Preeclampsia/Eclampsia - Program website - Path

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) Par voie d'un examen professionnel, ouvert par spécialités, correspondant aux fonctionsmentionnées aux 1°, 2° et 3° du I de l'article 4 du présent décret, accessible aux fonctionnairesappartenant aux corps des personnels d'exploitation des travaux publics de l'Etat, des expertstechniques des services techniques, des dessinateurs, des adjoints techniques des administrations del'Etat du ministère en charge du développement durable, des adjoints administratifs desadministrations de l'Etat du ministère en charge du développement durable, des syndics des gens demer justifiant, au 1er janvier de l'année au titre de laquelle les nominations interviennent, de septannées de services publics.II - Les concours mentionnés aux 1°, 2° et 3° du I sont ouverts par spécialités correspondant auxfonctions précisées aux 1°, 2° et 3° du I de l'article 4 du présent décret.III – Les dispositions des articles 5 et 8 du décret du 11 novembre 2009 susvisé sont applicables auxconcours mentionnés aux 1°, 2° et 3° du I.Article 7Le nombre de places offertes au concours mentionné au 1° du I de l'article 6 ne peut être inférieur à30 % du nombre total de places offertes aux concours mentionnés aux 1°, 2° et 3° du I de l'article 6.Le nombre de places offertes au 3° du I de l'article 6 ne peut être supérieur à 10% du nombre totaldes places offertes aux concours mentionnés aux 1°, 2° et 3° du I de l'article 6.Les places qui n'ont pas été pourvues au titre de l'un des concours mentionnés aux 1°, 2°, et 3° du Ide l'article 6 peuvent être reportées sur les autres concours ouverts dans la même spécialité.Les candidats reçus aux concours mentionnés aux 1°, 2° et 3° du I de l'article 6 sont nommés ettitularisés selon les modalités prévues aux I, III, IV, V de l'article 11 du décret du 11 novembre2009 susvisé.Section 2 : Dispositions relatives au recrutement dans le grade de techniciensupérieur principal du développement durableArticle 8I - Les techniciens supérieurs principaux du développement durable sont recrutés :1° Par voie de concours externe sur épreuves :Ce concours est ouvert aux candidats titulaires d'un titre ou diplôme sanctionnant deux années deformation classée au moins au niveau III, ou d'une qualification reconnue comme équivalente à l'unde ces titres ou diplômes dans les conditions fixées par le décret du 13 février 2007 susvisé.2° Par voie de concours interne sur épreuves :Ce concours est ouvert aux fonctionnaires et agents de l'Etat, des collectivités territoriales et desétablissements publics qui en dépendent, y compris ceux mentionnés à l'article 2 de la loi n°86-33du 9 janvier 1986 portant dispositions statutaires relatives à la fonction publique hospitalière, aux5

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationEfficacy/effectivenessCalcium tablets or powdersDiscrepancies in the evidence and conclusionsof the largest clinical trials with high variabilityin realized benefits related to genetics anddiet.TECHNOLOGY/SOLUTIONMicronutrient powders for women (e.g.,Sprinkles)Can potentially reduce maternalhypertensive disease-related mortality by20 percent and preterm birth by 24percent.Heart barsSupplementation during pregnancy with a medical foodcontaining L-arginine and antioxidant vitamins reducedthe incidence of PE in a population at high risk of thecondition.ManufacturingIntellectualproperty (IP)ownershipCost and costdriversDelivery/procurementchannelsSustainablebusiness modelsRecent research derived from Cochrane reviewused 20 percent efficacy to model calciumeffectiveness in lowering PE prevalence. Thiscorresponds to 19 averted maternal deaths per100,000 reached. Iron folate by contrast is 130averted maternal deaths per 100,000 reached. 7No suppliers were identified with product of1.5 g to 2.0 g dose. Currently, a 500-mg pilland sachets are available. Drug of adequatedose is not yet on UNICEF Essential MedicinesList nor does UNICEF supply any product forthis purpose.None. Generic product.Preliminary cost modeling suggests that thecost for a 1.5 g to 2.0 g dose of calcium atcurrent pricing would be US$0.096 to US$0.15per unit for calcium carbonate, US$0.264 toUS$0.375 for calcium citrate, and US$0.021 toUS$0.041 for a chewable calcium pill. 9 Thisdoes not compare favorably for example withiron-folic-acid pill (60 mg of ferrous fumarate)that costs US$5.34 per 1,000 orUS$0.00534/each.In the public sector, clinic- or communitybaseddistribution. In the private sector,community-based distribution through privatesectorvendors.Currently, large multinational donors andministries of health purchase the product.Private-sector distribution requires end usersto be willing to pay for the product.Clinical trials in Ghana and other countrieshave shown that Sprinkles supplementsare as efficacious in treating irondeficiencyanemia in infants as thestandard treatment of oral iron drops.Developed by researchers at the Hospitalfor Sick Children in Toronto. The SprinklesGlobal Health Initiative is the nonprofitentity. Not yet commercially available.The IP rights to Sprinkles are owned byPed Med, Ltd., a private incorporatedcompany owned by Dr. Stanley Zlotkin.The cost of producing Sprinkles isbetween US$0.03 and US$0.05 per sachet,depending on the volume that isproduced.In the public sector, clinic- or communitybaseddistribution. In the private sector,community-based distribution throughprivate-sector vendors.Business models not yet determined.Antioxidant vitamins alone did not have a protective effectfor prevention of PE. Supplementation with L-arginine plusantioxidant vitamins needs to be evaluated in a low-riskpopulation to determine the generalizability of theprotective effect, and the relative contributions of L-arginine and antioxidant vitamins to the observed effectsof the combined treatment need to be determined. 8Nellson Nutraceutical, LLC, has production facilities inIrwindale, California, and Salt Lake City, Utah, USA, andMontreal, Ontario, Canada. However, they are no longermanufacturing this product. The current manufacturer isunknown.Information not available.To be evaluated.In the public sector, clinic- or community-baseddistribution. In the private sector, community-baseddistribution through private-sector vendors.Not determined; US$1/day populations cannot affordunsubsidized, packaged food.Page 7 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012DemandInformationExisting demandAttractivenessPrice sensitivityPolicyenvironmentTECHNOLOGY/SOLUTIONCalcium tablets or powders Micronutrient powders for women (e.g., Sprinkles) Heart barsMarket size is driven by the number of Market size is driven by the number of pregnant Market size is driven by the number ofpregnant women with low dietary intake of women with low dietary intake of calcium (whether or pregnant women with low dietary intake ofcalcium (whether or not they havenot they have predisposing factors for PE). Broadly calcium (whether or not they have predisposingpredisposing factors for preeclampsia [PE]). speaking, the market size for these technologies factors for PE). Broadly speaking, the marketBroadly speaking, the market size for these includes all pregnant women in countries where size for these technologies includes alltechnologies includes all pregnant women in calcium deficiency is suspected to be prevalent. pregnant women in countries where calciumcountries where calcium deficiency isdeficiency is suspected to be prevalent.suspected to be prevalent.Widely available.Tablet form preferred.Iron and calcium cannot be taken together, soit complicates administration of both.Purchasers are likely to go with the lowestpricedproduct. Lack of strong evidence alsolimits consumer interest. Market research isneeded to determine what cost and quality ofproduct women are willing to pay for.World Health Organization (WHO) policy inareas where dietary calcium intake is low:calcium supplementation during pregnancy(at doses of 1.5 g to 2.0 g elemental calciumper day) is recommended for all women, butespecially those at high risk of developing PE.However, few countries currently have apolicy to give calcium in pregnancy and thosethat do, such as Bangladesh and Indonesia,only recommend 500 mg/day.The powder under development by SickKids willcontain differential time-released calcium and iron, toameliorate the competition of iron and calcium forabsorption, and have a smooth texture and appealingflavor. It should be noted that powders and otherforms of supplements (e.g., chewable tablets) will bedeveloped and tested for efficacy and consumeracceptability. Consumer research will be needed todetermine the best form (size, color, coating), anyproblems with side effects and how that will affectcompliance, and ways to increase compliance with theentire regimen of calcium.Purchasers are likely to go with the lowest-pricedproduct. Lack of strong evidence also limits consumerinterest. Market research is needed to determinewhat cost and quality of product women are willing topay for.WHO policy in areas where dietary calcium intake islow: calcium supplementation during pregnancy (atdoses of 1.5 g to 2.0 g elemental calcium per day) isrecommended for all women, but especially those athigh risk of developing PE. However, few countriescurrently have a policy to give calcium in pregnancyand those that do, such as Bangladesh and Indonesia,only recommend 500 mg/day.Appeal with populations with steadilyincreasing wealth. Some nice business models(e.g., PowerBar) abound; however, these areexpensive products that are likely never toreach US$1/day populations.Suspect that there is significant price sensitivitythat will require donor intervention to reducecosts in order to reach the most vulnerablepopulations.WHO policy in areas where dietary calciumintake is low: calcium supplementation duringpregnancy (at doses of 1.5 g to 2.0 g elementalcalcium per day) is recommended for allwomen, but especially those at high risk ofdeveloping PE. However, few countriescurrently have a policy to give calcium inpregnancy and those that do, such asBangladesh and Indonesia, only recommend500 mg/day.Page 8 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012DemandInformationDonors/stakeholdersPre- and post-salessupportNeed for demandcreationTECHNOLOGY/SOLUTIONCalcium tablets or powders Micronutrient powders for women (e.g., Sprinkles) Heart barsMultiple: United States Agency forInternational Development (USAID), WHO,United Nations Children’s Fund, World Bank.Providers need to advise mothers on therecommended dosage, emphasize adherence,and warn for side effects.Plenty of opportunity exists for additionallocalized and ministry of health-leveladvocacy to increase demand.SickKids won a Saving Lives at Birth Grand Challenge in2011. Saving Lives at Birth: A Grand Challenge forDevelopment is an initiative jointly funded by GrandChallenges Canada, USAID, Norway's Foreign Ministry,the World Bank, and the Bill & Melinda GatesFoundation. 10Providers need to advise mothers on therecommended dosage, emphasize adherence, andwarn for side effects.Plenty of opportunity exists for additional localizedand ministry of health-level advocacy to increasedemand.Funding for the clinical trial was provided bythe Bill & Melinda Gates Foundation and Fondode Salud, CONACYT. 7,11Providers need to advise mothers on therecommended dosage, emphasize adherence,and warn for side effects.It will be challenging to create demand forwhat is anticipated to be a more expensiveproduct.Demand strategies will need to focus onincreasing information to women on why andhow to take the entire regimen of calciumand how to manage any side effects thatoccur.Demand strategies will need to focus on increasinginformation to women on why and how to take theentire regimen of calcium and how to manage anyside effects that occur.Page 9 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012References1 World Health Organization (WHO). World Health Statistics Part I: Health-Related Millennium Development Goals. Geneva: WHO; 2011.Available at: http://www.who.int/gho/publications/world_health_statistics/EN_WHS2011_Part1.pdf. Accessed February 1, 2012.2 World Health Organization (WHO). WHO Recommendations for Prevention and Treatment of Preeclampsia and Eclampsia. Geneva: WHO; 2011.Available at http://whqlibdoc.who.int/publications/2011/9789241548335_eng.pdf. Accessed February 1, 2012.3 Galloway R, McGuire J. Daily versus weekly: how many iron pills do pregnant women need? Nutrition Reviews. 1996;54(10):318–323.4 Hofmeyr GJ, Lawrie TA, Atallah ÁN, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and relatedproblems. Cochrane Database of Systematic Reviews. 1998:CD001059.5 Hofmeyr GJ, Duley L, Atallah A. Dietary calcium supplementation for prevention of pre-eclampsia and related problems: a systematic reviewand commentary. BJOG. 2007;114(8):933–943.6Preeclampsia Risk Reduced in Women Taking L-Arginine Bar page. AlaskOmega website. Available at: http://www.nutritionaloutlook.com/news/preeclampsia-risk-reduced-women-taking-l-arginine-bar. Accessed February 1, 2012.7 Hodgins S, Pomeroy A, Belay H, Koblinsky M; Maternal & Child Health Integrated Program/John Snow, Inc. Pre-Eclampsia/EclampsiaInterventions and their Cost Effectiveness [PowerPoint]. Africa Regional Meeting on Interventions for Impact in Essential Obstetric and NewbornCare, February 21–25, 2011; Addis Ababa, Ethiopia. Available at: http://www.mchip.net. Accessed February 1, 2012.8 Effect of supplementation during pregnancy with L-arginine and antioxidant vitamins in medical food on pre-eclampsia in high risk population:randomised controlled trial. BMJ. 2011;342:d2901.9 Rae Galloway; written communication; February 2012.10 Prenatal calcium to prevent preeclampsia and preterm birth in resource-poor rural settings page. Saving Lives at Birth: A Grand Challenge forDevelopment website. Available at: http://www.savinglivesatbirth.net/summaries/88. Accessed February 1, 2012.11 Preeclampsia Risk Reduced in Women Taking L-Arginine Bar webpage. Nutrition Outlook website. Available at:http://www.nutritionaloutlook.com/news/preeclampsia-risk-reduced-women-taking-l-arginine-bar. Accessed February 1, 2012.Page 10 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012Biomarkers for Preeclampsia ScreeningPreeclampsia (PE) diagnosis is based on symptoms, and it is made when the disease is already expressed. In contrast, PE screening is performedbefore any symptoms appear and aims to estimate the risk that the disorder will develop. While numerous maternal and fetal factors maypredispose an individual woman to PE, screening by maternal history will detect only 30 percent of women who will develop PE, 1 and use of socalledrisk factors has a low positive and negative predictive value for PE. 2,3 To date, no reliable test or symptom complex predicts thedevelopment of PE, and providers continue to rely on measuring blood pressure and proteinuria during focused antenatal care (ANC)4 toidentify PE as early as possible (the onset of PE is usually after 20 weeks gestation). Unfortunately, although 80 percent of pregnant womenreceived ANC at least once during the period between 2000 and 2010, only 53 percent received the World Health Organization (WHO)recommended minimum of four antenatal visits, thus limiting the ability to identify PE. In addition, most cases of eclampsia present in the thirdtrimester of pregnancy, with approximately 80 percent of eclamptic seizures occurring intrapartum or within the first 48 hours followingdelivery. While the proportion of deliveries attended by skilled health personnel rose from 58 percent in 1990 to 68 percent in 2008, it hasremained low in the WHO African Region and the WHO South-East Asia Region where only around 50 percent of deliveries were attended byskilled health personnel, 5 meaning a large percentage of women are not being cared for by a skilled birth attendant when they most need it.A study on the effect of assessing risk factors on compliance with referral recommendations and found that of the various hypotheses tested,the geographic accessibility of the hospital and the pregnant woman’s perception of her risk status were the two most important factors indetermining the compliance rate. 6 If a biomarker 7 with reasonable specificity and sensitivity existed for PE and could be tested for as early aspossible in the pregnancy, it would not only have the potential to substantially improve care—ensuring access to preventive strategies, closerprenatal and postpartum monitoring, recognition of PE earlier in the disease course, and timely access to the treatment package—but wouldalso hopefully provide the additional benefit of assisting women in understanding their risk status. This in turn would improve attendance atANC and postpartum care, compliance with instructions for care, and increase the likelihood of the presence of a skilled birth attendant at thetime of birth. Authors of a WHO systematic review of screening tests for PE described the ideal test as being “simple, innocuous, rapid,inexpensive, reproducible, and noninvasive as well as easy to perform early in pregnancy to allow interventions to prevent when available or atleast mitigate the development of the disease.” 1 Identification of biomarkers for diagnosis of PE early in pregnancy is still largely in a stage ofdiscovery.Page 11 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012PE is marked by exquisitely small changing levels of small molecule biomarkers and presently cannot be qualitatively predicted through a cheap,easy-to-use instrument such as a lateral flow diagnostic. In fact, testing based on any one angiogenic/anti-angiogenic factor has poor accuracydue to the “multi-factorial nature of the disease;” and it is more likely that an algorithmic assessment of multiple biomarker factors would beneeded to make an accurate prediction.