Ronnestad 2005Schanler 2005Tyson 1983* Systematic Review/Meta-AnalysisC-118
Furman, 2003 [UI# 12517197]StudycharacteristicsMean GA (range):28 wkMean BW (range):1056 g% Male: 57%Race:Enrolled/Evaluate:119Location:Clevel<strong>and</strong>Sites: S<strong>in</strong>gleFund<strong>in</strong>g:Study design <strong>and</strong>follow-up durationProspective cohort;The study comparedthe effect of vary<strong>in</strong>gdosages of maternalmilk on neonataloutcomesEligibility criteriaS<strong>in</strong>gleton, birth weight 600-1499 g,gestational age < 33 wk, no positivedrug screen, major congenitalanomaly, <strong>in</strong>trauter<strong>in</strong>e <strong>in</strong>fection, or<strong>in</strong>surmountable maternal socialfactors<strong>Breastfeed<strong>in</strong>g</strong> Exposures or InterventionsIntravenous dextrose dur<strong>in</strong>g the first 24 hrs; enteral <strong>in</strong>take was begunby day 2 or 3 of life, parenteral nutrition was cont<strong>in</strong>ued until a dailyenteral <strong>in</strong>take of 120 mL/kg of body weight was reached. <strong>Infant</strong>sreceived their mother’s milk <strong>in</strong> the sequence it was expressed, exceptthat fresh rather than frozen milk was given if available. <strong>Maternal</strong> milkwas fortified, <strong>and</strong> preterm <strong>in</strong>fant formula was offered when the <strong>in</strong>fantreached a daily oral <strong>in</strong>take of at least 110 mL/kg. Limited availability ofmaternal milk was the sole reason <strong>in</strong>fants were fed preterm formula <strong>in</strong>addition to maternal milk.ControlExposures orInterventionsFurman, 2003 [UI# 12517197]Statistical analysesOutcome Def<strong>in</strong>ition<strong>and</strong> confoundersadjustedNEC <strong>in</strong> the 4 subgroups:Logistic regression;No maternal milkadjusted for birthDaily 1-24 mL/kg of maternal milk weight, ethnicity, <strong>and</strong>Daily 25-49 mL/kg of maternal milk sexDaily ≥ 50 mL/kg of maternal milkResults0 maternal milk 3/401-24 mL/kg 2/29 (OR 1.15 95% CI 0.8-12.13)25-49 mL/kg 2/18 (OR 1.99 95% CI 0.14-21.03)≥ 50 mL/kg 0/32 (OR 0 95% CI 0 – 3.56)Bias/limitationsCommentsA: strong, B: moderate, C: weak A B CSelectionStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdraw <strong>and</strong> dropout xAnalyses xIntervention <strong>in</strong>tegrity xC-119
Gross, 1983 [UI# :6848932]StudycharacteristicsMean GA (range):31 wkMean BW (range):1322 g% Male:Race:Enrolled/Evaluate:Location: USSites: S<strong>in</strong>gleFund<strong>in</strong>g:Study design <strong>and</strong> follow-up durationR<strong>and</strong>om number assignment <strong>in</strong>to 3 groups: mature humanmilk, preterm human milk, whey-based formula; any <strong>in</strong>fantwithdrawn from the study was replaced by the next <strong>in</strong>fantenrolled, until there were 20 <strong>in</strong>fants <strong>in</strong> each group; rema<strong>in</strong>ed<strong>in</strong> the study until they reached 1800 gEligibility criteria27 – 33 wk gestation; ≤ 1600 g; nocongenital abnormalities or majordiseases; ability to beg<strong>in</strong> enteral feed by6 th day of life; absence of breast milk fromown mother<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsFeed<strong>in</strong>gs beganbetween the first <strong>and</strong>sixth days of life.ControlExposures orInterventionsGross, 1983 [UI#:6848932]Outcome Def<strong>in</strong>itionNEC (abdom<strong>in</strong>al distention, gastric aspirates, guaiac-positivestools, <strong>and</strong> pneumatosis <strong>in</strong>test<strong>in</strong>alis)Statistical analyses <strong>and</strong> confoundersadjustedNEC was analyzed as <strong>in</strong>fants whowithdrew from the studyResults67 <strong>in</strong>fants recruited forthe study;1/41 (BM) vs. 3/26 (FM)with NECBias/limitationsCommentsA: strong, B: moderate, A B CC: weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdraw <strong>and</strong> dropout xAnalyses xIntervention <strong>in</strong>tegrityC-120
Lucas, 1984 [UI# 6476868]; 1990 [UI# 1979363]StudycharacteristicsMean GA (range): 31wkMean BW (SD): 1370g ( 320 g)% Male:Race:Enrolled/Evaluate:Location: UKSites: /MultiFund<strong>in</strong>g:Study design <strong>and</strong> follow-up durationR<strong>and</strong>omization with<strong>in</strong> 48 h of birth for <strong>in</strong>fants whose mothers decided not tobreastfeed, r<strong>and</strong>omized <strong>in</strong>to banked donor human milk vs. preterm formula;only <strong>in</strong>fants fed exclusively on donor milk or formula were comparedEligibility criteria
Evidence table for Systematic Reviews of <strong>Breastfeed<strong>in</strong>g</strong> <strong>and</strong> NECAuthor,Year[UI] Topic McGuire, 2001 [11687169] NECLiterature search (Dates)1966-10/2003Medl<strong>in</strong>e; Other databases searched? (yes, CENTRAL, EMBASE, CINAHL);unpublished data used? (no)Countries where primary studies NDconductedStudy eligibility / <strong>in</strong>clusion criteria RCT compar<strong>in</strong>g feed<strong>in</strong>g with formula milk versus term human milk <strong>in</strong> low birthweight or preterm <strong>in</strong>fantsStudy design [No. Of studies] RCT: 3 studies with outcomes re: NECNo. of subjects 287Study population (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)Gross 1983 27-33 wk, bw < 1600 gTyson 1983 very low birth weight <strong>in</strong>fantsIntervention/Exposure (def<strong>in</strong>ition<strong>in</strong> <strong>in</strong>cluded studies)Comparator (def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)<strong>Outcomes</strong> (def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Heterogeneity assessmentsQuality assessmentsPublication bias assessmentsStatistical Analysis or metaanalyticmethodsLucas 1984 preterm <strong>in</strong>fants < 1850 gGross 1983 unfortified term donor breast milk, fed until 1800 g or until withdrawalsecondary to feed <strong>in</strong>tolerance or NECTyson 1983 pooled banked term human milk, allocation at 10 th day of life, fed until2000 g or until withdrawal secondary to illness requir<strong>in</strong>g parenteral fat or prote<strong>in</strong>Lucas 1984 banked term human milk 200 mL/kg/d, fed until 2000 g or until d/cGross 1983 st<strong>and</strong>ard calorie (0.67 kcal/mL, prote<strong>in</strong> enriched (1.9 g/100 mL)formulaTyson 1983 enriched calorie (0.87 kcal/mL), prote<strong>in</strong> enriched (2.2 g/100 mL)formulaLucas 1984 enriched calorie (0.80 kcal/mL), prote<strong>in</strong> enriched (2.0 g/100 mL)formula at 180 mL/kg/dNecrotiz<strong>in</strong>g enterocolitisGross 1983 & Tyson 1983 The studies did not attempt bl<strong>in</strong>d<strong>in</strong>g of parents, carers,or assessors. Adverse events were not reported as primary end po<strong>in</strong>ts but rather aswithdrawal criteria.Lucas 1984 The study did not attempt bl<strong>in</strong>d<strong>in</strong>g of parents, carers, or assessors.Data on NEC on all 159 recruited <strong>in</strong>fants were reported3 trials were comb<strong>in</strong>ed <strong>in</strong> a meta-analysis: formula vs human milk, RR: 2.5 (95% CI0.9, 7.3); RD: 0.05 (95% CI 0.00, 0.1)Results Gross 1983 <strong>in</strong>cidence of NEC <strong>in</strong> formula vs human milk: RR 2.4 (95% CI 0.3,21.6); RD: 0.07 (95% CI 0.09, 0.22)Tyson 1983 <strong>in</strong>cidence of NEC <strong>in</strong> formula vs human milk: RR 4.2 (95% CI 0.2,85.3); RD: 0.05 (95% CI –0.03, 0.12)Lucas 1984 <strong>in</strong>cidence of NEC <strong>in</strong> formula vs human milk: RR 2.2 (95% CI 0.6, 8.4);RD: 0.04 (95% CI –0.03, 0.12)Quality of the systematic reviewAuthor’s <strong>in</strong>terpretations of theresultsComments / LimitationsWe did not f<strong>in</strong>d any statistically significant difference <strong>in</strong> the risk of NEC with formulamilk versus term human milk feed<strong>in</strong>g.Donor milk, not mother specific milkC-122
Author, yr: McGuire, 2001Topic of the systematic review*/MA:Report<strong>in</strong>g yes/noReport<strong>in</strong>g of Background1 Description of study outcomes Y2 Types of exposure or <strong>in</strong>tervention used Y3 Types of study designs used Y4 Study population YReport<strong>in</strong>g of Search strategy5 Search strategy, <strong>in</strong>clud<strong>in</strong>g time period <strong>and</strong> key words Y6 Effort to <strong>in</strong>clude all available studies (contact with authors) Y7 Databases <strong>and</strong> registries searched Y8 Method of address<strong>in</strong>g published articles other than English Y/N9 Method of h<strong>and</strong>l<strong>in</strong>g abstracts <strong>and</strong> unpublished studies NReport<strong>in</strong>g of Methods10 Rationale for selection <strong>and</strong>/or cod<strong>in</strong>g of data Y11 Assessment of confound<strong>in</strong>g Y/N12 Assessment of quality Y13 Assessment of heterogeneity Y14 Description of statistical methods sufficient to replicate Y15 Provision of appropriate tables <strong>and</strong> graphs YReport<strong>in</strong>g of Results16 Graphic summariz<strong>in</strong>g of <strong>in</strong>dividual study estimates <strong>and</strong> overall Y17 Tables giv<strong>in</strong>g descriptive <strong>in</strong>formation of each study <strong>in</strong>cluded N18 Results of sensitivity test<strong>in</strong>g (subgroup analysis) Y19 Indication of statistical uncerta<strong>in</strong>ty of f<strong>in</strong>d<strong>in</strong>gs Y20 Quantitative assessment of bias (eg. publication bias) NOverall quality*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyEvaluation of quality of a systematic review or meta-analysisYes /No/Partially1 Is search strategy appropriate/relevant to the key question(s)? Y2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to the studies of Y<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> Study YDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g the Y/Nrelevant data, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, various Y/Nbiases <strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or not Y/Nadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the use Yof a particular analytic method or model appropriate?8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity, Ydid the authors look at the actual differences <strong>in</strong> PICOS, for example?)?8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)? Y/N9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis? YC-123
Ronnestad, 2005 [UI# 15687416]Study designStudy characteristics <strong>and</strong> follow-updurationEligibility criteriaMean GA (range): 22- Prospective Participat<strong>in</strong>g centers had a common policy of27 wkcohortachiev<strong>in</strong>g full enteral feed<strong>in</strong>g with the mother’sMean BW (range): 845milk or banked donor milk as early asg (est.)possible, although there was no consensus <strong>in</strong>% Male: 56%terms of a detailed protocol for feed<strong>in</strong>gRace:strategies.Enrolled/Evaluate: 462All <strong>in</strong>fants born <strong>in</strong> Norway <strong>in</strong> 1999 <strong>and</strong> 2000enrolled; 405 survivedwith gestational age of
Schanler, 2005 [UI# 16061595]Study designStudy<strong>and</strong> follow-upcharacteristicsdurationMean GA (range): 23-26wk & 27-29 wkMean BW (range):952 g% Male: 53%Race: NDEnrolled/Evaluate:243Location: TexasChildren’s HospitalSites: MultiFund<strong>in</strong>g: governmentRCT4 days to 90 daysof age ordischarge fromthe hospitalEligibility criteria<strong>Infant</strong>s with mother expected tobreastfeed; if mother’s own milk wasunavailable; then <strong>in</strong>fants werer<strong>and</strong>omized to Donor Milk versusPreterm formula<strong>Breastfeed<strong>in</strong>g</strong> Exposures or InterventionsDonor milk (DM) (+ mother’s milk partially)Reference group: non-r<strong>and</strong>omized, exclusive mother’s milk (MM)Small quantities of mother’s milk (~20 mL/kg/day) was <strong>in</strong>itiated <strong>in</strong> thefirst week <strong>and</strong> cont<strong>in</strong>ued for ~3 to 5 days before the volume wasadvanced. Milk <strong>in</strong>take was <strong>in</strong>creased by ~20 mL/kg daily to 100mL/kg, at which time milk fortifier was added, this was advanced by~20 mL/kg daily until 160 mL/kg per day was achieved.ControlExposures orInterventionsPreterm formula(PF) (+ mother’smilk partially)Schanler, 2005 [UI# 16061595]Outcome Def<strong>in</strong>itionNECOnly cases of NEC that occurred afterthe <strong>in</strong>fant atta<strong>in</strong>ed a milk <strong>in</strong>take of ≥50mL/kg were analyzed for the primaryoutcome.Statistical analyses <strong>and</strong> confoundersadjusted17 <strong>in</strong>fants (21%) <strong>in</strong> DM were switched to PFbecause of poor weight ga<strong>in</strong>. All <strong>in</strong>fantsrema<strong>in</strong>ed <strong>in</strong> the orig<strong>in</strong>al assigned group foranalysis.ResultsIncidence of NEC:DM vs PF: 5/78 vs 10/88 (P=0.27)Non-r<strong>and</strong>omized group MM had fewer repeatedepisodes of late-onset-sepsis <strong>and</strong>/or NEC (OR0.18; 95% CI 0.04–0.79) compared with comb<strong>in</strong>edgroups DM <strong>and</strong> PFBias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collectionWithdraw <strong>and</strong>dropoutAnalyses xInterventionx<strong>in</strong>tegrityxC-125
Tyson, 1983 [UI# - 6864403]StudycharacteristicsMean GA (range):31.5 wkMean BW (range):1232 g% Male:Race:Enrolled/Evaluate:Location: USSites: S<strong>in</strong>gleFund<strong>in</strong>g:Study design <strong>and</strong> follow-up durationRCT; <strong>in</strong>fants were not enrolled until the 10 thday; enrolled <strong>in</strong>to donor human milk orformula milk groupsEligibility criteria<strong>Infant</strong>s whose mothers cont<strong>in</strong>ued to provide milkat 10 days were excluded, as <strong>in</strong>fants with anysignificant illnesses<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsControl Exposures orInterventionsTyson, 1983 [UI# - 6864403]Outcome Def<strong>in</strong>ition Statistical analyses <strong>and</strong> confounders adjusted ResultsNEC confirmed at surgery;suspected NECNEC was analyzed as subjects who dropped out ofthe study.0/37 (BM) vs. 1/44 (FM) forconfirmed NECBias/limitationsCommentsA: strong, B: moderate, C: A B CweakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdraw <strong>and</strong> dropout xAnalyses xIntervention <strong>in</strong>tegrityC-126
Appendix C. Evidence TablesPart III. <strong>Maternal</strong> <strong>Outcomes</strong>Breast CancerBernier 2000 SRMA*CGHFBC 2002 SRMA*Gammon 2002Jernstrom 2004Lee 2003Lipworth 2000 SRMA** Systematic Review/Meta-AnalysisC-127
Evidence table for Systematic Reviews of <strong>Breastfeed<strong>in</strong>g</strong>Author, Year[UI] Topic Bernier, 2000 Breast cancerLiterature search (Dates) Medl<strong>in</strong>e (1980-1998); Other databases searched? (yes-Embase); unpublished data used?(no)Countries where primarystudies conductedDeveloped <strong>and</strong> develop<strong>in</strong>g countries (Estonia, Canada, USA, Sicilia, Costa Rica, Australia,India, Ch<strong>in</strong>a, Greece, Italy, Mexico, New Zeal<strong>and</strong>)Study eligibility / <strong>in</strong>clusioncriteriaA study was <strong>in</strong>cluded <strong>in</strong> the analysis: 1) it was published between 1980 <strong>and</strong> 1998 2) itpresented primary orig<strong>in</strong>al data; 3) it was published either <strong>in</strong> English or French; 4) the type ofstudy was either a case-control, or a prospective cohort study; 5) data on breastfeed<strong>in</strong>gexposure were reported <strong>and</strong> used <strong>in</strong> the analysis 6) breast cancer was the event of <strong>in</strong>terest7) specific odds ratio measur<strong>in</strong>g the breastfeed<strong>in</strong>g <strong>and</strong> breast cancer association were givenor could be derived.Excluded were studies <strong>in</strong> which data from parous women who had not breastfed could notbe separated from nulliparous womenStudy design [No. Of 23 [Case-control studies]studies]No. of subjects25871 cases/44910 controlsStudy populationParous women with breast cancer(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Intervention/Exposure <strong>Breastfeed<strong>in</strong>g</strong> (Ever)(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Comparator (def<strong>in</strong>ition <strong>in</strong> <strong>Breastfeed<strong>in</strong>g</strong> (never)<strong>in</strong>cluded studies)<strong>Outcomes</strong> (def<strong>in</strong>ition <strong>in</strong> Breast cancer (histologically diagnosed)<strong>in</strong>cluded studies)HeterogeneityassessmentsQuality assessmentsPublication biasassessmentsStatistical Analysis ormeta-analytic methodsResultsYes; homogeneity graph <strong>and</strong> by subgroup analysis (menopausal status; duration ofbreastfeed<strong>in</strong>g)Unclear (MA discussed methodologic quality with subhead<strong>in</strong>g of orig<strong>in</strong> of the women; breastcancer diagnosis; <strong>and</strong> data collection)Yes (funnel plot)Both r<strong>and</strong>om <strong>and</strong> fixed effects modelBreast cancer risk ever vs never breastfeed<strong>in</strong>gPooled OR us<strong>in</strong>g the fixed effects model 0.90 (0.86-0.94)Pooled OR us<strong>in</strong>g r<strong>and</strong>om effects model 0.84 (0.78-0.91These results were not modified us<strong>in</strong>g adjusted ORsBreast cancer risk accord<strong>in</strong>g to the menopausal status at the time of the diagnosis <strong>in</strong>ever vs never breastfeed<strong>in</strong>g mothersMenopausal at the time of breast cancer diagnosisPooled OR us<strong>in</strong>g the fixed effects model 1.01 (0.94-1.09)Pooled OR us<strong>in</strong>g r<strong>and</strong>om effects model 0.84 (0.69-1.03)Non-menopausal at the time of breast cancer diagnosisPooled OR us<strong>in</strong>g the fixed effects model 0.83 (0.76-0.91)Pooled OR us<strong>in</strong>g r<strong>and</strong>om effects model 0.81 (0.72-0.91)Breast cancer risk accord<strong>in</strong>g to duration of breast feed<strong>in</strong>g0+ to 6 mo v neverPooled OR us<strong>in</strong>g the fixed effects model 1.02 (0.94-1.10)Pooled OR us<strong>in</strong>g r<strong>and</strong>om effects model 1.00 (0.86-1.16)6+ to 12 mo v neverPooled OR us<strong>in</strong>g the fixed effects model 0.97 (0.88-1.06)Pooled OR us<strong>in</strong>g r<strong>and</strong>om effects model 0.97 (0.86-1.09)12+ mo vs. neverPooled OR us<strong>in</strong>g the fixed effects model 0.75 (0.70-0.80)C-128
Author, Year[UI] Topic Bernier, 2000 Breast cancerPooled OR us<strong>in</strong>g r<strong>and</strong>om effects model 0.72 (0.65-0.80)Quality of the systematic BreviewAuthor’s <strong>in</strong>terpretations ofthe results<strong>Breastfeed<strong>in</strong>g</strong> appeared to be a protective factor but was of small magnitude compared withother known risk factors of breast cancerComments / Limitations Quality score for <strong>in</strong>dividual studies not assessedC-129
Author, yr: Bernier 2000Topic of the systematic review*/MA: Breast cancer <strong>and</strong> breastfeed<strong>in</strong>gReport<strong>in</strong>g yes/noReport<strong>in</strong>g of Background1 Description of study outcomes Y2 Types of exposure or <strong>in</strong>tervention used Y3 Types of study designs used Y4 Study population YReport<strong>in</strong>g of Search strategy5 Search strategy, <strong>in</strong>clud<strong>in</strong>g time period <strong>and</strong> key words Y6 Effort to <strong>in</strong>clude all available studies (contact with authors) N7 Databases <strong>and</strong> registries searched Y8 Method of address<strong>in</strong>g published articles other than English N9 Method of h<strong>and</strong>l<strong>in</strong>g abstracts <strong>and</strong> unpublished studies NReport<strong>in</strong>g of Methods10 Rationale for selection <strong>and</strong>/or cod<strong>in</strong>g of data Y11 Assessment of confound<strong>in</strong>g Y12 Assessment of quality Unclear13 Assessment of heterogeneity Y14 Description of statistical methods sufficient to replicate Y15 Provision of appropriate tables <strong>and</strong> graphs YReport<strong>in</strong>g of Results16 Graphic summariz<strong>in</strong>g of <strong>in</strong>dividual study estimates <strong>and</strong> overall Y17 Tables giv<strong>in</strong>g descriptive <strong>in</strong>formation of each study <strong>in</strong>cluded Partially yes18 Results of sensitivity test<strong>in</strong>g (subgroup analysis) Y19 Indication of statistical uncerta<strong>in</strong>ty of f<strong>in</strong>d<strong>in</strong>gs N20 Quantitative assessment of bias (eg. publication bias) YAuthors’ Conclusions21 Consistent with the presented results Y22 Comment<strong>in</strong>g on the validity of the conclusions Y23 Present<strong>in</strong>g alternative explanations YOverall qualityB*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyYes /NoEvaluation of quality of a systematic review or meta-analysis/Partially1 Is search strategy appropriate/relevant to the key question(s)? Yes2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to studies of Partially<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> Study YesDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g the relevant Partiallydata, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, various biases No<strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or not Yesadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the use of Yesa particular analytic method or model appropriate?8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity, didthe authors look at the actual differences <strong>in</strong> PICOS, for example?)?Yes8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)? No9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis? YesC-130
