Postnatal Glucose Homeostasis in Late-Preterm and Term Infants ...

FROM THE AMERICAN ACADEMY OF PEDIATRICSGuidance for the Clinician inRendering Pediatric CareClinical Report—Postnatal Glucose Homeostasis inLate-Preterm and Term InfantsDavid H. Adamkin, MD and COMMITTEE ON FETUS ANDNEWBORNKEY WORDSnewborn, glucose, neonatal hypoglycemia, late-preterm infantABBREVIATIONSNH—neonatal hypoglycemiaD 10 W—dextrose 10% in waterThis document is copyrighted and is property of the AmericanAcademy of Pediatrics and its Board of Directors. All authorshave filed conflict of interest statements with the AmericanAcademy of Pediatrics. Any conflicts have been resolved througha process approved by the Board of Directors. The AmericanAcademy of Pediatrics has neither solicited nor accepted anycommercial involvement in the development of the content ofthis publication.The guidance in this report does not indicate an exclusivecourse of treatment or serve as a standard of medical care.Variations, taking into account individual circumstances, may beappropriate.www.pediatrics.org/cgi/doi/10.1542/peds.2010-3851doi:10.1542/peds.2010-3851All clinical reports from the American Academy of Pediatricsautomatically expire 5 years after publication unless reaffirmed,revised, or retired at or before that time.PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).Copyright © 2011 by the American Academy of PediatricsabstractThis report provides a practical guide and algorithm for the screeningand subsequent management of neonatal hypoglycemia. Current evidencedoes not support a specific concentration of glucose that candiscriminate normal from abnormal or can potentially result in acuteor chronic irreversible neurologic damage. Early identification of theat-risk infant and institution of prophylactic measures to prevent neonatalhypoglycemia are recommended as a pragmatic approach despitethe absence of a consistent definition of hypoglycemia in theliterature. Pediatrics 2011;127:575–579INTRODUCTIONThis clinical report provides a practical guide for the screening andsubsequent management of neonatal hypoglycemia (NH) in at-risk latepreterm(34–36 6 ⁄7 weeks’ gestational age) and term infants. An expertpanel convened by the National Institutes of Health in 2008 concludedthat there has been no substantial evidence-based progress in definingwhat constitutes clinically important NH, particularly regarding how itrelates to brain injury, and that monitoring for, preventing, and treatingNH remain largely empirical. 1 In addition, the simultaneous occurrenceof other medical conditions that are associated with brain injury,such as hypoxia-ischemia or infection, could alone, or in concert withNH, adversely affect the brain. 2–5 For these reasons, this report doesnot identify any specific value or range of plasma glucose concentrationsthat potentially could result in brain injury. Instead, it is a pragmaticapproach to a controversial issue for which evidence is lackingbut guidance is needed.BACKGROUNDBlood glucose concentrations as low as 30 mg/dL are common inhealthy neonates by 1 to 2 hours after birth; these low concentrations,seen in all mammalian newborns, usually are transient, asymptomatic,and considered to be part of normal adaptation to postnatal life. 6–8Most neonates compensate for “physiologic” hypoglycemia by producingalternative fuels including ketone bodies, which are released fromfat.Clinically significant NH reflects an imbalance between supply and useof glucose and alternative fuels and may result from a multitude ofdisturbed regulatory mechanisms. A rational definition of NH mustaccount for the fact that acute symptoms and long-term neurologicsequelae occur within a continuum of low plasma glucose values ofvaried duration and severity.PEDIATRICS Volume 127, Number 3, March 2011 575