“Major challenges in screening with the new markers are the relatively novel origin of the markers and the lack of gold standards to assess theirconcentrations. The field requires an independent standard center to provide marker calibration. Moreover, in countries where the clinics arewidely distributed but testing is performed in a central laboratory, the issue of marker stability during transfer and storage becomesimportant.” 1An ideal marker should be minimally invasive to obtain the sample, stable in the sample, be accurate and sensitive, and be able to be integratedwithin routine testing already used as a part of prenatal testing, and integrated into existing test platforms to reduce the need to purchase majornew hardware. 1“Marker accuracy has not yet been set to evaluate the cost of surveillance since there is a need to decide on an acceptable detection rate and afalse positive rate. Product cost is another unknown factor since the only products in the market today are Doppler sonography, placentalprotein 13 (PP13), placental growth factor (PIGF), and pregnancy-associated plasma protein A testing, and only the latter is included today inpublically paid clinical services. 1The two tables below illustrate the various biomarkers currently being examined for prediction of preeclampsia.Page 12 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationDescriptionDELFIA® Xpress PlGF kit(product # 6007-0010)Quantitativedetermination ofplacental growth factor(PlGF) in maternal serum.In normal, uncomplicatedpregnancy, free, unboundPlGF levels increaseduring the first andsecond trimester and thendecline. The level of PlGFis typically decreased inmaternal serum duringboth the first and thesecond trimesters ofpregnancy in women wholater developpreeclampsia (PE).Elecsys PIGF/sFLT-1and Elecsys PlGFAutomatedimmunoassaysspecific for solublefms-like tyrosinekinase 1 (sFlt-1) andPlGF.TECHNOLOGY/SOLUTIONChemical Biomarkers—TABLE 1Congo Red Dot Test Placental protein 13maternal serum markerCongo red dye mayidentify eclampsia ifthe disease is due tomisfolded proteinsthat areCongophilic. 3PerkinElmer isdeveloping convenientassays for detection ofPlGF and the newserum maternal markerplacental protein 13(PP13) for earlyassessment of anelevated probability ofdevelopment of PEduring pregnancy.VEGFR-1preeclampsia markerMiraculins isinvestigatingbiomarkers (a VEGFR-1 polypeptide) thatcan predict the risk ofPE. 5Predicting preeclampsiain normal and low-riskpregnancies: proteomicsto profile urinaryproteinsA workflow for evaluatingthe urinary proteomicprofile of pregnantwomen to predict PE innormal and low-riskpregnancies has beendeveloped and validated:six proteins were presentonly in urine samplesfrom women with PE; anadditional single proteinwas present in controlsamples and absent frompreeclamptic samples. 6Characteristicsapplicable forlow-resourcesettingsThis solid-phase, two-sitefluoroimmunometricassay is based on thedirect sandwich techniquein which monoclonalantibodies and polyclonalantibodies are directedagainst the PlGF molecule.Limit of quantitation istypically 7 pg/mL.Currently validated,though needs to be madesimpler, less costly.Currently validated,though needs to bemade simpler, lesscostly.Highest potential forpoint-of-carescreening test (meetsASSURED criteria). 8Sample source is bloodserum.First tests on themarkets will not besuitable for lowresourcesettings.Sample source isblood serum.First tests on themarkets will not besuitable for lowresourcesettings.First tests on markets willnot be suitable for lowresourcesettings.Page 13 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationDeveloperand/ormanufacturerStatusEfficacy/effectivenessDELFIA® Xpress PlGF kit(product # 6007-0010)Elecsys PIGF/sFLT-1and Elecsys PlGFPerkinElmer, Inc. Roche Diagnostics Irina Buhimschi, YaleSchool of MedicineThe product was launchedin October 2010.Commercialized in theEuropean Union (EU).The DELFIA® Xpress PlGFkit has market approval inthe EU, but not in Canadaor the United States.Detection rate of 44%(when also tested withPP13) and false-positivethreshold is set at 5%.When combined with fiveother biomarkers, thedetection rate can be99%.The technology hasbeen commercializedin the EU andCanada.Has a CE mark. 9The sFlt-1/PlGF ratioshowed the bestdiagnostic power forboth early-onset andlate-onsetpreeclampsia. Inaddition, a cutoffvalue of 45 for thesFlt-1/PlGF ratioresulted in the bestsensitivity andspecificity for thediagnosis of all PE(97% and 95%,respectively), and forthe diagnosis ofearly-onset PE (100%and 95%,respectively). 12,13TECHNOLOGY/SOLUTIONChemical Biomarkers—TABLE 1Congo Red Dot Test Placental protein 13maternal serum markerClinical trialsinvolving 347 womenhave beencompleted; moreclinical studies areneeded. 10,11Congo Red retentionwas more accurate atpredicting indicateddelivery for PE thanprotein-to-creatinineratio (P

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationManufacturingquality andcapacityIntellectualpropertyownershipDELFIA® Xpress PlGF kit(product # 6007-0010)PerkinElmer, Inc. is a largecompany, and a supplierof medical technologies.The current market isdeveloped countries, thuscapacity exists toaccommodate othersettings as well.This company cancertainly arrange thefinancial resourcesnecessary to increasesupply if needed.Patent: Kit for diagnosis ofpreeclampsiaUnited States Patent No.8017734, issuedSeptember 13, 2011.Elecsys PIGF/sFLT-1and Elecsys PlGFRoche is a largecompany, and asupplier of medicaltechnologies.The current market isdeveloped countries,thus capacity existsto accommodateother settings aswell.This company cancertainly arrange thefinancial resourcesnecessary to increasesupply if needed.TECHNOLOGY/SOLUTIONChemical Biomarkers—TABLE 1Congo Red Dot Test Placental protein 13maternal serum markerNo, a technologytransfer will berequired.PerkinElmer, Inc. is alarge company, and asupplier of medicaltechnologies.The current market isdeveloped countries,thus capacity exists toaccommodate othersettings as well.Can certainly arrangethe financial resourcesnecessary to increasesupply if needed.VEGFR-1preeclampsia markerNo, a technologytransfer will berequired.No data available. No data available. No data available. Patent: Methods forEarly Diagnosing of anIncreased Risk ofPreeclampsiaUnited States PatentNo. 20090104649,issued in July 2009.Predicting preeclampsiain normal and low-riskpregnancies: proteomicsto profile urinaryproteinsNo, a technology transferwill be required.No data available.Page 15 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationCost and costdriversDELFIA® Xpress PlGF kit(product # 6007-0010)Immunoassay that resultsin a colorimetric changethat requires detectionand quantification by areader (ELISA).The specific hardwareconsumable of amicrotiter plate coated byantibody is required.Elecsys PIGF/sFLT-1and Elecsys PlGFImmunoassay thatresults in acolorimetric changethat requiresdetection andquantification by areader (ELISA).The specifichardwareconsumable of amicrotiter platecoated by antibody isrequired.TECHNOLOGY/SOLUTIONChemical Biomarkers—TABLE 1Congo Red Dot Test Placental protein 13maternal serum markerThe technology is tooupstream for costestimates.The technology is tooupstream for costestimates.VEGFR-1preeclampsia markerThe technology is tooupstream for costestimates.Predicting preeclampsiain normal and low-riskpregnancies: proteomicsto profile urinaryproteinsThe technology is tooupstream for costestimates.Page 16 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationDelivery/procurementchannelsSustainablebusinessmodelsDELFIA® Xpress PlGF kit(product # 6007-0010)Depending on the level oftechnology and the typeof personnel required, thetechnology may be at thereferral, clinic, orcommunity level (if it canbe a point-of-care [POC]test).Depending on thecountry, some countrieshave labs in healthcenters, but most will nothave labs in the mostperipheral health carefacilities. Ideally,biomarker screeninghappens at the firstantenatal visit and isintegrated into routineantenatal care (ANC).PerkinElmer, Inc. is amultinational companywith reported revenue ofapproximately US$1.7billion in 2010, servingcustomers in more than150 countries.Elecsys PIGF/sFLT-1and Elecsys PlGFDepending on thelevel of technologyand the type ofpersonnel required,the technology maybe at the referral,clinic, or communitylevel (if it can be aPOC test).Depending on thecountry, somecountries have labsin health centers, butmost will not havelabs in the mostperipheral healthcare facilities. Ideally,biomarker screeninghappens at the firstantenatal visit and isintegrated intoroutine ANC.Roche is the world’slargest biotechcompany.TECHNOLOGY/SOLUTIONChemical Biomarkers—TABLE 1Congo Red Dot Test Placental protein 13maternal serum markerDepending on thelevel of technologyand the type ofpersonnel required,the technology maybe at the referral,clinic, or communitylevel (if it can be aPOC test).Depending on thecountry, somecountries have labsin health centers, butmost will not havelabs in the mostperipheral healthcare facilities. Ideally,biomarker screeninghappens at the firstantenatal visit and isintegrated intoroutine ANC.Not determined.Depending on the levelof technology and thetype of personnelrequired, thetechnology may be atthe referral, clinic, orcommunity level (if itcan be a POC test).Depending on thecountry, some countrieshave labs in healthcenters, but most willnot have labs in themost peripheral healthcare facilities. Ideally,biomarker screeninghappens at the firstantenatal visit and isintegrated into routineANC.PerkinElmer, Inc. is amultinational companywith reported revenueof approximatelyUS$1.7 billion in 2010,serving customers inmore than 150countries.VEGFR-1preeclampsia markerDepending on thelevel of technologyand the type ofpersonnel required,the technology may beat the referral, clinic,or community level (ifit can be a POC test).Depending on thecountry, somecountries have labs inhealth centers, butmost will not havelabs in the mostperipheral health carefacilities. Ideally,biomarker screeninghappens at the firstantenatal visit and isintegrated into routineANC.Not determined.Predicting preeclampsiain normal and low-riskpregnancies: proteomicsto profile urinaryproteinsDepending on the level oftechnology and the typeof personnel required, thetechnology may be at thereferral, clinic, orcommunity level (if it canbe a POC test).Depending on thecountry, some countrieshave labs in healthcenters, but most will nothave labs in the mostperipheral health carefacilities. Ideally,biomarker screeninghappens at the firstantenatal visit and isintegrated into routineANC.Not determined.Page 17 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012DemandInformationExistingdemandAttractivenessPricesensitivityPolicyenvironmentDonors/stakeholdersPre- and postsalessupportNeed fordemandcreationDELFIA® Xpress PlGF kit(product # 6007-0010)The market size is drivenby the number ofpregnant women.Requires high capitalexpenditure and alaboratory setting.Elecsys PIGF/sFLT-1and Elecsys PlGFThe market size isdriven by thenumber of pregnantwomen.The test can be runin 18 minutes.TECHNOLOGY/SOLUTIONChemical Biomarkers—TABLE 1Congo Red Dot Test Placental protein 13maternal serummarkerThe market size isdriven by thenumber of pregnantwomen.This is possibly a POCtest.The market size isdriven by the numberof pregnant women.Early stage technology,not yet optimized forlow-resource settings.VEGFR-1preeclampsia markerThe market size isdriven by the numberof pregnant women.Early stagetechnology, not yetoptimized for lowresourcesettings.Predicting preeclampsiain normal and low-riskpregnancies: proteomicsto profile urinary proteinsThe market size is drivenby the number ofpregnant women.Early stage technology,not yet optimized for lowresourcesettings.No data available. No data available. No data available. No data available. No data available. No data available.Low-resource settingreferral systems are notyet set up toaccommodate positiveresults from a predictivePE/E screening test.Low-resource settingreferral systems arenot yet set up toaccommodatepositive results froma predictive PE/Escreening test.None. None. McKern Award forA POC test will requiretraining but little support.There is a strong need todevelop a system aroundthis technology whensensitivity and specificityare sufficient to warrantclinical use.A POC test willrequire training butlittle support.There is a strongneed to develop asystem around thistechnology whensensitivity andspecificity aresufficient to warrantclinical use.Low-resource settingreferral systems arenot yet set up toaccommodatepositive results froma predictive PE/Escreening test.Low-resource settingreferral systems are notyet set up toaccommodate positiveresults from apredictive PE/Escreening test.Low-resource settingreferral systems arenot yet set up toaccommodate positiveresults from apredictive PE/Escreening test.Low-resource settingreferral systems are notyet set up toaccommodate positiveresults from a predictivePE/E screening test.Perinatal Research. 14 None. Unknown at this time. Tommy’s.A POC test willrequire training butlittle support.There is a strongneed to develop asystem around thistechnology whensensitivity andspecificity aresufficient to warrantclinical use.A POC test will requiretraining but littlesupport.There is a strong needto develop a systemaround this technologywhen sensitivity andspecificity are sufficientto warrant clinical use.A POC test will requiretraining but littlesupport.There is a strong needto develop a systemaround thistechnology whensensitivity andspecificity aresufficient to warrantclinical use.A POC test will requiretraining but little support.There is a strong need todevelop a system aroundthis technology whensensitivity and specificityare sufficient to warrantclinical use.Page 18 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationDescriptionCharacteristicsapplicable for lowresourcesettingsDeveloper and/ormanufacturerProteomics in PEOver 500 plasmaproteins have beenidentified and developedin a novel massspectrometry method tosimultaneously measureup to 30 proteins in asingle sample.Researchers aim tomeasure the proteins ina much larger sample setto determine whichcombination of proteinswill be the most sensitivepredictive test for PE.Part of the Screening forPregnancy Endpoints(SCOPE) Consortium(known as the MAPSstudy in the UnitedKingdom). 10Screening anddiagnosis in high riskpregnant women: acombinationbiomarker assayProject to combinebiomarkerssimultaneously in asingle blood assay toenhance theirpredictivecapabilities and toprovide a convenienttool for clinical useand allow fast andeffective decisionmaking.10TECHNOLOGY/SOLUTIONChemical Biomarkers—TABLE 2Chronichypertension inpregnancy: urinebiomarkers for apredictive testProject to identifynovel chemicals inthe urine of womenwith hypertensionwhich may be usedto identify womenlikely to haveproblems in theirpregnancy. Urinarybiomarkers that willallow betterdiscriminationbetween raisedblood pressure andpreeclampsia willalso beinvestigated. 10Academic R&D level. Academic R&D level. Academic R&Dlevel.Richard Blankney,Manchester University,St. Mary's Hospital,Manchester, UKIan Crocker, St.Mary's Hospital,Manchester, UKDr. Kate Bramham,Dr. Lucy Chappell,Dr. Hiten Mistry, Pr.Lucilla PostonEpigenetic tool for PEpredictionProject to develop adatabase of epigeneticsignatures, changes inDNA and proteinscaused by nongeneticfactors such as poornutrition, smoking, andenvironmentalcontaminants thatcould be used aspredictors of PE, and acost-effectivediagnostic tool todetect these markers inblood or urine. 15Marinobufagenin as aPE indicatorStudy of initialevidence thatelevated levels of thesteroid hormonemarinobufagenin(MBG) in urine are avery early indicator ofPE in pregnantwomen. If true, thiscommon anddangerous conditioncould be diagnosedearly with a simpleurine dipstick test andpotentially preventedor treated with amolecule calledresibufogenin, whichcounteracts MBG. 16Low-cost sensing stripfor early detectionProject to develop a lowcostsensing strip with adiagnostic reader todiagnose PE. Thediagnosis is based uponthe fact that there is anelectrical current changewhen PE is present forthe early detection andmonitoring of thiscondition to avoid latestagepregnancycomplications. 