Evidence table for Systematic Reviews of <strong>Breastfeed<strong>in</strong>g</strong>Author, Year[UI] Topic Collaborative Group on Hormonal Factors <strong>in</strong> Breast Cancer Breast Cancer(CGHFBC) 2002 [12133652]Literature search (Dates) ND Available <strong>in</strong> prior publicationsMedl<strong>in</strong>e (nd); Other databases searched? (nd); unpublished data used? (yes)Countries where primary International studies <strong>in</strong>clud<strong>in</strong>g developed <strong>and</strong> develop<strong>in</strong>g nationsstudies conductedStudy eligibility / <strong>in</strong>clusioncriteriaStudies that had data on at least 100 women with <strong>in</strong>cident <strong>in</strong>vasive breast cancer <strong>and</strong> hadrecorded <strong>in</strong>formation on each women with respect to reproductive factors <strong>and</strong> use ofhormonal preparations. For the cohort studies, a nested case-control study design wasused, <strong>in</strong> which four r<strong>and</strong>omly selected controls per case were matched for age atdiagnosis <strong>and</strong> where appropriate, broad geographical regioncase-control <strong>and</strong> cohort studies [47]Study design [No. Ofstudies]No. of subjects 50,302/96,973Study populationWomen with breast cancer <strong>and</strong> controls(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Intervention/Exposure(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Comparator (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)<strong>Outcomes</strong> (def<strong>in</strong>ition <strong>in</strong><strong>in</strong>cluded studies)HeterogeneityassessmentsQuality assessmentsPublication biasassessmentsStatistical Analysis ormeta-analytic methodsResultsQuality of the systematicreviewAuthor’s <strong>in</strong>terpretations ofthe resultsComments / Limitations<strong>Breastfeed<strong>in</strong>g</strong> (Ever <strong>and</strong> lifetime months of breastfeed<strong>in</strong>g (median))<strong>Breastfeed<strong>in</strong>g</strong> NeverBreast cancer (ND)Subgroup analyses <strong>in</strong>clud<strong>in</strong>g women from developed <strong>and</strong> develop<strong>in</strong>g countries, women ofdifferent ages, ethnic orig<strong>in</strong>s, familial patterns of disease, <strong>and</strong> 11 other possible relevantfactorsNoneNDAnalyses were rout<strong>in</strong>ely stratified by study, by center with<strong>in</strong> study, by f<strong>in</strong>e divisions of age, byage at first birth <strong>and</strong> by menopausal status. Where appropriate, parous women are furtherstratified by f<strong>in</strong>e divisions of parity.Data comb<strong>in</strong>ed by means of the Mantel-Haenszel stratification technique, the stratumspecific quantities calculated be<strong>in</strong>g the st<strong>and</strong>ard observed m<strong>in</strong>us expected numbers ofwomen with breast cancer, together with their variances <strong>and</strong> covariates.% reduction <strong>in</strong> relative risk of breast cancer per 12 months of breastfeed<strong>in</strong>g <strong>and</strong> 99% (SE)=4.3 (0.8)Data also available for float<strong>in</strong>g absolute risk <strong>and</strong> floated SE for subgroupsParous women who never breastfed v ever breastfedLife time months of breastfeed<strong>in</strong>gAThe longer women breastfeed the more they are protected aga<strong>in</strong>st breast cancer. The lackof or short lifetime duration of breastfeed<strong>in</strong>g typical of women <strong>in</strong> developed countries makesa major contribution to the high <strong>in</strong>cidence of breast cancer <strong>in</strong> these countries.Individual patient level dataC-131
Author, yr: Collaborative group on Hormonal factors <strong>in</strong> breast cancer, 2002Topic of the systematic review*/MA: Breast cancer <strong>and</strong> breastfeed<strong>in</strong>gReport<strong>in</strong>g yes/noReport<strong>in</strong>g of Background1 Description of study outcomes Y2 Types of exposure or <strong>in</strong>tervention used Y3 Types of study designs used Y4 Study population YReport<strong>in</strong>g of Search strategy5 Search strategy, <strong>in</strong>clud<strong>in</strong>g time period <strong>and</strong> key words N6 Effort to <strong>in</strong>clude all available studies (contact with authors) N7 Databases <strong>and</strong> registries searched N8 Method of address<strong>in</strong>g published articles other than English N9 Method of h<strong>and</strong>l<strong>in</strong>g abstracts <strong>and</strong> unpublished studies NReport<strong>in</strong>g of Methods10 Rationale for selection <strong>and</strong>/or cod<strong>in</strong>g of data Y11 Assessment of confound<strong>in</strong>g Y12 Assessment of quality N13 Assessment of heterogeneity Y14 Description of statistical methods sufficient to replicate Y15 Provision of appropriate tables <strong>and</strong> graphs YReport<strong>in</strong>g of Results16 Graphic summariz<strong>in</strong>g of <strong>in</strong>dividual study estimates <strong>and</strong> overall Y17 Tables giv<strong>in</strong>g descriptive <strong>in</strong>formation of each study <strong>in</strong>cluded Y18 Results of sensitivity test<strong>in</strong>g (subgroup analysis) Y19 Indication of statistical uncerta<strong>in</strong>ty of f<strong>in</strong>d<strong>in</strong>gs N20 Quantitative assessment of bias (eg. publication bias) NAuthors’ Conclusions21 Consistent with the presented results Y22 Comment<strong>in</strong>g on the validity of the conclusions Y23 Present<strong>in</strong>g alternative explanations YOverall qualityA*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyEvaluation of quality of a systematic review or meta-analysisYes /No/Partially1 Is search strategy appropriate/relevant to the key question(s)? No2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to the studies of yes<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> Study yesDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g the partiallyrelevant data, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, variousbiases <strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or notadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the useof a particular analytic method or model appropriate?Individualpatientlevel datayesyesC-132
Evaluation of quality of a systematic review or meta-analysis Yes /No/Partially8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity, yesdid the authors look at the actual differences <strong>in</strong> PICOS, for example?)?8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)? yes9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis? yesC-133
Gammon 2002 [12206514]Study characteristicsMean age (range):
Jernstrom 2004 [15265971]Subjects’StudyhealthcharacteristicsconditionsMean age (range):39Menopause: NDRace: Jewish 30%casesFrench Canadian10%Other white 59%Black1%Other 0.5%Enrolled/Evaluate:1927/1830Location: hospitalbasedSites: MultiFund<strong>in</strong>g: NDWomen withcarriers of genemutationBRCA1 <strong>and</strong>BRCA2Study design <strong>and</strong>follow-up durationCase-control studydesignFollow-up 8.2 (timebetween breastcancer diagnosis <strong>and</strong>the completion ofstudy questionnaire.Eligibility criteriaSelectedEligible subjectswho carried amutation <strong>in</strong> eitherthe BRCA1 or theBRCA2 gene weredrawn from adatabase<strong>Breastfeed<strong>in</strong>g</strong> Exposures or InterventionsFor women who gave an approximate length ofbreastfeed<strong>in</strong>g (e.g., 3–5 months), the midpo<strong>in</strong>t ofduration was used.The year of breast cancer diagnosis <strong>and</strong> years of allpregnancies were recorded. If both occurred dur<strong>in</strong>gthe same calendar year, it was not possible toestablish the sequence of breast cancer <strong>and</strong>pregnancy. Only live births that occurred at least onecalendar year before a diagnosis of breast cancerwere captured. Tw<strong>in</strong> births were considered to be onebirth with respect to breast-feed<strong>in</strong>g.Control Exposures orInterventionsExposure <strong>in</strong>formation on controlsubjects (e.g., breast-feed<strong>in</strong>g,parity) was restricted to the periodbefore the date of a diagnosis ofbreast cancer <strong>in</strong> the matchedcase subject.Jernstrom 2004 [15265971]OutcomeDef<strong>in</strong>itionBreastcanceramongBRCA1<strong>and</strong>BRCA 2Statistical analyses <strong>and</strong> confoundersadjustedConditional logistic regression forodds ratios (ORs) <strong>in</strong> the univariate <strong>and</strong>multivariate analyses. Inthe first analysis, parity <strong>and</strong> oral contraceptiveuse were used ascovariate variables. Because of the strongassociation between parity <strong>and</strong> breast-feed<strong>in</strong>g,secondary analysis was performed a thatexcluded all nulliparous women. All analyseswere adjusted for oral contraceptive use.ResultsIn univariate analyses subjects who had breastfed theirkids >1y <strong>and</strong> had BRCA1 gene polymorphism (OR 0.56;95% CI 0.41 to 0.76) had statistically significant reducedodds of breast cancer compared to none breastfeed<strong>in</strong>g.<strong>Breastfeed<strong>in</strong>g</strong> ≤1 yr + BRCA1 (OR 0.89; 95% CI 0.70,1.15; p1y<strong>and</strong> had BRCA1 gene polymorphism (OR 0.55; 95% CI0.38 to 0.80) had statistically significant reduced odds ofbreast cancer compared to none breastfeed<strong>in</strong>g.The trend per month of breast feed<strong>in</strong>g also decreased theodds of breast cancerBias/limitationsCommentsA: strong, B: moderate, C: weak A B CSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>gData collection xWithdraw <strong>and</strong> dropout xAnalyses xIntervention <strong>in</strong>tegrity xOverall grade: BC-135
Lee SY, 2003 [12704674]StudycharacteristicsMean age (range):33-44Menopause: PreRace: Asian 100%Enrolled/Evaluate:110604Location: populationbasedSites: MultiFund<strong>in</strong>g: GovSubjects’ healthconditionsEarlier menarcheOral contraceptiveuseEver smokeAlcohol useExercise (yes)[data available byduration of lactation]Study design <strong>and</strong>follow-up durationProspectiveobservational cohortFollow-up 6 yrsEligibility criteriaPremenopausal women who were enrolled <strong>in</strong> the KoreanMedical Insurance Corporation (KMIC) <strong>and</strong> participated <strong>in</strong>the Korean Women’s cohort<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsEver vs NeverPeriods of lactation1-12 months13-24 monthsControl Exposures orInterventionsEver vs NeverPeriods of lactation1-12 months13-24 monthsLee SY, 2003 [12704674]Outcome Statistical analyses <strong>and</strong>Def<strong>in</strong>ition confounders adjustedIncident breastcancersIn bivariate analyses, the authorsexam<strong>in</strong>ed the relation between lactation<strong>and</strong> traditional breast cancer risk factors,adjust<strong>in</strong>g for age. In these bivariateanalyses, the authors tested for trendsacross categories of duration of lactation,us<strong>in</strong>g parous women who never breastfedas the reference. In Cox proportionalhazard models, age, age at menarche,number of children, age at first pregnancy,oral contraceptives, smok<strong>in</strong>g, exercise<strong>and</strong> obesity were controlled to del<strong>in</strong>eatethe <strong>in</strong>dependent effects of lifetimelactation. In all analyses, a 2-sided alphalevel of 0.05 was considered statisticallysignificant.ResultsCompared to parous women who had no history of lactation, periods of lactation of 1–12 months or13–24 months were associated with decreased risk of breast cancer (RR, 0.8; 95% CI, 0.7–1.0 orRR, 0.7; 95% CI, 0.5–1.1, respectively), <strong>and</strong> this risk decreased even further for those with whobreastfed for more than 24 months (RR, 0.6; 95% CI, 0.3–1.0)PersonyearsBreast Multivariate modelcancer RR(95%CI)Never 263,472 161 Ref1-12 256,199 149 0.8(0.7-1.0)NS13-24 39,125 32 0.7(0.5-1.1)NS>24 23,556 18 0.6(0.3-1.0)p = 0.0438p for trend
Evidence table for Systematic Reviews of <strong>Breastfeed<strong>in</strong>g</strong>Author, Year[UI] Topic Lipworth, 2000 [10675379] Breast CancerLiterature search (Dates) Medl<strong>in</strong>e (1966-1998); Other databases searched? (no); unpublished data used? (no)Countries where primary International studies <strong>in</strong>clud<strong>in</strong>g developed <strong>and</strong> develop<strong>in</strong>g nationsstudies conductedStudy eligibility / <strong>in</strong>clusioncriteriaStudies that <strong>in</strong>cluded more than 200 cases overall <strong>and</strong> explicitly controlled for number offull-term pregnancies <strong>and</strong> age at first birthStudy design [No. Of studies] Case-control studiesNo. of subjects 23461/52948Study population (def<strong>in</strong>ition <strong>in</strong> Premenopausal women with breast cancer <strong>and</strong> controls (nd)<strong>in</strong>cluded studies)Intervention/Exposure<strong>Breastfeed<strong>in</strong>g</strong> (ever)(def<strong>in</strong>ition <strong>in</strong> <strong>in</strong>cludedstudies)Comparator (def<strong>in</strong>ition <strong>in</strong> <strong>Breastfeed<strong>in</strong>g</strong> (never)<strong>in</strong>cluded studies)<strong>Outcomes</strong> (def<strong>in</strong>ition <strong>in</strong> Breast cancer (nd)<strong>in</strong>cluded studies)Heterogeneity assessments NoneQuality assessmentsNDPublication bias assessments NDStatistical Analysis or metaanalyticNo meta-analysis; only qualitative reviewmethodsResults“Ever” breastfeed<strong>in</strong>g effect rema<strong>in</strong>s <strong>in</strong>conclusive with results <strong>in</strong>dicat<strong>in</strong>g either noassociation or a weak protective effect aga<strong>in</strong>st breast cancer. Few studies also reportedan <strong>in</strong>verse association between <strong>in</strong>creas<strong>in</strong>g life-time breastfeed<strong>in</strong>g <strong>and</strong> breast cancer risk<strong>in</strong> parous women.Quality of the systematic BreviewAuthor’s <strong>in</strong>terpretations of theresults“Evidence support<strong>in</strong>g protective factor of breastfeed<strong>in</strong>g for breast cancer is limited <strong>and</strong>should be <strong>in</strong>terpreted with caution.”Comments / LimitationsC-137
Author, yr: Lipworth, 2000 [10675379]Topic of the systematic review*/MA: Breast CancerReport<strong>in</strong>g yes/noReport<strong>in</strong>g of Background1 Description of study outcomes Yes2 Types of exposure or <strong>in</strong>tervention used Yes3 Types of study designs used Yes4 Study population YesReport<strong>in</strong>g of Search strategy5 Search strategy, <strong>in</strong>clud<strong>in</strong>g time period <strong>and</strong> key words Yes6 Effort to <strong>in</strong>clude all available studies (contact with authors) Partially7 Databases <strong>and</strong> registries searched Partially8 Method of address<strong>in</strong>g published articles other than English No9 Method of h<strong>and</strong>l<strong>in</strong>g abstracts <strong>and</strong> unpublished studies NoReport<strong>in</strong>g of Methods10 Rationale for selection <strong>and</strong>/or cod<strong>in</strong>g of data Yes11 Assessment of confound<strong>in</strong>g Yes12 Assessment of quality No13 Assessment of heterogeneity Yes14 Description of statistical methods sufficient to replicate Not applicable15 Provision of appropriate tables <strong>and</strong> graphs PartiallyReport<strong>in</strong>g of Results16 Graphic summariz<strong>in</strong>g of <strong>in</strong>dividual study estimates <strong>and</strong> overall Not applicable17 Tables giv<strong>in</strong>g descriptive <strong>in</strong>formation of each study <strong>in</strong>cluded Yes18 Results of sensitivity test<strong>in</strong>g (subgroup analysis) Not applicable19 Indication of statistical uncerta<strong>in</strong>ty of f<strong>in</strong>d<strong>in</strong>gs Not applicable20 Quantitative assessment of bias (eg. publication bias) Not applicableOverall qualityB*When grad<strong>in</strong>g a systematic review, please skip item #14, 18-20Please fill the white areas onlyYes /NoEvaluation of quality of a systematic review or meta-analysis/Partially1 Is search strategy appropriate/relevant to the key question(s)? yes2 Did authors give justifications for <strong>in</strong>clusion/exclusion criteria perta<strong>in</strong><strong>in</strong>g to the studies of no<strong>in</strong>terest?3 Were Population, Intervention/Exposure, Comparator/Control, <strong>Outcomes</strong>, <strong>and</strong> Study yesDesigns well-def<strong>in</strong>ed?4 Did authors attempt to m<strong>in</strong>imize errors <strong>in</strong> data extraction (such as collect<strong>in</strong>g the ndrelevant data, double data extraction, verification of data extraction…etc.)?5 Was <strong>in</strong>dividual study quality (such as sample size, study design, bl<strong>in</strong>d<strong>in</strong>g, various Partiallybiases <strong>and</strong> confounders, study subject attrition rate…etc.) assessed?6 Did authors consider appropriate confounders <strong>and</strong> justification for adjust<strong>in</strong>g or not yesadjust<strong>in</strong>g for those confounders?7 Was the justification for comb<strong>in</strong><strong>in</strong>g or not-comb<strong>in</strong><strong>in</strong>g data for meta-analysis, or the use noof a particular analytic method or model appropriate?8 Was heterogeneity explored (this is <strong>in</strong> addition to any statistical test of heterogeneity, nodid the authors look at the actual differences <strong>in</strong> PICOS, for example?)?8 Were results reported accurately (eg, no discrepancies between text <strong>and</strong> tables)? no9 Were conclusions justified by the reported/collected data <strong>and</strong> analysis? yesC-138
Appendix C. Evidence TablesPart III. <strong>Maternal</strong> <strong>Outcomes</strong>Osteoporosis-BMDHansen 1991Matsushita 2002Sowers 1992Uusi-Rasi 2002Osteoporosis-FractureAlderman 1986Chan 1996Cumm<strong>in</strong>g 1993Hoffman 1993Kreiger 1982Michaelsson 2001C-139
Hansen, 1991 [UI#1790399]Subjects’StudyhealthcharacteristicsconditionsMean age (range):51Menopause: postRace: NDEnrolled/Evaluate:178/121Location: DenmarkSites: S<strong>in</strong>gleFund<strong>in</strong>g:healthyStudy design<strong>and</strong> follow-updurationProspectivecohort (12years)Eligibility criteriaIn 1979, 178 women completed a 2-year, prospective studyreceiv<strong>in</strong>g placebo. They had been selected by questionnaire <strong>and</strong> amedical screen<strong>in</strong>g exam<strong>in</strong>ation. All had passed a naturalmenopause 6 months to 3 years earlier <strong>and</strong> were free of disease ormedications known to <strong>in</strong>fluence the calcium metabolism.In 1989, 12 years after the start of the orig<strong>in</strong>al study, all 178women were re-contacted for a follow-up exam<strong>in</strong>ation. Of these, 24(13%) were unable to participate: 6 women had died, 9 sufferedfrom diseases which made participation impossible, 6 unwill<strong>in</strong>g toparticipate for personal reasons, 2 had emigrated, <strong>and</strong> 1 could notbe located. Among the 154 women underwent the follow-upexam<strong>in</strong>ation, 24 women were excluded due to ow<strong>in</strong>g to post-trialtreatment with sex hormones for more than 1 year <strong>and</strong> another 9women present<strong>in</strong>g with disease known to <strong>in</strong>fluence calciummetabolism were excluded as well.<strong>Breastfeed<strong>in</strong>g</strong> Exposures orInterventions111 women (92%) hadexperienced 1 or morepregnancies (mean: 2.6); 87%breast fed for a mean totallactation period of 13 monthsControlExposures orInterventionsNo lactationHansen, 1991 [UI#1790399]Outcome Def<strong>in</strong>itionLumbar sp<strong>in</strong>e BMD, measured by DEXA. BMD is calculatedas BMC divided by the area of <strong>in</strong>terest from L2 to L4 <strong>in</strong>clud<strong>in</strong>gthe <strong>in</strong>tervertebral discs. BMD only measured <strong>in</strong> the follow-up.Forearm BMC was measured by s<strong>in</strong>gle photon absorptiometry( 125 I). The rate of postmenopausal bone loss (% per year) wasdeterm<strong>in</strong>ed as the difference <strong>in</strong> % between the measurement<strong>in</strong> 1979 <strong>and</strong> the measurement obta<strong>in</strong>ed <strong>in</strong> 1989 divided by 10years.Statisticalanalyses <strong>and</strong>confoundersadjustedStudent’s t test forunpaired dataResults∆BMCarm% ∆BMDsp<strong>in</strong>eper yearLactation -1.8±0.8 0.84±0.18(-)Lactation -1.7±0.8 0.88±0.14(+)p-value NS NSBias/limitationsCommentsA: strong, B: moderate, C: A B CweakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdraw <strong>and</strong> dropout xAnalyses xIntervention <strong>in</strong>tegrityOverall: CUnivariate analyses for BMD/BMC outcomes<strong>and</strong> lactation. Unclear whether no lactationgroup <strong>in</strong>clud<strong>in</strong>g non-parous womenC-140
Matsushita, 2001 [UI#12200655]Subjects’StudyhealthcharacteristicsconditionsMean age (range):30.1Menopause: preRace: Asian(assumed)Enrolled/Evaluate:113/113Location: JapanSites: S<strong>in</strong>gleFund<strong>in</strong>g: ND<strong>Health</strong>y, wellnourishedStudy design <strong>and</strong>follow-up durationLongitud<strong>in</strong>al cohortstudyMean <strong>in</strong>tervalbetween eachdelivery = 2.5 yearsEligibility criteriaPostpartum Japanese women, aged 20-40 years,who delivered a s<strong>in</strong>gleton <strong>in</strong>fant at the universityhospital between 1994 <strong>and</strong> 1999. Women whohad 2 nd pregnancy were <strong>in</strong>cluded.Exclusion criteria <strong>in</strong>cluded complications <strong>and</strong>medications before or dur<strong>in</strong>g pregnancy, thatwould affect bone metabolism, delivery before 36weeks’ gestation, or bed rest <strong>in</strong> excess of 7 days.<strong>Breastfeed<strong>in</strong>g</strong> Exposures orInterventionsControl Exposures orInterventionsLactation <strong>in</strong>formation <strong>in</strong>clud<strong>in</strong>g length <strong>and</strong> source of lactation(breast-fed or formula-fed) was collected by questionnaireimmediately after the subsequent delivery.Only 1 woman had formula-fed, <strong>and</strong> the other breast fed with(n=46) or without (n=66) formula fed.Whether breast-feed<strong>in</strong>g had been exclusive, predom<strong>in</strong>ant, oron-dem<strong>and</strong>, <strong>and</strong> when alternative food had been <strong>in</strong>troduced,was not available because of ambiguous memory.Matsushita, 2001 [UI#12200655]Outcome Def<strong>in</strong>itionBMD of the lumbar sp<strong>in</strong>e (L2-L4) wasmeasured by DEXA with<strong>in</strong> 7 days ofdelivery. 113 of women became pregnantaga<strong>in</strong> <strong>and</strong> they had 2 nd BMDmeasurement with<strong>in</strong> 7 days of the nextdelivery.The percent change <strong>in</strong> BMD (∆BMD%)was calculated by subtract<strong>in</strong>g the valueat the time of the first pregnancy from thevalue at the time of the secondpregnancy.Statistical analyses <strong>and</strong> confoundersadjustedBMD <strong>and</strong> backgrounds of consecutivepregnancies were compared us<strong>in</strong>g apaired t-test.Multiple regression analysis wasperformed to look for <strong>in</strong>dependentpredictors of ∆BMD%. BMD after the <strong>in</strong>itialdelivery was <strong>in</strong>cluded as an <strong>in</strong>dependentvariable to adjust for regression toward themean.ResultsLumbar BMD of 110 women after the <strong>in</strong>itial <strong>and</strong> thesubsequent delivery was 1.006±0.117 <strong>and</strong>1.019±0.115 g/cm 2 , respectively. BMD after thesubsequent delivery was significantly higher thanthat after the <strong>in</strong>itial delivery (p=0.001), with a∆BMD% of 1.4±4.2%.Independent determ<strong>in</strong>ants of ∆BMD% were exploredby multiple regression analysis: the length oflactation between the scans showed no correlationwith ∆BMD% (coefficient=-0.06±0.157 SEM,p=0.702). Age was the most significant predictor for∆BMD% <strong>in</strong> the model.Bias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdraw <strong>and</strong> xdropoutAnalyses xIntervention<strong>in</strong>tegrityOverall: AC-141