The authors of several literature reviewshave concluded that there is nota specific plasma glucose concentrationor duration of hypoglycemia thatcan predict permanent neurologic injuryin high-risk infants. 3,9,10 Data thathave linked plasma glucose concentrationwith adverse long-term neurologicoutcomes are confounded by variabledefinitions of hypoglycemia and its duration(seldom reported), the omissionof control groups, the possible inclusionof infants with confoundingconditions, and the small number ofasymptomatic infants who were followed.3,11,12 In addition, there is no singleconcentration or range of plasmaglucose concentrations that is associatedwith clinical signs. Therefore,there is no consensus regarding whenscreening should be performed andwhich concentration of glucose requirestherapeutic intervention in theasymptomatic infant. The generallyadopted plasma glucose concentrationthat defines NH for all infants(47 mg/dL) is without rigorous scientificjustification. 1,3,4,9,12WHICH INFANTS TO SCREENFIGURE 1Screening for and management of postnatal glucose homeostasis in late-preterm (LPT 34–36 6 ⁄7weeks) and term small-for-gestational age (SGA) infants and infants who were born to mothers withdiabetes (IDM)/large-for-gestational age (LGA) infants. LPT and SGA (screen 0–24 hours), IDM and LGA34 weeks (screen 0–12 hours). IV indicates intravenous.Because plasma glucose homeostasisrequires glucogenesis and ketogenesisto maintain normal rates of fueluse, 13 NH most commonly occurs in infantswith impaired glucogenesisand/or ketogenesis, 14,15 which may occurwith excessive insulin production,altered counterregulatory hormoneproduction, an inadequate substratesupply, 14–16 or a disorder of fatty acidoxidation. 15 NH occurs most commonlyin infants who are small for gestationalage, infants born to motherswho have diabetes, and late-preterminfants. It remains controversialwhether otherwise normal infantswho are large for gestational age areat risk of NH, largely because it is difficultto exclude maternal diabetes ormaternal hyperglycemia (prediabetes)with standard glucose-tolerancetests.A large number of additional maternaland fetal conditions may also place infantsat risk of NH. Clinical signs arecommon with these conditions, and itis likely that patients with such a conditionare already being monitoredand that plasma glucose analyses arebeing performed. 13,17 Therefore, forpracticality, “at risk” in the managementapproach outlined in Fig 1 includesonly infants who are small forgestational age, infants who are largefor gestational age, infants who wereborn to mothers who have diabetes,and late-preterm infants. Routinescreening and monitoring of blood glucoseconcentration is not needed inhealthy term newborn infants after anentirely normal pregnancy and delivery.Blood glucose concentrationshould only be measured in term infantswho have clinical manifestationsor who are known to be at risk. Plasmaor blood glucose concentration shouldbe measured as soon as possible (minutes,not hours) in any infant who manifestsclinical signs (see “ClinicalSigns”) compatible with a low bloodglucose concentration (ie, the symptomaticinfant).Breastfed term infants have lower concentrationsof plasma glucose buthigher concentrations of ketone bodiesthan do formula-fed infants. 13,17 It is postulatedthat breastfed infants toleratelower plasma glucose concentrationswithout any clinical manifestations or sequelaeof NH because of the increasedketone concentrations. 8,12–14WHEN TO SCREENNeonatal glucose concentrations decreaseafter birth, to as low as 30mg/dL during the first 1 to 2 hours afterbirth, and then increase to higherand relatively more stable concentrations,generally above 45 mg/dL by 12hours after birth. 6,7 Data on the optimaltiming and intervals for glucosescreening are limited. It is controversialwhether to screen the asymptomaticat-risk infant for NH during this576 FROM THE AMERICAN ACADEMY OF PEDIATRICS

FROM THE AMERICAN ACADEMY OF PEDIATRICSnormal physiologic nadir. No studieshave demonstrated harm from a fewhours of asymptomatic hypoglycemiaduring this normal postnatal periodof establishing “physiologic glucosehomeostasis.” 9Infants born to mothers with diabetesmay develop asymptomatic NH as earlyas 1 hour after birth 18 and usually by 12hours of age. 18 In contrast, infants whoare large for gestational age or smallfor gestational age may develop lowplasma glucose concentrations at asearly as 3 hours of age, 19 and theseinfants may be at risk of NH for up to 10days after birth. 