16Academic R&D level. Academic R&D level. Academic R&D level.Mahua Choudhury ofUniversity of Colorado,USAJules Puschett, TAMUSHealth Science CenterResearch, USAZhenan Bao of StanfordUniversity, USAStatus Preclinical. Preclinical. Preclinical. Preclinical. Preclinical. Preclinical.Efficacy/Not yet determined. Not yet determined. Not yet determined. Not yet determined. Not yet determined. Not yet determined.effectivenessManufacturingquality andcapacityEarly-stagedevelopment—too soonto determine.Early-stagedevelopment—toosoon to determine.Early-stagedevelopment—toosoon to determine.Early-stagedevelopment—toosoon to determine.Early-stagedevelopment—toosoon to determine.Early-stagedevelopment—too soonto determine.Page 19 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationIntellectualpropertyownershipCost and costdriversDelivery/procurementchannelsSustainablebusiness modelsProteomics in PEScreening anddiagnosis in high riskpregnant women: acombinationbiomarker assayTECHNOLOGY/SOLUTIONChemical Biomarkers—TABLE 2Chronichypertension inpregnancy: urinebiomarkers for apredictive testEpigenetic tool for PEpredictionMarinobufagenin as aPE indicatorLow-cost sensing stripfor early detectionNot determined. Not determined. Not determined. Not determined. Not determined. Not determined.Technology tooupstream for costestimates.Depending on the levelof technology and thetype of personnelrequired, the technologymay be at the referral,clinic, or communitylevel (if it can be a POCtest).Depending on thecountry, some countrieshave labs in healthcenters but most will nothave labs in the mostperipheral health carefacilities. Ideally,biomarker screeninghappens at the firstantenatal visit and isintegrated into routineANC.Too early to determine.Technology tooupstream for costestimates.Depending on thelevel of technologyand the type ofpersonnel required,the technology maybe at the referral,clinic, or communitylevel (if it can be aPOC test).Depending on thecountry, somecountries have labs inhealth centers butmost will not havelabs in the mostperipheral healthcare facilities. Ideally,biomarker screeninghappens at the firstantenatal visit and isintegrated intoroutine ANC.Too early todetermine.Technology tooupstream for costestimates.Depending on thelevel of technologyand the type ofpersonnel required,the technology maybe at the referral,clinic, or communitylevel (if it can be aPOC test).Depending on thecountry, somecountries have labsin health centersbut most will nothave labs in themost peripheralhealth carefacilities. Ideally,biomarkerscreening happensat the firstantenatal visit andis integrated intoroutine ANC.Too early todetermine.Technology tooupstream for costestimates.Depending on the levelof technology and thetype of personnelrequired, thetechnology may be atthe referral, clinic, orcommunity level (if itcan be a POC test).Depending on thecountry, somecountries have labs inhealth centers but mostwill not have labs in themost peripheral healthcare facilities. Ideally,biomarker screeninghappens at the firstantenatal visit and isintegrated into routineANC.Too early to determine.Technology tooupstream for costestimates.Depending on thelevel of technologyand the type ofpersonnel required,the technology maybe at the referral,clinic, or communitylevel (if it can be aPOC test). Dependingon the country, somecountries have labs inhealth centers butmost will not havelabs in the mostperipheral health carefacilities. Ideally,biomarker screeninghappens at the firstantenatal visit and isintegrated intoroutine ANC.Too early todetermine.Technology tooupstream for costestimates.Depending on the levelof technology and thetype of personnelrequired, the technologymay be at the referral,clinic, or communitylevel (if it can be a POCtest).Depending on thecountry, some countrieshave labs in healthcenters but most will nothave labs in the mostperipheral health carefacilities. Ideally,biomarker screeninghappens at the firstantenatal visit and isintegrated into routineANC.Too early to determine.Page 20 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012DemandInformationExisting demandAttractivenessProteomics in PEThe market size is drivenby the number ofpregnant women.Early stage technology,not yet optimized forlow-resource settings.Screening anddiagnosis in high riskpregnant women: acombinationbiomarker assayThe market size isdriven by thenumber of pregnantwomen.Early stagetechnology, not yetoptimized for lowresourcesettings.TECHNOLOGY/SOLUTIONChemical Biomarkers—TABLE 2Chronichypertension inpregnancy: urinebiomarkers for apredictive testThe market size isdriven by thenumber of pregnantwomen.Early stagetechnology, not yetoptimized for lowresourcesettings.Epigenetic tool for PEpredictionThe market size isdriven by the numberof pregnant women.Early stagetechnology, not yetoptimized for lowresourcesettings.Marinobufagenin asa PE indicatorThe market size isdriven by thenumber of pregnantwomen.Early stagetechnology, not yetoptimized for lowresourcesettings.Low-cost sensing strip forearly detectionThe market size is drivenby the number ofpregnant women.Early stage technology,not yet optimized for lowresourcesettings.Price sensitivity Undetermined. Undetermined. Undetermined. Undetermined. Undetermined. Undetermined.PolicyenvironmentDonors/stakeholdersPre- and post-salessupportNeed for demandcreationLow-resource settingreferral systems are notyet set up toaccommodate positiveresults from a predictivePE/E screening test.Low-resource settingreferral systems arenot yet set up toaccommodatepositive results froma predictive PE/Escreening test.Low-resource settingreferral systems arenot yet set up toaccommodatepositive results froma predictive PE/Escreening test.Low-resource settingreferral systems arenot yet set up toaccommodate positiveresults from apredictive PE/Escreening test.Tommy’s Tommy’s Tommy’s Gates GrandChallenge, Round 6—April 2011.A POC test will requiretraining but littlesupport.There is a strong need todevelop a system aroundthis technology whensensitivity and specificityare sufficient to warrantclinical use.A POC test willrequire training butlittle support.There is a strongneed to develop asystem around thistechnology whensensitivity andspecificity aresufficient to warrantclinical use.A POC test willrequire training butlittle support.There is a strongneed to develop asystem around thistechnology whensensitivity andspecificity aresufficient to warrantclinical use.A POC test will requiretraining but littlesupport.There is a strong needto develop a systemaround thistechnology whensensitivity andspecificity aresufficient to warrantclinical use.Low-resource settingreferral systems arenot yet set up toaccommodatepositive results froma predictive PE/Escreening test.Gates GrandChallenge, Round 6—April 2011.A POC test willrequire training butlittle support.There is a strongneed to develop asystem around thistechnology whensensitivity andspecificity aresufficient to warrantclinical use.Low-resource settingreferral systems are notyet set up toaccommodate positiveresults from a predictivePE/E screening test.Gates Grand Challenge,Round 6—April 2011.A POC test will requiretraining but little support.There is a strong need todevelop a system aroundthis technology whensensitivity and specificityare sufficient to warrantclinical use.Page 21 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationDescriptionCharacteristicsapplicable for lowresourcesettingsDeveloper and/ormanufacturerStatusEfficacy/effectivenessManufacturingquality andcapacityIntellectualproperty (IP)ownershipCost and costdriversDelivery/procurementchannelsSustainablebusiness modelsTECHNOLOGY/SOLUTIONPhysical BiomarkersDoppler ultrasoundThe vascular dysfunction present in PE has been well documented. In normal pregnancies, the uterine vascular bed is a low-resistance circuit and bloodflow continues throughout diastole. As resistance increases, diastolic velocity diminishes in relation to systolic flow. Vascular resistance can be estimatedusing arterial velocity waveforms obtained by Doppler ultrasonography.The procedure requires an ultrasound instrument capable of performing Doppler analyses—as an example, the MicroMaxx TM ultrasound system (SonoSite,Inc.), a third-generation hand-carried product. The MicroMaxx TM system weighs less than eight pounds, is the size of a laptop computer, and deliversimage resolution and performance comparable to costly, conventional cart-based ultrasound systems weighing more than 200 pounds. SonoSitemanufactures durable portable ultrasound devices designed to withstand military usage, including a 30-inch drop test, and to require no maintenance.The moderate predictive power that can be achieved, and relatively high resources required, do not make uterine artery Doppler ultrasoundmeasurements a strong standalone candidate as a biomarker to be measured in resource-limited settings. Typically, this would be part of a screeningalgorithm.Multiple.Multiple commercialized.The currently available hemodynamic biomarkers—the uterine artery Doppler ultrasound measures—provide only moderate performance for detectingthe pathology underlying PE, and would be challenging to implement, due to the high level of resources required.Multiple in production capable of meeting anticipated demand.Highly competitive IP landscape.Instrument cost (US$20,000–US$60,000) is driven by IP and by the sensitive probe components.Data not available.Data not available.Page 22 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012DemandInformationExisting demandAttractivenessPrice sensitivityPolicyenvironmentDonors/stakeholdersPre- and post-salessupportNeed for demandcreationDoppler ultrasoundData not available.Data not available.Data not available.None.Imaging the World, etc.Requires extensive training.Data not available.TECHNOLOGY/SOLUTIONPhysical BiomarkersPage 23 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012References1 Cetin I, Huppertz B, Burton G, et al. Pregenesys pre-eclampsia markers consensus meeting: What do we require from markers, risk assessmentand model systems to tailor preventive strategies. Placenta. 2011;32(Suppl):S4–S16.2 PerkinElmer. Pre-eclampsia countdown newsletter. Waltham, MA: PerkinElmer, Inc.; 2009. Available at:http://www.perkinelmer.de/Content/RelatedMaterials/NLT_PlGFCountdownNews032010.pdf. Accessed January 12, 2012.3 Congo Red Dot Test for preeclampsia page. Maternal and Neonatal Directed Assessment of Technology (MANDATE) website. Available at:http://www.mnhtech.org/technology/technologies-in-development/congo-red-dot-test/. Accessed January 31, 2012.4 NOTE: Focused ANC is evidence-based, goal-directed care that is tailored to the gestational age of pregnancy and individualized to eachwoman. It emphasizes quality of visits over quantity of visits and is conducted by a skilled health care provider. Goals of focused ANC includeearly detection and treatment of complications, prevention of problems, birth preparedness/complication readiness, and the promotion ofhealthy practices to help ensure a positive health outcome for the woman and her baby. Focused ANC is provided through a women-centeredapproach that values the dignity and value of each woman and her family.5 Miraculins preeclampsia markers page. MANDATE website. http://mnhtech.org/technology/technologies-in-development/miraculins-preeclampsia-markers/.Accessed January 31, 2012.6 Preeclampsia page. Tommy’s website. Available at: www.tommys.org/Page.aspx?pid=358. Accessed January 31, 2012.7 NOTE: The official National Institutes of Health definition of a biomarker is a characteristic that is objectively measured and evaluated as anindicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.8 NOTE: The World Health Organization Sexually Transmitted Diseases Diagnostics Initiative (SDI) has developed the ASSURED criteria as abenchmark to decide if tests address disease control needs: Affordable, Sensitive, Specific, User-friendly, Rapid and robust, Equipment-free andDeliverable to end-users.9 Roche Diagnostics announces CE launch of first diagnostic Preeclampsia Test [press release] Rotkreuz, Switzerland: Roche Diagnostics; January6, 2009.10 Huynh N. Congo red dot test: a groundbreaking method to diagnose preeclampsia. Yale Scientific Magazine. 2003. Available at:http://www.yalescientific.org/2010/12/congo-red-dot-test-a-groundbreaking-method-to-diagnose-preeclampsia/. Accessed January 31, 2012.11 Mateus J, Lu F, Bytautiene E, et al. Effect of continuous infusion of vascular endothelial growth factor on blood pressure in a mouse model ofpreeclampsia induced by SFLT-1 overexpression. American Journal of Obstetrics and Gynecology. 2009;201(6 suppl):S12–S13.Page 24 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 201212 Ohkuchi A, Hirashima C, Suzuki H, et al. Evaluation of a new and automated electrochemiluminescence immunoassay for plasma sFlt-1 andPlGF levels in women with preeclampsia. Hypertension Research. 2010;33(5):422–427.13 Schiettecatte J, Russcher H, Anckaert E, et al. Multicenter evaluation of the first automated Elecsys sFlt-1 and PlGF assays in normalpregnancies and preeclampsia. Clinical Biochemistry. 2010;43(9):768–770.14 Yale-developed test can help predict and diagnose preeclampsia page. Innovations Report website. Available at: http://www.innovationsreport.com/html/reports/medicine_health/yale_developed_test_predict_diagnose_preeclampsia_147908.html.Accessed January 31, 2012.15 Epigenetic Diagnostic Tool page. MANDATE website. Available at: http://mnhtech.org/technology/technologies-in-development/epigeneticdiagnostic-tool/.Accessed January 31, 2012.16 Grants awarded page. Grand Challenges in Global Health website. Available at:http://www.grandchallenges.org/Explorations/Pages/GrantsAwarded.aspx?Topic=Create%20New%20Technologies%20to%20Improve%20the%20Health%20of%20Mothers%20and%20Newborns%20&Round=6&Phase=all. Accessed January 31, 2012.Page 25 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012Blood Pressure MeasurementHypertension in pregnancy is defined as a diastolic blood pressure (BP) reading >90 mm Hg or a systolic blood pressure reading >140 mm Hg ontwo consecutive readings four hours apart. It is generally accepted that the onset of a new episode of hypertension during pregnancy (withpersistent diastolic BP >90 mm Hg) with the occurrence of substantial proteinuria can be used as criteria for identifying preeclampsia. 1Unfortunately, in low-resource settings the detection of hypertension is often missed because suitable, accurate, and reliable BP measurementdevices are not available. If equipment is available in these settings, there is too often a lack of training in the skills and methods necessary to geta reliable measurement. 2World Health Organization (WHO) experts have determined that although the ausculatory 3 technique has remained essentially unchanged forover a century, this technique can be inaccurate due to a faulty application of the method and poor distinction of the different Korotkoff soundphases. In particular, the estimation of diastolic blood pressure using the auscultatory technique is limited in accuracy 2 and subject to observererror such as digit preference and observer bias. 4,5 Furthermore, concerns about the toxicity of mercury for the users and the environment haveadded to the body of evidence that traditional devices are inappropriate for low-resource settings. Some countries have banned the use ofmercury devices. There is a need for accurate and affordable BP measurement technologies.There are several barriers to accurate and affordable blood pressure measurement, particularly in developing countries. These include:The absence of accurate, easily-obtainable, inexpensive devices for BP measurement.The frequent marketing of non-validated BP measuring devices.The relatively high cost of BP devices given the limited resources available.Limited awareness of the problems associated with conventional BP measurement techniques.A general lack of trained manpower and limited training of personnel.The dabl® Educational Trust, Ltd. nonprofit sponsored by industry 6 maintains an up-to-date accuracy analysis of currently available BPmeasurement devices. To fulfill the requirements related to BP measurement in low-resource settings, a BP measuring device should beaffordable, easy to calibrate, and extremely simple to use but at the same time be accurate and robust so that it can be easily used for repeatedBP measurements. 2 In 2002 WHO established a committee to develop technical specifications for an accurate and affordable BP measuringdevice for clinical use in low-resource countries. 7 The objectives of the project were to elaborate on the preferred characteristics and to developPage 26 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012technical specifications for such a device. A challenge was issued by WHO to industry stipulating that devices fulfilling the specifications mustthen be subjected to independent validation according to the International Protocol of the European Society of Hypertension, 8 and havingfulfilled this requirement the device had then to undergo testing in field conditions according to a predetermined protocol in clinical andenvironmental circumstances that would reflect the ultimate circumstances of use.Out of several devices 9 tested, only one device—the Omron HEM-Solar—fulfilled the validation criteria of the International Protocol8 for systolicblood pressure and also performed well in field testing carried out on 716 subjects in three centers in Uganda and Zambia where health careworkers preferred it to the mercury sphygmomanometer. 