Sowers, 1992 [UI#4543]Subjects’StudyhealthcharacteristicsconditionsMean age (range): NDMenopause: mixRace: EuropeanEnrolled/Evaluate:217/181Location: USSites: S<strong>in</strong>gleFund<strong>in</strong>g:GovernmentStudy design<strong>and</strong> follow-updurationProspectivecohort (5 year)Eligibility criteriaIn 1984, BMD of women In aged 22-54 years liv<strong>in</strong>g <strong>in</strong> a s<strong>in</strong>glerural community were measured by s<strong>in</strong>gle-photon densitometry.The community was selected for study because of the m<strong>in</strong>eralcharacteristics of the community water supply.Women were eligible to participate <strong>in</strong> the basel<strong>in</strong>e study if theyhad lived <strong>in</strong> the community the previous 5 years, were able tocomplete face-to-face <strong>in</strong>terview, were ambulatory <strong>and</strong> reportedthemselves to be of northern European heritage.In 1989, a follow-up survey reexam<strong>in</strong>ed 181 of the 217 womenwho participated <strong>in</strong> the basel<strong>in</strong>e survey. Nonrespondents to thefollow-up survey were less likely to be married, were younger,had a greater Quetelet <strong>in</strong>dex, <strong>and</strong> had a slightly greater BMDthan participants at basel<strong>in</strong>e<strong>Breastfeed<strong>in</strong>g</strong> Exposuresor InterventionsSubjects were <strong>in</strong>terviewed atbasel<strong>in</strong>e <strong>and</strong> follow-up forvarious factors, <strong>in</strong>clud<strong>in</strong>glactation.ControlExposures orInterventionsSowers, 1992 [UI#4543]Statistical analyses <strong>and</strong> confoundersOutcome Def<strong>in</strong>itionadjustedBMD was expressed asthe bone m<strong>in</strong>eral tobone width ratio.Percent change wascalculated as 100% -follow-up value/basel<strong>in</strong>evalueMultiple-variable regression analyses wereused to assess relationships betweenBMD change or basel<strong>in</strong>e BMD values <strong>and</strong>the explanatory variables adjust<strong>in</strong>g for age<strong>and</strong> estrogen status.Stepwise regression was used to generatemodels consider<strong>in</strong>g all other importantvariables, <strong>in</strong>clud<strong>in</strong>g age, estrogen status,parity, age at first pregnancy, <strong>and</strong> weight.ResultsNulliparous women (n=12) had significantly lower BMD at basel<strong>in</strong>e<strong>and</strong> follow-up than parous women (n=169) before <strong>and</strong> after adjust<strong>in</strong>gfor age <strong>and</strong> estrogen status.A recalled history of breast-feed<strong>in</strong>g <strong>in</strong> parous women did not predictsignificant differences <strong>in</strong> BMD level or amount of BMD change. Wehad <strong>in</strong>sufficient sample size to test whether duration of breast-feed<strong>in</strong>g<strong>in</strong> excess of 6 months for a s<strong>in</strong>gle <strong>in</strong>fant or 6 months cumulative timefrom breast-feed<strong>in</strong>g multiple <strong>in</strong>fants was associated with significantdifferences <strong>in</strong> BMD.Bias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection XStudy design XConfounder XBl<strong>in</strong>d<strong>in</strong>g XData collection XWithdraw <strong>and</strong>XdropoutAnalyses XIntervention<strong>in</strong>tegrityOverall: BC-142
Uusi-Rasi, 2002 [UI#11991440]Subjects’StudyhealthcharacteristicsconditionsMean age (range):28.4Menopause: preRace: NDEnrolled/Evaluate:132/92Location: F<strong>in</strong>l<strong>and</strong>Sites: S<strong>in</strong>gle/MultiFund<strong>in</strong>g: privatehealthyStudy design<strong>and</strong> follow-updurationProspectivecohort4.2 (range 3.2-5.4) yearsEligibility criteria<strong>Health</strong>y, non-smok<strong>in</strong>g women will<strong>in</strong>g to participate <strong>in</strong> orig<strong>in</strong>al crosssectionalstudy. Inclusion criteria were a daily dietary calcium <strong>in</strong>take ofover 1200 mg (Ca+) or under 800 mg (Ca-) <strong>and</strong> vigorous physicalactivity more than twice a week, or light to moderate activity no morethan once a week. Women who had <strong>in</strong>termediate levels of physicalactivity or calcium <strong>in</strong>take or used calcium supplements were excluded.Altogether 92 women out of the 132 orig<strong>in</strong>al 25- to 30-year-old subjectsparticipated <strong>in</strong> the follow-up measurements.<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsTotal duration ofbreastfeed<strong>in</strong>g (one longperiod or sum of manyperiods of breastfeed<strong>in</strong>gControlExposures orInterventionsUusi-Rasi, 2002 [UI#11991440]Outcome Def<strong>in</strong>ition Statistical analyses <strong>and</strong> confounders adjusted ResultsBMC at the proximal femoralneck <strong>and</strong> total trochanterregion <strong>and</strong> the distal radius ofthe dom<strong>in</strong>ant side wasmeasured with dual energy X-ray absorptiometry.Repeated-measures analyses of variance were usedto analyze the between group differences <strong>in</strong> changes<strong>in</strong> site-specific BMC.Regression models for % bone loss us<strong>in</strong>g amultivariate stepwise regression analysis that<strong>in</strong>cluded basel<strong>in</strong>e variables: age, body weight,muscle strength, estimated maximal oxygen uptake<strong>and</strong> calcium <strong>in</strong>take, the absolute changes <strong>in</strong> bodyweight, muscle strength, estimated maximal oxygenuptake, calcium <strong>in</strong>take, physical activity, duration ofbreastfeed<strong>in</strong>g <strong>and</strong> time from wean<strong>in</strong>g.The mean decrease <strong>in</strong> BMC (95% CI) was 1.5%(0.7% to 2.4%) for the femoral neck, 0.6% (-0.8% to1.9%) for the trochanter <strong>and</strong> 6.0% (4.5% to 7.4%) forthe distal radius dur<strong>in</strong>g the follow-upAccord<strong>in</strong>g to the multiple stepwise regressionanalyses, the statistically significant <strong>in</strong>dependentpredictors for site-specific bone loss were low calcium<strong>in</strong>take at the basel<strong>in</strong>e <strong>and</strong> change <strong>in</strong> body weightboth at the proximal femur <strong>and</strong> at the distal radius.High calcium <strong>in</strong>take, as well as an <strong>in</strong>crease <strong>in</strong> bodyweight, were associated with less bone loss at all themeasured bone site.In addition, breastfeed<strong>in</strong>g was associated withradial bone loss; the longer the duration ofbreastfeed<strong>in</strong>g the greater the bone loss (Multipleregression coefficient= -0.34 +- 0.14 SE, p=0.015).<strong>Breastfeed<strong>in</strong>g</strong> was not associated with femoral neckor trochanter BMC lossBias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xDataxcollectionWithdraw <strong>and</strong> xdropoutAnalyses xIntervention<strong>in</strong>tegrityOverall: BC-143
Alderman, 1986 [UI#3728442]StudycharacteristicsMean age (range):50-74Menopause: post(assumed)Race: WhiteEnrolled/Evaluate:355/344 for cases;562/318 for controlsLocation: USSites: MultiFund<strong>in</strong>g: GovernmentSubjects’healthconditionsNDStudydesign<strong>and</strong>follow-updurationCasecontrolstudyEligibility criteriaCases: Between 1976 <strong>and</strong> 1980, all women with hipfracture who sought care from a 62% sample oforthopedic surgeons were eligible. Women withforearm fracture who sought care from theseorthopedists were eligible if the physician’s practicehad records that allowed trac<strong>in</strong>g of all outpatients.Women who sought care for vertebral fractures werenot eligible because we believed that theyrepresented a small <strong>and</strong> probably unrepresentativegroup of women with vertebral fracture. Exclusion:nonwhite, younger than 50 or older than 74 years ofage, nonresidents of K<strong>in</strong>g County, residents of<strong>in</strong>stitutions at the time of fracture, or if they hadmultiple or pathologic fractures.Controls: unmatched control women were identifiedthrough 3 door-to-door area-based surveys of thegeneral population of K<strong>in</strong>g Country conducted <strong>in</strong>1976, 1977, <strong>and</strong> 1979. Comparable exclusion criteriawere used.<strong>Breastfeed<strong>in</strong>g</strong> Exposures orInterventionsThe duration of lactation was calculatedby summ<strong>in</strong>g the number of months oflactation associated with each birth, <strong>and</strong>was treated <strong>in</strong> separate analyses as acategorical variable (tak<strong>in</strong>g values 0, 1 to12, 13 to 24 <strong>and</strong> more than 24 months)<strong>and</strong> as cont<strong>in</strong>uous variable (tak<strong>in</strong>g valuesfrom 0 to 109 months)11/355 cases miss<strong>in</strong>g data on lactationControlExposures orInterventions253/562 controlwomen miss<strong>in</strong>gdata on lactationC-144
Alderman, 1986 [UI#3728442]OutcomeDef<strong>in</strong>itionRisk of hip orforearmfracturesStatistical analyses <strong>and</strong> confounders adjustedLogistic regression was used. The logistic model was evaluatedfor confound<strong>in</strong>g by forward selection method. Only parity <strong>and</strong>variables with <strong>in</strong>dependent confound<strong>in</strong>g effects were <strong>in</strong>cluded <strong>in</strong>the f<strong>in</strong>al model. The same procedure was repeated to exam<strong>in</strong>ethe association between fracture <strong>and</strong> duration of lactation.ResultsLogistic regression analysis did not reveal a substantialchange <strong>in</strong> risk of fracture with <strong>in</strong>creas<strong>in</strong>g duration oflactation when lactation was treated as a categoricalvariable. Adjustment for confound<strong>in</strong>g effects of age, relativeweight, <strong>and</strong> duration of estrogen use did not alter theseresults.Similar results were obta<strong>in</strong>ed when lactation was treated asa cont<strong>in</strong>uous variable. Separate analysis of women with hipfracture suggested that an <strong>in</strong>crease <strong>in</strong> months ofbreastfeed<strong>in</strong>g was associated with an irregular decreased<strong>in</strong> risk of fracture.Bias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdraw <strong>and</strong> xdropoutAnalyses xIntervention<strong>in</strong>tegrityOverall: BC-145
Chan, 1996 [UI#8783297]Subjects’StudyhealthcharacteristicsconditionsMean age (range): ND75 (70-79)Menopause: postRace: Ch<strong>in</strong>eseEnrolled/Evaluate:481/481Location: HongKongSites: S<strong>in</strong>gleFund<strong>in</strong>g:GovernmentStudy design<strong>and</strong> follow-updurationCase-controlstudyEligibility criteriaCh<strong>in</strong>ese women aged 70-79 years who were liv<strong>in</strong>g<strong>in</strong> Geriatric Hous<strong>in</strong>g Scheme <strong>in</strong> Hong Kong.Subjects with a known history of metabolic bonedisorder, cancer, or who were on long-term steroidtreatment, were excluded. No subjects with suchhistories but 3 subjects on steroid therapy wereexcluded from the study.Cases: def<strong>in</strong>ite or doubtful vertebral fractureControl: the rema<strong>in</strong><strong>in</strong>g enrolled subjects (womenwith no fractures)<strong>Breastfeed<strong>in</strong>g</strong> Exposures orInterventionsHome-visit <strong>in</strong>terviews by a st<strong>and</strong>ardized,structured questionnaire wasadm<strong>in</strong>istered by 2 tra<strong>in</strong>ed researchnurses who was bl<strong>in</strong>ded to the fracturestatus.Period of lactation: less than 24 months,or 24 months or moreControlExposures orInterventionsPeriod of lactation:neverChan, 1996 [UI#8783297]Outcome Def<strong>in</strong>itionDiagnosis of vertebral fractureaccord<strong>in</strong>g to Black et al.: def<strong>in</strong>itevertebral fracture: when any ofthe 3 vertebral ratios was 3 SDor more away from the mean;doubtful fracture: any of the 3vertebral ratios was 2-2.99 SDaway from the mean.A woman with 1 or more def<strong>in</strong>itefractures was classified as adef<strong>in</strong>ite case, a woman with nodef<strong>in</strong>ite fractures but one ormore doubtful fractures as adoubtful case, <strong>and</strong> the rest ascontrols.Statistical analyses<strong>and</strong> confoundersadjustedLogistic regression:OR for vertebrafracture amongdef<strong>in</strong>ite case <strong>and</strong>control; doubtful cases<strong>and</strong> controls.Analysis adjusted forage.ResultsThere were no significant differences <strong>in</strong> the age of menarche <strong>and</strong> menopausebetween def<strong>in</strong>ite cases, doubtful cases, <strong>and</strong> controls. The risk of def<strong>in</strong>ite fracturedecreased with the number of children given birth to <strong>and</strong> the duration of breastfeed<strong>in</strong>g.Period oflactation% <strong>in</strong>def<strong>in</strong>itecases(n=144)% <strong>in</strong>doubtfulcases(n=174)% <strong>in</strong>controls(n=163)Age-adj OR (95% CI)Def<strong>in</strong>itecases &controlDoubtfulcases &controlNever 63 45 53 1.0 1.0
Cumm<strong>in</strong>g, 1993 [UI#8225744]StudycharacteristicsMean age (range):65-100Menopause: postRace: DEnrolled/Evaluate:Location: AustraliaSites: MultiFund<strong>in</strong>g: NDSubjects’ healthconditionsSelf-reported heath (fordirectly <strong>in</strong>terviewedsubjects only: 104 cases<strong>and</strong> 114 controls)Cases: 23% excellent,50% good, 20% fair; 6%poorControls: 26% excellent,51% good, 21% fair; 5%poorStudy design<strong>and</strong> follow-updurationPopulationbasedcasecontrolstudyEligibility criteriaAll people aged ≥65 liv<strong>in</strong>g <strong>in</strong> a postcode-def<strong>in</strong>ed area <strong>in</strong>Sydney between 3/1990 <strong>and</strong> 8/1991. Total of 11 hospitalswere <strong>in</strong>cluded <strong>in</strong> the study.Cases: People with hip fractures present<strong>in</strong>g to thehospitals. The case ascerta<strong>in</strong>ment varied across hospitals.Controls: People liv<strong>in</strong>g <strong>in</strong> private homes <strong>in</strong> the community<strong>and</strong> from people liv<strong>in</strong>g <strong>in</strong> nurs<strong>in</strong>g homes <strong>and</strong> hostels. Thecontrols comprised a probability sample of people aged ≥65years liv<strong>in</strong>g <strong>in</strong> the 11 postcodes of the study base dur<strong>in</strong>g thesame time period as the cases.Proxy respondents were used for elderly people withcognitive impairment <strong>and</strong> those with various other healthproblems. A shortened questionnaire was used to <strong>in</strong>terviewproxy respondents.<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsFor all women:Ever breastfeed<strong>in</strong>gFor parous womenonly:Average duration ofbreastfeed<strong>in</strong>g perchild (months)ControlExposures orInterventionsFor all women:Neverbreastfeed<strong>in</strong>gC-147
Cumm<strong>in</strong>g, 1993 [UI#8225744]OutcomeDef<strong>in</strong>itionRisk of hipfractureStatistical analyses <strong>and</strong> confoundersadjustedData analysis: crude, stratified <strong>and</strong>multivariate methods to produce OR forassociations between hip fracture <strong>and</strong>exposure variables. Age is the strongestpredictor of hip fracture <strong>and</strong> so all resultswere adjusted for age.Multiple logistic regressions werecontroll<strong>in</strong>g for several confound<strong>in</strong>gvariables. Selection of confounders for<strong>in</strong>clusion <strong>in</strong> these models was based apriori knowledge of risk factors for hipfracture <strong>and</strong> the strength of univariateassociations between exposure variables<strong>and</strong> hip fracture. Confounders (other thanage) were entered <strong>in</strong>to models ascategorical variables.ResultsThere were 311 women <strong>in</strong> this study: 174 cases <strong>and</strong> 137 controls. Theresponse rate was 96% for cases <strong>and</strong> 82% for controls. Proxy <strong>in</strong>terviews wererequired for 93 subjects. Most cases (78%) were recruited from 1 teach<strong>in</strong>ghospital. A history of use of HRT was more common among controls than amongcases (age-adj OR: 0.55, 95%CI 0.24-1.27).Age- <strong>and</strong> proxy-adjustedCases Ctrl OR (95%CI)Multivariate-adjustedNo. subjects<strong>in</strong> the modelOR (95%CI)All womenBF- N=176Never 60 42 1.00 1.00Ever 106 95 0.72 (0.43-1.20) 0.64 (0.30-1.38)Parous womenBF- N=140Never 25 12 1.00 1.00Ever 106 95 0.47 (0.22-0.99) 0.55 (0.10-2.90)Average duration ofN=136BF per child (mo)0 19 11 1.00 1.000.5-3 17 16 0.56 (0.19-1.68) 0.64 (0.13-3.06)3-6 17 24 0.41 (0.15-1.13) 0.79 (0.18-3.51)6-9 18 23 0.47 (0.19-1.19) 0.41 (0.09-1.82)>9 7 10 0.28 (0.07-1.18) 0.24 (0.04-1.53)For women who had one or two children, breastfeed<strong>in</strong>g markedly reduce therisk of hip fracture <strong>in</strong> later life. After adjust<strong>in</strong>g for age <strong>and</strong> number of children, theOR <strong>in</strong> parous women for breastfeed<strong>in</strong>g all children versus breastfeed<strong>in</strong>g none was0.26 (95%CI 0.10-0.69)Bias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection XStudy design XConfounder XBl<strong>in</strong>d<strong>in</strong>g XData collection XWithdraw <strong>and</strong>dropoutAnalyses XIntervention N/A<strong>in</strong>tegrityOverall: BMiss<strong>in</strong>g data for covariates <strong>in</strong> themultivariate model, so the numberof subjects <strong>in</strong> the model is limited.XC-148
Hoffman, 1993 [UI#8338971]Subjects’Study characteristics healthconditionsMean age (range): 50- Hospital cases103<strong>and</strong> controlsMenopause: postRace: WhiteEnrolled/Evaluate:286/174 cases; 311/174controlsLocation: USASites: MultiFund<strong>in</strong>g: NDStudy design<strong>and</strong> follow-updurationCase-controlstudyEligibility criteriaCases: a sample of radiologically confirmed cases of first hipfracture among white women aged 45 years <strong>and</strong> older wasdrawn from among admissions to one of 30 hospitals between9/1987 <strong>and</strong> 7/1989Controls: white hospital controls, frequency-matched to casesby 10-year age group <strong>and</strong> by hospital of admission dur<strong>in</strong>g thesame time period.Exclude subjects with a prior hip fracture, pathological fracturesecondary to cancer, evidence of bony metastases, severecognitive, language, or hear<strong>in</strong>g impairment, died <strong>in</strong> the hospitalshortly after surgery, or medically unstable<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsEver lactatedLactated ≤ 12 moLactated > 12 moControlExposures orInterventionsNever lactatedHoffman, 1993 [UI#8338971]OutcomeStatistical analyses <strong>and</strong> confounders adjustedDef<strong>in</strong>itionRisk of hipfractureConditional logistic regression models were usedto remove the effect of match<strong>in</strong>g cases <strong>and</strong>controls. Because the age <strong>in</strong>tervals were wide,age was controlled for as cont<strong>in</strong>uous variable.Variables that changed crude estimates by 10% orgreater were reta<strong>in</strong>ed as confound<strong>in</strong>g variables.For lactation, only the number of live births wasreta<strong>in</strong>ed.ResultsLactation was associated with reduced odds of hip fracture among allwomen (OR=0.66 [0.41-1.05])Restrict<strong>in</strong>g the analysis to parous women <strong>and</strong> controll<strong>in</strong>g for number oflive births, there was no association between ever hav<strong>in</strong>g lactated orduration of lactation <strong>and</strong> hip fracture (OR for lactation of 12 months orless=0.80 [0.42-1.55]); OR for lactation of more than 12 months=1.08[0.45-2.60])Duration of lactation did not confound the negative association betweenparity <strong>and</strong> hip fracture.Bias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection XStudy design XConfounder XBl<strong>in</strong>d<strong>in</strong>g XData collection XWithdraw <strong>and</strong>dropoutAnalyses XIntervention<strong>in</strong>tegrityOverall: BXC-149
Kreiger, 1982 [UI#7102649]Subjects’Study characteristics healthconditionsMean age (range): 45- Hospital74cases <strong>and</strong>Menopause: post controlsRace: NDEnrolled/Evaluate:149/98 for cases;1345/884Location: USSites: MultiFund<strong>in</strong>g: NDStudy design<strong>and</strong> followupdurationCase-controlstudyEligibility criteriaWomen aged 45-74 years admitted to surgicalservices of 4 Connecticut hospitals between 9/1977<strong>and</strong> 5/1979.Cases: women admitted to 1 of the 4 studyhospitals with a first diagnosis of hip fracture, either<strong>in</strong>tra- or extra- capsular, confirmed by x-ray.Controls: systematic sample of women admitted tothe <strong>in</strong>patient surgical services of the 3 largesthospitals. Controls <strong>in</strong>cluded had a wide variety ofdiagnoses, <strong>and</strong> no more than 5% of the controlswere <strong>in</strong> any s<strong>in</strong>gle diagnostic category.Exclusion: women with reproductive cancers, whodid not speak English, who lived outside ofConnecticut, or last menstrual period was with<strong>in</strong> 1year of hospital admission or if the admitt<strong>in</strong>gdiagnosis of a disease related to estrogen use.<strong>Breastfeed<strong>in</strong>g</strong> Exposuresor Interventions98 of 149 cases (66%) ofhip fracture <strong>and</strong> 884 of1345 controls (66%) were<strong>in</strong>terviewed.Variable: <strong>Breastfeed<strong>in</strong>g</strong> 12-month <strong>in</strong>creaseControl Exposures orInterventionsBefore the data analysis began,the controls were divided <strong>in</strong>to 2groups: trauma control group<strong>and</strong> nontrauma control.Kreiger, 1982 [UI#7102649]Statistical analyses <strong>and</strong>Outcome Def<strong>in</strong>itionconfounders adjustedOdds ratio of hipfracture, comparedcases to trauma ornontrauma controls.L<strong>in</strong>ear logistic regression,adjusted for age <strong>and</strong> forQuetelet <strong>in</strong>dex (similar toBMI), bilateral ovariectomy,<strong>and</strong> estrogen replacementtherapy.ResultsL<strong>in</strong>ear logistic regression, adjusted for age <strong>and</strong> for Quetelet<strong>in</strong>dex (0.01 <strong>in</strong>crease), bilateral ovariectomy (yes/no), <strong>and</strong>estrogen replacement therapy (60-month <strong>in</strong>crease):Cases <strong>and</strong>trauma controlVariable Unit Adj OR(95% CI)<strong>Breastfeed<strong>in</strong>g</strong> 12-0.5month (0.2, 0.9)<strong>in</strong>creaseCases <strong>and</strong>non-traumacontrolAdj OR(95% CI)0.6(0.3, 1.0)Bias/limitationsCommentsA: strong, B: moderate, C: weak A B CSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdraw <strong>and</strong> dropout xAnalyses xIntervention <strong>in</strong>tegrityOverall: CSample size <strong>in</strong> breastfeed<strong>in</strong>g analysis was notdescribed. Did not separate out parous women.C-150