20 Therefore, at-risk infantsshould be screened for NH with afrequency and duration related to riskfactors specific to the individual infant.5 Screening the asymptomatic atriskinfant can be performed withinthe first hours of birth and continuedthrough multiple feed-fast cycles. Latepreterminfants and infants who aresmall for gestational age should be fedevery 2 to 3 hours and screened beforeeach feeding for at least the first 24hours. After 24 hours, repeatedscreening before feedings should becontinued if plasma glucose concentrationsremain lower than 45 mg/dL.LABORATORY DATAWhen NH is suspected, the plasma orblood glucose concentration must bedetermined immediately by using oneof the laboratory enzymatic methods(eg, glucose oxidase, hexokinase, ordehydrogenase method). Plasmablood glucose values tend to be approximately10% to 18% higher thanwhole-blood values because of thehigher water content of plasma. 21,22Although a laboratory determination isthe most accurate method of measuringthe glucose concentration, the resultsmay not be available quicklyenough for rapid diagnosis of NH,which thereby delays the initiation oftreatment. 23 Bedside reagent test-stripglucose analyzers can be used if thetest is performed carefully and the clinicianis aware of the limited accuracyof these devices. Rapid measurementmethods available at the bedside includethe handheld reflectance colorimeterand electrode methods. Theblood sample is usually obtained froma warmed heel.Test-strip results demonstrate a reasonablecorrelation with actualplasma glucose concentrations, butthe variation from the actual level maybe as much as 10 to 20 mg/dL. 24–27 Unfortunately,this variation is greatestat low glucose concentrations. There isno point-of-care method that is sufficientlyreliable and accurate in the lowrange of blood glucose to allow it to beused as the sole method for screeningfor NH.Because of limitations with “rapid”bedside methods, the blood or plasmaglucose concentration must be confirmedby laboratory testing orderedstat. A long delay in processing thespecimen can result in a falsely lowconcentration as erythrocytes in thesample metabolize the glucose in theplasma. This problem can be avoidedby transporting the blood in tubes thatcontain a glycolytic inhibitor such asfluoride.Screening of the at-risk infant for NH andinstitution of prophylactic measures toprevent prolonged or symptomatic NH isareasonablegoal.TreatmentofsuspectedNH should not be postponedwhile waiting for laboratory confirmation.However, there is no evidence toshow that such rapid treatment will mitigateneurologic sequelae.CLINICAL SIGNSThe clinical signs of NH are not specificand include a wide range of local orgeneralized manifestations that arecommon in sick neonates. 12,13,17 Thesesigns include jitteriness, cyanosis, seizures,apneic episodes, tachypnea,weak or high-pitched cry, floppiness orlethargy, poor feeding, and eye-rolling.It is important to screen for other possibleunderlying disorders (eg, infection)as well as hypoglycemia. Suchsigns usually subside quickly with normalizationof glucose supply andplasma concentration. 9,13 Coma andseizures may occur with prolonged NH(plasma or blood glucose concentrationslower than 10 mg/dL range) andrepetitive hypoglycemia. The more serioussigns (eg, seizure activity) usuallyoccur late in severe and protractedcases of hypoglycemia and arenot easily or rapidly reversed with glucosereplacement and normalizationof plasma glucose concentrations. 28–30Development of clinical signs may beameliorated by the presence of alternativesubstrates. 31Because avoidance and treatment ofcerebral energy deficiency is the principalconcern, greatest attentionshould be paid to neurologic signs. Toattribute signs and symptoms to NH,Cornblath et al 12 have suggested thatthe Whipple triad be fulfilled: (1) a lowblood glucose concentration; (2) signsconsistent with NH; and (3) resolutionof signs and symptoms after restoringblood glucose concentrations to normalvalues. 12MANAGEMENTAny approach to management needs toaccount for the overall metabolic andphysiologic status of the infant andshould not unnecessarily disrupt themother-infant relationship and breastfeeding.The definition of a plasma glucoseconcentration at which interventionis indicated needs to be tailored tothe clinical situation and the particularcharacteristics of a given infant. Forexample, further investigation and immediateintravenous glucose treatmentmight be instituted for an infantwith clinical signs and a plasma glucoseconcentration of less than 40 mg/PEDIATRICS Volume 127, Number 3, March 2011 577