10 Since a number of studies have demonstrated that oscillometric monitors mayproduce inaccurate measures in patients with heart and circulation problems (including preeclampsia), it is important to note that the OmronHEM-Solar has not yet been tested with pregnant women.Furthermore, the WHO specification for low-cost BP devices has forced oscillometric device manufacturers to choose lower-quality sensors thatare more subject to drift and errors associated with mishandling. Thus, the importance of frequent calibration cannot be underestimated. Thatsaid, adherence to a calibration schedule and any equipment maintenance is a general shortcoming in most low-resource settings, thus there is atradeoff between cost of the device and accuracy when normal calibrations cannot be guaranteed. In conjunction with advancing novel BPmeasurement technologies, there is a need to solve the calibration challenge by developing calibration technologies and devices that need lessfrequent calibration or none at all and by developing calibration standards and processes that are low cost and require minimal skills toimplement. Duke University is working on a simple calibration tool design that leverages basic manometer principles and a column of water thatcan be fabricated on site from local materials.To impact morbidity and mortality from preeclampsia/eclampsia, access to BP measurement should be extended to the community level, thusgreatly improving identification of women with hypertension and, by consequence, increasing the chance that she will have access to thetreatment package 1 and increasing the likelihood that she and her baby will survive.The two tables below scrutinize promising BP measurement devices and methods.Page 27 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationDescriptionCharacteristicsapplicable forlow-resourcesettingsDeveloperand/ormanufacturerGeneric ausculatory mercury bloodpressure measurement kits withstethoscopeThese devices are used to measure BPaccording to the original ausculatorytechnique described by Riva Rocci andKorotkoff over a century ago. The measuringobserver must be trained to use astethoscope to auscultate the Korotkoffsounds over the brachial artery. Thistechnique is usually referred to asconventional blood pressure measurement.Gold standard with regards to accuracy ingeneral population and pregnant women.No external power requirements,TECHNOLOGY/SOLUTION—TABLE 1Generic ausculatory (aneroid and digital) bloodpressure measurement kits with stethoscopesuch as the PrestigeUse same ausculatory principle as traditionalmercury BP measurement devices. Both aneroidand digital have the advantage of obviating useof toxic mercury though aneroid is moresusceptible to terminal digit bias. Both aneroidand digital require frequent calibration and aresubject to inaccurate readings when exposed toharsh handling.No toxic mercury.Digital blood pressure measurement kits requirebatteries.Accoson Greenlight 300Manual, self-calibrating, Hg-free, ausculatory device.Self-calibration obviates need for gold standard andappropriate skill set for six-month calibration cycle andensures accuracy.No toxic mercury; needs batteries.Multiple. Multiple. Accoson; developed in a joint project by AC Cossor &Son, the Regional Medical Physics Department of theFreeman Hospital, and the University of Newcastle.Status Multiple commercialized and validated. Multiple commercialized and validated to BritishHypertension Society (BHS) protocol.Efficacy/effectivenessOnly one model of the many mercurysphygmomanometers available, the PyMah(Pymah Corporation, Flemington, NJ), hasbeen validated according to both protocolsand is recommended. Because mercurysphygmomanometers generally adhere to abasic design with standard components, it isprobably reasonable to assume that most, ifnot all, mercury sphygmomanometers wouldbe of similar accuracy.The standard aneroid sphygmomanometer hasonly been formally validated according to thecalibration procedure of the BHS protocol, andthe results support reservations about aneroiddevices because of their susceptibility tobecoming inaccurate with use without this beingapparent to the user.Commercialized and validated to BHS protocol.US Food and Drug Administration approved.Compliant with the European standards EN1060-1,EN1060-2 and EN1060-3.First non-automated mercury-free device forausculatory BP measurement to pass the InternationalProtocol for validation of BP measuring devices inadults. 11The Greenlight 300 has been validated to theInternational Protocol by Graves, et al. 11Not evaluated yet for use in detecting hypertension inpregnant women.No evidence of use or acceptability for low-resourcesettings though the self-calibration feature is verystrong and is unique to this device.Page 28 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationManufacturingquality andcapacityIntellectualproperty (IP)ownershipCost and costdriversDelivery/procurementchannelsSustainablebusiness modelsTECHNOLOGY/SOLUTION—TABLE 1Generic ausculatory mercury bloodpressure measurement kits withstethoscopeGeneric ausculatory (aneroid and digital) bloodpressure measurement kits with stethoscopesuch as the PrestigeAccoson Greenlight 300Multiple manufacturers of this technology. Multiple manufacturers of this technology. Manufactured in the UK; likely high ability to meetpotential demand as the manufacturer exportsproducts to more than 70 countries.Mature technology, no IP barriers. Mature technology, very low IP barriers. Very likely the self-calibrating feature is covered by IP.US$30The market is highly competitive withsourcing of production to low-cost regionssuch as Asia-Pacific. 1 ~US$10; branded devices ~US$25. US$230Could be used at the community level. Could be used at the community level. Three US distribution offices and one internationaldistribution office in the United Kingdom. Noindications of low-resource setting distribution.Presence of multiple manufacturers isevidence that this market is sustainable.Presence of multiple manufacturers is evidencethat this market is sustainable.Could be used at the community level.The company is a registered, quality-assured firm underISO9001:2000.Page 29 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012DemandInformationExisting demandAttractivenessPrice sensitivityPolicyenvironmentGeneric ausculatory mercury bloodpressure measurement kits withstethoscopeThe application of this technology is broaderthan just screening or diagnosis forhypertension in pregnant women. Thereforethe market size is driven by the number ofhealth facilities, providers, and communities.Jhpiego estimates that the BP measurementmarket is 10 million units (unsubstantiatedestimate) 12A market research report forecasts that theBP measurement market will be US$2.2billion by 2015, driven largely by “anexpanding proportion of old age peoplesuffering from BP problems, technologicaladvancements in monitors, growingconsumer awareness about benefits ofregular measurements and monitoring,intensifying direct-to-consumer advertisingand growing stress on health care indeveloping countries.” 13Gold standard but requires extensivetraining.Mercury is an expensive commodity and themarket is decreasing. Expect both supplyand demand to drop off substantially overthe next decade. Customers will be lessinterested over time.Mercury sphygmomanometers are typicallythe gold standard for the European Societyof Hypertension International Protocol (ESH-IP) protocols. Alternative approaches such asintra-arterial blood measurement are notpractical.TECHNOLOGY/SOLUTION—TABLE 1Generic ausculatory (aneroid and digital) bloodpressure measurement kits with stethoscopesuch as the PrestigeThe application of this technology is broaderthan just screening or diagnosis forhypertension in pregnant women. Therefore themarket size is driven by the number of healthfacilities, providers, and communities.Jhpiego estimates that the BP measurementmarket is 10 million units (unsubstantiatedestimate) 12A market research report forecasts that the BPmeasurement market will be US$2.2 billion by2015, driven largely by “an expandingproportion of old age people suffering from BPproblems, technological advancements inmonitors, growing consumer awareness aboutbenefits of regular measurements andmonitoring, intensifying direct-to-consumeradvertising and growing stress on health care indeveloping countries.” 13Low cost but requires frequent calibration.In general, hospital market is used to payingquite a bit for these as sophisticated medicaldevices in developed countries while developingcountries are discovering the big box store,Chinese-made versions that are typically notrobust and do not offer any indication to theuser that accuracy is inadequate. Need usertraining to identify calibration and qualityconcerns in order to increase willingness to payfor quality.In 2010, a revised version of the ESH-IP withmore stringent criteria was published.Accoson Greenlight 300The application of this technology is broader than justscreening or diagnosis for hypertension in pregnantwomen. Therefore the market size is driven by thenumber of health facilities, providers, and communities.Jhpiego estimates that the BP measurement market is10 million units (unsubstantiated estimate). 12A market research report forecasts that the BPmeasurement market will be US$2.2 billion by 2015,driven largely by “an expanding proportion of old agepeople suffering from BP problems, technologicaladvancements in monitors, growing consumerawareness about benefits of regular measurements andmonitoring, intensifying direct-to-consumer advertisingand growing stress on health care in developingcountries.” 13Self-calibration feature is a very strong feature that isunique to this device.Willingness to pay for zero calibration has not beendetermined. Need a cost-effectiveness study that looksat both improvement in clinical outcomes and the costsavings associated with obviating need for thecalibration process.Negotiated prices for large-scale public healthpurchases have not been determinedIn 2010, a revised version of the ESH-IP with morestringent criteria was published.Page 30 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012DemandInformationDonors/stakeholdersPre- and postsalessupportNeed fordemandcreationTECHNOLOGY/SOLUTION—TABLE 1Generic ausculatory mercury bloodpressure measurement kits withstethoscopeGeneric ausculatory (aneroid and digital) bloodpressure measurement kits with stethoscopesuch as the PrestigeAccoson Greenlight 300None. None. Mayo Clinic, Rochester, and the Mayo Foundation.Requires the most training. Requires frequent calibration. Does not require calibration.Cost and how easy the device is to calibrateare important factors if the device isintended for care at the community level.However, at this point, there is a trade-offbetween cost and how easy the device is tocalibrate.Cost and how easy the device is to calibrate areimportant factors if the device is intended forcare at the community level. However, at thispoint, there is a trade-off between cost and howeasy the device is to calibrate.Cost and how easy the device is to calibrate areimportant factors if the device is intended for care atthe community level. However, at this point, there is atrade-off between cost and how easy the device is tocalibrate.Page 31 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationDescriptionCharacteristicsapplicable forlow-resourcesettingsDeveloperand/ormanufacturerAutomated and semi-automated oscillometricdevices (Omron HEM-Solar [M1 Plus])Automated and semi-automated (requiring handpumping to pressurize cuff) devices removesources of error such as observer bias andterminal digit preference and thereby improvethe overall accuracy.Oscillometric devices do not use the auscultationof Korotkoff sounds but instead detectoscillations in the occluded artery as the cuff isdeflated and calculate BP using algorithms.The Omron HEM-Solar is a semiautomatic solarpoweredBP monitor and the only one of its classto receive a recommendation from the dabl®Educational Trust.Oscillometric devices are becoming moreaccurate, and the revised ESH-IP, byacknowledging this trend, will allow moreaccurate devices to enter the market.The indirect nature of oscillatory BPmeasurement poses particulary problems forensuring accuracy. Critical assessment has donemuch to improve standards, but a solidtheoretical understanding of the technique hasnot been formulated, and further work isrequired.Eliminates observer bias and terminal digitrounding.The device can run on batteries as well as solarpower.Omron.TECHNOLOGY/SOLUTION—TABLE 2Tensoval duo-control deviceNoninvasive BP measurement is typicallydependent on either auscultation or oscillometry.The Tensoval duo-control device uses auscultatoryand oscillometric technology to determine BP.Uses two modes to improve accuracy in subsetpopulations such as pregnant women.Needs batteries.Hartmann-Ricowww.hartmann.dewww.tensoval.comStatus Commercialized and validated to BHS protocol. Commercialized and validated to BHS with a gradeA recommendation. 14Clinical study underway in rural Africa (Ethiopia,Tanzania, and Zambia) under the CRADLE (formerlyCOBRA) project. 15Center for Bioengineering Innovation & Designhypertension detection device 12Handcrank power source; no readout—simplyyes/no result for hypertension; designed for lowcost

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationEfficacy/effectivenessManufacturingquality andcapacityIntellectualpropertyownershipCost and costdriversDelivery/procurementchannelsAutomated and semi-automated oscillometricdevices (Omron HEM-Solar [M1 Plus])The Omron HEM-Solar is the only BPmeasurement device that meets WHOspecifications and has been validated accordingto the International Protocol of the EuropeanSociety of Hypertension. While this devicepassed laboratory testing, field tests in Ugandaand Zambia demonstrated the device fulfilledcriteria for systolic BP but not diastolic BP. Thedevice has not been evaluated yet for use indetecting hypertension in pregnant women.Manufactured in Japan.Likely high ability to meet potential demand asthe manufacturer is a large international supplierof BP measurement technology.A live teardown indicates that there is nopatentable hardware to the technology thoughthe algorithms are coded and are thereforeTECHNOLOGY/SOLUTION—TABLE 2Tensoval duo-control deviceValidated to the BHS standard.Not evaluated yet for use in detectinghypertension in pregnant women.Manufactured in Germany.Likely high ability to meet potential demand as themanufacturer is a large international supplier ofmedical products.Center for Bioengineering Innovation & Designhypertension detection device 12Not yet determined per establishedinternational protocols. Not evaluated yet foruse in detecting hypertension in pregnantwomen.Developer is investigating Chinesemanufacturing due to low costs.Proprietary technology. Needs to be evaluated.~US$32 to US$130 ~US$75 17 A sub US$10 device seems aspirational. Jhpiegostates that cost of goods is currently at US$15per unit, 12 however this has not beenconfirmed. There are similar devices on themarket for ~US$30. At this low end, it may bevery difficult to sell at 1M units per year. Hand-crankcharging may not be cost effective usingPowerfree Education and Technology (PET) andFreeplay Energy technologies as a baseline forthe added cost of hand-crank power. There isconsiderable extra cost for the crank parts andstorage capacitor.Could be used at the community level. Product launched in Europe in drugstores in 2007.In 2008, Tensoval captured 20 percent of the BPmeasuring devices in the European pharmacymarket.Product launched in China in July 2010. 18Could be used at the community level.Not yet commercialized.Could be used at the community level.Page 33 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationSustainablebusiness modelsAutomated and semi-automated oscillometricdevices (Omron HEM-Solar [M1 Plus])Surprisingly, manufacturers have been slow toproduce automated sphygmomanometers forclinical use in hospitals to satisfy the large marketthat has arisen from the banning of mercury insome countries and the recommendation not toreplace mercury sphygmomanometers in others,such as the United Kingdom and Ireland. There isevidence that the manufacturing industry is nowaware of the need for accurate automateddevices to replace mercurysphygmomanometers. 19TECHNOLOGY/SOLUTION—TABLE 2Tensoval duo-control deviceThis is a new class of BP measurement devicestargeted at niche markets/specific populationswith pathologies that lead to common BPmeasurement error.Center for Bioengineering Innovation & Designhypertension detection device 12Product still in development phase.DemandInformationExisting demandAutomated and semi-automated oscillometricdevices (Omron HEM-Solar [M1 Plus])The application of this technology is broader thanjust screening or diagnosis for hypertension inpregnant women. Therefore the market size isdriven by the number of health facilities,providers, and communities.TECHNOLOGY/SOLUTION—TABLE 2Tensoval duo-control deviceThe application of this technology is broader thanjust screening or diagnosis for hypertension inpregnant women. Therefore the market size isdriven by the number of health facilities,providers, and communities.Center for Bioengineering Innovation & Designhypertension detection device 12The application of this technology is broaderthan just screening or diagnosis forhypertension in pregnant women. Therefore themarket size is driven by the number of healthfacilities, providers, and communities.Jhpiego estimates that the BP measurementmarket is 10 million units (unsubstantiatedestimate). 12Jhpiego estimates that the BP measurementmarket is 10 million units (unsubstantiatedestimate). 12Jhpiego estimates that the BP measurementmarket is 10 million units (unsubstantiatedestimate). 12A market research report forecasts that the BPmeasurement market will be US$2.2 billion by2015, driven largely by “an expanding proportionof old age people suffering from BP problems,technological advancements in monitors, growingconsumer awareness about benefits of regularmeasurements and monitoring, intensifyingdirect-to-consumer advertising and growingstress on health care in developing countries.” 13A market research report forecasts that the BPmeasurement market will be US$2.2 billion by2015, driven largely by “an expanding proportionof old age people suffering from BP problems,technological advancements in monitors, growingconsumer awareness about benefits of regularmeasurements and monitoring, intensifying directto-consumeradvertising and growing stress onhealth care in developing countries.” 13A market research report forecasts that the BPmeasurement market will be US$2.2 billion by2015, driven largely by “an expandingproportion of old age people suffering from BPproblems, technological advancements inmonitors, growing consumer awareness aboutbenefits of regular measurements andmonitoring, intensifying direct-to-consumeradvertising and growing stress on health care indeveloping countries.” 13Page 34 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012DemandInformationAttractivenessPrice sensitivityAutomated and semi-automated oscillometricdevices (Omron HEM-Solar [M1 Plus])According to WHO-sponsored researchers:“There was no need to assess competencebecause unlike auscultatory measurement thedevice is simple to use and no testing ofindividual competence is required.”It performed well in field testing carried on 716subjects in three centers in Uganda and Zambiawhere health care workers preferred it to themercury sphygmomanometer. 