Michaelsson, 2001 [UI#2001082617]Subjects’StudyhealthcharacteristicsconditionsMean age (range):Cases=72.5;Controls=70.5Menopause: postRace: NDEnrolled/Evaluate:715/664 for casesevaluatedLocation: SwedenSites: MultiFund<strong>in</strong>g: NDNDStudy design <strong>and</strong> follow-updurationCase-control study; acomprehensive questionnaire ata mean <strong>in</strong>terval of 95 days afterthe fracture; associationsbetween lactation <strong>and</strong> hipfracture were only analyzed forparous womenEligibility criteriaCases: All fractures of the proximal femur that occurredbetween 10/ 1993 <strong>and</strong> 2/1995 among womenresident <strong>in</strong> 6 counties <strong>in</strong> Sweden who were bornafter 1913. Us<strong>in</strong>g cl<strong>in</strong>ical records or operationregisters <strong>in</strong> all 24 hospitals <strong>in</strong> the study area, a totalof 1,597 possible <strong>in</strong>cident cases were identified.Those with a fracture due to malignancy (n=26);high-energy trauma (n-4); <strong>in</strong>correct diagnosis(n=41); old fracture (n-10); bl<strong>in</strong>dness (n=5); birthoutside Sweden (n=202); excluded: severealcoholic abuse, psychosis, or senile dementia(n=576); or death with<strong>in</strong> 3 months of the fracture(n=123). After exclusions, 1,610 eligible casesrema<strong>in</strong>ed <strong>and</strong> were approached with. The Swedish<strong>in</strong>patient register identified 34 additional cases.Controls: Native-born women were r<strong>and</strong>omly selectedfrom the national population register <strong>in</strong> the monthbefore the start of the study. Potential controls aged70-80 years were frequency matched (2 controlsper 1 case) to the expected hip fracture agedistribution with<strong>in</strong> county of residence. Controlsaged 50-69 years were r<strong>and</strong>omly selected from thepopulation register as part of a breast cancer studybe<strong>in</strong>g conducted at the same time with the samequestionnaire. For these women, frequencymatch<strong>in</strong>g to the expected number of breast cancercases provided 2-4 times as many controls as hipfracture cases <strong>in</strong> each 5-year age group <strong>and</strong>country of residence. Of the 4,870 c<strong>and</strong>idatecontrols <strong>in</strong> the hip fracture analysis, 4,059 wereeligible for the study, 610 were born outside ofSweden, 257 died before be<strong>in</strong>g approached, 44were senile or psychotic, <strong>and</strong> 2 were bl<strong>in</strong>d.<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsControlExposures orInterventionsDuration of breastfeed<strong>in</strong>g was considered <strong>in</strong>4 classes def<strong>in</strong>ed by the quartiles of eithertotal duration or mean duration per child ofbreastfeed<strong>in</strong>g among controlsC-151
Michaelsson, 2001 [UI#2001082617]OutcomeDef<strong>in</strong>itionOR of hipfractureStatistical analyses <strong>and</strong> confoundersadjustedUnconditional logistic regression were usedas measure of association. The multivariateanalyses <strong>in</strong>cluded the covariates age, BMI,oral contraceptive use, HRT use, <strong>and</strong>smok<strong>in</strong>g status. Interactions wereconsidered.Associations between lactation <strong>and</strong> hipfracture were only analyzed for parouswomenResultsLong total duration of breastfeed<strong>in</strong>g was associated with a reduction <strong>in</strong> risk(table 3 <strong>in</strong> paper), but this association disappeared after adjustment for parity,body mass <strong>in</strong>dex, <strong>and</strong> use of exogenous estrogens. There were no substantialrisk differences <strong>in</strong> analyses that considered mean duration of breastfeed<strong>in</strong>g perchild (quartiles 0–2, 3–4, 5–6, <strong>and</strong> 7 months per child or more) (data notshown). Long duration of breastfeed<strong>in</strong>g also had no substantial association withhip fracture risk among those with their first pregnancy as a teenager or amongthose with their first pregnancy after age 30 years. The relative risk estimatesfor lactation <strong>and</strong> parity were similar for cervical <strong>and</strong> trochanteric hip fracture(data not shown).Bias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdraw <strong>and</strong> xdropoutAnalyses xIntervention<strong>in</strong>tegrityOverall: BC-152
Appendix C. Evidence TablesPart III. <strong>Maternal</strong> <strong>Outcomes</strong>Ovarian CancerChiaffar<strong>in</strong>o 2005Cramer 1983Greggi 2000Gw<strong>in</strong>n 1990Hartge 1989John 1993Modugno 2003Ness 2000Riman 2002Risch 1983Risch 1994Sisk<strong>in</strong>d 1997Titus-ernstoff 2001Tung 2003, 2005West 1966Whittemore 1992Wynder 1969Yen 2003C-153
Chiaffar<strong>in</strong>o, 2005 [UI# 15975644]StudycharacteristicsMedian age(range):Cases: 56 (18-79)Controls: 57median (17-79)Menopause: NDRace: NDEnrolled/Evaluate:Cases: 1031/1028Controls:2411/2390Location: ItalySites: Multi-centerFund<strong>in</strong>g: Private,governmentSubjects’ health conditionsCases: NDControls: traumatic conditions 26%,nontraumatic orthopedic disorders28%, acute surgical conditions mostlyabdom<strong>in</strong>al diseases 15%,miscellaneous illnesses (ear, nosethroat, teeth) 31%Study design <strong>and</strong>follow-up durationCase-controlData collection by<strong>in</strong>terviews us<strong>in</strong>gstructuredquestionnaireEligibility criteriaCase: Histologicaly confirmed epithelialovarian cancer diagnosed <strong>in</strong> past year,admitted to major or teach<strong>in</strong>g hospitalControl: residents of same geographic area,admitted to same network of hospitals foracute, non-neoplastic, unrelated to known orlikely risk factors for ovarian cancer, exclusion<strong>in</strong>clude hormonal <strong>and</strong> gynecological diseases,or ovariectomized<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsBreast feed<strong>in</strong>gstatus determ<strong>in</strong>edby questionnaireControlExposures orInterventionsBreast feed<strong>in</strong>gstatus determ<strong>in</strong>edby questionnaireC-154
Chiaffar<strong>in</strong>o, 2005 [UI# 15975644]OutcomeDef<strong>in</strong>itionOvarian cancerconfirmed byhistologyStatistical analyses <strong>and</strong> confoundersadjustedUnconditioned multiple logistic regressionadjust<strong>in</strong>g for age, center, education, parity,oral contraceptive use, family history ofovarian/breast cancer <strong>in</strong> first degreerelativesResultsExposure statusCases Controls ORadj (95%n (%) n (%)CI)Never breastfed 368(36) 878 (37) 1.0Ever breastfed 660 (64) 1512 (63) 1.16 (0.93-1.43)Breastfed 1-4 months 157 (15) 358 (15) 1.20 (0.91-1.59)Breastfed 5-8 months 180 (18) 366 (15) 1.24 (0.95-1.62)Breastfed 9-16months195 (19) 451 (19) 1.01 (0.77-1.33)Breastfed ≥17months128 (12) 337 (14) 1.21 (0.85-1.71)x 2 for trend 0.03 (p=0.87)ExposurestatusSerousOdds ratioadj(95% CI)Muc<strong>in</strong>ousOthersubtypesNeverbreastfed1 1 1Ever1.591.1 (0.85-1.48)breastfed(0.82-3.07)Breastfed 1-4 mo1.3 (0.90-1.85)Breastfed 5-8 mo1.16 (0.81-1.65)Breastfed 9-16 mo1.06 (0.74-1.51)Breastfed≥17 mo0.87 (0.55-1.39)x 2 for trend 0.14p=0.711.08(0.71-1.62)Bias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection XStudy design XConfounder XBl<strong>in</strong>d<strong>in</strong>g XData collection XWithdraw <strong>and</strong> XdropoutAnalyses XIntervention<strong>in</strong>tegrityPotential recall biasC-155
Cramer, 1983 [UI# 6578366]Study Subjects’ healthcharacteristics conditionsMean age: 53 NDMenopause: NDRace: WhiteEnrolled/Evaluate:Cases: 215Controls: 215Location: USASites: Multi-centerFund<strong>in</strong>g:GovernmentStudy design <strong>and</strong>follow-up durationCase-controlData collection byquestionnairesEligibility criteriaCases: white females with epithelial ovariancancer resid<strong>in</strong>g <strong>in</strong> greater Boston areaControls: matched residents of same prec<strong>in</strong>ct,age with<strong>in</strong> 2 years, race. Only bilateraloophorectomy excluded.<strong>Breastfeed<strong>in</strong>g</strong> Exposuresor Interventions<strong>Breastfeed<strong>in</strong>g</strong> statusdeterm<strong>in</strong>ed byquestionnaireControl Exposures orInterventions<strong>Breastfeed<strong>in</strong>g</strong> statusdeterm<strong>in</strong>ed byquestionnaireCramer, 1983 [UI# 6578366]Statistical analyses <strong>and</strong>Outcome Def<strong>in</strong>itionconfounders adjustedAll types of epithelial Chi-squareovarian cancerResultsCrude relative risks 1.11 (0.70-1.76) never breastfed parouscases (86/137) vs controls (106/176)Non-significant trend <strong>in</strong> risk for ovarian cancer with number ofchildren breastfed.Bias/limitationsCommentsA: strong, B: moderate, A B CC: weakSelection XStudy design XConfounder XBl<strong>in</strong>d<strong>in</strong>g XData collection XWithdraw <strong>and</strong> dropout XAnalyses XIntervention <strong>in</strong>tegrityM<strong>in</strong>imal report<strong>in</strong>g of dataPotential recall biasC-156
Greggi, 2000 [UI# 11006030]StudycharacteristicsMedian age(range):Cases: 54 (13-80)Controls: 55 (19-80)Menopause: mixRace: NDEnrolled/Evaluate*:Cases: 440/330Controls 868/721Location: ItalySites: S<strong>in</strong>gleFund<strong>in</strong>g: Private*ParousCases: NDSubjects’ health conditionsControls: traumatic conditions 29%,nontraumatic orthopedic disorders 21%, acuteabdom<strong>in</strong>al diseases generally requir<strong>in</strong>g surgery17%, miscellaneous illnesses (ear, nose throat,teeth) 33%Study design<strong>and</strong> follow-updurationCase-controlData collectionby hospital<strong>in</strong>terviewsEligibility criteriaCases: admitted histologicallyconfirmed diagnosis of epithelialovarian cancerControls: admitted to same hospital,similar age strata, acutenongynecological, nonhormonal, ornonneoplastic condition<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsBreast feed<strong>in</strong>gstatus determ<strong>in</strong>ed by<strong>in</strong>terviewControl Exposuresor InterventionsBreast feed<strong>in</strong>gstatus determ<strong>in</strong>edby <strong>in</strong>terviewGreggi, 2000 [UI# 11006030]OutcomeDef<strong>in</strong>itionEpithelial ovariancancer confirmedby histologyStatistical analyses <strong>and</strong> confoundersadjustedMantel-Haenzel adjusted for age;unconditional multiple logistic regressionestimates <strong>in</strong>clud<strong>in</strong>g terms for age, education,parity, oral contraceptive use, family historyof ovarian cancerResultsExposure Cases Controls ORadj (95% CI)status*330 (%) 721 (%) Mantel-HaenzelMultivariateregressionNever breastfed 84 (25) 120 (17) 1.0 1.0Breastfed ≤12months136 (41) 294 (41) 0.6(0.5-0.9)0.8 (1.0-1.1)Breastfed >12months110 (33) 307 (43) 0.5(0.3-0.7)0.5(0.4-0.8)*ParousBias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection XStudy design XConfounder XBl<strong>in</strong>d<strong>in</strong>g XData collection XWithdraw <strong>and</strong>XdropoutAnalyses XIntervention<strong>in</strong>tegrityPotential recall biasC-157
Gw<strong>in</strong>n, 1990 [UI# 2348208]Subjects’StudyhealthcharacteristicsconditionsMean age (range): NDNDMenopause: mixRace: NDEnrolled/Evaluate:Cases: 494/436Controls:4236/3833Location: USASites: Multi centerFund<strong>in</strong>g:Study design <strong>and</strong>follow-up durationCase-controlControls contacted byr<strong>and</strong>om telephoneData collection by<strong>in</strong>terview of st<strong>and</strong>ardquestionnaireEligibility criteriaCases: 20-54 year, resides <strong>in</strong> 1 of 8study areas, ovarian cancer byhistologyControls: matched for age, resides <strong>in</strong>same 8 areas, no ovaries or unknownnumber of ovaries are exclusion<strong>Breastfeed<strong>in</strong>g</strong> Exposures orInterventionsBreast feed<strong>in</strong>g status determ<strong>in</strong>ed by<strong>in</strong>terview, duration <strong>in</strong> monthsregardless of patternControl Exposures orInterventionsBreast feed<strong>in</strong>g statusdeterm<strong>in</strong>ed by <strong>in</strong>terviewGw<strong>in</strong>n, 1990 [UI# 2348208]Statistical analyses <strong>and</strong>Outcome Def<strong>in</strong>itionconfounders adjustedEpithelial ovarian cancerconfirmed by histologyLogistic regression adjusted forpregnancy, oral contraceptive use,age, <strong>and</strong> age-pregnancy <strong>in</strong>teraction<strong>Breastfeed<strong>in</strong>g</strong>duration(month)*Casesn (%)ResultsControlsn (%)RRadj(95% CI)0 184 1517 1.0(57) (46)1-2 40 (12) 552 (17) 0.6(0.5-0.9)3-5 32 (10) 330 (10) 0.86-11 33 (10) 379 (11) 0.812-23 25 (8) 321 (10) 0.7≥ 24 7 (2.2) 213 (6.4) 0.3* Parous women onlyβ –0.024Each month of breastfeed<strong>in</strong>g reduced risk by 2.4%Most protection due to first exposure rather than numberof pregnanciesBias/limitationsCommentsA: strong, B: moderate, C: A B CweakSelection XStudy design XConfounder XBl<strong>in</strong>d<strong>in</strong>g XData collection XWithdraw <strong>and</strong> dropout XAnalyses XIntervention <strong>in</strong>tegrityOvarian cancer confirmed by histology <strong>in</strong>majority of casesC-158
Hartge, 1989 [UI# 2750791]Study characteristicsMean age (range):Cases: 54 (20-79)Controls: 55Menopause: mixRace:Cases: 12% blackControls: 14% blackEnrolled/Evaluate:Cases: 296/203*Controls: 343/257*Location: USASites: MultiFund<strong>in</strong>g: Government*Parous women(evaluated)Subjects’ health conditionsSerous 28%Serous, low malignant potential12%Muc<strong>in</strong>ous 6%Muc<strong>in</strong>ous, low malignantpotential 3%Endometrioid, low malignantpotential 26%Clear cell 4%Mixed epithelial 8%Undifferentiated 10%Controls:Infectious 2%Neoplasm 5%Endocr<strong>in</strong>e-metabolic 5%Blood disease or blood-form<strong>in</strong>gorgans 1%Nervous system 8%Eye, ear, mastoid 8%Varicose ve<strong>in</strong>s, hemorrhoids 1%Respiratory 8%Digestive system 16%Ur<strong>in</strong>ary 5%Sk<strong>in</strong> 2%Musculoskeletal 22%Congenital 1%Ill-def<strong>in</strong>ed 5%Fractures/<strong>in</strong>juries 11%Study design <strong>and</strong>follow-up durationCase-controlData collection with<strong>in</strong>terviewer ofst<strong>and</strong>ardquestionnaire <strong>and</strong>medical recordsreviewEligibility criteriaCases: primary epithelial ovariancancer confirmed by microscopicslides <strong>and</strong> medical records, <strong>in</strong>cludedlow malignant potential tumors aswell as malignant tumorsControls: hospitalized for otherconditions, matched for age,hospital, race, at least one ovary.Excluded if psychiatric diagnosis orrelated to major exposures of<strong>in</strong>terest<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventions<strong>Breastfeed<strong>in</strong>g</strong> statusdeterm<strong>in</strong>ed by <strong>in</strong>terviewControl Exposuresor Interventions<strong>Breastfeed<strong>in</strong>g</strong> statusdeterm<strong>in</strong>ed by<strong>in</strong>terviewC-159
Hartge, 1989 [UI# 2750791]Outcome Def<strong>in</strong>ition Statistical analyses <strong>and</strong> confounders adjusted ResultsPrimary epithelialovarian cancerconfirmed bymicroscopic slides<strong>and</strong> medical recordsRate ratio of ovarian cancer <strong>in</strong>cidence <strong>in</strong> exposed group tocorrespond<strong>in</strong>g unexposed group, adjusted for confound<strong>in</strong>gvariables by stratified cont<strong>in</strong>gency table analysis <strong>and</strong> bylogistic regression models, adjustments for age <strong>and</strong> race,<strong>and</strong> parity, difficulty conceiv<strong>in</strong>g, oral contraceptives, surgicalmenopause, HRT, or family history of ovarian cancer asneeded<strong>Breastfeed<strong>in</strong>g</strong>duration(month)*Casesn (%)Controlsn (%)Rateratioadj(95% CI)1.00 112(55)121(47)1-9 62 (31) 84 (33) 0.8(0.5-1.2)10-18 16 (7.9) 37 (18) 0.5(0.2-0.9)19-110 13 (6.4) 15 (7.4) 1.1(0.5-2.6)* Parous women onlyAdjusted for age <strong>and</strong> raceTrend test p = 0.14Bias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection XStudy design XConfounder XBl<strong>in</strong>d<strong>in</strong>g XDataXcollectionWithdraw <strong>and</strong> XdropoutAnalyses XIntervention<strong>in</strong>tegrityNumber of months breastfeed<strong>in</strong>g not related to riskC-160
John, 1993 [UI# 8418303]Subjects’StudyhealthcharacteristicsconditionsMean age (range):Cases:Invasive 53Borderl<strong>in</strong>e 37Controls: NDMenopause: mixRace: BlackEnrolled/Evaluate:Cases: 110/53Controls: 365/25969% population31% hospitalLocation: USASites: 7 of 12studiesFund<strong>in</strong>g:GovernmentInvasive cancer65%Low malignant32%Unknown 3%Study design <strong>and</strong> follow-up durationCase-controlData from 7 studies of cases diagnosed between1971 <strong>and</strong> 1986. Individual patient data collectedby <strong>in</strong>terview from 7 case-control studiesconducted <strong>in</strong> USEligibility criteriaEpithelial ovarian cancerControls: population <strong>and</strong>hospital subjects, bilateraloophorectomy excluded<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventions<strong>Breastfeed<strong>in</strong>g</strong> statusdeterm<strong>in</strong>ed by<strong>in</strong>terviewControl Exposuresor Interventions<strong>Breastfeed<strong>in</strong>g</strong> statusdeterm<strong>in</strong>ed by<strong>in</strong>terviewJohn, 1993 [UI# 8418303]OutcomeDef<strong>in</strong>itionEpithelialovarian cancerStatistical analyses <strong>and</strong>confounders adjustedConditional logistic regressionadjusted for study, birth year,reference age, parityOverlap with Hartge 1989 <strong>and</strong> Cramer 1983Results<strong>Breastfeed<strong>in</strong>g</strong>duration (month)*Casesn (%)Controlsn (%)RRadj(95% CI)Never breastfed 24 (45) 102 (39) 1.0Ever breastfed 29 (55) 157 (61) 0.90(0.42-1.9)1-5 11 (21) 52 (20) 1.0(0.39-2.6)≥6 18 (34) 103 (40) 0.85(0.36-2.0)Trend per month 0.99p=0.57* ParousBias/limitationsCommentsA: strong, B: moderate, C: A B CweakSelection XStudy design XConfounder XBl<strong>in</strong>d<strong>in</strong>g XData collection XWithdraw <strong>and</strong> dropout XAnalyses XIntervention <strong>in</strong>tegrityData unavailable for use of oralcontraceptives <strong>and</strong> years of ovulationC-161
Modugno, 2003 [UI# 12946038]Subjects’StudyhealthcharacteristicsconditionsMean age (range):BRCA1 51BRCA2 61BRCA- 58Menopause: mixRace: 100%JewishEnrolled/Evaluate:Cases: 95Controls: 147Location: USA,IsraelSites: MultiFund<strong>in</strong>g:GovernmentNDCase-controlStudy design <strong>and</strong> follow-up durationCases screened for Ashkenazi founder mutationsBRCA1 (185delAG or 5382<strong>in</strong>sC) or BRCA2 (6174delT)Controls were ovarian cases without BRCA1/2 genotypeIndividual patient data collected by <strong>in</strong>terview from 4case-control studies. Two US population studies (100cases), one hospital-based study from 11 US <strong>and</strong> Israelcenters (208 cases), <strong>and</strong> one US genetic counsel<strong>in</strong>gcenter (14 cases)Eligibility criteriaJewish women with epithelialovarian cancer, no breastcancer history, BRCA1/2confirmed by data sequenc<strong>in</strong>g<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsNDControlExposures orInterventionsNDModugno, 2003 [UI# 12946038]OutcomeDef<strong>in</strong>itionInvasiveepithelial ovariancancer confirmedby histologyStatistical analyses <strong>and</strong>confounders adjustedUnconditioned logistic regressionadjusted for age at diagnosis,year of birth, number of livebirths, oral contraceptive use,history of tubal ligation. Mantel-Haenszel test for heterogeneityOne population study, Ness 2000, has been reportedResultsORadj(95% CI)BRCA-(n=147)BRCA1/2(n=95)BRCA1(n=64)<strong>Breastfeed<strong>in</strong>g</strong> 1.0 1.09 1.36(0.61-1.97) (0.68-2.73)<strong>Breastfeed<strong>in</strong>g</strong> 1.0 1.02 1.01duration*(0.99-1.04) (0.98-1.04)* Parous womenBRCA2(n=31)0.70(0.28-1.72)1.02(0.99-1.05)Bias/limitationsCommentsA: strong, B: moderate, A B CC: weakSelection XStudy design XConfounder XBl<strong>in</strong>d<strong>in</strong>g XData collection XWithdraw <strong>and</strong> dropout XAnalyses XIntervention <strong>in</strong>tegrity10% overlap <strong>in</strong> samples between the USgenetic center & hospital-based studyClassification of Jewish varied betweenstudiesC-162
Ness, 2000 [UI# 11021606]Modugno, 2001 [UI# 11308435]StudycharacteristicsSubjects’ healthconditionsMean age (range): Invasive epithelial 616Cases:Serous 45%Invasive 53Muc<strong>in</strong>ous 8%Borderl<strong>in</strong>e 45 Endometrioid 22%Controls: 49 Other 24%Menopause: mixRace: NDBorderl<strong>in</strong>e epithelial 151Enrolled/Evaluate: Serous 52%Cases: 767/531* Muc<strong>in</strong>ous 40%Controls: 1215/1190* Endometrioid 2%Location: USA Other 6%Sites: MultiFund<strong>in</strong>g:Government*Parous women(evaluated)Other <strong>in</strong>cludes clear cell,mixed cell,undifferentiated or poorlydifferentiatedStudy design <strong>and</strong>follow-up durationCase-controlData collection by<strong>in</strong>terviewControls identifiedby r<strong>and</strong>om-digitdial<strong>in</strong>g from HFCAlistsEligibility criteriaHistologically confirmed epithelial ovariancancer diagnosed past 6 months, 20-69yearsControls: ≤ 65 years, matched by 5 years<strong>and</strong> 3 digit exchangeExclusion: outside counties of referralhospital, prior diagnosis of ovarian cancer,non-English speak<strong>in</strong>g, mentally<strong>in</strong>competent, critically ill, prior bilateraloophorectomy<strong>Breastfeed<strong>in</strong>g</strong> Exposuresor Interventions<strong>Breastfeed<strong>in</strong>g</strong> statusdeterm<strong>in</strong>ed by <strong>in</strong>terview,length recorded on lifecalendarControl Exposures orInterventions<strong>Breastfeed<strong>in</strong>g</strong> statusdeterm<strong>in</strong>ed by <strong>in</strong>terview,length recorded on lifecalendarC-163
Ness, 2000 [UI# 11021606]Modugno, 2001 [UI# 11308435]OutcomeDef<strong>in</strong>itionEpithelialovarian cancerconfirmed byhistologyStatistical analyses <strong>and</strong> confounders adjustedMultivariate unconditional logistic regression adjusted forage, number of pregnancies, family history of ovarian cancer,race, oral contraceptive use, tubal ligation, hysterectomy,breastfeed<strong>in</strong>gFor analyses by histology: multivariate unconditional logisticregression adjusted for age, number of live births, years oforal contraceptive use, years of noncontraceptive estrogenuse <strong>and</strong> months breastfed, tubal ligation, hysterectomy,family history of ovarian <strong>and</strong> breast cancer, ethnicity<strong>Breastfeed<strong>in</strong>g</strong>duration(month)*Casesn (%)ResultsControlsn (%)Oddsratioadj(95% CI)0 299 (56) 577 (48) 1.01-5 117 (22) 259 (22) 0.9(0.7-1.2)6-11 46 (8.7) 119 (10) 0.9(0.6-1.3)12-23 40 (7.5) 124 (10) 0.7(0.5-1.1)≥24 29 (5.5) 111 (9.3) 0.6(0.4-1.0)* Parous women onlyHistologic subgroup (N)Months breastfedOdds ratioadj(95% CI)Serous (357) 1.00(0.98-1.01)Muc<strong>in</strong>ous (112) 1.00(0.98-1.02)Endometrioid (139) 0.97(0.94-1.00)Other (159) 0.97(0.94-1.00)All (767) 0.99(0.98-1.00)Bias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection XStudy design XConfounder XBl<strong>in</strong>d<strong>in</strong>g XData collection XWithdraw <strong>and</strong>dropoutAnalyses XIntervention<strong>in</strong>tegrityXC-164