FROM THE AMERICAN ACADEMY OF PEDIATRICSprevent (feeding) and treat (feedingand intravenous glucose infusion) lowconcentrations are primary goals.Follow-up glucose measurements arealways indicated to be sure an infantcan maintain normal glucose concentrationsover several feed-fast cycles.This will also permit recognition of infantswith persistent hyperinsulinemichypoglycemia and infants with fattyacid oxidation disorders.REFERENCES1. Hay W Jr, Raju TK, Higgins RD, Kalhan SC,Devaskar SU. Knowledge gaps and researchneeds for understanding and treating neonatalhypoglycemia: workshop report fromEunice Kennedy Shriver National Institute ofChild Health and Human Development. J Pediatr.2009;155(5):612–6172. Adamkin DH. Update on neonatal hypoglycemia.Arch Perinat Med. 2005;11(3):13–153. Sinclair JC. Approaches to definition of neonatalhypoglycemia. Acta Paediatr Jpn.1997;39(suppl 1):S17–S204. McGowan JE. Commentary, neonatal hypoglycemia.Fifty years later, the questions remainthe same. 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Boluyt N, van Kempen A, Offringa M. Neurodevelopmentafter neonatal hypoglycemia:LEAD AUTHORDavid H. Adamkin, MDCOMMITTEE ON FETUS AND NEWBORN,2009–2010Lu-Ann Papile, MD, ChairpersonDavid H. Adamkin, MDJill E. Baley, MDVinod K. Bhutani, MDWaldemar A. Carlo, MDPraveen Kumar, MDRichard A. Polin, MDRosemarie C. Tan, MD, PhDKasper S. Wang, MDa systematic review and design of an optimalfuture study. Pediatrics. 2006;117(6):2231–224312. Cornblath M, Hawdon JM, Williams AF, et al.Controversies regarding definition of neonatalhypoglycemia: suggested operationalthresholds. Pediatrics. 2000;105(5):1141–114513. Cornblath M, Ichord R. Hypoglycemia in theneonate. Semin Perinatol. 2000;24(2):136–14914. Hawdon JM, Ward Platt MP, Aynsley-Green A.Patterns of metabolic adaptation for pretermand term infants in the first neonatalweek. Arch Dis Child. 1992;67(4 spec No.):357–36515. Kalhan S, Parmimi P. Gluconeogenesis inthe fetus and neonate. Semin Perinatol.2000;24(2):94–10616. 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Barth Jr, MD – American College ofObstetricians and GynecologistsAnn L. Jefferies, MDRosalie O. Mainous, PhD, RNC, NNP – NationalAssociation of Neonatal NursesTonse N. K. Raju, MD, DCH – National Institutesof HealthSTAFFJim Couto, MA22. Aynsley-Green A. Glucose: a fuel for thought!J Paediatr Child Health. 1991;27(1):21–3023. Cornblath M, Schwartz R. Hypoglycemia inthe neonate. JPediatrEndocrinol.1993;6(2):113–12924. Altimier L, Roberts W. One Touch II hospitalsystem for neonates: correlation with serumglucose values. Neonatal Netw. 1996;15(2):15–1825. GiepTN,HallRT,HarrisK,BarrickB,SmithS.Evaluationof neonatal whole blood versus plasmaglucose concentration by ion-selective electrodetechnology and comparison with two wholeblood chromogen test strip methods. JPerinatol.1996;16(4):244–24926. Maisels MJ, Lee C. Chemstrip glucose teststrips: correlation with true glucose valuesless than 80 mg/dL. Crit Care Med. 1983;11(4):293–29527. Hussain K, Sharief N. The inaccuracy of venousand capillary blood glucose measurementusing reagent strips in the newbornperiod and the effect of haematocrit. EarlyHum Dev. 2000;57(2):111–12128. de Lonlay P, Touati G, Robert JJ, SaudubrayJM. Persistent hyperinsulinaemic hypoglycaemia.Semin Neonatol. 2002;7(1):95–10029. Meissner T, Brune W, Mayatepek E. Persistenthyperinsulinaemic hypoglycaemia ofinfancy: therapy, clinical outcome and mutationalanalysis. Eur J Pediatr. 1997;156(10):754–75730. Menni F, deLonlay P, Sevin C, et al. Neurologicoutcomes of 90 neonates and infantswith persistent hyperinsulinemic hypoglycemia.Pediatrics. 2001;107(3):476–47931. Adam PA, Raiha N, Rahiala EL, Kekomaki M.Oxidation of glucose and D-B-OH-butyrate bythe early human fetal brain. Acta PaediatrScand. 1975;64(1):17–2432. Kalhan S, Peter-Wohl S. Hypoglycemia: whatis it for the neonate? Am J Perinatol. 2000;17(1):11–18PEDIATRICS Volume 127, Number 3, March 2011 579