10 Some 85 percentof health care professionals rated the solar deviceas good or very good, with 97 percentrecommending its use.In general, the hospital market is use to payingquite a bit for these as sophisticated medicaldevices in developed countries while developingcountries are discovering the big box store,Chinese-made versions that are typically notrobust and do not offer any indication to the userthat accuracy is inadequate.TECHNOLOGY/SOLUTION—TABLE 2Tensoval duo-control deviceUses two modes to improve accuracy.Niche market will prevent scaling required todecrease prices to be competitive. Customerswilling to pay quite a bit to get the performance.Center for Bioengineering Innovation & Designhypertension detection device 12It will be very difficult for this product to meetthe WHO specifications for appropriatetechnologies for low-resource settings and for itto pass BHS protocol as there is no BP readout.This limits its utility and market as BP trending isan important metric to rule out whitecoathypertension etc.Seems the limited performance (non-numericreadout) will limit the market to lowestresourceniche.Decreased willingness to pay.PolicyenvironmentDonors/stakeholdersPre- and postsalessupportNeed fordemandcreationNeed user training to identify calibration andquality concerns in order to increase willingnessto pay for quality.In 2010, a revised version of the ESH-IP withmore stringent criteria was published.Validation study supported by the WHOCommittee on Blood Pressure Measurement inLow-Resource Settings.Requires calibration.Requires 15 minutes of training.Cost and how easy the device is to calibrate areimportant factors if the device is intended forcare at the community level. However, at thispoint, there is a trade-off between cost and howeasy the device is to calibrate.Nothing specific to note.Clinical study funded by Tommy’s—a charityregistered in England that funds research. 15Research partners include:Women's Academic Health Centre, King’s HealthPartners, King’s College London.Requires calibration.Cost and how easy the device is to calibrate areimportant factors if the device is intended for careat the community level. However, at this point,there is a trade-off between cost and how easy thedevice is to calibrate.In 2010, a revised version of the ESH-IP withmore stringent criteria was published.Jhpiego developed this technology under a fiveyearproject called Accelovate which is fundedby the United States Agency for InternationalDevelopment. 20Requires calibration.Cost and how easy the device is to calibrate areimportant factors if the device is intended forcare at the community level. However, at thispoint, there is a trade-off between cost and howeasy the device is to calibrate.Page 35 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012References1 World Health Organization (WHO).WHO Recommendations for Prevention and Treatment of Pre-Eclampsia and Eclampsia. Geneva: WHO;2011. Available at: http://whqlibdoc.who.int/publications/2011/9789241548335_eng.pdf. Accessed February 1, 2012.2 WHO. Affordable Technology. Blood Pressure Measuring Devices for Low Resource Settings. Geneva: WHO; 2005. Available at:http://whqlibdoc.who.int/publications/2005/9241592648.pdf. Accessed February 1, 2012.3 NOTE: The auscultatory technique for measuring BP consists of the transmission and interpretation of the Korotkoff sound signals from asubject to an observer via a device. This technique requires that observers be trained and assessed for accuracy and auditory acuity and requiresa good quality stethoscope and a mercury or aneroid sphygmomanometer.4 Villar J, Repke J, Markush L, Calverty W. The measuring of blood pressure during pregnancy. American Journal of Obstetrics & Gynecology.October 1989;161(4):1019–1024.5 Villar J, Say L, Shennan A, et al. Methodological and technical issues related to the diagnosis, screening, prevention, and treatment of preeclampsiaand eclampsia. International Journal of Gynaecology and Obstetrics. 2004:S28–S41.6 Sphygmomanometers for clinical use web page. dabl ® Educational Trust website. Available at:http://www.dableducational.org/sphygmomanometers/devices_1_clinical.html#ManualTable. Accessed February 1, 2012.7 Parati G, Mendis S, Abegunde D, et al. Recommendations for blood pressure measuring devices for office/clinic use in low resource settings.Blood Press Monitoring. 2005;10:3–10.8 O’Brien E, Pickering T, Asmar R, et al. on behalf of the Working Group on Blood Pressure Monitoring of the European Society of Hypertension.International protocol for validation of blood pressure measuring devices in adults. Blood Pressure Monitoring. 2002;7:3–17.9 NOTE: Three devices were tested from manufacturers Spacelabs, Microlife, and Omron.10 Parati G, Ochan Kilama M, Faini A, et al. A new solar powered blood pressure measuring device for low resource settings. Hypertension.2010;56:1047–1053.11 Graves JW, Tibor M, Murtagh B, Klein L, Sheps SG. The Accoson Greenlight 300—the first non-automated mercury-free blood pressuremeasurement device to pass the International Protocol for blood pressure measuring devices in adults. Blood Pressure Monitoring. 2004;9:13–17.12 Trachtenberg M, Lee S, Jayaram G, Acharya S, Sanghvi H, Thakor N. Hypertension detector for developing countries. Available at:https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/34123/BP_paper1.pdf. Accessed February 1, 2012.Page 36 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 201213 Market research on blood pressure monitoring and measuring instruments. Available at:http://www.prweb.com/releases/blood_pressure_monitoring/BP_measurement_instrument/prweb4720184.htm. Accessed February 1, 2012.14 De Greeff A, Arora J, Hervey S, et al. Accuracy assessment of the Tensoval duo control according to the British and European HypertensionSocieties' standards. Blood Pressure Monitoring. April 2008;13(2):111-116.15Pre-eclampsia web page. Tommy’s website. Available at: http://www.tommys.org/Page.aspx?pid=358. Accessed February 1, 2012.16 UBM TechInsights presentation on Omron-HEM-Solar device. Available at:http://www.ubmtechinsights.com/uploadedFiles/Public_Website/Website_Pages/Markets_Served/Medical_Devices/Omron-HEM-Solar-LTD-DesignMed.pdf. Accessed February 1, 2012.17 Tensoval Duo Control product pricing and information. http://www.docsimon.com/article/tensoval-duo-control-digital-blood-pressuremonitor-cuff-22-32cm.Accessed February, 2012.18 Hartman news and media web page. Hartman website. Available at: http://en.cn.hartmann.info/81.php. Accessed February 3, 2012.19 Classification of sphygmomanometers web page. dabl ® Educational Trust website. Available at:http://www.dableducational.org/sphygmomanometers.html#mercury. Accessed February 1, 2012.20 LoLordo A. Jhpiego receives $24.9 mill to innovate lifesaving tech. The JHU Gazette. October 24, 2011. Available at:http://gazette.jhu.edu/2011/10/24/jhpiego-receives-24-9-mill-to-innovate-lifesaving-tech/.Page 37 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012Proteinuria MeasurementProteinuria is defined as more than 300 mg of protein in the urine per 24 hours, and its presence along with hypertension, confirms diagnosis ofpreeclampsia in a pregnant woman. Positive maternal and perinatal outcomes for women with preeclampsia/eclampsia (PE/E) depend on howsoon the condition is identified and how quickly the woman has access to the treatment package. 1 Secondary prevention for PE/E has focused onantenatal screening for high blood pressure and proteinuria as part of focused antenatal care (ANC). 2 The presence of proteinuria changes thediagnosis from gestational hypertension to PE, and detection of proteinuria is vital for making a diagnosis of PE. There are currently several waysto measure protein in the urine, but these vary in accuracy, cost, simplicity, and feasibility. Measurement of protein in a 24-hour urine collectionis considered the gold standard and more recently 12-hour collections (and even 2-hour collections) have been validated, but such collectionsare not always feasible and may be impractical in low-resource settings. Although the use of dipsticks to analyze random urine samples isrelatively simple, several challenges hinder their effectiveness including poor correlation with protein analysis in 24-hour urines, inaccuracy dueto the hour-to-hour variability of protein excretion, inaccuracy if the urine is dilute, dependency on observer interpretation, a possible falsepositive if the pregnant woman has a urinary tract infection or the urine is contaminated with blood or vaginal secretions, and the susceptibilityof dipsticks to deterioration from humidity and temperature. Problems with dipstick analysis can be avoided by measuring the urine’s proteinto-creatinineratio, but this may be impractical if urgent assessment is needed and cannot be used for monitoring or quantifying proteinuria inpregnancy. There are urinalysis devices that are promising, such as a cartridge-based automated analyzer and creatinine/protein dipsticks, butthese require additional testing and/or adaptation to make them more accurate, simple, or affordable.In low-resource settings, protein dipsticks are often used at the point of care. This is because implementing the gold standard of proteinmeasurement (urine collection over 24 hours and analysis using a manual or automated methods) is not practical in such a setting. Commondipsticks typically detect albumin through a reaction with a blue dye. However, their correlation with 24-hour test results can vary. Moreadvanced dipsticks measure the ratio of protein to creatinine which can correlate more closely to 24-hour tests. Dipsticks can be assessedagainst a standard color or fed into an automated reader. Automated readers help standardize dipstick results.The table below examines several options for proteinuria measurement—both technologies commonly used and in development.Page 38 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationDescriptionCharacteristicsapplicable forlow-resourcesettingsDeveloper and/ormanufacturerUNICEF Supply Catalogueurine dipstickMedi-Test Combi 2 teststrips detect the presenceof glucose and protein(albumin) in urine.Results in 60 seconds.Point of use. No powersupply needed.TECHNOLOGY/SOLUTIONBayer Multistix Pro 10LS Bayer Clinitek 50 Bayer DCA 2000 (nowcalled DCA Vantage)Creatinine/protein dipstick;firm plastic strips with severalseparate reagent areas;results in 60 seconds.The strips may be readvisually, requiring noadditional laboratoryequipment for testing.However, dipstick resultsagree better with thequantitative assays if read bya reflectometer. 3Can be read instrumentally,using the Bayer Clinitek®family of urine chemistryanalyzers and theappropriate programmodule/card. An example isthe Bayer Clinitek 50 UrineChemistry Analyzer.Point of use. No powersupply needed.Quantitative dipstickreader.Lightweight, portable.Does not correct forcreatinine thus bettersuited to 12- or 24-hourassessment (not spot).Less than a minute.No interpretation of resultsrequired.Multiple markets across allurinalysis including:leukocytes, ketone, pH,blood, glucose, specificgravity, protein, bilirubin,nitrite, and urobilinogen.Optional battery packallows 200 dipstick readsper charge—obviatingneed for reliable power.Cartridge-basedautomatedalbumin/creatinine ratio(ACR) analyzer thatprovides an immediateresult (7 minutes) of theACR on spot urine.Load cartridge with sampleand insert into theanalyzer. Device stores upto 4000 records; easilydownloaded andtransferred to a PC. Printresults.Color touch-screen display.Corrects for creatinine.Power supply needed; ACRcan be performed on spoturine by an automatedanalyzer.Center for BioengineeringInnovation and Design(CBID) proteinuria penA pregnant woman’s urineis exposed to a mark onpaper made by a felt-tip orballpoint pen filled withtesting solution, which isthen exposed to a pregnantwoman’s urine. If the markturns the color of the pen’scap, the test is positive.Gives albumin but notcreatinine.Takes less than a minute.Point of use. No powersupply needed.Macherey-Nagel GmbH Bayer/Siemens Bayer/Siemens Bayer/Siemens CBID and Jhpiego at theJohns Hopkins University.Status Commercialized. Commercialized. Commercialized. Commercialized. Preclinical; Jhpiego andCBID will continue to refinethe design and engineeringand then conduct a pilotstudy in rural southernNepal to assess the test’sacceptability and feasibilityfor use at the communityand household levels bycommunity health workersand pregnant women.Page 39 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationEfficacy/effectivenessUNICEF Supply Catalogueurine dipstickPoor correlation withprotein analysis in 24-hoururines; inaccuracy due tothe hour-to-hour variabilityof protein excretion;inaccuracy if the urine isdilute; dependency onobserver interpretation; apossible false positive if thepregnant woman has aurinary tract infection orthe urine is contaminatedwith blood or vaginalsecretions.TECHNOLOGY/SOLUTIONBayer Multistix Pro 10LS Bayer Clinitek 50 Bayer DCA 2000 (nowcalled DCA Vantage)Protein/creatinine dipstickshave limited utility as ascreening tool in pregnantwomen. While nonpregnantcohorts show sensitivity andspecificity of 53.7% and97.6%, respectively, thedevice does not work as wellfor pregnant cohorts(sensitivity: 19%–59%;specificity: 45.4%–84.2%). 4As a quantitative tool,enables trend tracking. Nostudies correlate thisdevice directly to PE/Eoutcomes, and systematicreviews have called intoquestion the correlation ofproteinuria quantificationto clinical outcomes.As a spot reader, a veryquestionable correlation toclinical outcomes and not asubstantial improvementover dipsticks to warrant$500.As a total protein readerover 12/24 hours, clinicalcorrelation is weak but isbetter than a spot dipstick.Much better as a spotreader than non-creatininecorrection tests, thoughcorrelation of albumin-onlyprotein readers to overallmaternal outcomes is quiteweak.The ACR (DCA 2000) isstrongly predictive for thepresence or absence ofsignificant proteinuria,with positive likelihoodratio of 27.4 and negativelikelihood rates of 0.0. 5The device tested washighly accurate, allowingthe authors to set athreshold that detectedsignificant proteinuria witha sensitivity of 94% and aspecificity of 94%. 5Center for BioengineeringInnovation and Design(CBID) proteinuria penPilot study in Nepal; resultsare not yet available.It has been hypothesizedthat microalbuminuria mayfacilitate diagnosis ofpreeclampsia earlier in itsclinical course, as it mayaccurately reflectglomerular dysfunction.However, currently theevidence for this isinconclusive. 6Page 40 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationManufacturingIntellectualpropertyownershipCost and costdriversDelivery/procurementchannelsSustainablebusiness modelsUNICEF Supply Catalogueurine dipstickThere are a series of Medi-Test paper strip tests formultiple diagnoses, andthey distribute worldwide.Unclear; distributed byUNICEF but perhapsMacherey-Nagel GmbH stillretains IP for private-sectordistribution.US$3.28 for a pack of 100or ~US$.04 per test for. 8TECHNOLOGY/SOLUTIONBayer Multistix Pro 10LS Bayer Clinitek 50 Bayer DCA 2000 (nowcalled DCA Vantage)We do not see significant Large market, multipleincreased demand for this analytes. This technology istype of test until both representative of severalsensitivity and specificity in that do similar urinalysisdetecting proteinuria in function. Competitionpregnant women increases. exists though Bayer is asubstantial player in thismarket. Suspect changes indemand will not overcomemanufacturing capacity orability to predict and adjustcapacity.Priority technology by This is a simple dipstickSiemens/Bayer. However, it is reader—many similarlikely all relevant patents are products with someexpired since this technology variation in the actualhas been on the market since reagents and strip tests IP1978 or earlier. 7 (likely patents andmanufacturing know-how).As a mature technology,patents are likely expired.One bottle of 100 strips forUS$349.95 or US$3.50 pertest. 9Lowest cost of quantitativereaders at US$500.Large market, multipleanalytes. This technology isrepresentative of severalthat do similar urinalysisfunction. Competitionexists though Bayer is asubstantial player in thismarket. Suspect changes indemand will not overcomemanufacturing capacity orability to predict and adjustcapacity.Priority technology bySiemens/Bayer.The analyzer costsUS$2,500 to US$5000. Themicroalbumin/ creatinineregent kits cost US$100 forten (US$10 each).Community. Community. Clinic. Point-of-care test;therefore can be used inantenatal clinics.These products have beenon the market for a longtime. Less risk here until abetter product comes up.Multinational corporationwith this product on themarket for a long time. Lessrisk here until a betterproduct comes up.This could be positioned asa more portable labindependenttechnologybased on the batterypower flexibility.This test was originallydeveloped for women withdiabetes to screen formicro-albuminuria as anearly indicator of renaldisease but has beenassessed specifically forpregnancy hypertension.Center for BioengineeringInnovation and Design(CBID) proteinuria penManufacturing strategy notyet developed.Data not available.Designed to be cheaperthan current strip tests.Developers assert that theprice will be ~US$1.00/pen(400 tests).Community.Unknown, as the exactniche of this product isunclear.Page 41 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012DemandInformationExisting demandAttractivenessUNICEF urine dipstick(Medi-Test Combi 2)Market size is driven bythe number of pregnantand postpartum women.All pregnant womenshould receive a dipsticktest at the first ANC visit,at 20 weeks, if bloodpressure is elevated,when they arrive in labor,and at postpartum visits(2 days and 7 dayspostpartum). Once PE isdiagnosed, a woman willbe tested many times.Can be read visually.Result in 1 minute.TECHNOLOGY/SOLUTIONBayer Multistix Pro 10LS Bayer Clinitek 50 Bayer DCA2000 (nowcalled DCA Vantage)Market size is driven by thenumber of pregnant andpostpartum women. Allpregnant women shouldreceive a dipstick test at thefirst ANC visit, at 20 weeks, ifblood pressure is elevated,when they arrive in labor,and at postpartum visits (2days and 7 dayspostpartum). Once PE isdiagnosed, a woman will betested many times.Can be read visually. Resultin 1 minute.Market size is driven by thenumber of pregnant andpostpartum women. Allpregnant women shouldreceive a dipstick test atthe first ANC visit, at 20weeks, if blood pressure iselevated, when they arrivein labor, and at postpartumvisits (2 days and 7 dayspostpartum). Once PE isdiagnosed, a woman will betested many times.Quantitative result—nointerpretation of resultsrequired. Result in 1minute.Market size is driven by thenumber of pregnant andpostpartum women. Allpregnant women shouldreceive a dipstick test atthe first ANC visit, at 20weeks, if blood pressure iselevated, when they arrivein labor, and at postpartumvisits (2 days and 7 dayspostpartum). Once PE isdiagnosed, a woman will betested many times.Quantitative result—nointerpretation of resultsrequired. Results in 7minutes.Center for BioengineeringInnovation and Design (CBID)proteinuria penMarket size is driven by thenumber of pregnant andpostpartum women. Allpregnant women shouldreceive a dipstick test at thefirst ANC visit, at 20 weeks, ifblood pressure is elevated,when they arrive in labor, andat postpartum visits (2 daysand 7 days postpartum). OncePE is diagnosed, a woman willbe tested many times.This test is designed to beeasy for both semiliteratehealth care workers andpregnant women.Price sensitivityPolicyenvironmentCustomers in lowresourcesettings buythese because they arethe lowest cost and theyare willing (knowingly ornot) to sacrifice accuracy.No policy barriers, thoughthere is little motivationto champion andadvocate for such a lowperformingtest.Slight increase in accuracy(seen in clinical results) forthese tests does not seem tojustify the added costs.No policy barriers, thoughthere is little motivation tochampion and advocate forsuch a low-performing test.Difficult to estimate untilthere is a cleardetermination of accuracy.No policy barriers, thoughthere is little motivation tochampion and advocate fortests with