Riman, 2002 [UI# 12181107]StudycharacteristicsMean age (range):Cases: 62Controls: 63Menopause: mixRace: NDEnrolled/Evaluate:Cases: 914/655Controls: 4148/3899Location: SwedenSites:NAFund<strong>in</strong>g: Private,governmentSubjects’ healthconditionsAll <strong>in</strong>vasive (655)Serous (337)Muc<strong>in</strong>ous (60)Endometrioid (180)Clear cell (43)Other/undifferentiated(35)Study design <strong>and</strong> follow-updurationCase-controlData collected by self-adm<strong>in</strong>isteredquestionnaires followed up byphone for miss<strong>in</strong>g or <strong>in</strong>consistentdetailsEligibility criteriaSwedish born women 50-74 years oldwith epithelial ovarian cancerconfirmed by histology identified bynational registryControls: r<strong>and</strong>omly selectedpopulation national registryExclusion: previous ovarianmalignancy or bilateral oophorectomy<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventions<strong>Breastfeed<strong>in</strong>g</strong> statusdeterm<strong>in</strong>ed byquestionnairesControl Exposuresor Interventions<strong>Breastfeed<strong>in</strong>g</strong> statusdeterm<strong>in</strong>ed byquestionnairesC-165
Riman, 2002 [UI# 12181107]OutcomeDef<strong>in</strong>itionEpithelialovariancancerconfirmed byhistologyStatistical analyses <strong>and</strong>confounders adjustedUnconditional logisticregression adjusted forage, bmi, parity, age atmenopause, duration oforal contraceptive use,HRT useResults<strong>Breastfeed<strong>in</strong>g</strong> duration(months)Casesn (%)Controlsn (%)ORadj (95%CI)
Risch, 1983 [UI# 6681935]Subjects’StudyhealthcharacteristicsconditionsMean age (range): NDCases: 20-74Controls: 21-75Menopause: mixRace: whiteEnrolled/Evaluate:Cases: 284Controls: 705Location: USASites: MultiFund<strong>in</strong>g:GovernmentStudy design<strong>and</strong> follow-updurationCase-controlData collectionby <strong>in</strong>terviewCasesEligibility criteriaEpithelial ovarian cancer diagnosed <strong>in</strong> past 18 months, reside <strong>in</strong> 6specified counties of Wash<strong>in</strong>gton <strong>and</strong> Utah <strong>and</strong> identified bypopulation-based cancer report<strong>in</strong>g systems, age 34-74 for Wash<strong>in</strong>gtoncases, age 20-74 for Utah casesControls: household survey conducted <strong>in</strong> same counties by st<strong>and</strong>ardgeographic sampl<strong>in</strong>g methods or telephone selected from directories.Utah samples matched for age <strong>and</strong> Wash<strong>in</strong>gton samples matched forage range. Exclusion <strong>in</strong>cluded bilateral oophorectomy ≤ 1 yearAdditional case-control exclusion: nonwhite, <strong>in</strong>complete reproductivehistories<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventions<strong>Breastfeed<strong>in</strong>g</strong> statusdeterm<strong>in</strong>ed by<strong>in</strong>terviewControl Exposuresor Interventions<strong>Breastfeed<strong>in</strong>g</strong> statusdeterm<strong>in</strong>ed by<strong>in</strong>terviewRisch, 1983 [UI# 6681935]OutcomeStatistical analyses <strong>and</strong> confounders adjustedDef<strong>in</strong>itionEpithelialovarian cancerL<strong>in</strong>ear logistic regression adjusted for age at diagnosis 20-44,nulliparous, no miscarriages, < 1 year total exposure to comb<strong>in</strong>ed oralcontraceptives, nonobeseResultsRR 0.79 per year of lactation p=0.034, isassociated with decreased ovarian cancerriskCases reported less time breastfeed<strong>in</strong>gthan controls3+ total months lactation – RR 0.69 (0.50-0.96) p=0.026Bias/limitationsCommentsA: strong, B: A B Cmoderate, C: weakSelection XStudy design XConfounder XBl<strong>in</strong>d<strong>in</strong>g XData collection XWithdraw <strong>and</strong>XdropoutAnalyses XIntervention<strong>in</strong>tegrityC-167
Risch, 1994 [UI# 7942759]Subjects’StudyhealthcharacteristicsconditionsMean age (range): NDCases: 57Controls: 58Menopause: mixRace: 96% whiteEnrolled/Evaluate:Cases: 450Controls: 564Location: CanadaSites: MultiFund<strong>in</strong>g:GovernmentStudy design <strong>and</strong> follow-updurationCase-controlData collection by <strong>in</strong>terviewus<strong>in</strong>g questionnaire<strong>in</strong>corporat<strong>in</strong>g life events calendar– conducted at subject’s homeEligibility criteriaPrimary malignant or borderl<strong>in</strong>e malignant epithelialovarian cancer confirmed by histology, age 35-79,residents of Ontario located through Ontario CancerRegistry, liv<strong>in</strong>g subjectsControls: obta<strong>in</strong>ed from Enumeration CompositeRecord list<strong>in</strong>g compiled by Ontario M<strong>in</strong>istry ofRevenue, matched for area of residence <strong>and</strong> agerange, exclusion <strong>in</strong>cluded bilateral oophorectomy < 1year, liv<strong>in</strong>g subjects<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventions<strong>Breastfeed<strong>in</strong>g</strong> statusdeterm<strong>in</strong>ed by<strong>in</strong>terviewControl Exposuresor Interventions<strong>Breastfeed<strong>in</strong>g</strong>status determ<strong>in</strong>edby <strong>in</strong>terviewRisch, 1994 [UI# 7942759]Statistical analyses <strong>and</strong>Outcome Def<strong>in</strong>itionconfounders adjustedPrimary malignant orborderl<strong>in</strong>e malignantepithelial ovariancancer confirmed bypathology reportsMultivariate unconditionalcont<strong>in</strong>uous logistic regressionadjusted for 3 age groups,cont<strong>in</strong>uous variables age, totalduration of oral contraceptiveuseResultsNo of full-termMean Oddspregnancies Cases Controls ratioadj(95% CI)Total duration*(year)0.51 0.65 0.89(0.75-1.05)Average duration oflactation/pregnancy*2.24 2.72 0.87(0.76-0.99)(months)*Adjusted for number of full-term pregnanciesInverse association with total duration of lactationInverse association with average duration per pregnancy,p=0.030Pregnancies with lactation slightly more protective thanpregnancies withoutBias/limitationsCommentsA: strong, B: moderate, C: weak A B CSelection XStudy design XConfounder XBl<strong>in</strong>d<strong>in</strong>g XData collection XWithdraw <strong>and</strong> dropout XAnalyses XIntervention <strong>in</strong>tegritySlightly greater number for controls born <strong>in</strong> Canadaor US, smaller percentage of cases were parous orever used OC <strong>and</strong> among those cases had fewer fulltermpregnancies <strong>and</strong> used OC for shorter periods oftimeC-168
Sisk<strong>in</strong>d, 1997 [UI# 9229212]Subjects’StudyhealthcharacteristicsconditionsMean age* (range): NDCases: 57Controls: 56Menopause: mixPremenopausalCases: 35%Controls: 36%Race: NDEnrolled/Evaluate*:Cases: 824/618Controls: 855/724Location: AustraliaSites: MultiFund<strong>in</strong>g:Government, private*ParousStudy design <strong>and</strong> follow-up durationCase-controlData collection by <strong>in</strong>terviewer withquestionnaire at discharge or cl<strong>in</strong>ic followup,<strong>in</strong> homes for all controls <strong>and</strong> homes orcl<strong>in</strong>ics for casesControls r<strong>and</strong>omly selected throughelectoral rollEligibility criteriaCases: Histologically confirmedprimary epithelial ovarian cancer,18-79 years, ≥ 1 live birthControls: similar age <strong>and</strong> regionExclusion: history of ovarian canceror bilateral oophorectomy,<strong>in</strong>capable of complet<strong>in</strong>gquestionnaire<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventions<strong>Breastfeed<strong>in</strong>g</strong> statusdeterm<strong>in</strong>ed byquestionnaireControl Exposuresor Interventions<strong>Breastfeed<strong>in</strong>g</strong> statusdeterm<strong>in</strong>ed byquestionnaireC-169
Sisk<strong>in</strong>d, 1997 [UI# 9229212]OutcomeDef<strong>in</strong>itionPrimaryepithelialovarian cancerconfirmed byhistologyStatistical analyses <strong>and</strong>confounders adjustedMultiple logistic regression withcovariates: age, parity, age at 1 stbirth, education, oral contraceptiveuse, smok<strong>in</strong>g history, menopausalstatusResults<strong>Breastfeed<strong>in</strong>g</strong>duration (month)Casesn (%)Controlsn (%)Odds ratioadj(95% CI)0 168 (27) 155 (21) 1.01-6 180 (29) 190 (26) 0.89(0.65-1.2)7-12 125 (20) 187 (26) 0.68(0.49-0.94)13-24 107 (17) 141 (19) 0.84(0.59-1.2)25-36 25 (4) 39 (5) 0.69(0.38-1.3)>36 13 (2) 12 (2) 0.77(0.34-1.8)Any 450 (73) 569 (79) 0.80(0.61-1.04)Per month 0.99(0.98-1.0)* Parous women onlyBias/limitationsCommentsA: strong, B: A B Cmoderate, C: weakSelection XStudy design XConfounder XBl<strong>in</strong>d<strong>in</strong>g XData collection XWithdraw <strong>and</strong>XdropoutAnalyses XIntervention<strong>in</strong>tegrityC-170
OutcomeDef<strong>in</strong>itionPrimaryepithelialovarian cancerconfirmed byhistologyStatistical analyses <strong>and</strong>confounders adjustedMultiple logistic regression withcovariates: age, parity, age at 1 stbirth, education, oral contraceptiveuse, smok<strong>in</strong>g history, menopausalstatusResultsPremenopausalPostmenopausalCases Controls Cases Controls<strong>Breastfeed<strong>in</strong>g</strong>n (%) n (%) n (%) n (%)duration (month)Odds ratioadjOdds ratioadj(95% CI)(95% CI)075 (35) 66 (25) 93 (23) 89 (19)1.00 1.001-669 (32) 78 (29) 111 (27) 112 (24)0.75 (0.46-1.21) 0.98 (0.65-1.47)7-1234 (16) 72 (27) 91 (23) 115 (25)0.53 (0.31-0.94) 0.83 (0.54-1.26)13-2433 (15) 36 (14) 74 (18) 105 (23)1.03 (0.54-1.95) 0.88 (0.56-1.38)>244 (4) 12 (5)0.29 (0.08-1.04)---25-36 ---21 (5) 27 (6)0.93 (0.46-1.88)>36 ---13 (3) 12 (3)1.27 (0.50-3.2)* Parous women onlyBias/limitationsCommentsA: strong, B: A B Cmoderate, C: weakSelection XStudy design XConfounder XBl<strong>in</strong>d<strong>in</strong>g XData collection XWithdraw <strong>and</strong>XdropoutAnalyses XIntervention<strong>in</strong>tegrityC-171
Titus-Ernstoff, 2001 [UI# 11237375]Study characteristicsMean age (%):Cases Controls60years by Town BooksEligibility criteriaCancer registry <strong>and</strong> hospital board cases ofepithelial ovarian cancer <strong>in</strong>clud<strong>in</strong>g lesions ofborderl<strong>in</strong>e malignancy, 20-74 years,Controls: matched by age with<strong>in</strong> 4 years <strong>and</strong>telephone sampl<strong>in</strong>g unit, >60 years werematched by age <strong>and</strong> prec<strong>in</strong>ct, exclusion<strong>in</strong>cluded bilateral oophorectomy<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventions<strong>Breastfeed<strong>in</strong>g</strong>status determ<strong>in</strong>edby <strong>in</strong>terviewControlExposures orInterventions<strong>Breastfeed<strong>in</strong>g</strong>status determ<strong>in</strong>edby <strong>in</strong>terview* Parous women onlyC-172
Titus-Ernstoff 2001 [UI# 11237375]Statistical analysesOutcome Def<strong>in</strong>ition <strong>and</strong> confoundersadjustedEpithelial ovarian Unconditional logisticcancer by pathology regression adjusted forreport or microscopy age, state, parityslidesResults<strong>Breastfeed<strong>in</strong>g</strong> duration(month)*Casesn (%)Controlsn (%)Odds ratioadj(95% CI)0 239 (63) 223 (53) 1.06 42 (11) 70 (17) 0.7(0.4-1.0)Ever 139 (37) 194 (47) 0.7(0.5-1.0)P for trend 0.21* Parous women only<strong>Breastfeed<strong>in</strong>g</strong>StatusSerousborderl<strong>in</strong>e(n=86)Odds Ratioadj (95% CI)Serous<strong>in</strong>vasive(n=229)Muc<strong>in</strong>ous(n=83)Endometrioid/Clear cell(n=130)Neverbreastfed1.0 1.0 1.0 1.0Everbreastfed0.8(0.4-1.6)1.0(0.6-1.4)0.6(0.3-1.2)P for trend 1 0.61 0.34 0.88 0.041 Average duration (months) per breastfed child0.4(0.2-0.7)Bias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection XStudy design XConfounder XBl<strong>in</strong>d<strong>in</strong>g XData collection XWithdraw <strong>and</strong> XdropoutAnalyses XIntervention<strong>in</strong>tegrityC-173
Tung, 2003 [UI# 14507598], Tung 2005 [UI# 15692075]Study characteristicsMean age (range):Cases: 50 Muc<strong>in</strong>ous55 Nonmuc<strong>in</strong>ousControls: 56Menopause: premenopausal 39%Race %:Cases CasesMuc<strong>in</strong>ous Nonmuc<strong>in</strong>ous ControlsAsian 51 34 42White 30 50 44Other 19 16 14Enrolled/Evaluate:Cases: 558Controls: 607Location: USASites: MultiFund<strong>in</strong>g: GovernmentSubjects’ healthconditionsInvasive n=431Muc<strong>in</strong>ous 11%Serous 51%Endometrioid 17%Clear cell 11%Other(undifferentiated,squamous, transitional)10%Borderl<strong>in</strong>e n=127Muc<strong>in</strong>ous 48%Serous 52%Study design<strong>and</strong> follow-updurationCase-controlData collection by<strong>in</strong>terviewer withquestionnaire<strong>in</strong>clud<strong>in</strong>g lifecalendar <strong>in</strong> homesfor 95% of all<strong>in</strong>terviewedEligibility criteriaCases: ≥18 years, epithelial ovariancancer confirmed by histology, identified bypopulation-based cancer registry, reside <strong>in</strong>Los Angeles, California or Hawaii for 1year prior to diagnosisControls: ≥18 years, reside <strong>in</strong> LosAngeles, California or Hawaii for 1 yearprior to Interview, no prior history ofovarian cancer, ≥1 <strong>in</strong>tact ovary, matchedfor age (±5 years), ethnicity, study site,r<strong>and</strong>omly selected from neighborhood walkprocedure <strong>in</strong> LA <strong>and</strong> Hawaii Department of<strong>Health</strong> state-wide annual survey list<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventions<strong>Breastfeed<strong>in</strong>g</strong>status determ<strong>in</strong>edby <strong>in</strong>terviewControlExposures orInterventions<strong>Breastfeed<strong>in</strong>g</strong>status determ<strong>in</strong>edby <strong>in</strong>terviewC-174
Epithelialovarian cancerconfirmed byhistologyPolytomous logistic modeladjusted for age, ethnicity,study site, education, oralcontraceptive use, tuballigationUnconditional logisticregression adjusted for age,ethnicity, study site,education, tubal ligation, HRT,ovulation variablesOdds ratioadj<strong>Breastfeed<strong>in</strong>g</strong>(95% CI)All cases Muc<strong>in</strong>ous Nonmuc<strong>in</strong>ousNever 1 1 1Ever0.60.80.5(0.4-0.7) (0.5-1.4) (0.4-0.7)<strong>Breastfeed<strong>in</strong>g</strong>duration (month)*0 1 1 1≤5 0.6(0.4-0.9)0.6(0.4-1.4)0.7(0.4-0.9)6-16 0.6(0.4-0.9)0.7(0.3-1.3)0.5(0.3-0.7)>16 0.6(0.4-0.8)0.9(0.8-1.8)0.4(0.3-0.7)P for trend* 0.011 0.99 0.0005*Based on likelihood ratio test compar<strong>in</strong>g models with <strong>and</strong> without a trendvariable that was assigned median values for the categoriesTotalbreastfeed<strong>in</strong>gOdds ratioadj(95% CI)duration Premenopausal Postmenopausal(year)*0 11.0 0.46 (0.22-0.97) 0.69 (0.43-1.12)P for trend 0.003 0.08A: strong, B: moderate, C: A B CweakSelection XStudy design XConfounder XBl<strong>in</strong>d<strong>in</strong>g XData collection XWithdraw <strong>and</strong> dropout XAnalyses XIntervention <strong>in</strong>tegrityControls were better educated had greaternumber of full-term pregnancies, use oralcontraceptive more, higher frequency of tuballigationOdds ratioadj <strong>Breastfeed<strong>in</strong>g</strong> <strong>Breastfeed<strong>in</strong>g</strong> duration (month)*(95% CIInvasivecasesNever Ever ≤5 6-16 >16 P fortrend*All cases 1 0.5 0.6 0.5 0.5 0.002(0.4-0.7)(0.4-0.9)(0.4-0.8) (0.3-0.7)Muc<strong>in</strong>ous 1.2(0.6-2.7)0.7(0.3-1.8)1.1(0.5-2.6)1.2(0.5-3.0)0.30Serous 0.5(0.3-0.7)Endometrioid 0.5(0.3-0.9)Clear cell 0.5(0.2-1.0)0.6(0.4-0.9)0.6(0.3-1.2)C-175 0.6(0.3-1.5)0.5(0.3-0.8)0.6(0.3-1.3)0.5(0.3-1.4)0.4(0.2-0.7)0.3(0.1-1.0)0.3(0.1-1.1)0.960.100.40
C-176
West, 1966 [UI# 5939299]StudycharacteristicsMean age (range):Cases: 53Controls: 50Menopause: mixRace: NDEnrolled/Evaluate:Cases: 97/76Controls: 91/76Location: USASites: MultiFund<strong>in</strong>g: NDSubjects’ healthconditionsCases:Pseudo-muc<strong>in</strong>ouscystadenocarc<strong>in</strong>oma 23Serouscystadenocarc<strong>in</strong>oma 16Cystadenocarc<strong>in</strong>oma <strong>and</strong>adenocarc<strong>in</strong>oma 43Carc<strong>in</strong>oma 6Granulosa cell 5Teratoma 1Dysgerm<strong>in</strong>oma 1Meso-meta-nephroma 1Unclassified 1Study design<strong>and</strong> follow-updurationCase-controlData collectionby <strong>in</strong>terviewEligibility criteriaCases: malignancy of ovary, 50 mile radius of Boston,exclusion <strong>in</strong>cludes >75 years <strong>and</strong> co-existentmalignancy of another organ that was not metastaticfrom ovary <strong>and</strong> recurrent casesControls: female hospital patients matched for age ± 5years, residence <strong>and</strong> date of surgery, next operatedcase of benign ovarian neoplasms from same hospitalas malignant case<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsBreast feed<strong>in</strong>g statusdeterm<strong>in</strong>ed by<strong>in</strong>terviewControl Exposuresor InterventionsBreast feed<strong>in</strong>g statusdeterm<strong>in</strong>ed by<strong>in</strong>terviewControls: (25 diagnoses)Endometriosis 19Simple cyst 10Pseudo-muc<strong>in</strong>ouscystadenoma 9Dermoid cyst 8C-177
West, 1966 [UI# 5939299]Statistical analysesOutcome Def<strong>in</strong>ition <strong>and</strong> confoundersadjustedMalignant ovarian T test with p level ofcancer confirmed by 0.01 for significancepathologyResults76 matched pairsLactation (months)Cases Controls6.6 5.8p > 0.3Bias/limitationsCommentsA: strong, B: moderate, C: weak A B CSelection XStudy design XConfounder XBl<strong>in</strong>d<strong>in</strong>g XData collection XWithdraw <strong>and</strong> dropout XAnalyses XIntervention <strong>in</strong>tegrityCases <strong>and</strong> controls classified as private <strong>and</strong> service with more control taken from service careimply<strong>in</strong>g differ SES. Only descriptive statistics given for education. Not adjust<strong>in</strong>g for potentialconfoundersC-178
Whittemore, 1992 [UI# 1476141]Subjects’Study characteristics healthconditionsMean age (range): NDCase-controlCases: NDControls: NDMenopause: mixRace: WhiteEnrolled/Evaluate:Cases: 2197/1071Controls: 8893/5705Location: USASites: 12 studies, ofwhich 7 withbreastfeed<strong>in</strong>g dataFund<strong>in</strong>g: GovernmentStudy design <strong>and</strong> follow-updurationData from 12 studies conductedfrom 1956-1986. 6 hospital <strong>and</strong> 6population (r<strong>and</strong>om-digit dial<strong>in</strong>g)controls.<strong>Breastfeed<strong>in</strong>g</strong> data from 7studies; 2 hospital- <strong>and</strong> 5population-based studiesEligibility criteriaStudies with <strong>in</strong>dividual patient data collectedfrom personal <strong>in</strong>terviews through structuredquestionnaires, data coded <strong>and</strong> storedelectronically, variable def<strong>in</strong>itions documentedCases: newly diagnosed <strong>in</strong>vasive epithelialtumors at US hospitalControls: reside <strong>in</strong> US, dur<strong>in</strong>g time of caseascerta<strong>in</strong>ment, no gynecological condition ifhospital controls<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventions<strong>Breastfeed<strong>in</strong>g</strong> statusdeterm<strong>in</strong>ed by<strong>in</strong>terviewControl Exposuresor Interventions<strong>Breastfeed<strong>in</strong>g</strong>status determ<strong>in</strong>edby <strong>in</strong>terviewC-179
Whittemore, 1992 [UI# 1476141]OutcomeDef<strong>in</strong>itionStatistical analyses <strong>and</strong>confounders adjustedResultsBias/limitationsCommentsInvasiveepithelialtumorsConditional logistic regressionwith odds ratio adjusted for age,study, parity, oral contraceptiveuseHospital-based studies overlap with Hartge 1989Population-based studies overlap with Cramer 1983<strong>Breastfeed<strong>in</strong>g</strong>duration (month)*Casesn (%)Controlsn (%)RRadj(95% CI)Hospital studies0 117 (58) 612 (57) 1.01-5 49 (24) 237 (22) 0.95(0.62-1.5)6-11 13 (6) 110 (10) 0.40†(0.20-0.78)12-23 16 (8) 78 (7) 0.70(0.36-1.4)≥24 6 (3) 44 (4) 0.59(0.22-1.6)Anybreastfeed<strong>in</strong>g84 (42) 469 (43) 0.73(0.51-1.0)Trend per month 0.99p=0.18Population studies0 478 (55) 2152 (47) 1.01-5 208 (24) 1188 (26) 0.87(0.72-1.1)6-11 88 (10) 567 (12) 0.74(0.57-0.96)12-23 61 (7) 449 (10) 0.69(0.51-0.94)≥24 35 (4) 268 (6) 0.74(0.49-1.1)Anybreastfeed<strong>in</strong>g392 (45) 2472 (53) 0.81†(0.68-0.95)Trend per month 0.99†* Parous† p
Wynder, 1969 [UI# 5764976]StudycharacteristicsMean age (range):Cases: 52Controls: NDMenopause: mixRace:Cases:91% White9% BlackControls:94% White6% BlackEnrolled/Evaluate:Cases: 158Controls: 300Location: USASites: MultiFund<strong>in</strong>g:GovernmentSubjects’ healthconditionsSerouscystadenocarc<strong>in</strong>oma 28Pseudo-muc<strong>in</strong>ouscystadenocarc<strong>in</strong>oma 10Endometrioid carc<strong>in</strong>oma 11Solid adenocarc<strong>in</strong>oma 91MiscellaneousGranulose cell tumor 4Teratoma 1Carc<strong>in</strong>oid 1Others 2Unspecified 10Study design <strong>and</strong>follow-up durationCase-controlHospital-basedpopulationData collection by<strong>in</strong>terviewEligibility criteriaEpithelial ovarian cancer confirmed byhistology, functionary or dysontogenetictumors excludedEight additional cases of diagnosis otherthan adenocarc<strong>in</strong>oma <strong>and</strong> endometrioidcancersControls matched for age<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventions<strong>Breastfeed<strong>in</strong>g</strong> statusdeterm<strong>in</strong>ed by <strong>in</strong>terviewControl Exposures orInterventions<strong>Breastfeed<strong>in</strong>g</strong> statusdeterm<strong>in</strong>ed by <strong>in</strong>terviewWynder, 1969 [UI# 5764976]Statistical analysesOutcome Def<strong>in</strong>ition <strong>and</strong> confoundersadjustedEpithelial ovarian NDcancer confirmed byhistologyResultsNo difference between groups for age of first nurs<strong>in</strong>g or never nurs<strong>in</strong>gBF ≥12months158 Cases 300 ControlsPremenopausal(55)Postmenopausal(95)Premenopausal(95)Postmenopausal(205)10% 24% 7% 21%Bias/limitationsCommentsA: strong, B: A B Cmoderate, C: weakSelection XStudy design XConfounder XBl<strong>in</strong>d<strong>in</strong>g XData collection XWithdraw <strong>and</strong>XdropoutAnalyses xIntervention <strong>in</strong>tegrityC-181
Yen, 2003 [UI# 12713998]StudycharacteristicsMedian age(range):Cases: 47 (20-75)Controls: 44 (20-75)Menopause: mixRace: NDEnrolled/Evaluate:Cases: 86Controls: 369Location: TaiwanSites: MultiFund<strong>in</strong>g:GovernmentSubjects’ healthconditionsCases:Serous (27%0Muc<strong>in</strong>ous (27%)Endometrioid (21%)Clear cell (15%)Unspecifiedadenocarc<strong>in</strong>oma (2%)Controls:Trauma (28%)Nontraumaticorthopedic conditions(30%)Surgery (19%)Miscellaneous (23%)medical, eye, nose,throat, dentalStudy design<strong>and</strong> follow-updurationCase-controlData collectionby <strong>in</strong>-hospital<strong>in</strong>terviewEligibility criteriaNewly diagnosed primary <strong>in</strong>vasive epithelial ovarian cancerconfirmed by histology, Taiwan resident for > 20 yearsControls: matched for age, same hospital admission atsame time for nonmalignant, nongynecologic condition,nonhormonal or nondigestive tract diseases, no long termmodification of dietExclusion: major gynecologic operation <strong>in</strong>clud<strong>in</strong>ghysterectomy with or without oophorectomy oroophorectomy only, severe illness<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsBreast feed<strong>in</strong>g statusdeterm<strong>in</strong>ed by<strong>in</strong>terviewControl Exposuresor InterventionsBreast feed<strong>in</strong>g statusdeterm<strong>in</strong>ed by<strong>in</strong>terviewYen, 2003 [UI# 12713998]Outcome Def<strong>in</strong>itionPrimary <strong>in</strong>vasive epithelialovarian cancer confirmed byhistologyStatistical analyses <strong>and</strong>confounders adjustedConditional multivariate logisticregression model adjusted fornumber of live birthResults<strong>Breastfeed<strong>in</strong>g</strong>duration (years)Casesn (%)Controlsn (%)ORadj(95% CI)0 41 (48) 176 (48) 1.0≤1 8 (9) 42 (11) 0.82 (0.35-1.9)>1 37 (43) 151 (41) 0.55 (0.29-1.01)<strong>Breastfeed<strong>in</strong>g</strong> for more than one year is trend for protectionBias/limitationsCommentsA: strong, B: A B Cmoderate, C: weakSelection XStudy design XConfounder XBl<strong>in</strong>d<strong>in</strong>g XData collection XWithdraw <strong>and</strong>XdropoutAnalyses XIntervention<strong>in</strong>tegrityC-182
Appendix C. Evidence TablesPart III. <strong>Maternal</strong> <strong>Outcomes</strong>Postpartum DepressionChaudron 2001Cooper 1993Hannah 1992Henderson 2003Murray 2003Seimyr 2004Warner 1996C-183
Chaudron 2001, [UI# 1446151]Subjects’StudyhealthcharacteristicsconditionsMean age (range):29 yr (SD 4.4)Race: 69% whiteEnrolled/Evaluate:465Location: USSites: MultiFund<strong>in</strong>g:Study design <strong>and</strong> follow-up durationProspective cohort; the study exam<strong>in</strong>ed predictorsof new-onset postpartum depression dur<strong>in</strong>gpostpartum months 1-4; data from the Wiscons<strong>in</strong>Maternity Leave <strong>and</strong> <strong>Health</strong> Project (WMLHP);subjects participated <strong>in</strong> a 90-m<strong>in</strong>ute home<strong>in</strong>terviews dur<strong>in</strong>g the second trimester, <strong>and</strong> at 1 <strong>and</strong>4 months after delivery; both the DIS <strong>and</strong> CES-Dwere adm<strong>in</strong>istered at each <strong>in</strong>terview; DIS questionsabout fatigue <strong>and</strong> sleep were modified to accountfor disturbances caused by night-time <strong>in</strong>fant careEligibility criteriaBetween weeks 12 <strong>and</strong> 25 of a non-highriskpregnancy; >18 yr; non-h<strong>and</strong>icapped;liv<strong>in</strong>g with<strong>in</strong> Milwaukee or Dane counties;liv<strong>in</strong>g with the baby’s father; one of thecouple was employed; had a telephone;spoke English well enough to underst<strong>and</strong><strong>in</strong>terviewer; able to complete questionnaire;not depressed at 1 month postpartum;Excluded subjects who did not completefollow up at 4 months<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsControlExposures orInterventionsChaudron 2001, [UI# 1446151]Statistical analyses <strong>and</strong>Outcome Def<strong>in</strong>itionconfounders adjustedPostpartum depression def<strong>in</strong>edby:1. Diagnosis of majordepression on NIMHDiagnostic InterviewSchedule (DIS) perDSM-III-R criteria2. ≥16 on the Center forEpidemiologic StudiesDepression Scale(CES-D); <strong>and</strong> /or3. receiv<strong>in</strong>gantidepressantsAge, depression dur<strong>in</strong>gpregnancy, postpartumthoughts of death <strong>and</strong> dy<strong>in</strong>g,difficulty fall<strong>in</strong>g asleep (see fulldiscussion <strong>in</strong> paper)Results327/465 breastfed; 27/465 became depressed between 1 <strong>and</strong> 4months;Women who breastfed their <strong>in</strong>fants were not significantly different <strong>in</strong>their development of depression from women who bottlefed their<strong>in</strong>fants. Of those women who were breastfeed<strong>in</strong>g at 1 monthpostpartum (n=327), women who worried about breastfeed<strong>in</strong>g weresignificantly more likely to become depressed than those who did notworry (relative risk 3.0, CI 1.041-9.216, P=0.04)Bias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdraw <strong>and</strong>dropoutAnalyses xIntervention<strong>in</strong>tegrityC-184
Cooper, 1993 [UI# 8463993]Study characteristicsMean age (range):Enrolled/Evaluate: 243women at Oxford; 113 atCambridgeLocation: UKSites: MultiFund<strong>in</strong>g:Subjects’healthconditionsStudy design <strong>and</strong>follow-up duration2 separate prospectivecohort studies (Oxford<strong>and</strong> Cambridge)Eligibility criteriaSee ref 12 <strong>in</strong> paper for criteria forOxford;For Cambridge: primiparous, 20-40yr, had a partner, 37-42 wk gestation,<strong>in</strong>fant ≥ 2.5 Kg, <strong>and</strong> no grosscongenital abnormality<strong>Breastfeed<strong>in</strong>g</strong> Exposures orInterventionsOf those who attempted to <strong>in</strong>itiatebreastfeed<strong>in</strong>g, those who term<strong>in</strong>atedbefore 8 wk were compared with thosewho did notControlExposures orInterventionsCooper, 1993 [UI# 8463993]Outcome Def<strong>in</strong>itionAt Oxford, Present State Exam<strong>in</strong>ation (PSE) was used todeterm<strong>in</strong>e psychiatric symptoms.At Cambridge, prospective subjects were screened at 6wk postpartum us<strong>in</strong>g the Ed<strong>in</strong>burgh Postnatal DepressionScale (EPDS). All high scorers (≥13), 78% of the<strong>in</strong>termediate scorers (10-12), <strong>and</strong> a r<strong>and</strong>om sample of lowscorers (≤ 9) received full psychiatric assessmentbetween 2 <strong>and</strong> 3 months postpartum. 58 who metResearch Diagnostic Criteria (RDC) criteria for major <strong>and</strong>m<strong>in</strong>or depression, <strong>and</strong> 55 who were psychiatrically wellwere <strong>in</strong>terviewed <strong>in</strong> full.At Cambridge, St<strong>and</strong>ardized Psychiatric Interview (SPI)was used.Statisticalanalyses <strong>and</strong>confoundersadjustedSocial class,age, <strong>and</strong>educationResultsAt Oxford, 14/25 subjects (56%) with psychiatric symptomsversus 40/175 subjects (23%) without psychiatric symptomshad given up breastfeed<strong>in</strong>g by 8 wk postpartum (P
Hannah 1992, [UI# 1617360]Subjects’StudyhealthcharacteristicsconditionsMean age ND(range):Evaluated: 231Location: UKSites: MultiFund<strong>in</strong>g:Study design <strong>and</strong> follow-up durationProspective cohort, questionnaires (general questionnaire <strong>and</strong>Ed<strong>in</strong>burgh Postnatal Depression Scale (EPDS)) on 5 th daypostpartum <strong>and</strong> repeat EPDS at 6 weeks postpartumEligibility criteriaWomen who haddelivered a livebabyND<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsControl Exposuresor InterventionsHannah 1992, [UI# 1617360]Outcome Def<strong>in</strong>itionPostpartum depression def<strong>in</strong>ed byEPDS score ≥ 13 at 6 weeks.Statistical analyses <strong>and</strong>confounders adjustedChi-squareResultsAt 6 weeks, 8/26 (31%) women with EPDS score ≥ 13 vs25/200 (12%) women with EPDS < 13 only did bottle feed<strong>in</strong>g(P
Henderson 2003, [UI# 12911800]Subjects’StudyhealthcharacteristicsconditionsMean age (range):Race:Enrolled/Evaluate:1745 enrolledLocation: AustraliaSites: MultiFund<strong>in</strong>g:Study design <strong>and</strong> follow-up durationProspective cohort, population from a RCT on theeffectiveness of maternal debrief<strong>in</strong>g on the <strong>in</strong>cidence ofpostnatal psychological morbidity; self-reportedquestionnaires were completed at 2, 6, <strong>and</strong> 12 monthsafter birth; the questionnaire <strong>in</strong>cluded a measure ofcurrent breastfeed<strong>in</strong>g status; The Ed<strong>in</strong>burgh PostnatalDepression Scale (EPDS) was used to screen forsymptoms of depression at each of the follow-up <strong>in</strong>tervals.All subjects who scored > 12 on the scale, subjects be<strong>in</strong>gtreated for a psychological disorder, subjects tak<strong>in</strong>gantidepressants, <strong>and</strong> a stratified sample of women withlow EPDS scores were offered a diagnostic <strong>in</strong>terview. The<strong>in</strong>terview enabled a diagnosis of depression to be madebased on DSM IV.Eligibility criteriaBefore 72 hr postpartum, given birthto health <strong>in</strong>fants >35 wk gestation,English speak<strong>in</strong>g, >18 yrs, not underpsychological care at the time ofrecruitment; cases were excluded ifno <strong>in</strong>formation about breastfeed<strong>in</strong>gstatus was given at any <strong>in</strong>terval(n=56)<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsPrimary endpo<strong>in</strong>twas duration ofbreastfeed<strong>in</strong>gControlExposures orInterventionsHenderson 2003, [UI# 12911800]Statistical analysesOutcome Def<strong>in</strong>ition <strong>and</strong> confoundersadjustedDiagnosis of depression Adjusted forbased on DSM IV (data demographic, per<strong>in</strong>atal,obta<strong>in</strong>ed from diagnostic <strong>and</strong> postnatal factors<strong>in</strong>terview)Results<strong>Breastfeed<strong>in</strong>g</strong> was <strong>in</strong>itiated by 1670/1745 women (96%); 57% still breastfeed<strong>in</strong>gat 6 months (30% fully); 22% still breastfeed<strong>in</strong>g to some extent at 12 months.314/1745 (18%) developed depression <strong>in</strong> the 12 months after birth, 63%show<strong>in</strong>g the first symptom by 2 months.After adjustment for confound<strong>in</strong>g factors, early cessation of breastfeed<strong>in</strong>g wasfound to be associated with postnatal depression (adjusted hazard ratio 1.25,95% CI 1.03 to 1.52). Onset of postnatal depression occurred before cessationof breastfeed<strong>in</strong>g <strong>in</strong> most cases.Bias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdraw <strong>and</strong> xdropoutAnalyses xIntervention<strong>in</strong>tegrityC-187
Murray, 2003 [UI# 12848402]Study characteristicsMean age (range): 25yr <strong>in</strong> self-exclusiongroup; 28 yr <strong>in</strong> take-upgroupMenopause:pre/post/mixRace: 75 <strong>in</strong> selfexclusiongroup; 81 <strong>in</strong>take-up groupLocation: UKSites: S<strong>in</strong>gle/MultiFund<strong>in</strong>g:Subjects’ healthconditionsHistory of depressionwas common, as werehealth problems, <strong>and</strong>depressed or anxiousmood <strong>in</strong> pregnancyStudy design <strong>and</strong> follow-up durationCohort study; 403 women from a RCT of a preventive<strong>in</strong>tervention for postpartum depression were identified as be<strong>in</strong>ghigh risk for depression from antenatal screen<strong>in</strong>g; 2 groupswere formed; one group from the control arm (rout<strong>in</strong>e care) ofthe RCT was will<strong>in</strong>g to receive additional home-based <strong>Health</strong>Visit<strong>in</strong>g <strong>in</strong> the last 5 weeks of pregnancy <strong>and</strong> the first 8 weekspostpartum; the other group refused the <strong>in</strong>terventionEligibilitycriteriaVulnerable topostpartumdepression perscreen<strong>in</strong>g results<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsControlExposures orInterventionsMurray, 2003 [UI# 12848402]Statistical analyses <strong>and</strong>Outcome Def<strong>in</strong>itionconfounders adjustedPredictive Index forPostpartumDepressionResultsCompar<strong>in</strong>g the self-exclusion group (n=75) with the take-up group (n=81), the <strong>in</strong>fants<strong>in</strong> the self-exclusion group were less likely to be breastfed, both immediately afterbirth (63% vs 83%, P=0.007) <strong>and</strong> at 10 days (31% vs 54%, P=0.01)Bias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdraw <strong>and</strong> xdropoutAnalyses xIntervention<strong>in</strong>tegrityC-188
Seimyr 2004, [UI# 15376402]Subjects’StudyhealthcharacteristicsconditionsMean age (range): 29yr (18-43)Race:Enrolled/Evaluate:352 womenLocation: SwedenSites: MultiFund<strong>in</strong>g:Study design <strong>and</strong> follow-up durationProspective cohort, Ed<strong>in</strong>burgh PostnatalDepression Scale (EPDS) result at 2 monthsbefore childbirth (I), 2 months (II )<strong>and</strong> 12months (III) after childbirthEligibility criteriaAll Swedish speak<strong>in</strong>g pregnantwomen at six antenatal cl<strong>in</strong>ics were<strong>in</strong>vited to participate, with theirpartners or alone<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsControlExposures orInterventionsSeimyr 2004, [UI# 15376402]Statistical analyses <strong>and</strong> confoundersOutcome Def<strong>in</strong>itionadjustedCut-off po<strong>in</strong>t of 9/10 onEPDS scale is used to setthe threshold forvulnerability to depressionDid not report actual adjustment, but reportedthat there was no difference with regards toage, education, parity, <strong>and</strong> length of maritalrelationship between low <strong>and</strong> high-scor<strong>in</strong>gwomenResults63 women (21%) scored high on EPDS at the end ofpregnancy; 54 (17%) at 2 months; 28 (12%) at 12 months.~50% of the high EPDS (I) scorers also scored high on EPDS(II), <strong>and</strong> 39% of those who were high EPDS (II) scorerscont<strong>in</strong>ued to score high on EPDS (III).Fewer high EPDS (I) scorers breastfed compared to the lowscorers (82% vs 94%, P
Warner, 1996 [UI# 8733800]Subjects’StudyhealthcharacteristicsconditionsMean age (range):28 yr (15-46 yr)Race:Eligible/Enrolled:2978/2375Location: UKSites: MultiFund<strong>in</strong>g:ProspectivecohortStudy design <strong>and</strong> follow-up durationRecruited subjects over a 20-month period from twopostnatal wards prior to discharge, subjects agreed to ahome visit 6-8 wk after delivery; Ed<strong>in</strong>burgh PostnatalDepression Scale (EPDS) was completed at the <strong>in</strong>terviewEligibility criteriaLiv<strong>in</strong>g outside the district<strong>and</strong> <strong>in</strong>sufficient English tounderst<strong>and</strong> thequestionnaire<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsControlExposures orInterventionsWarner, 1996 [UI# 8733800]OutcomeStatistical analyses <strong>and</strong> confounders adjustedDef<strong>in</strong>itionEPDS score> 1213 socio-demographic <strong>and</strong> obstetric variables were entered <strong>in</strong>dividually<strong>in</strong>to a logistic regression analysis with high <strong>and</strong> low EPDS as theoutcome variable us<strong>in</strong>g a threshold of 12/13; those variables show<strong>in</strong>g asignificant association with high EPDS scores were entered <strong>in</strong>to astepwise logistic regression analysisResults280/2375 scored >12 on EPDS;Unplanned pregnancy, not breastfeed<strong>in</strong>g at 6 wk(OR 1.52, 95%CI 1.12-2.06), unemployment <strong>in</strong>mother or head of household were associated withan EPDS score >12 <strong>in</strong> a stepwise logistic analysisBias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdraw <strong>and</strong> xdropoutAnalyses xIntervention<strong>in</strong>tegrityC-190
Appendix C. Evidence TablesPart III. <strong>Maternal</strong> <strong>Outcomes</strong><strong>Maternal</strong> WeightBrewer 1989Janney 1997L<strong>in</strong>ne 2003Ohl<strong>in</strong> 1990Olson 2003Sichieri 2003Walker 2004C-191
Brewer 1989 [2916446]StudycharacteristicsMean age (range):Pre-pregnancy BW(range): NDPre-pregnancy BMI(range): NDRace: whiteEnrolled/Evaluate:70/56Location: USSites: S<strong>in</strong>gleFund<strong>in</strong>g:PopulationWell-educated,middle to uppermiddle <strong>in</strong>comerangeStudy design <strong>and</strong> follow-up durationProspective cohort; to study postpartum changes <strong>in</strong> body weight <strong>in</strong>lactat<strong>in</strong>g vs. nonlactat<strong>in</strong>g women up to 6 mo postpartum; mothers werevisited <strong>in</strong> the hospital with<strong>in</strong> 1 to 2 d of delivery <strong>and</strong> at home at 3 <strong>and</strong> 6mo postpartum, weights were objectively measured; detailed <strong>in</strong>formationon <strong>in</strong>fant diet was collected by monthly questionnaires completed by themothers. Mother’s calorie <strong>in</strong>take measured. Three-day maternal foodrecords were also completed at 3 <strong>and</strong> 6 months postpartum. Energy<strong>in</strong>take (kcal) was calculated by computer from food records with theNutritional Analysis System (Louisiana State University, Baton Rouge,LA).EligibilitycriteriaGood health, ≥18 yr, mothersof full term<strong>in</strong>fants<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsControlExposures orInterventionsBrewer 1989 [2916446]Statistical analyses <strong>and</strong>Outcome Def<strong>in</strong>itionconfounders adjustedExclusivebreastfeed<strong>in</strong>g;exclusive formulafeed<strong>in</strong>g; mixed breast<strong>and</strong> formula feed<strong>in</strong>gANCOVA; covariables <strong>in</strong>cludedmaternal age, parity, prepregnancyweight, <strong>in</strong>itial postpartummeasurement for each variable,<strong>and</strong> othersResults“If weight change dur<strong>in</strong>g the first 3 mo is corrected for an <strong>in</strong>itial fluid loss of 2 kg,weight loss averaged 1.6, 2.1, <strong>and</strong> 1.5 kg/mo for exclusive breastfeed,exclusive formula feed, <strong>and</strong> mixed feed, respectively. Exclusive breastfeedresulted <strong>in</strong> an additional 0.43 kg/mo loss over the second 3 mo with mixed feedaverag<strong>in</strong>g a 0.27 kg loss <strong>and</strong> nonlactat<strong>in</strong>g women experienc<strong>in</strong>g essentially nochange.”No significant differences <strong>in</strong> total weight loss were observed between thelactat<strong>in</strong>g <strong>and</strong> non-lactat<strong>in</strong>g groups. Exclusive breastfeed<strong>in</strong>g resulted <strong>in</strong> asignificant decrease <strong>in</strong> weight between 3 <strong>and</strong> 6 months (P < 0.05).Bias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdraw <strong>and</strong>dropoutAnalyses xIntervention<strong>in</strong>tegrityOverall: BxC-192
Janney, 1997 [9356528]Study characteristicsMean age (range): 29.3 (20-40)Pre-pregnancy BW (range):59.7 (43.1-93.0) kgPre-pregnancy BMI (range):22.2 (16.9-33.7) kg/m 2Race: 96% WhiteEnrolled/Evaluate: 110/71Location: USSites: S<strong>in</strong>gleFund<strong>in</strong>g: NDSubjects’healthconditionsStudy design <strong>and</strong>follow-up durationProspective, longitud<strong>in</strong>alstudy(0.5, 2, 4, 6, 12, <strong>and</strong> 18mo post-partum)Eligibility criteriaPregnant nulliparous <strong>and</strong> primiparous womenaged 20-40 y <strong>in</strong> their 3 rd trimester were recruitedfrom birth<strong>in</strong>g education classes <strong>and</strong> obstetricpractices. To be eligible for participation, thewomen must have declared either that they hadno <strong>in</strong>tention of breastfeed<strong>in</strong>g or that they <strong>in</strong>tendedto breast-feed for >= 6 months.Exclusion criteria were a history of endocr<strong>in</strong>e,renal, liver, or chronic respiratory illness;complications of pregnancy, <strong>in</strong>clud<strong>in</strong>g HTN <strong>and</strong>GDM; fetal complications or complications atdelivery; delivery of an <strong>in</strong>fant small for gestationalage; <strong>and</strong> delivery of tw<strong>in</strong>s.<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsFully breast-feed<strong>in</strong>g wasdef<strong>in</strong>ed as provid<strong>in</strong>g atleast 2/3 of the neededenergy <strong>in</strong>take per kilogramof the <strong>in</strong>fant’s weight <strong>in</strong>breast milk. See article forhow this estimation wasmade.ControlExposures orInterventionsPartly breastfeed<strong>in</strong>gorbottle-fedJanney, 1997 [9356528]StatisticalOutcome analyses <strong>and</strong>Def<strong>in</strong>ition confoundersadjustedPostpartumweightretentionover timeLongitud<strong>in</strong>alregressionanalysis: procmixed <strong>and</strong> glmproceduresResultsMost women (66.7%) fully breastfed for 6 mo.Duration of lactation practice was a significant predictor of postpartum weight retention over time -(P
Janney, 1997 [9356528]StatisticalOutcome analyses <strong>and</strong>Def<strong>in</strong>ition confoundersadjustedResultsThe follow<strong>in</strong>g data were estimated from Figure 5 <strong>in</strong> the orig<strong>in</strong>al paper:1) Time returned to prepregnancy weights:Bottle-feed<strong>in</strong>g only: ~18 months postpartumPartly breast-feed<strong>in</strong>g at 2 mo, <strong>and</strong> bottle-feed<strong>in</strong>g or <strong>in</strong>fant weaned at 4, 6, 12, <strong>and</strong> 18 months:~12 months postpartumFully breast-feed<strong>in</strong>g for 6 month <strong>and</strong> bottle-feed<strong>in</strong>g or <strong>in</strong>fant weaned at 12 <strong>and</strong> 18 month: ~11months postpartumFully breastfeed<strong>in</strong>g for 6 month, partly breast-feed<strong>in</strong>g for 12 month, <strong>and</strong> bottle-feed<strong>in</strong>g or <strong>in</strong>fantweaned at 18 month: ~ 10 months postpartum2) Weight retention at 6 months postpartum:Fully breastfeed<strong>in</strong>g for 6 months (n=57): ~ +3 kgPartly breastfeed<strong>in</strong>g at 2 month <strong>and</strong> bottle-feed<strong>in</strong>g at 4 <strong>and</strong> 6 months (n=10): ~ +3.5 kgFully bottle-feed<strong>in</strong>g for 6 months (n=12): ~ +5 kgBias/limitationsCommentsA: strong, B: A B Cmoderate, C: weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>gData collection xWithdraw <strong>and</strong>xdropoutAnalyses xIntervention <strong>in</strong>tegrityOverall: BC-194