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012DemandInformationDonors/stakeholdersPre- and post-salessupportNeed for demandcreationUNICEF urine dipstick(Medi-Test Combi 2)UNICEF is presumably astakeholder.Dipstick tests are easy touse and require littletraining. However, visuallyread dipsticks are open tomisinterpretation.TECHNOLOGY/SOLUTIONBayer Multistix Pro 10LS Bayer Clinitek 50 Bayer DCA2000 (nowcalled DCA Vantage)Center for BioengineeringInnovation and Design (CBID)proteinuria penNone known at this time. None known at this time. None known at this time. CBID and Jhpiego received$100,000 from USAID, andhave collected ~$50,000 inadditional funds throughbusiness plan competitionsand grants. They receivedaccolades from the LemelsonFoundation, the Duke GlobalHealth Institute, and ABCNews.Dipstick tests are easy to useand require little training.However, visually readdipsticks are open tomisinterpretation.Require no interpretation.Training required isminimal.Require no interpretation.Training required isminimal.Not recommended. Not recommended. Too soon to tell. Only at levels higher thanthe primary health center.Dipstick tests are easy to useand require little training.However, visually readdipsticks are open tomisinterpretation.Only at levels higher than theprimary health center.Page 43 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012References1 NOTE: The treatment package includes inpatient monitoring, anticonvulsive and antihypertensive therapy, optimal timing of childbirth, andskilled attendance at birth.2 NOTE: Focused ANC is evidence-based, goal-directed care that is tailored to the gestational age of pregnancy and individualized to eachwoman. It emphasizes quality of visits over quantity of visits and is conducted by a skilled health care provider. Goals of focused ANC includeearly detection and treatment of complications, prevention of problems, birth preparedness/complication readiness, and the promotion ofhealthy practices to help ensure a positive health outcome for the woman and her baby. Focused ANC is provided through a women-centeredapproach that values the dignity and value of each woman and her family.3 Wallace JF, Pugia MJ, Lott JA, et al. Multisite evaluation of a new dipstick for albumin, protein, and creatinine. Journal of Clinical LaboratoryAnalysis. 2001;15(5):231–235.4 Croal BL, Finlay D, Davidson E, et al. Evaluation of the Bayer Multistix PRO 10LS Point-of-Care Urine Test. Point of Care. 2003;2(2):144–148.5 Waugh J, Kilby MD, Lambert P, et al. Validation of the DCA 2000 Microalbumin: Creatinine Ratio Urinanalyser for its use in pregnancy andpreeclampsia. Hypertens Pregnancy. 2003;22(1):97–113.6 Kyle PM, Fielder JN, Pullar B, Horwood LJ, Moorea MP. Comparison of methods to identify significant proteinuria in pregnancy in the outpatientsetting. British Journal of Obstetrics and Gynaecology. 2008;115(4):523–527.7 James GP, Bee DE, Fuller JB. Proteinuria: Accuracy and precision of laboratory diagnosis by dipstick analysis. Clinical Chemistry. 1978;24(11):1934–1939.8 UNICEF supply catalogue website. Details for test strips for urine analysis; product number S0584005. Available at: https://supply.unicef.org/.Accessed February 1, 2012.9 Bayer Multistix product webpage. CLIAwaived website. Available at: http://tinyurl.com/6qxlz32. Accessed January 12, 2012.Page 44 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012Risk Management Tools for Adverse Outcomes Associated with PreeclampsiaDeterminants of risk associated with preeclampsia remain unclear. 1 Conventional wisdom and guidelines that inform preeclampsia managementperform poorly when tested for their adverse outcome predictive strength. 2 Furthermore, 24-hour urine collections and dipstick evaluation forproteinuria analysis and blood pressure measurement—the diagnostic tools for preeclampsia—are unreliable indicators of preeclampsiaoutcomes for a variety of reasons. 3,4 New approaches to risk assessment are needed to assist in the management of pregnant women presentingwith preeclampsia symptoms in order to ensure those needing definitive treatment (induction or Cesarean section) are prioritized, and toprevent unnecessary and potentially dangerous intervention when risks are low.Several recent studies have examined multifactorial contributions to preeclampsia risk. 3,5 In this briefing, we present risk assessment tools thatmay have applications in low-resource settings to assist with preeclampsia management after a positive diagnosis has been made. While manysingle measurements have promising performance, none have sufficient performance to be used as an individual risk indicator. As an example,we highlight oxygen saturation as a variable that has one of the strongest autonomous correlations with risk. To further clarify the focus of thisbriefing, we make a distinction between preeclampsia screening tools, diagnostic tools, and risk management tools as follows:Screening. Preeclampsia screening is performed before any symptoms appear and aims to estimate the risk that the disorder will develop.Diagnosis. Preeclampsia diagnosis is based on symptoms, and it is made when the disease is already expressed. Diagnosis is solely based oncombined hypertension with expressed proteinuria.Risk management. New evidence suggests correlation between a number of variables that may identify women at increased risk of adverseoutcomes up to seven days before complications arise and can thereby modify direct patient care (e.g., timing of delivery, place of care),improve the design of clinical trials, and inform biomedical investigations related to preeclampsia. 3The table below provides a summary of two risk management tools for adverse outcomes associated with preeclampsia.Page 45 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationDescriptionCharacteristicsapplicable for lowresourcesettingsDeveloper and/ormanufacturerStatusEfficacy/effectivenessTECHNOLOGY/SOLUTIONPreeclampsia Integrated Estimate of RiSk (PIERS) multivariate Pulse oximetry (e.g., Lifebox)analysisThe fullPIERS model was designed as a preeclampsia outcomeLifebox is the lowest-cost detection of oxygen (O2) saturation. Designedprediction model for use in well-resourced settings.specifically to World Health Organization (WHO) specifications for use in lowresourcesettings.Recently, Dr. Peter von Dadelszen (Child and Family Institute,University of British Columbia) received a grant from the Bill &Melinda Gates Foundation to implement a comprehensive project onpreeclampsia monitoring, prevention, and treatment, which includesPIERS validation in developing countries as a major component.University of British Columbia (Canada).Study in well-resourced countries is complete and results published.This fullPIERS model can identify women at increased risk of adverseoutcomes up to seven days before complications arise and canthereby modify direct patient care (e.g., timing of delivery, place ofcare), improve the design of clinical trials, and inform biomedicalinvestigations related to preeclampsia.A study took place in Fiji, Pakistan, South Africa, and Uganda. Studycompletion was scheduled for 2011. Awaiting results.Stratification identified that for the highest-risk group (4% of thepopulation tested), the true positive rate of the test is 44% and thefalse positive rate is 1.6%.Designed to the following WHO specifications: Robust design and durable (dropability). Accurate oxygen saturation measurement (+/- 2%). Audible and visual alarms:• Fixed 90% oxygen saturation alarm.• Heart rate alarm (high 120/low 60).• High and low alarm priorities.• Low battery alarm. Pulse waveform display. Variable pulse tone (lower saturation, deeper tone). Numeric displays for oxygen saturation and pulse rate. Ergonomic display. Mains electrical supply with a rechargeable battery.Acare Technology Co., Ltd. (Taiwan).Commercialized and distributed through Lifebox Global Not-For-Profit.SpO2 successfully predicted adverse maternal outcomes.The area under the receiver-operator characteristic curve (AUC ROC) was 0.71(95% Confidence Interval [CI] 0.65 to 0.77).Combining the symptoms of chest pain and/or dyspnea with pulse oximetryimproved this predictive ability (AUC ROC 0.73; 95% CI 0.67 to 0.78).When SpO2 was stratified into risk groups using inflection points on the ROCcurve, the highest-risk group (SpO2 90% to 93%) had an odds ratio of 18.1 (95%CI 8.2 to 40.2) for all outcomes within 48 hours when compared with thebaseline group (SpO2 98% to 100%). 6Page 46 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationManufacturingquality andcapacityIntellectualpropertyownershipCost and costdriversDelivery/procurementchannelsSustainablebusiness modelsPreeclampsia Integrated Estimate of RiSk (PIERS) multivariateanalysisNot applicable. This is a model, not a device.Not applicable. This is a model, not a device.No data available.No data available.TECHNOLOGY/SOLUTIONPulse oximetry (e.g., Lifebox)The WHO-audited manufacturer meets all requirements and is capable of scalingto meet need.None.Margins are low. The price of US$200 seems to be the floor for this class ofnoninvasive detection devices at the projected sales volumes.No data available.Lifebox Global Not-For-Profit is funded in part by Smile Train. Smile Train alsoinfluences the organization through strategic executive involvement.Acare Technology Co. is assumed to make a very small profit on each sale.DemandInformationTECHNOLOGY/SOLUTIONPulse oximetry (e.g., Lifebox)Preeclampsia Integrated Estimate of RiSk (PIERS)multivariateanalysisExisting demand No data available. Market size is driven by the number of health facilities, providers, orcommunities. According to Lifebox’s website, the unmet need is 75,000 units,though it is not clear how this was determined. The global pulse oximetrymarket is substantially larger—estimated toward US$1 million unit market.Attractiveness No data available. The cost of the unit and replacement probes sets a new low-cost standard forpulse oximetry, while product quality and appropriateness for low-resourcesettings is high.Price sensitivity No data available. No data available.PolicyenvironmentDonors/stakeholdersPre- and post-salessupportNeed for demandcreationPolicy does not address risk management.Bill & Melinda Gates Foundation.No data available.No data available.The Global Pulse Oximetry Project has increased awareness and demand for thistechnology.Global Pulse Oximetry Project; Lifebox; PIERS; Smile Train; WHO.A distribution chain for replacement probes is necessary.Initial training is minimal; no calibration is required.The Global Pulse Oximetry Project’s advocacy has increased demand, thoughmore advocacy is warranted.Page 47 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012References1 Thangaratinam S, Coomarasamy A, Sharp S, et al. Tests for predicting complications of pre-eclampsia: a protocol for systematic reviews. BMCPregnancy & Childbirth. 2008;8:38.2 Menzies J, Magee LA, Macnab YC, et al. Current CHS and NHBPEP criteria for severe preeclampsia do not uniformly predict adverse maternal orperinatal outcomes. Hypertension in Pregnancy. 2007;26(4):447–462.3 von Dadelszen P, Payne B, Li J, et al. Prediction of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERSmodel. The Lancet. 2011;377(9761):219–227.4 Jaschevatzky OE, Rosenberg RP, Shalit A, et al. Protein/creatinine ratio in random urine specimens for quantitation of proteinuria inpreeclampsia. Obstetrics and Gynecology. 1990;75(4):604–606.5 Ganzevoort W, Rep A, de Vries JI, et al. Prediction of maternal complications and adverse infant outcomes at admission for temporizingmanagement of early-onset severe hypertensive disorders of pregnancy. American Journal of Obstetrics and Gynecology. 2006;195(2):495–503.6 Millman AL, Payne B, Qu Z, et al. Oxygen saturation as a predictor of adverse maternal outcomes in women with preeclampsia. Journal ofObstetrics and Gynaecology Canada. 2011;33(7):705–714.Page 48 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012Delivery of Magnesium SulfateThe World Health Organization (WHO) has identified magnesium sulfate (MgSO 4 ) as the most effective, safe, and low-cost medication forpreventing and treating convulsions in severe preeclampsia and eclampsia (PE/E). 1 Despite its endorsement by WHO, MgSO 4 is still eitherunderused or unavailable in many low-resource settings; even when MgSO 4 is used, convulsions in hospitalized women are most frequentlycaused by undertreatment due to a combination of provider and supply factors. To improve consistent, safe use of MgSO 4 , the following itemsmust be available at all levels of care 2 : MgSO 3 4 and a delivery system that facilitates its safe administration, calcium gluconate (the antidote forMgSO 4 ), lignocaine (for intramuscular [IM] injections), a simple treatment protocol, and job aids to assist with measuring the correct dose anddeciding on the route of administration. 4 A key element of managing severe PE/E is adequate administration of MgSO 4 to prevent or controlconvulsions. The loading dose of MgSO 4 may be administered by continuous intravenous (IV) infusion or, alternately, by giving an IV bolus and IMdoses. This is followed by four-hourly IM injections. 