L<strong>in</strong>ne, 2003 [14634683]StudycharacteristicsMean age (range):45 yr (at 15 yr followup)Pre-pregnancy BW(range): 59.8 kgPre-pregnancy BMI(range): 21.5 kg/m 2Race:Enrolled/Evaluate:1423/563 (at 15 yr)Location:StockholmSites: MultiFund<strong>in</strong>g:PopulationCross section of themetropolitan populationfrom both <strong>in</strong>ner city ofStockholm <strong>and</strong> itssuburbs; a range ofsocioeconomic groupsStudy design <strong>and</strong> follow-up durationProspective cohort; longitud<strong>in</strong>al study of women’sweight ga<strong>in</strong> dur<strong>in</strong>g pregnancy, at 1 yr postpartum<strong>and</strong> at 15 yr follow up; feed<strong>in</strong>g data were collectedretrospectively by questionnaires at 2.5, 6, 12 mo<strong>and</strong> at 15 yr; for women who still lived <strong>in</strong> theStockholm area, weights were measured <strong>in</strong> theUniversity hospital (n=363); for women who lived faraway, weights were self-reported (n=200)Eligibilitycriteria2 outlierswereexcluded: BMIof 47; firstchild at 49 yr<strong>Breastfeed<strong>in</strong>g</strong> Exposures orInterventionsMeasured by lactation score:every month of full lactation wasgiven 4 po<strong>in</strong>ts, every month ofmixed lactation was given 2po<strong>in</strong>ts; total sum (0-48)<strong>in</strong>dicated the <strong>in</strong>dividual lactationamountControlExposures orInterventionsL<strong>in</strong>ne, 2003 [14634683]OutcomeStatistical analyses <strong>and</strong> confounders adjustedDef<strong>in</strong>itionOverweight (BMI >25), normal weight(BMI 20-25);ANOVA was used to analyze weight change at four time po<strong>in</strong>ts;women who were overweight at prepregnancy <strong>and</strong> at follow up<strong>and</strong> those who lost weight <strong>and</strong> rega<strong>in</strong>ed a BMI <strong>in</strong> the normalrange at 15 yr were excluded from the analysisResultsThose women who became overweight hadlower lactation scores than women whorema<strong>in</strong>ed normal weight at 15 years follow up(21.7 ± 11.0 vs. 24.0 ± 9.4, t=2.25, df = 488,P < 0.05).Responders were slightly older, had highereducational atta<strong>in</strong>ment, <strong>and</strong> higher <strong>in</strong>comethan non-responders. Nonresponse wasmore common <strong>in</strong> non-Nordic citizens.Bias/limitationsCommentsA: strong, B:A B Cmoderate, C: weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdraw <strong>and</strong> dropout xAnalyses xIntervention <strong>in</strong>tegrityOverall: CC-195
Ohl<strong>in</strong>, 1990 [2341224]; Ohl<strong>in</strong>, 1996 [8732961]Subjects’StudyStudy design <strong>and</strong>healthcharacteristicsfollow-up durationconditionsMean age (range):29.5 (17-49)Pre-pregnancy BW(range): 59.6 (39-129) kgPre-pregnancy BMI(range): 21.5 (15.4-43.0) kg/m 2Race: NDEnrolled/Evaluate:2295 (at 2 mo) /1423(at 1 yr)Location: SwedenSites: MultiFund<strong>in</strong>g:GovernmentWomen were studiedretrospectively dur<strong>in</strong>gpregnancy at maternitycl<strong>in</strong>ics, <strong>and</strong> monitoredprospectively up to 1 yearafter delivery.Eligibility criteriaAll mothers who, dur<strong>in</strong>g one year, came tothe maternity cl<strong>in</strong>ic for the last rout<strong>in</strong>econtrol, i.e. 6-15 weeks after the delivery,were <strong>in</strong>vited by their midwives to take part <strong>in</strong>the study. Women who were go<strong>in</strong>g to movewith<strong>in</strong> a short time <strong>and</strong> those with obviouslanguage <strong>and</strong> communication problemswere not <strong>in</strong>vited.Exclusion: tw<strong>in</strong> births, use of <strong>in</strong>sul<strong>in</strong> dur<strong>in</strong>gpregnancy, GI problems with severe energylosses (heavy vomit<strong>in</strong>g or diarrhea) <strong>and</strong> prepregnantbody weights were not available.<strong>Breastfeed<strong>in</strong>g</strong> Exposures orInterventionsLactation score: a scor<strong>in</strong>g system wasconstructed <strong>in</strong> order to express duration<strong>and</strong> <strong>in</strong>tensity of breast feed<strong>in</strong>g. Everymonth with full lactation was given 4po<strong>in</strong>ts, <strong>and</strong> every month with mixedfeed<strong>in</strong>g was given 2 po<strong>in</strong>ts. The totalsum (0-48) <strong>in</strong>dicated the <strong>in</strong>dividuallactation amount.ControlExposures orInterventionsOhl<strong>in</strong>, 1990 [2341224]; Ohl<strong>in</strong>, 1996 [8732961]Statistical analysesOutcome<strong>and</strong> confoundersDef<strong>in</strong>itionadjustedThe body weight1 year afterdelivery (∆weight)Ranged <strong>in</strong>fluence ofdifferent factors onthe ∆ weight wasanalyzed by amultiple stepwiseregression analysisResults30% lost weight, 56% ga<strong>in</strong> 0-5 kg, 13% ga<strong>in</strong>ed 5-10 kg <strong>and</strong> 1.5% ga<strong>in</strong>ed >=10 kg 1 yearafter delivery. Frequency of overweight women (BMI>=23.9) <strong>in</strong>creased from 13% beforepregnancy to 21% 1 year post-partum (p
Olson, 2003 [12532163]Study characteristics Population Study design <strong>and</strong> follow-up durationMean age (range):Pre-pregnancy BW (range):kgPre-pregnancy BMI(range): kg/m 2Race: white (96%)Enrolled/Sample/Evaluate:622/597/540Location: USSites: S<strong>in</strong>gleFund<strong>in</strong>g:Rural, socioeconomicallydiverseProspective cohort; to study the relative importance ofgestational weight ga<strong>in</strong>, postpartum exercise, food<strong>in</strong>take <strong>and</strong> breastfeed<strong>in</strong>g to weight change from earlypregnancy to 1 yr postpartum; weight was measuredat antenatal <strong>and</strong> 1 yr postpartum visit (varied between9 <strong>and</strong> 19 mo); 32/540 self-reported weight at 1 yr;breastfeed<strong>in</strong>g data collected at 6 wk obstetric visit; 6mo <strong>and</strong> 1 yr questionnaires.Food frequency questionnaires were completed at 1 stor 2 nd trimester of pregnancy, 6 months postpartum,<strong>and</strong> 1 yr postpartum.Eligibilitycriteria≥ 18 yr;healthy, gavebirth to fullterms<strong>in</strong>gletons<strong>Breastfeed<strong>in</strong>g</strong> Exposures orInterventions<strong>Breastfeed<strong>in</strong>g</strong> after 6 mo wasconsidered to be non-exclusive; abreastfeed<strong>in</strong>g score similar to Ohl<strong>in</strong><strong>and</strong> Rossner’s was constructed: 1po<strong>in</strong>t for each wk of exclusivebreastfeed<strong>in</strong>g <strong>and</strong> 0.5 po<strong>in</strong>t foreach wk of mixed feed<strong>in</strong>gControlExposures orInterventionsOlson, 2003 [12532163]Outcome Def<strong>in</strong>ition Statistical analyses <strong>and</strong> confounders adjusted ResultsWeight change from earlypregnancy to 1 yrpostpartum; major weightga<strong>in</strong> was def<strong>in</strong>ed as ≥4.55 kg at 1 yrpostpartumUnivariate <strong>and</strong> multiple l<strong>in</strong>ear regression; weights taken between 9<strong>and</strong> 19 mo were eligible for <strong>in</strong>clusion, actual number of mopostpartum at the measurement of the “1 yr postpartum body weight”was entered <strong>in</strong>to all of the regression models; variables <strong>in</strong> the <strong>in</strong>itialmodel <strong>in</strong>cluded age, education, smok<strong>in</strong>g status, <strong>in</strong>come, maritalstatus, prepregnancy BMI category <strong>and</strong> parity; 3 subjects with poorfit were removed from the analysis; a model reduction method wasapplied at the 10% significance level to produce an <strong>in</strong>clusive,reduced modelUs<strong>in</strong>g food frequency data, the difference <strong>in</strong> the daily energy <strong>in</strong>takefrom 6 months to 1 yr postpartum was calculated for each woman.The Wilcoxon rank sum test was used to assess change <strong>in</strong> total dailyenergy <strong>in</strong>take across the five categories of self-reported behaviorchange <strong>in</strong> amount of food <strong>in</strong>take.Only the 597 women who delivered fullterm <strong>in</strong>fants were <strong>in</strong>cluded <strong>in</strong> the sample;540 had 1 yr weight recorded;Women who were breastfeed<strong>in</strong>g at 1 yrreta<strong>in</strong>ed less weight compared with thewomen who weren’t (P = 0.04).<strong>Breastfeed<strong>in</strong>g</strong> at all other time po<strong>in</strong>ts <strong>and</strong>the breastfeed<strong>in</strong>g score were notsignificantly related to postpartum weightretention.Bias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xDataxcollectionWithdraw <strong>and</strong> xdropoutAnalyses xIntervention<strong>in</strong>tegrityOverall: BC-197
Sichieri, 2003 [12821967]Study characteristicsMean age (range): 24-40 yrPre-pregnancy BW (range):Stratified by BMI atbasel<strong>in</strong>ePre-pregnancy BMI (range):% BMI < 25kg/m 2 <strong>in</strong> 1989: 81.5%BW mean, ALL: 58.0 kgs% BMI > 25kg/m 2 <strong>in</strong> 1989: 18.5%BW mean, ALL: 80.4 kgsRace: NDEnrolled/Evaluate:1,538/1,538 nulliparous at basel<strong>in</strong>e; 2,810/2,810primiparous at basel<strong>in</strong>eLocation: USASites: S<strong>in</strong>gle/Multi: mailed questionnaireFund<strong>in</strong>g: Supported by FundaCBoCAPESCoordenaq20 de Aperfeicoamentode Pessoal de Nivel Superior <strong>and</strong> Boston ObesityNutrition Research Center (DK 46200)Subjects’ healthconditionsNone documentedStudy design <strong>and</strong> follow-updurationThe cohort of the Nurse's <strong>Health</strong>Study II, with analysis restricted towomen who were aged 24 to 40 y atbasel<strong>in</strong>e (1989), who had a history ofno more than one past full-termpregnancy at basel<strong>in</strong>e, gave birth toone child between 1990 <strong>and</strong> 1991, buthad no other pregnancies dur<strong>in</strong>g thefollow-up. SUBJECTS: 1,538 of the33,082 nulliparous women <strong>and</strong> 2,810of the 20,261 primiparous, <strong>in</strong> 1989.The NHS II Cohort has been followedup every 2 yr to ascerta<strong>in</strong> <strong>in</strong>cidentdiseases <strong>and</strong> exposures <strong>in</strong>clud<strong>in</strong>gparity <strong>and</strong> body weight.Individual breastfeed<strong>in</strong>g data werecollected retrospectively <strong>in</strong> the 1997follow-up. Women were asked torecall their lifetime breastfeed<strong>in</strong>ghistory.Eligibility criteriaExcluded fromanalysis: those whoreported use of<strong>in</strong>sul<strong>in</strong>, hypoglycemicdrugs, or thyroiddisease at basel<strong>in</strong>eor followup wereexcluded fromanalysis<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsControlExposures orInterventionsFor each birth, women were askedif they had breastfed for at least amonth <strong>and</strong> if so they were asked toreport the month <strong>in</strong> which they<strong>in</strong>troduced the formula.Introduction of daily formula/milkwas assumed to represent the endof exclusive breastfeed<strong>in</strong>g period.Duration of exclusivebreastfeed<strong>in</strong>g was categorized <strong>in</strong>to0, 1-3, 4-7, 8-11, <strong>and</strong> 12 months ormore.Exclusive breastfeed<strong>in</strong>g: Womenwere asked to recall their lifetimebreastfeed<strong>in</strong>g history. They wereasked to answer 2 questions: 1)“Did you breastfeed at least onemonth?” 2) “Which month did you<strong>in</strong>troduce formula?” If the answerto the 1 st questions was “no, not atall”, the duration was considered tobe zero. Data from these 2questions were comb<strong>in</strong>ed withparity data from 1991 <strong>and</strong> 1993questionnaires.C-198
Outcome Def<strong>in</strong>ition Statistical analyses <strong>and</strong> confounders adjusted ResultsTo assess whether women whobreastfed were different <strong>in</strong>terms of their weight changesthan women who did not, weightchange from prepregnancy (<strong>in</strong>1989) to postpregnancy(<strong>in</strong> 1993) was estimatedaccord<strong>in</strong>g to exclusivebreastfeed<strong>in</strong>g duration us<strong>in</strong>gl<strong>in</strong>ear regression models.The longitud<strong>in</strong>al models were based on mixed effectsanalysis. These models permitted the authors to testdifferences <strong>in</strong> prepregnancy weight at basel<strong>in</strong>e (group effect),weight ga<strong>in</strong> with pregnancy (time-dependent effect of periodI), <strong>and</strong> weight change after pregnancy (time-dependent effectof period II) by breastfeed<strong>in</strong>g status. If breastfeed<strong>in</strong>g groupsdiffered at basel<strong>in</strong>e but had the same change <strong>in</strong> weightdur<strong>in</strong>g follow-up, a group effect but not a time-dependenteffect would be seen.After adjust<strong>in</strong>g for age, physicalactivity, <strong>and</strong> BMI, lactation was associatedwith a weight ga<strong>in</strong> from 1989 to 1993 ofapproximately 1 kg (statistically significantonly for women nulliparous <strong>in</strong> 1989 with aBMI 0.40 forall comparisons).<strong>Maternal</strong> weight change associatedwith breastfeed<strong>in</strong>g is m<strong>in</strong>imal amongnormal weight women, <strong>and</strong> for overweightwomen the weight ga<strong>in</strong>ed <strong>in</strong> pregnancy Isnot reduced by breastfeed<strong>in</strong>g.Bias/limitationsCommentsA: strong, B: A B Cmoderate, C: weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData collection xWithdraw <strong>and</strong>xdropoutAnalyses xIntervention<strong>in</strong>tegrityOverall: BC-199
Walker, 2004 [15778139]Study characteristicsMean age (range): ND (>18 yr)Pre-pregnancy BW (range): NDPre-pregnancy BMI (range): NDRace: 26% African American, 44%Hispanic, 30% WhiteEnrolled/Evaluate: ND/382Location: USSites: S<strong>in</strong>gleFund<strong>in</strong>g: GovernmentSubjects’healthconditionshealthyStudy design <strong>and</strong> follow-updurationProspective, longitud<strong>in</strong>al cohort(post-delivery, <strong>and</strong> 6 wk, <strong>and</strong> 3,6, <strong>and</strong> 12 months postpartum).Energy <strong>in</strong>takes were measuredat above times by average ofone 24-hour recall <strong>and</strong> two foodrecords at each observation. Fat<strong>in</strong>takes measured by FoodHabits Questionnaire (Kristal,1990).Eligibility criteria<strong>Health</strong>y women, s<strong>in</strong>gletonpregnancies with prenatalcare funded throughMedicaid; had a parity notexceed<strong>in</strong>g III; wereconversant <strong>in</strong> English; <strong>and</strong>were age 18 or higher.<strong>Breastfeed<strong>in</strong>g</strong>Exposures orInterventionsControl Exposures orInterventionsFull (exclusive) or partial breastfeed<strong>in</strong>g, or bottlefeed<strong>in</strong>g, measured at post-delivery, 6 wk, <strong>and</strong> 3, 6,<strong>and</strong> 12 months postpartumWalker, 2004 [15778139]OutcomeDef<strong>in</strong>itionPostpartumBMIStatistical analyses <strong>and</strong> confoundersadjustedGeneral l<strong>in</strong>ear mixed models, alsoknown as hierarchical l<strong>in</strong>ear models,were used.Forward additive method (or forwardselection) was used to select variablesfor <strong>in</strong>clusion <strong>in</strong> the model.Results<strong>Infant</strong> feed<strong>in</strong>g method was not associated with postpartum BMI (p=0.140) whenethnicity, time, pre-pregnant BMI <strong>and</strong> a bunch of other variables (such as parity,gestational weight ga<strong>in</strong>, Cesarean section, etc) were <strong>in</strong>cluded <strong>in</strong> the model.Bias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>gData collection xWithdraw <strong>and</strong>xdropoutAnalyses xIntervention<strong>in</strong>tegrityOverall: BC-200
Appendix C. Evidence TablesPart III. <strong>Maternal</strong> <strong>Outcomes</strong>Type 2 DMStuebe 2005C-201
Stuebe, 2005 [16304074]Subjects’StudyhealthcharacteristicsconditionsMean age (range): ND52 at follow-upMenopause: mixRace: NDEnrolled/Evaluate:see resultsLocation: USSites: MultiFund<strong>in</strong>g:GovernmentStudy design<strong>and</strong> follow-updurationProspective,longitud<strong>in</strong>alstudyEligibility criteriaThe Nurses’ <strong>Health</strong> Studies consist of 2large cohorts enrolled <strong>in</strong> prospective,longitud<strong>in</strong>al studies of women’s healthThe Nurses’ <strong>Health</strong> Study (NHS) was<strong>in</strong>itiated <strong>in</strong>1976 <strong>and</strong> enrolled 121,700 womenfrom 11 states. Participants were between 30<strong>and</strong> 55 years of age at basel<strong>in</strong>e, <strong>and</strong> eachwoman completed a detailed basel<strong>in</strong>equestionnaire regard<strong>in</strong>g diseases <strong>and</strong> healthrelated topics.The second cohort, the Nurses’ <strong>Health</strong> StudyII (NHS II), began <strong>in</strong> 1989, enroll<strong>in</strong>g 116,671women from 14 states. Participants werebetween 25 <strong>and</strong> 42 years of age <strong>and</strong> completeda similar basel<strong>in</strong>e questionnaire as well asbiennial follow-up questionnaires.<strong>Breastfeed<strong>in</strong>g</strong> Exposures orInterventionsControl Exposures orInterventionsWomen <strong>in</strong> the Nurses’ <strong>Health</strong> Studies (NHS) reported parity atbasel<strong>in</strong>e <strong>in</strong> 1976. Lactation history was assessed once, <strong>in</strong> 1986,when women were asked to report total lifetime duration lactation.In NHS II, women reported the number of pregnancies last<strong>in</strong>gmore than 5 months at basel<strong>in</strong>e <strong>and</strong> on each biennial questionnaire.Lactation history was assessed 3 times. In 1993, 1997, <strong>and</strong> 2003.Information on parity was used to derive retrospectively eachparticipant’s total cumulative lactation at each 2-year <strong>in</strong>terval.Total duration of lactation was calculated based on the number ofmonths after birth that the participant reported stopp<strong>in</strong>gbreastfeed<strong>in</strong>g altogether. Us<strong>in</strong>g the 1997 <strong>and</strong> 2003 NHS II data,duration of exclusive lactation could be calculated based on thereported tim<strong>in</strong>g of <strong>in</strong>troduction of formula or solid food.C-202
Stuebe, 2005 [16304074]Outcome Def<strong>in</strong>itionAscerta<strong>in</strong>ment of Type 2 DiabetesMellitusA case of diabetes was confirmed if a womanreported 1 of the follow<strong>in</strong>g: (1) 1 or more classicsymptoms plus either a fast<strong>in</strong>g glucose of ≥140mg/dL or r<strong>and</strong>om plasma glucose ≥ 200 mg/dL; (2) at least 2 <strong>in</strong>stances of elevated plasmaglucose concentration (fast<strong>in</strong>g glucose ≥140mg/dL, r<strong>and</strong>om plasma glucose ≥200 mg/dL, ororal glucose tolerance test ≥200 mg/dL after 2hours) on different occasions <strong>in</strong> the absence ofsymptoms; or (3) treatment with <strong>in</strong>sul<strong>in</strong> or anoral hypoglycemic agent.The criteria for diagnosis of diabetes changed<strong>in</strong> 1997, when a fast<strong>in</strong>g glucose level of ≥126mg/dL was made the diagnostic threshold.Ascerta<strong>in</strong>ment of Gestational DiabetesWomen <strong>in</strong> the NHS II were asked to reportthe diagnosis of gestational diabetes on eachbiennial questionnaire. To validate the study’sdiagnostic criteria, 20,422 participantscompleted a detailed questionnaire, <strong>and</strong> 92%corroborated their diagnosis. A review ofmedical records for 120 of these womenStatistical analyses <strong>and</strong> confoundersadjustedLifetime lactation history among parouswomen was stratified <strong>in</strong>to 6 groups: None(referent), > 0 to 3 mo, > 3 to 6 mo, > 6 to 11mo,> 11 to 23 mo, <strong>and</strong> > 23 mo. In the NHS,lactation <strong>in</strong>formation was used from the 1986questionnaire. In the NHS II analysis,lactation history was derived from selfreportedpregnancies assessed every 2years <strong>and</strong> lactation reports <strong>in</strong> 1997 <strong>and</strong> 2003.Lifetime duration was updated every 2 years.L<strong>in</strong>ear trend was assessed us<strong>in</strong>gmidpo<strong>in</strong>ts of lactation categories.All models were age-adjusted. Potentialconfounders, <strong>in</strong>clud<strong>in</strong>g parity, body mass<strong>in</strong>dex at age 18 years, diet, physical activity,family history of diabetes, <strong>and</strong> smok<strong>in</strong>gstatus, were <strong>in</strong>cluded <strong>in</strong> the multivariatemodel.ResultsIn the NHS cohort, 83,585 parous womenreported lifetime duration of lactation; ofthese, 64% had ever breastfed. In the NHS IIcohort, 73,418 parous women reportedduration of lactation, <strong>and</strong> 85% had everbreastfed.In the NHS, women who had everbreastfed had a covariate-adjusted HR fortype 2 diabetes of 0.97 (95%CI 0.91 - 1.02)compared with women who never breastfed.There was a modest but statisticallysignificant <strong>in</strong>verse association betweenduration of lactation <strong>and</strong> the risk of type 2diabetes. In the multivariate-adjusted model<strong>in</strong>clud<strong>in</strong>g current BMI, each additional year oflactation was associated with an HR of 0.96(95%CI 0.92 - 0.99) for type 2 diabetes.Among women who had ever breastfed <strong>in</strong>the NHS II, the covariate-adjusted HR fortype 2 diabetes was 0.90 (95%CI 0.77 -1.04). Each year of lactation was associatedwith a covariate-adjusted HR of 0.84 (95%CI0.78 - 0.89). When BMI was added to thismodel, the HR was 0.88 (95%CI 0.82 - 0.94)Bias/limitationsCommentsA: strong, B: A B Cmoderate, C:weakSelection xStudy design xConfounder xBl<strong>in</strong>d<strong>in</strong>g xData xcollectionWithdraw x<strong>and</strong> dropoutAnalyses xIntervention<strong>in</strong>tegrityOverall: AC-203
Outcome Def<strong>in</strong>itionconfirmed def<strong>in</strong>ite or probable gestationaldiabetes <strong>in</strong> 94%. To assess screen<strong>in</strong>g forgestational diabetes, a r<strong>and</strong>om sample of 100study participants was surveyed, of whom 83%reported undergo<strong>in</strong>g a 50-g, 1-hour glucosechallenge test. Gestational diabetes history wasnot assessed <strong>in</strong> the NHS cohort.Statistical analyses <strong>and</strong> confoundersadjustedResultsfor each additional year of lactation.Women with a history of GDM had an<strong>in</strong>creased risk of type 2 diabetes <strong>in</strong> the NHSII cohort, with 624 cases per 100,000 personyears compared with 118 cases per 100,000person-years among those without such ahistory. Lactation had no effect on diabetesrisk <strong>in</strong> the GDM group, with a covariateadjustedHR of 0.96 (95% CI 0.84 - 1.09) peradditional year of lactation.The effects of exclusive versus totalbreastfeed<strong>in</strong>g could be compared <strong>in</strong> the NHSII cohort data. In models controll<strong>in</strong>g for age<strong>and</strong> parity, each year of lifetime exclusivebreastfeed<strong>in</strong>g was associated with an HR fortype 2 diabetes of 0.63 (95%CI 0.54 - 0.73),while each year of total breastfeed<strong>in</strong>g wasassociated with an HR of 0.76 (95%CI 0.71 -0.81).Bias/limitationsCommentsC-204
Appendix D. List of Excluded StudiesAbouSaleh MT, Ghubash R, Karim L, et al. Hormonalaspects of postpartum depression.Psychoneuroendocr<strong>in</strong>ology 1998 Jul;23(5):465-75.Develop<strong>in</strong>g countryAbuSabha R, Greene G. Body weight, bodycomposition, <strong>and</strong> energy <strong>in</strong>take changes <strong>in</strong>breastfeed<strong>in</strong>g mothers. J Hum Lact 1998Jun;14(2):119-24. Non-comparative studyAdair LS, Pollitt E, Mueller WH. <strong>Maternal</strong>anthropometric changes dur<strong>in</strong>g pregnancy <strong>and</strong>lactation <strong>in</strong> a rural Taiwanese population. Hum Biol1983 Dec;55(4):771-87. Non-comparative studyAff<strong>in</strong>ito P, Tommaselli GA, di Carlo C, et al. Changes<strong>in</strong> bone m<strong>in</strong>eral density <strong>and</strong> calcium metabolism <strong>in</strong>breastfeed<strong>in</strong>g women: a one year follow-up study. JCl<strong>in</strong> Endocr<strong>in</strong>ol Metab 1996 Jun;81(6):2314-8. Lessthan 1 year follow-upAlder E, Bancroft J. The relationship between breastfeed<strong>in</strong>g persistence, sexuality <strong>and</strong> mood <strong>in</strong> postpartumwomen. Psychol Med 1988 May;18(2):389-96.N
Bradshaw MK, Pfeiffer S. Feed<strong>in</strong>g mode <strong>and</strong>anthropometric changes <strong>in</strong> primiparas. Hum Biol1988 Apr;60(2):251-61. Insufficient sample sizeButte NF, Garza C, Stuff JE, et al. Effect of maternaldiet <strong>and</strong> body composition on lactational performance.Am J Cl<strong>in</strong> Nutr 1984 Feb;39(2):296-306. NoncomparativestudyButte NF, Hopk<strong>in</strong>son JM. Body composition changesdur<strong>in</strong>g lactation are highly variable among women.[Review] [45 refs]. J Nutr 1998Feb;128(2:Suppl):Suppl-385S. ReviewCarranza-Lira S, Mera JP. Influence of number ofpregnancies <strong>and</strong> total breast-feed<strong>in</strong>g time on bonem<strong>in</strong>eral density. Int J Fertil Womens Med 2002Jul;47(4):169-71. Develop<strong>in</strong>g countryChan GM, Ronald N, Slater P, et al. Decreased bonem<strong>in</strong>eral status <strong>in</strong> lactat<strong>in</strong>g adolescent mothers. JPediatr 1982 Nov;101(5):767-70. Less than 1 yearfollow-upChan SM, Nelson EA, Leung SS, et al. Bone m<strong>in</strong>eraldensity <strong>and</strong> calcium metabolism of Hong KongCh<strong>in</strong>ese postpartum women--a 1-y longitud<strong>in</strong>al study.Eur J Cl<strong>in</strong> Nutr 2005 Jul;59(7):868-76. Less than 1year follow-upChang-Claude J, Eby N, Kiechle M, et al.<strong>Breastfeed<strong>in</strong>g</strong> <strong>and</strong> breast cancer risk by age 50 amongwomen <strong>in</strong> Germany. Cancer Causes Control 2000Sep;11(8):687-95. Pre 2001Coit<strong>in</strong>ho DC, Sichieri R, qu<strong>in</strong>o Benicio MH. Obesity<strong>and</strong> weight change related to parity <strong>and</strong> breast-feed<strong>in</strong>gamong parous women <strong>in</strong> Brazil. Public <strong>Health</strong> Nutr2001 Aug;4(4):865-70. Develop<strong>in</strong>g countryCox JL, Chapman G, Murray D, et al. Validation ofthe Ed<strong>in</strong>burgh Postnatal Depression Scale (EPDS) <strong>in</strong>non-postnatal women. J Affect Disord 1996 Jul29;39(3):185-9. Reference, not relevantCox JL, Connor Y, Kendell RE. Prospective study ofthe psychiatric disorders of childbirth. Br J Psychiatry1982 Feb;140:111-7. N
F<strong>in</strong>deisen M, Vennemann M, Br<strong>in</strong>kmann B, et al.German study on sudden <strong>in</strong>fant death (GeSID):design, epidemiological <strong>and</strong> pathological profile. Int Jof Legal Med 2004 Jun;118(3):163-9. Duplicate dataof Venneman 2005Fituch CC, Palkowetz KH, Goldman AS, et al.Concentrations of IL-10 <strong>in</strong> preterm human milk <strong>and</strong> <strong>in</strong>milk from mothers of <strong>in</strong>fants with necrotiz<strong>in</strong>genterocolitis. Acta Paediatr 2004 Nov;93(11):496-500. Not relevantFlorey CD, Leech AM, Blackhall A. <strong>Infant</strong> feed<strong>in</strong>g<strong>and</strong> mental <strong>and</strong> motor development at 18 months ofage <strong>in</strong> first born s<strong>in</strong>gletons.[see comment]. Int JEpidemiol 1995;24 Suppl 1:S21-S26. Included <strong>in</strong>systematic reviewFox KM, Magaz<strong>in</strong>er J, Sherw<strong>in</strong> R, et al. Reproductivecorrelates of bone mass <strong>in</strong> elderly women. Study ofOsteoporotic Fractures Research Group. J BoneM<strong>in</strong>er Res 1993 Aug;8(8):901-8. Cross-sectionalstudyFregene A, Newman LA. Breast cancer <strong>in</strong> sub-Saharan Africa: how does it relate to breast cancer <strong>in</strong>African-American women? Cancer 2005 Apr15;103(8):1540-50. Develop<strong>in</strong>g countryFurberg H, Newman B, Moorman P, et al. Lactation<strong>and</strong> breast cancer risk. Int J Epidemiol 1999Jun;28(3):396-402. Pre 2001Gale CR, Martyn CN. <strong>Breastfeed<strong>in</strong>g</strong>, dummy use, <strong>and</strong>adult <strong>in</strong>telligence.[see comment]. Lancet 1996 Apr20;347(9008):1072-5. Included <strong>in</strong> systematic reviewGaller JR, Ramsey FC, Harrison RH, et al. Postpartummaternal moods <strong>and</strong> <strong>in</strong>fant size predict performanceon a national high school entrance exam<strong>in</strong>ation. JChild Psychol Psychiatry 2004 Sep;45(6):1064-75. Nooutcomes of <strong>in</strong>terestGao YT, Shu XO, Dai Q, et al. Association ofmenstrual <strong>and</strong> reproductive factors with breast cancerrisk: results from the Shanghai Breast Cancer Study.Int J Cancer 2000 Jul 15;87(2):295-300. Develop<strong>in</strong>gcountryGeervani P, Jayashree G. A study on nutritional statusof adolescent <strong>and</strong> adult pregnant <strong>and</strong> lactat<strong>in</strong>g women<strong>and</strong> growth of their <strong>in</strong>fants. J Trop Pediatr 1988Oct;34(5):234-7. Develop<strong>in</strong>g countryGhannam NN, Hammami MM, Bakheet SM, et al.Bone m<strong>in</strong>eral density of the sp<strong>in</strong>e <strong>and</strong> femur <strong>in</strong>healthy Saudi females: relation to vitam<strong>in</strong> D status,pregnancy, <strong>and</strong> lactation. Calcif Tissue Int 1999Jul;65(1):23-8. Cross-sectional study, develop<strong>in</strong>gcountryGillil<strong>and</strong> FD, Hunt WC, Baumgartner KB, et al.Reproductive risk factors for breast cancer <strong>in</strong> Hispanic<strong>and</strong> non-Hispanic white women: the New MexicoWomen's <strong>Health</strong> Study. Am J Epidemiol 1998 Oct1;148(7):683-92. Pre 2001Greene GW, Smiciklas-Wright H, Scholl TO, et al.Postpartum weight change: how much of the weightga<strong>in</strong>ed <strong>in</strong> pregnancy will be lost after delivery? ObstetGynecol 1988 May;71(5):701-7. Not relevantHadji P, Ziller V, Kalder M, et al. Influence ofpregnancy <strong>and</strong> breast-feed<strong>in</strong>g on quantitativeultrasonometry of bone <strong>in</strong> postmenopausal women.Climacteric 2002 Sep;5(3):277-85. Cross-sectionalstudyHarlow BL, Weiss NS, Roth GJ, et al. Case-controlstudy of borderl<strong>in</strong>e ovarian tumors: reproductivehistory <strong>and</strong> exposure to exogenous female hormones.Cancer Res 1988 Oct 15;48(20):5849-52. Borderl<strong>in</strong>etumorHarrison GA, Boyce AJ, Platt CM, et al. Bodycomposition changes dur<strong>in</strong>g lactation <strong>in</strong> a New Gu<strong>in</strong>eapopulation. Ann Hum Biology 1975 Oct;2(4):395-8.Cross-sectional studyHart S, Boylan LM, Carroll S, et al. Brief report:breast-fed one-week-olds demonstrate superiorneurobehavioral organization. J Pediatr Psychology2003 Dec;28(8):529-34. Not relevantHartge P, Hoover R, McGowan L, et al. Menopause<strong>and</strong> ovarian cancer. Am J Epidemiol 1988May;127(5):990-8. Duplicate study to Harge ’89; noadditional dataHawker GA, Forsmo S, Cadarette SM, et al.Correlates of forearm bone m<strong>in</strong>eral density <strong>in</strong> youngNorwegian women: the Nord-Trondelag <strong>Health</strong> Study.Am J Epidemiol 2002 Sep 1;156(5):418-27. CrosssectionalstudyHejar AR, Chong FB, Rosnan H, et al. Breast cancer<strong>and</strong> lifestyle risks among Ch<strong>in</strong>ese women <strong>in</strong> the KlangValley <strong>in</strong> 2001. Med J Malaysia 2004 Jun;59(2):226-32. Develop<strong>in</strong>g countryHildreth NG, Kelsey JL, Li Volsi VA, et al. Anepidemiologic study of epithelial carc<strong>in</strong>oma of theovary. Am J Epidemiol 1981 Sep;114(3):398-405. Noquantitative dataHilson JA, Rasmussen KM, Kjolhede CL. Highprepregnant body mass <strong>in</strong>dex is associated with poorlactation outcomes among white, rural women<strong>in</strong>dependent of psychosocial <strong>and</strong> demographiccorrelates. J Hum Lact 2004 Feb;20(1):18-29. Nooutcomes of <strong>in</strong>terestD-3
Holt GM, Wolk<strong>in</strong>d SN. Early ab<strong>and</strong>onment of breastfeed<strong>in</strong>g: causes <strong>and</strong> effects. Child Care <strong>Health</strong> Dev1983 Nov;9(6):349-55. N
Lovelady CA, Garner KE, Moreno KL, et al. Theeffect of weight loss <strong>in</strong> overweight, lactat<strong>in</strong>g womenon the growth of their <strong>in</strong>fants.[see comment]. N EnglJ Med 2000 Feb 17;342(7):449-53. Not relevantLumachi F, Ermani M, Br<strong>and</strong>es AA, et al. Breastcancer risk <strong>in</strong> healthy <strong>and</strong> symptomatic women:results of a multivariate analysis. A case-control study.Biomed Pharmacother 2002 Oct;56(8):416-20.Population not well-def<strong>in</strong>edMalloy MH, Berendes H. Does breast-feed<strong>in</strong>g<strong>in</strong>fluence <strong>in</strong>telligence quotients at 9 <strong>and</strong> 10 years ofage? Early Hum Dev 1998 Jan 9;50(2):209-17.Included <strong>in</strong> systematic reviewMarcus PM, Baird DD, Millikan RC, et al. Adolescentreproductive events <strong>and</strong> subsequent breast cancer risk.Am J Public <strong>Health</strong> 1999 Aug;89(8):1244-7. Pre 2001Mar<strong>in</strong>i A, Vegni C, Gangi S, et al. Influence ofdifferent types of post-discharge feed<strong>in</strong>g on somaticgrowth, cognitive development <strong>and</strong> their correlation <strong>in</strong>very low birthweight preterm <strong>in</strong>fants. Acta PaediatrSuppl 2003 Sep;91(441):18-33. Not relevantMatsumoto I, Kosha S, Noguchi S, et al. Changes ofbone m<strong>in</strong>eral density <strong>in</strong> pregnant <strong>and</strong> postpartumwomen. J Obstet Gynaecol 1995 Oct;21(5):419-25.Less than 1 year follow-upMcCredie M, Paul C, Skegg DC, et al. Reproductivefactors <strong>and</strong> breast cancer <strong>in</strong> New Zeal<strong>and</strong>. Int JCancer 1998 Apr 13;76(2):182-8. Pre 2001McCredie M, Paul C, Skegg DC, et al. Breast cancer<strong>in</strong> Maori <strong>and</strong> non-Maori women. Int J Epidemiol1999 Apr;28(2):189-95. Pre 2001McKeown T, Aaby P. The <strong>in</strong>fluence of reproductionon body weight <strong>in</strong> women. J Endocr<strong>in</strong>ol 1957;15:393-409. Cross-sectional studyMcLennan JD, Kotelchuck M, Cho H. Prevalence,persistence, <strong>and</strong> correlates of depressive symptoms <strong>in</strong>a national sample of mothers of toddlers. J Am AcadChild Adolesc Psychiatry 2001 Nov;40(11):1316-23.Not relevantMeeske K, Press M, Patel A, et al. Impact ofreproductive factors <strong>and</strong> lactation on breast carc<strong>in</strong>oma<strong>in</strong> situ risk. Int J Cancer 2004 May 20;110(1):102-9.No hormonal data givenMelton LJ, III, Bryant SC, Wahner HW, et al.Influence of breastfeed<strong>in</strong>g <strong>and</strong> other reproductivefactors on bone mass later <strong>in</strong> life. Osteoporos Int 1993Mar;3(2):76-83. Cross-sectional studyMezzacappa ES, Katl<strong>in</strong> ES. Breast-feed<strong>in</strong>g isassociated with reduced perceived stress <strong>and</strong> negativemood <strong>in</strong> mothers. <strong>Health</strong> Psychol 2002Mar;21(2):187-93. N
gestational age: a r<strong>and</strong>omized trial of nutrient-enrichedversus st<strong>and</strong>ard formula <strong>and</strong> comparison with areference breastfed group. Pediatrics 2004 Mar;113(3Pt 1):515-21. Not relevantMorrison J, Najman JM, Williams GM, et al. Socioeconomicstatus <strong>and</strong> pregnancy outcome. AnAustralian study. Br J Obstet Gynaecol 1989Mar;96(3):298-307. Not relevantMotil KJ, Sheng H, Kertz BL, et al. Lean body massof well-nourished women is preserved dur<strong>in</strong>glactation. Am J Cl<strong>in</strong> Nutr 1998 Feb;67(2):292-300.Exclusive <strong>and</strong> mixed feed<strong>in</strong>g data comb<strong>in</strong>edMurphy S, Khaw KT, May H, et al. Parity <strong>and</strong> bonem<strong>in</strong>eral density <strong>in</strong> middle-aged women. OsteoporosInt 1994 May;4(3):162-16. Cross-sectional studyMurray L, Woolgar M, Murray J, et al. Self-exclusionfrom health care <strong>in</strong> women at high risk for postpartumdepression. J Public <strong>Health</strong> Med 2003 Jun;25(2):131-7. Not relevantNaismith DJ, Ritchie CD. The effect of breast-feed<strong>in</strong>g<strong>and</strong> artificial feed<strong>in</strong>g on body-weights, sk<strong>in</strong>foldmeasurements <strong>and</strong> food <strong>in</strong>takes of forty-twoprimiparous women. Proc Nutr Soc 1975Dec;34(3):116A-117A, 1975 Dec. AbstractNajman JM, Morrison J, Williams GM, et al. Theemployment of mothers <strong>and</strong> the outcomes of theirpregnancies: an Australian study. Public <strong>Health</strong> 1989Maya;103(3):189-98. Not relevant to any outcomesNajman JM, Morrison J, Williams GM, et al.Unemployment <strong>and</strong> reproductive outcome. AnAustralian study. Br J Obstet Gynaecol 1989Marb;96(3):308-13. Not relevant to any outcomesNasca PC, Greenwald P, Chorost S, et al. Anepidemiologic case-control study of ovarian cancer<strong>and</strong> reproductive factors. Am J Epidemiol 1984May;119(5):705-13. No BF exposureNewcomb PA, Egan KM, TitusErnstoff L, et al.Lactation <strong>in</strong> relation to postmenopausal breast cancer.Am J Epidemiol 1999 Jul 15;150(2):174-82. Pre 2001Niemela M, Uhari M, Mottonen M. A pacifier<strong>in</strong>creases the risk of recurrent acute otitis media <strong>in</strong>children <strong>in</strong> day care centers. Pediatrics 1995Nov;95(5 Pt 1):884-8. Not relevantO'Neill T, Murphy P, Greene VT. Postnataldepression--aetiological factors. Irish Med J 1990Mar;83(1):17-8. N
comment]. Lancet 1996 Jan 27;347(8996):227-30. Nobreastfeed<strong>in</strong>g exposurePettitt DJ, Knowler WC. Long-term effects of the<strong>in</strong>trauter<strong>in</strong>e environment, birth weight, <strong>and</strong> breastfeed<strong>in</strong>g<strong>in</strong> Pima Indians. Diabetes Care 1998Aug;21(Suppl 2):B138-B141. Included <strong>in</strong> systematicreviewPiers LS, Diggavi SN, Thangam S, et al. Changes <strong>in</strong>energy expenditure, anthropometry, <strong>and</strong> energy <strong>in</strong>takedur<strong>in</strong>g the course of pregnancy <strong>and</strong> lactation <strong>in</strong> wellnourishedIndian women. Am J Cl<strong>in</strong> Nutr 1995Mar;61(3):501-13. Develop<strong>in</strong>g countryPitt B. "Atypical" depression follow<strong>in</strong>g childbirth. BrJ Psychiatry 1968 Nov;114(516):1325-35. N
S<strong>in</strong>gh Y, Sayami P, Sayami G, et al. Nepalese breastcancer <strong>in</strong> relation to reproductive factors: comparisonbetween Nepalese <strong>and</strong> Japanese cases. Anticancer Res2002 Jan;22(1A):319-23. Develop<strong>in</strong>g countryS<strong>in</strong>igaglia L, Varenna M, B<strong>in</strong>elli L, et al. Effect oflactation on postmenopausal bone m<strong>in</strong>eral density ofthe lumbar sp<strong>in</strong>e. J Reprod Med 1996 Jun;41(6):439-43. Cross-sectional studySoltesz G, Jeges S, Dahlquist G. Non-genetic riskdeterm<strong>in</strong>ants for type 1 (<strong>in</strong>sul<strong>in</strong>-dependent) diabetesmellitus <strong>in</strong> childhood. Hungarian Childhood DiabetesEpidemiology Study Group. Acta Paediatr 1994Jul;83(7):730-5. Develop<strong>in</strong>g countrySowers M, Corton G, Shapiro B, et al. Changes <strong>in</strong>bone density with lactation.[see comment]. JAMA1993 Jun 23;269(24):3130-5. Less than 1 yearfollow-upSowers M, Wallace RB, Lemke JH. Correlates offorearm bone mass among women dur<strong>in</strong>g maximalbone m<strong>in</strong>eralization. Prev Med 1985 Sep;14(5):585-96. Cross-sectional studySowers M, Zhang D, Janney CA. Interpregnancyweight retention pattern<strong>in</strong>g <strong>in</strong> women who breastfed.J Matern Fetal Med 1998 Mar;7(2):89-94. No dataStene LC, Joner G, Norwegian Childhood DiabetesStudy Group. Atopic disorders <strong>and</strong> risk of childhoodonsettype 1 diabetes <strong>in</strong> <strong>in</strong>dividuals. Cl<strong>in</strong> Exp Allergy2004 Feb;34(2):201-6. No BF exposureSteyn NP, Mann J, Bennett PH, et al. Diet, nutrition<strong>and</strong> the prevention of type 2 diabetes. [Review] [248refs]. Public <strong>Health</strong> Nutr 2004 Feb;7(1A):147-65.ReviewSusman VL, Katz JL. Wean<strong>in</strong>g <strong>and</strong> depression:another postpartum complication. Am J Psychiatry1988 Apr;145(4):498-501. Case reportTamm<strong>in</strong>en T. The impact of mother's depression onher nurs<strong>in</strong>g experiences <strong>and</strong> attitudes dur<strong>in</strong>gbreastfeed<strong>in</strong>g. Acta Paediatr Sc<strong>and</strong> Suppl No 3441988;77:87-94. N
Vennemann MM, Bajanowski T, Butterfass-BahloulT, et al. Do risk factors differ between expla<strong>in</strong>edsudden unexpected death <strong>in</strong> <strong>in</strong>fancy (SUDI) <strong>and</strong>SIDS? Arch Dis Child Epub ahead of pr<strong>in</strong>t doi:101136/adc 2006 101337 2006 Aug 25. Duplicate ofVennemann 2005Verge CF, Howard NJ, Irwig L, et al. Environmentalfactors <strong>in</strong> childhood IDDM. A population-based, casecontrolstudy. Diabetes Care 1994 Dec;17(12):1381-9. Included <strong>in</strong> MAVirtanen SM, Rasanen L, Ylonen K, et al. Early<strong>in</strong>troduction of dairy products associated with<strong>in</strong>creased risk of IDDM <strong>in</strong> F<strong>in</strong>nish children. TheChildhood <strong>in</strong> Diabetes <strong>in</strong> F<strong>in</strong>l<strong>and</strong> Study Group.Diabetes 1993 Dec;42(12):1786-90. Studies <strong>in</strong> theMAWalker LO, Freel<strong>and</strong>Graves J. Lifestyle factors relatedto postpartum weight ga<strong>in</strong> <strong>and</strong> body image <strong>in</strong> bottle<strong>and</strong>breastfeed<strong>in</strong>g women. J Obstet Gynecol NeonatalNurs 1998 Mar;27(2):151-60. Cross-sectional studyWebster J, Moore K, McMullan A. <strong>Breastfeed<strong>in</strong>g</strong>outcomes for women with <strong>in</strong>sul<strong>in</strong> dependent diabetes.J Hum Lact 1995 Sep;11(3):195-200. Not relevantWeiss NS, Lyon JL, Liff JM, et al. Incidence ofovarian cancer <strong>in</strong> relation to the use of oralcontraceptives. Int J Cancer 1981 Dec;28(6):669-71.No BF exposureWhiteman MK, Hillis SD, Curtis KM, et al.Reproductive history <strong>and</strong> mortality after breast cancerdiagnosis. Obstet Gynecol 2004 Jul;104(1):146-54.No outcomes of <strong>in</strong>terestW<strong>in</strong>kvist A, Rasmussen KM. Impact of lactation onmaternal body weight <strong>and</strong> body composition.[Review] [71 refs]. J Mammary Gl<strong>and</strong> Biol Neoplasm1999 Jul;4(3):309-18. ReviewWosje KS, Kalkwarf HJ. Lactation, wean<strong>in</strong>g, <strong>and</strong>calcium supplementation: effects on body composition<strong>in</strong> postpartum women. Am J Cl<strong>in</strong> Nutr 2004Aug;80(2):423-9. <strong>Breastfeed<strong>in</strong>g</strong> exclusivity unclearYasumizu T, Nakamura Y, Hoshi K, et al. Bonemetabolism after human parturition <strong>and</strong> the effect oflactation: longitud<strong>in</strong>al analysis of serum bone-relatedprote<strong>in</strong>s <strong>and</strong> bone m<strong>in</strong>eral content of the lumbar sp<strong>in</strong>e.Endocr J 1998 Oct;45(5):679-86. Less than 1 yearfollow-upYen ML, Yen BL, Bai CH, et al. Risk factors forovarian cancer <strong>in</strong> Taiwan: a case-control study <strong>in</strong> alow-<strong>in</strong>cidence population. Gynecol Oncol 2003May;89(2):318-24. Develop<strong>in</strong>g countryYoung TK, Martens PJ, Taback SP, et al. Type 2diabetes mellitus <strong>in</strong> children: prenatal <strong>and</strong> early<strong>in</strong>fancy risk factors among native Canadians. ArchPediatr Adolesc Med 2002 Jul;156(7):651-5. Included<strong>in</strong> systematic reviewZhang J, Liu G, Wu J, et al. Pregnancy-associatedbreast cancer: a case control <strong>and</strong> long-term follow-upstudy <strong>in</strong> Ch<strong>in</strong>a. J Exp Cl<strong>in</strong> Cancer Res 2003Mar;22(1):23-7. Develop<strong>in</strong>g countryZhang M, Lee AH, B<strong>in</strong>ns CW. Reproductive <strong>and</strong>dietary risk factors for epithelial ovarian cancer <strong>in</strong>Ch<strong>in</strong>a. Gynecol Oncol 2004 Jan;92(1):320-6.Develop<strong>in</strong>g countryZhang M, Xie X, Lee AH, et al. Prolonged lactationreduces ovarian cancer risk <strong>in</strong> Ch<strong>in</strong>ese women. Eur JCancer Prev 2004 Dec;13(6):499-502. Develop<strong>in</strong>gcountryZheng T, Duan L, Liu Y, et al. Lactation reducesbreast cancer risk <strong>in</strong> Sh<strong>and</strong>ong Prov<strong>in</strong>ce, Ch<strong>in</strong>a. Am JEpidemiol 2000 Dec 15;152(12):1129-35. Nohormonal data givenZheng T, Holford TR, Mayne ST, et al. Lactation <strong>and</strong>breast cancer risk: a case-control study <strong>in</strong> Connecticut.Br J Cancer 2001 Jun 1;84(11):1472-6. Pre 2001Ziegler AG, Schmid S, Huber D, et al. Early <strong>in</strong>fantfeed<strong>in</strong>g <strong>and</strong> risk of develop<strong>in</strong>g type 1 diabetesassociatedautoantibodies.[see comment]. JAMA2003 Oct 1;290(13):1721-8. No outcomes of <strong>in</strong>terestD-9
Appendix E. Peer ReviewersThe peer reviewer comments on a prelim<strong>in</strong>ary draft of this report were considered by the EPC <strong>in</strong>preparation of this f<strong>in</strong>al report. Synthesis of the scientific literature presented here does notnecessarily represent the views of <strong>in</strong>dividual reviewers. The authors gratefully acknowledge thepeer reviewers.David Atk<strong>in</strong>s, MD, MPHChief Medical OfficerCenter for <strong>Outcomes</strong> <strong>and</strong> EvidenceAgency for <strong>Health</strong>care Research <strong>and</strong> QualityRockville, Maryl<strong>and</strong>Pamela D. Hill, PhD, RN, CBE, FAANProfessorCollege of Nurs<strong>in</strong>gUniversity of Ill<strong>in</strong>ois at ChicagoDirector, Quad Cities Regional ProgramMol<strong>in</strong>e, Ill<strong>in</strong>oisLawrence M. Gartner, MDProfessor EmeritusDepartments of Pediatrics <strong>and</strong>Obstetrics/GynecologyThe University of ChicagoChicago, Ill<strong>in</strong>oisRepresentative for theAmerican Academy of PediatricsInternational Formula CouncilAtlanta, GeorgiaPeer ReviewersRussell Merritt, MD, PhD, FAAPCarol Lynn Berseth, MD, FAAPJose Saavedra, MD, FAAPJohn Wall<strong>in</strong>gford, PhDJeanne-Marie Guise, MD, MPHAssociate ProfessorDirector of Cl<strong>in</strong>ical ResearchDivision of General Obstetrics & GynecologyOregon <strong>Health</strong> <strong>and</strong> Science UniversityPortl<strong>and</strong>, OregonNanette Pazdernik, PhDCenter for <strong>Breastfeed<strong>in</strong>g</strong> InformationLa Leche League InternationalSchaumberg, Ill<strong>in</strong>oisJane He<strong>in</strong>ig, PhD, IBCLCAcademic Adm<strong>in</strong>istratorDepartment of NutritionDirector, Human Lactation CenterUniversity of California, DavisLaurie P. Shornick, PhDAssistant ProfessorDepartment of BiologySa<strong>in</strong>t Louis UniversitySt. Louis, MissouriE-1