5 Both IV and IM administration are appropriate. IM administration of the undiluted 50 percentsolution results in therapeutic plasma levels in 60 minutes, whereas IV doses will provide a therapeutic level almost immediately.The WHO-recommended regimens are:Loading dose. Slow IV injection of 4 g (20 mL of 20 percent solution in saline) at a rate of 1 g/5 minutes over 5 to 20 minutes.Maintenance regimen (IM). Immediately after the loading dose, administer 5 g of 50 percent solution to each buttock (10 g total IM dose) as adeep IM injection. This should be followed by 5 g of 50 percent solution every 4 hours to alternate buttocks. MgSO 4 treatment should becontinued for 24 hours after delivery or the last convulsion, whichever occurs last. IM injections should preferably be given with 1 mL of 2percent lignocaine in the same syringe to make them less painful.Maintenance regimen (IV). After the loading dose, administer 1 to 2 g/hour in 100 mL of maintenance solution.In low-resource settings, the IM maintenance regimen is usually promoted for the following reasons: (1) ease of IM injections relative to IV injections,and (2) relative safety of IM over IV doses in settings that do not have pumps to control the IV infusion.A 2010 Cochrane review 6 identified that there are several important questions about how best to use MgSO 4 for women with severe PE/E. Theseinclude: (1) what is the minimum effective dose (loading and maintenance); (2) what are the advantages and disadvantages of IM and IVadministration; (3) can the initial dose be safely given at community or primary health care levels before transfer to the hospital; (4) is theloading dose alone sufficient for treatment of severe PE/E; and (5) when is it best to stop treatment. To address these questions would requirePage 49 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012large randomized trials of women with severe PE/E that compare alternative regimens and assess the comparative effects on mortality, seriousmorbidity, adverse effects, and use of hospital resources for both the women and their babies.The two tables below examine various options for MgSO 4 delivery.Page 50 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationDescriptionSyringe forintramuscular (IM) ormanual intravenous (IV)injectionThis is the standard ofcare at all levels of thehealth care system; ituses commoditymedical technologies.The IM regimen is themost affordable and iswidely used in lowresourcesettings.Gravity-fed IV bagand stand (IV)This is a readilyavailable deliverymethod forcontinuous IV. Itconsists of an IV bagand a stand andrelies on gravity toadminister theMgSO 4 dose. There ispotential to augmentthe function with acontrol valvecurrently underdevelopment at RiceUniversity.TECHNOLOGY/SOLUTION—TABLE 1Programmable nonmechanicalIVinfusion pumpElectricity-free infusionpump, such as theSpringfusor® (IV)syringe infusion pumpThis technology canmake administrationeasier and safer, as theSpringfusor® limits therate of administration.Springfusor® isavailable in 10 mL and30 mL versions.This technologyrequires no batteries.This technology uses aproprietary,expandable polymerfor continuous orbolus drug delivery.The device consists ofa plastic case, a bag(container) for thedrug, and anexpandable polymer.The dosage andapplication methodcan be programmableat the factory or at thepoint-of-care (via auser interface installedin a computer).Programmableelectronic infusionpump (IV)This is the standard ofcare in the UnitedStates.MgSO 4 prefilled readyto-usepremixes forsyringes and IV bagsThe Ansyr® Syringeoffers one-piece,polypropylene plasticconstruction and aneedle-free luer locktip. An extensiveportfolio of emergencymedications isavailable. The flexibleluer lock system makesit easy to connect toany valve, or to add aneedle or blunt tip. TheAnsyr® Syringe isprefilled.Characteristicsapplicable for lowresourcesettingsUses commoditytechnologies; therefore,a unique supply specificto preeclampsia (PE) isnot required.Electricity free.Simpler userinterface than IVinjection.Can run with no powersource.Easier and safer sincethe administration rateis tightly controlled.This device is currentlydesigned as a singleuse,disposable deviceto deliver narcotics forpain management.Can run with nopower source.Easier and safer sincethere is no need formixing and theadministration rate islimited.Needs electricity oranother power source.Prohibitive cost.Easier and safer sincethis is prefilled.Specifications can bemodified for use inlow-resource settings,including making thedevice semidisposablefor costreduction.Page 51 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationDeveloper and/ormanufacturerSyringe forintramuscular (IM) ormanual intravenous (IV)injectionThis is a generictechnology and hasmany manufacturers.Gravity-fed IV bagand stand (IV)This is a generictechnology and hasmany manufacturers.TECHNOLOGY/SOLUTION—TABLE 1Electricity-free infusion Programmable nonmechanicalIVpump, such as theSpringfusor® (IV) infusion pumpsyringe infusion pumpThere are multipleelastomer- and springbasedpumps. Oneexample is theSpringfusor® made byGo Medical IndustriesPty., Ltd. (WA,Status Commercialized. Commercialized. This technology hasbeen commercializedwith US Food and DrugAdministration (USFDA)approval, CE Mark, andTherapeutic GoodsAdministrationregulatory approval.Efficacy/effectivenessManufacturingquality andcapacityThis is a generictechnology and isproven to be safe.This technology hasnumerousmanufacturers, so scalecan be easily achievedto meet demand.This is a generictechnology and isproven to be safe.This technology hasnumerousmanufacturers, soscale can be easilyachieved to meetdemand.Programmableelectronic infusionpump (IV)Medipacs (CA, USA). There are variousdevices andmanufacturers. Forexample, the SIGMASpectrum InfusionPump manufacturedThis technology is inlate-stagedevelopment. Thereare plans to file forUSFDA 510k clearancewithin a year.Regulatory hurdles aresignificant if this is aprefill device.by SIGMAInternational, LLC, andcommercialized byBaxter International.Commercialized.No data available. No data available. This is the standard ofcare in the UnitedStates and is proven tobe safe.Go Medical hasmanufacturing facilitiesin Australia, Europe,and Asia and anestablished globaldistribution network. 7Medipacs is a start-upcompany with series-Afunding. Ability tomeet global demand isunclear. They willlikely need to partnerwith a manufacturingfacility.Because of prohibitivecost, it may not beappropriate for use inlow-resource settings.MgSO 4 prefilled readyto-usepremixes forsyringes and IV bagsHospira Ansyr® (HospiraAccessoriesTechnologies). 8Commercialized.This technology shouldhave effectiveness onpar with any otherdelivery regimen butremoves userdependence and thusimproves safety.Hospira is the globalmarket leader forgeneric injectablepharmaceuticals, sothey could easily scaleto demand.Page 52 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationIntellectualproperty (IP)ownershipCost and costdriversDelivery/procurementchannelsSyringe forintramuscular (IM) ormanual intravenous (IV)injectionGravity-fed IV bagand stand (IV)None. None. Many of the availabletechnologies are offpatentor nearing theend of patent terms.The cost isapproximately US$1 forsingle use.The cost of thisdevice isapproximatelyUS$20.TECHNOLOGY/SOLUTION—TABLE 1Electricity-free infusion Programmable nonmechanicalIVpump, such as theSpringfusor® (IV) infusion pumpsyringe infusion pumpThe cost isapproximately US$20.The device can bereused indefinitely ondifferent patients;however, flow controltubing needs to bereplaced after each use.Uses a proprietary,expandable polymer.The cost isapproximately US$20. 9The device is made oflow-cost componentsfor single use.Programmableelectronic infusionpump (IV)None. IP is not asmuch a barrier toentry in this market asis the expected lowreturn on investment.The cost isapproximatelyUS$2,500.MgSO 4 prefilled readyto-usepremixes forsyringes and IV bagsProprietary.Expected to addconsiderable cost toeach successfullytreated individual.Estimated prefilledcartridge costs are asmuch as US$0.25 basedon PATH experience.Contributed costs canraise overall cost by anorder of magnitude.Both a willingness topay and a costeffectivenessanalysisare stronglyrecommended to justifyfurther research anddevelopment.Clinic-based delivery. Clinic-based delivery. Clinic-based delivery. Clinic-based delivery. Clinic-based delivery. Clinic-based delivery.Page 53 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationSustainablebusiness modelsSyringe forintramuscular (IM) ormanual intravenous (IV)injectionGravity-fed IV bagand stand (IV)TECHNOLOGY/SOLUTION—TABLE 1Electricity-free infusion Programmable nonmechanicalIVpump, such as theSpringfusor® (IV) infusion pumpsyringe infusion pumpExist. Exist. Current deviceconsumable costs seemto be too high, as thecontributed cost ofinfusor flow controltubing can add morethan US$1 to a US$0.05injection. This needs tobe looked at moreclosely.This device can delivera variety ofmedications, such asbiologics, insulin,hormones, fertilitydrugs, anticoagulationdrugs, andpain medication,thereby making thepotential market sizeof the product quitelarge.Programmableelectronic infusionpump (IV)This technology existsin different markets.There may be toomany hurdles toovercome to build asustainable,affordable supply atthe lowest levels ofthe health caresystem. Thistechnology is moreappropriate fornational hospitals,where the devicecould be used formultiple indications—not just PE/eclampsiaemergencies.MgSO 4 prefilled readyto-usepremixes forsyringes and IV bagsMore information isneeded to justify thistechnology. This willlikely require donordrivenclinical evidencefor a simplified doseregimen. It is possiblethere will beconsiderable donorinvestment prior toestablishing a supplysidereturn oninvestment-drivensustainability.Page 54 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012DemandInformationExisting demandSyringe forintramuscular (IM) ormanual intravenous (IV)injectionPE/E market size isdriven by the numberof women with severePE/E. With new WHOrecommendations forinduction of labor,women with severe PEwill be on MgSO 4 muchlonger than previously.However, if preventivesupplements are used,this number would beconsiderably lower.Assuming the devicescan deliver anydrug/vaccine, themarket size would bemuch larger and wouldbe driven by thenumber of IV or IMinjections.Gravity-fed IV bag andstand (IV)PE/E market size isdriven by the numberof women with severePE/E. With new WHOrecommendations forinduction of labor,women with severe PEwill be on MgSO 4 muchlonger than previously.However, if preventivesupplements are used,this number would beconsiderably lower.Assuming the devicescan deliver anydrug/vaccine, themarket size would bemuch larger and wouldbe driven by thenumber of IV or IMinjections.TECHNOLOGY/SOLUTION—TABLE 1Electricity-free infusionpump, such as theSpringfusor® (IV)syringe infusion pumpPE/E market size isdriven by the numberof women with severePE/E. With new WHOrecommendations forinduction of labor,women with severe PEwill be on MgSO 4 muchlonger than previously.However, if preventivesupplements are used,this number would beconsiderably lower.Assuming the devicescan deliver anydrug/vaccine, themarket size would bemuch larger and wouldbe driven by thenumber of IV or IMinjections.Programmable nonmechanicalIVinfusion pumpPE/E market size isdriven by the numberof women with severePE/E. With new WHOrecommendations forinduction of labor,women with severe PEwill be on MgSO 4much longer thanpreviously. However,if preventivesupplements are used,this number would beconsiderably lower.Assuming the devicescan deliver anydrug/vaccine, themarket size would bemuch larger andwould be driven bythe number of IV orIM injections.Programmableelectronic infusionpump (IV)PE/E market size isdriven by the numberof women with severePE/E. With t new WHOrecommendations forinduction of labor,women with severe PEwill be on MgSO 4much longer thanpreviously. However,if preventivesupplements are used,this number would beconsiderably lower.Assuming the devicescan deliver anydrug/vaccine, themarket size would bemuch larger andwould be driven bythe number of IV orIM injections.MgSO 4 prefilled readyto-usepremixes forsyringes and IV bagsPE/E market size isdriven by the numberof women with severePE/E. With new WHOrecommendations forinduction of labor,women with severe PEwill be on MgSO 4 muchlonger than previously.However, if preventivesupplements are used,this number would beconsiderably lower.Assuming the devicescan deliver anydrug/vaccine, themarket size would bemuch larger and wouldbe driven by thenumber of IV or IMinjections.Page 55 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012DemandInformationAttractivenessPrice sensitivityPolicyenvironmentSyringe forintramuscular (IM) ormanual intravenous (IV)injectionThis technologyrequires somewhatcomplicatedpreparation of 50percent and 20 percentfrom available MgSO 4preparations, andaddition of lignocaineto the MgSO 4 solutionto reduce pain from theinjection.Saturated market. Lowelasticity.Consistent with WHOguidelines.Gravity-fed IV bag andstand (IV)The health workerprepares the IV bag bymixing a correct MgSO 4dose regimen for the IVmaintenance dose,which requires carefulcalculations of dropsper minute based onthe drip set used (10,15, 20, or 60 drops permL) and strength of theMgSO 4 solution.Saturated market. Lowelasticity.Consistent with WHOguidelines.TECHNOLOGY/SOLUTION—TABLE 1Electricity-free infusionpump, such as theSpringfusor® (IV)syringe infusion pumpIn India, trials showedreduced side effectsassociated with MgSO 4and that this device ishighly acceptable towomen. The trialcompared manuallyadministered IV loadingdose followed bymaintenance therapyIM via syringe withloading dose andmaintenance therapyusing IV infusion bySpringfusor ® . 10 Manualadministration of theloading dose causedsignificantly more sideeffects.Not determined.Consistent with WHOguidelines.Programmable nonmechanicalIVinfusion pumpThis is a new productstill underdevelopment.Significant complexitymay contribute tohigher than expectedcosts, as the devicehas a microprocessor,a reservoir for thedrug, a printed circuitboard, and theproprietary polymer,which acts as themotor to push thedrug out of thereservoir as itprecisely expands,gradually displacingthe drug.This is a niche productand could be veryattractive within theniche: there is highvalue, high price;generic painmedications andchemo are covered byinsurance.This device would bebetter suited to asingle-dose regimen.Programmableelectronic infusionpump (IV)This device iscompletely automatedand precise. This isoverkill for MgSO 4 ,which has a widetherapeutic window.Several big companiesin this market;customers havechoices.This technology is themost flexible.MgSO 4 prefilled readyto-usepremixes forsyringes and IV bagsThis technology iseasier and safer sincethere is no need formixing.Not determined.A simpler dosingregimen needs to beestablished before thislooks attractive.Page 56 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012DemandInformationDonors/stakeholdersSyringe forintramuscular (IM) ormanual intravenous (IV)injectionInternational standardof care.Gravity-fed IV bag andstand (IV)International standardof care.TECHNOLOGY/SOLUTION—TABLE 1Electricity-free infusionpump, such as theSpringfusor® (IV)syringe infusion pumpGynuity.Programmable nonmechanicalIVinfusion pumpReceived US$4.6million in grant fundsand angel investormoney. 11Programmableelectronic infusionpump (IV)None. Cost prohibitivein developingcountries.MgSO 4 prefilled readyto-usepremixes forsyringes and IV bagsThe University of BritishColumbia and Jhpiegoare also investigatingthis technology.Medipacs received theAssociation ofUniversity ResearchParks’ InnovationAward for 2009.Pre- and postsalessupportNo support provided.A simple dosingcalculator job aid wouldhelp to minimize errors.There is no calibrationand no maintenance.Requires the providerto manually countdrops per minute toregulate the drip rateand achieve thetherapeutic dose.Speed of infusion couldchange based on thepatient’s position.Potential for eitherunderdosing oroverdosing the patient.A simple dosingcalculator job aid wouldhelp and minimizeerrors.No support provided.A simple dosingcalculator job aid wouldhelp and minimizeerrors.No calibration required,as flow control tubesare precalibrated.Minimal trainingrequired.The National ScienceFoundation provided agrant of US$700,000for development.Minimal trainingrequired.Prefill eliminates usercomplexity and errors.Requires calibration.Requires the providerto manually countdrops per minute toregulate the drip rateand achieve thetherapeutic dose.Speed of infusion couldchange based on thepatient’s position.Potential for eitherunderdosing oroverdosing the patient.Prefill eliminates usercomplexity and errors.This technologyrequires calibration.Page 57 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012DemandInformationNeed fordemandcreationSyringe forintramuscular (IM) ormanual intravenous (IV)injection90 percent EssentialDrugs List (EDL)coverage for the drugdoes not ensure 90percent coverage forconsumables.Vertical supplychannels can create amismatch betweendrug availability anddelivery methodconsistency andavailability—thusleading to dose errors.Gravity-fed IV bag andstand (IV)90 percent EDLcoverage for the drugdoes not ensure 90percent coverage forconsumables.Vertical supplychannels can create amismatch betweendrug availability anddelivery methodconsistency andavailability—thusleading to dose errors.TECHNOLOGY/SOLUTION—TABLE 1Electricity-free infusionpump, such as theSpringfusor® (IV)syringe infusion pumpNo current demand.Simplified dose regimenwould help.Programmable nonmechanicalIVinfusion pumpNo current demand.Simplified doseregimen would help.Programmableelectronic infusionpump (IV)Not appropriate forthe lowest levels ofthe health system.MgSO 4 prefilled readyto-usepremixes forsyringes and IV bagsNo current demand.Simplified dose regimenwould help.Page 58 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationDescriptionCharacteristicsapplicable for lowresourcesettingsRectal suppositoryEarly concept. The feasibility ofusing rectal suppositories inwomen who are laboring andgiving birth has not been tested;expulsion may be an issue. Thistechnology has the potential tosimplify dosing, provide a lesspainful delivery method, and allowuse at lower levels of care.Zero delivery technologiesrequired.TECHNOLOGY/SOLUTION—TABLE 2Preeclampsia/eclampsia (PE/E) mHealth application for dilution andtreatment kitdosing of MgSO 4Kits could contain 1 (1) calcium PATH and the University of Washingtoncarbonate (antidote); (2) job aids to (UW) are currently developing andemonstrate dilution and decide on application that could be modified indose; (3) a simple monitoring sheet various forms, such as a simple paperto record pulse, blood pressure dosing wheel or a computer- or mobile(BP), respirations, urine output, phone-based dosing calculator.proteinuria, reflexes, fetal heartrate, and administration of thedrug; (4) a reliable BP measuringdevice, stethoscope, and fetalstethoscope; (5) reflex hammer; (6)urinary collection system; (7)dipsticks to measure proteinuria; (8)timing device with a second hand;and (9) infection prevention andinjection safety supplies.Eliminates problems with thevertical supply system.Digitalization of dilution and dosingcalculations running on a mobile deviceprovide frontline health workers who donot regularly see complications as aresult of eclampsia the confidence to docomplicated calculations for appropriateuse of MgSO 4 .Animated game for correctdose/dilution usesJhpiego developed an animatedgame to teach providers correctdose/dilution combinations.Interactive.Developer and/or Early concept; no data available. Local variations of kits exist. PATH/UW. Jhpiego.manufacturerStatus Early concept. Local variations of kits exist. Early development. Beta prototype.Efficacy/effectivenessEarly concept; no data available. Some case studies have indicatedimproved compliance with the kit.Researchers have demonstrated that theuse of an electronic checklist developedto consistently prompt clinicians toprovide comprehensive dischargeinstructions showed significantimprovement, from 37 percent to 93percent in instruction delivery. 12Not determined.No studies have been conductedexamining the use of digital guidelineson MgSO 4 usage.Page 59 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationManufacturingquality andcapacityIntellectualpropertyownershipTECHNOLOGY/SOLUTION—TABLE 2Rectal suppositoryPreeclampsia/eclampsia (PE/E)treatment kitmHealth application for dilution anddosing of MgSO 4Early concept; no data available. Additional costs are associated with No data available at this time.assembly and waste when suppliesare not used and the kit needs to berestocked or disposed.Early concept; no data available. None. Leveraging the open-source Open DataKit platform developed by UW andGoogle.Animated game for correctdose/dilution usesSimple phone application.Very low manufacturingbarriers.Not determined.Code belongs to Jhpeigo.Cost and costdriversDelivery/procurement channelsSustainablebusiness modelsEarly concept; no data available.Standard pharma distribution.Could incentivize pharma toengage with a drug with ahistorically low profit margin bycreating a new dosage form.Additional costs are associated withassembly and waste when suppliesare not used and the kit needs to berestocked or disposed.The most cost-effective approach isthe locally assembled and restockedapproach.The most cost-effective approach isa locally assembled and restockedapproach; therefore, thesustainable business model may bedevelopment of a facility-driven kit.Costs of the technology are variable andare driven by the level of sophisticationof the tool and the level of integration.Phones can cost between US$80 andUS$200. Greater costs are in training andchanges to existing workflows.Phones leverage off-the-shelfcomponents that are readily available incountry, as well as existing cellularnetworks.Sustainable business models are beingexplored broadly within the category ofmHealth and clear strategies have yet tobe determined.Should be free.Costs associated withdevelopment and advocacyonly.Internet.Not determined.Suspect best suited to a freesoftware application (i.e., nosustainable business model).Page 60 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012DemandInformationExisting demandAttractivenessPrice sensitivityRectal suppositoryMarket size is driven by thenumber of women with severepreeclampsia/eclampsia (PE/E).With the new World HealthOrganization (WHO)recommendations for inductionof labor, women with severe PEwill be on MgSO 4 much longerthan previously. However, ifpreventive supplements are used,this number would beconsiderably lower.Assuming the device can deliverany drug/vaccine, the market sizewould be much larger. It wouldbe driven by the number ofintravenous or IM injections.Suppository methods may havecultural barriers if not standard ofpractice.Not determined, thoughcomparative MgSO 4 dosing is

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012DemandInformationPre- and post-salessupportNeed for demandcreationTECHNOLOGY/SOLUTION—TABLE 2Rectal suppositoryPreeclampsia/eclampsia (PE/E)treatment kitmHealth application for dilution anddosing of MgSO 4Low training hurdles. Low training hurdles. Development of both pre- and postsalessupport is necessary for themaintenance of human and technicalresources. No projects have left thepilot stage where local scalablesupport has been demonstrated.Required.None, though facility- or higherlevelOne main benefit of digital guidelinespolicies and standardized is the ability to support task-shiftingprotocols could assist in facilitybasedto lower cadres of health workers.kit demand.The tool provides global standardsand defines clear delineation forwhich services are appropriate forthe health worker to provide andwhich should be referred.Animated game for correct dose/dilution usesAnecdotal user comments suggest itmay be challenging (at least initially)to understand and use.None.Page 62 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012References1 World Health Organization (WHO). WHO Recommendations for Prevention and Treatment of Preeclampsia and Eclampsia. Geneva: WHO; 2011.2 NOTE: The recommended level of health care for management of severe preeclampsia and eclampsia is in a facility with comprehensiveobstetric and neonatal care capacity. Each level of the care would therefore have specific treatment guidelines—for example, initialmanagement—intramuscular injections for the loading dose or starting the intravenous infusion would be provided at all levels of care, andongoing management would be provided at a facility with the capacity to provide comprehensive obstetric and neonatal care services.3 NOTE: Promoting treatment with MgSO 4 assumes that MgSO 4 is already on the Essential Medicines List (EML) and that appropriate policies andtreatment protocols promoting its correct use are in place. In countries where MgSO 4 is not on the EML, or appropriate policies and treatmentprotocols promoting its correct use are not in place, initial project activities would necessarily include work on policies and clinical standards.4 NOTE: To ensure safe administration of maintenance doses and ongoing management of a woman with severe preeclampsia or eclampsia, thefollowing accompanying equipment and supplies are also needed: (1) a simple monitoring sheet to record pulse, blood pressure (BP),respirations, urine output, proteinuria, reflexes, fetal heart rate, and administration of the drug; (2) a reliable BP measuring device, stethoscope,and fetal stethoscope; (3) reflex hammer; (4) urinary collection system; (5) dipsticks to measure proteinuria; (6) timing device with a secondhand; and (7) infection prevention and injection safety supplies.5 Atallah AN. Anticonvulsant therapy for eclampsia: RHL practical aspects. The WHO Reproductive Health Library. Geneva: World HealthOrganization; 2003.6 Duley L, Matar HE, Almerie MQ, et al. Alternative magnesium sulphate regimens for women with pre-eclampsia and eclampsia. CochraneDatabase of Systematic Reviews. 2010;8:CD007388.7 Go Medical website. Available at: http://www.gomedical.com.au/company.php. Accessed February 1, 2012.8 Hospira website. Available at: http://www.hospira.com/default.aspx. Accessed February 1, 2012.9 Darcé K. Wireless reaches into health care arena. The San Diego Union-Tribune. May 23, 2010. Available at:http://www.utsandiego.com/news/2010/may/23/wireless-reaches-health-care-arena/?page=2#article. Accessed February 3, 2012.10 Treatment approaches for preeclampsia in low-resource settings web page. Clinical trials.gov website. Available at:http://clinicaltrials.gov/ct2/show/NCT00666133. Accessed February 3, 2012.11 Beal T. Tucsonan’s drug pump among top inventions. Arizona Daily Star. May 22, 2010. Available at:http://azstarnet.com/business/local/article_5b6390fb-f1f4-522a-a7b1-df96c2ac4fc1.html. Accessed February 3, 2012.12 Riggio JM, Sorokin R, Moxey ED, et al. Effectiveness of a clinical-decision-support system in improving compliance with cardiac-care qualitymeasures and supporting resident training. Academic Medicine. 2009;84(12):1719–1726.Page 63 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012Antihypertensive DrugsHypertension is the most common medical problem encountered during pregnancy, complicating approximately 10% of pregnancies. 1Preeclampsia and eclampsia account for about half of these cases worldwide. 2 Hypertensive disorders during pregnancy are classified ashypertension without proteinuria, mild preeclampsia, severe preeclampsia, and eclampsia, as described by the World Health Organization(WHO). 3Hypertension without proteinuria is a relatively rare cause of maternal mortality. The vast majority of the hypertension-related deaths inpregnant women are associated with both hypertension and proteinuria, with eclampsia accounting for the great majority of these maternaldeaths.An important objective in the care of a woman with severe hypertension (diastolic blood pressure [dBP] is 110 mmHg or more), with or withoutproteinuria, is to reduce blood pressure (BP) in order to avoid hypertensive encephalopathy, cerebral hemorrhage, placental abruption, andintrauterine growth restriction. For this reason, the aim in treating severely hypertensive women is to keep the dBP between 90 and 100mmHg. 4 Due to the fact that available evidence on treatment of mild and moderate hypertension in pregnancy is controversial, WHO can neitherrecommend nor discourage use of antihypertensive drugs for their management, 2 though their treatment protocols do not includeantihypertensive treatment in these cases. 1While the goal of treatment of hypertension in pregnancy is to reduce maternal risk, careful attention must be made not to harm the fetus.Antihypertensive medications may permit prolongation of the pregnancy and thereby improve fetal maturity, but administration of a powerfulvasodilator will result in decreased intervillous blood flow. Acute falls in maternal systemic BP may thus result in fetal compromise.There is scarce evidence on whether treating pregnant women who develop mild to moderate hypertension in pregnancy can reduce the risk ofpreeclampsia. Of all the antihypertensive medications available, labetalol, nifedipine, and hydralazine are most commonly recommended foracute management of severe hypertensive disorders in pregnancy. Recent research conducted by the Maternal and Child Health IntegratedProgram indicates hydralazine and nifedipine are the most commonly used antihypertensives in low-resource settings. 5 A systematic review ofthe literature has shown that labetalol is the most promising drug to achieve a protective effect. To test its effectiveness, a randomized clinicaltrial is ongoing in Argentinean hospitals. The tight control needed on blood-pressure management and the relative scarcity of eligible subjectsmakes this trial a long-lasting investment to be conducted by well-trained research teams over several years. Approximately 10% of the pilotPage 64 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012sample size (200 subjects) has been recruited. After the pilot phase is complete, it will be possible to assess if the study could be realisticallyexpanded to other centers. 6If antihypertensive treatment is required, guidelines differ widely. WHO recommends the following: (1) women with severe hypertension duringpregnancy should receive treatment with antihypertensive drugs; (2) the choice and route of administration of an antihypertensive drug forsevere hypertension during pregnancy, in preference to others, should be based primarily on the prescribing clinician’s experience with thatparticular drug, its cost, and local availability; and (3) diuretics, particularly thiazides, are not recommended for the prevention of preeclampsiaand its complications. Despite having documented side effects (maternal hypotension and decreased blood flow to the fetus), 7 the WHOmidwifery education guide recommends use of IV hydralazine for management of hypertension in pregnancy. 8 National Institute for Health andClinical Excellence (NICE) guidelines recommend oral labetalol despite the fact that it has a narrow therapeutic window and side effects includingmaternal hypotension. Recent research by the Pre-eclampsia, Eclampsia, Monitoring, Prevention, and Treatment Initiative (PRE-EMPT), fundedby the Bill & Melinda Gates Foundation, indicates alternative approaches including the use of two-drug therapy as well as propranolol.In addition to building evidence that differentiates and substantiates the effectiveness and safety of the leading hypertensive drugs for use inantenatal and prenatal care, there is a need to increase access to oral dosing options through additional measures such as clear national clinicalguidelines; inclusion in national formularies; and increased training on their use.The table below provides information on the four most commonly used antihypertensive medications for managing hypertensive disorders inpregnancy. 9,10Page 65 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationDescriptionCharacteristicsapplicable for lowresourcesettingsDeveloper and/ormanufacturerTECHNOLOGY/SOLUTIONHydralazine Labetalol Nifedipine MethyldopaPure vasodilator.Balanced α-ß blocker.Calicium antagonist.Third line for acute managementintravenous (IV).Third line for refractoryhypertension.Pros: Commonly available in lowresourcesettings; fast acting: 5 to20 minutes.Cons: associated with morematernal and perinatal adverseeffects than other drugs includingmaternal headache andhemodynamic instability.WHO does not recommendcontinuous infusion for practicaland safety issues. The long durationof action, combined with difficultyin accurately monitoring infusionrates, can result in large cumulativedoses and bottoming out of BP.Narrow therapeutic window.Commonly available in low-resourcesettings; fast acting: 5 to 20minutes, though 5 mg IV format isnot ideal for low-resource settings.Multiple manufacturers includingbrand name Apresolinemanufactured by Apotex, Inc.Oral: 200 mg (weak beta effect).IV over 1 minute: 10 mg to 20 mg.Second line for acute management(IV).Second line for chronicmanagement.Pros: none of these agents hasbeen associated with anyconsistent ill effects; extensivelyused in pregnancy; low potentialfor clinical hypotension.Cons: limited availability, moreexpensive, potentially limitedpotency as an oral agent (littleexperience).Wide therapeutic window.Availability of oral dosing and fastacting: 30 minutes.A number of companiesmanufacture generic labetalol,including (but not limited to):Sandoz, Teva Pharmaceuticals,Watson Pharmaceuticals, EonLaboratories.First line for acute management.Pros: a multicenter prospectivecohort study of first-trimester drugexposures reported no increase inmajor teratogenicity from theseagents; extensively used inpregnancy (antihypertensive,tocolytic); widely available; verypotent oral agent.Cons: experience with calciumantagonists is limited; headachesare a common side effect; mayincrease cerebral perfusionpressure; may not be cerebroprotective.Commonly available in low-resourcesettings; availability of oral dosingand fast acting: 5 to 10 minutes.Multiple manufacturers includingbrand name Procardiamanufactured by Pfizer.Oral: load with 500 mg, then 250mg twice daily to maximum of 1 gthree times daily.First line for chronic management.Pros: limited data suggests stableuteroplacental blood flow andfetal hemodynamics.No long-term adverse effects ondevelopment among childrenexposed to methyldopa in utero.Broad usage and familiarity, andwidely available.Cons: causes somnolence in manyindividuals; limited potency;delayed onset in action (that is,slow acting 8 to 10 hours).Broad usage and familiarity, andwidely available.Multiple manufacturers includingbrand name Aldometmanufactured by AspinPharmacare.Status Commercialized. Commercialized. Commercialized. Commercialized.Page 66 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationEfficacy/effectivenessManufacturingquality andcapacityIntellectualpropertyownershipCost and costdriversDelivery/procurementchannelsTECHNOLOGY/SOLUTIONHydralazine Labetalol Nifedipine MethyldopaData are scarce.Systematic review indicates this is Data are scarce.Data are scarce.the most promising drug toachieve a protective effect; clinicaltrial currently in progress. Largelyon IV use. Large oral doses 1600mg to 2400 mg per day are used inthe United Kingdom.Hypertension in pregnant women Hypertension in pregnant women Hypertension in pregnant women is Hypertension in pregnant womenis a small market in comparison to is a small market in comparison to a small market in comparison to the is a small market in comparison tothe overall hypertensive drug the overall hypertensive drug overall hypertensive drug market. the overall hypertensive drugmarket. Therefore, scale to meet market. Therefore, scale to meet Therefore, scale to meet demand market. Therefore, scale to meetdemand can be easily achieved. demand can be easily achieved. can be easily achieved.demand can be easily achieved.Low barriers to entry as thepharmacopeia standards arepublicly available, and there are nointellectual property (IP) hurdles.Due to applicability ofantihypertensives for variousmarkets, there are vast economiesof scale allowing for lowproduction costs.Low barriers to entry as thepharmacopeia standards arepublicly available, and there are noIP hurdles.Due to applicability ofantihypertensives for variousmarkets, there are vast economiesof scale allowing for lowproduction costs.Low barriers to entry as thepharmacopeia standards arepublicly available, and there are noIP hurdles.Due to applicability ofantihypertensives for variousmarkets, there are vast economiesof scale allowing for low productioncosts.Low barriers to entry as thepharmacopeia standards arepublicly available, and there are noIP hurdles.Due to applicability ofantihypertensives for variousmarkets, there are vast economiesof scale allowing for lowproduction costs.Generic drug; off patent. Generic drug; off patent. Generic drug; off patent. Generic drug; off patent.Cost is US$0.026 per tablet of 25 mg(mean public-sector price in 2007across countries in sub-SaharanAfrica). 11Antihypertensives requiresomeone with prescriptiveauthority as the choice of type ofantihypertensive and dosing can becomplex. Prescription occurs ata health care facility.To be evaluated. Price in theUnited States is US$0.62 per 100-mg tablet.Antihypertensives requiresomeone with prescriptiveauthority as the choice of type ofantihypertensive and dosing canbe complex. Prescription occurs ata health care facility.Cost is US$0.097 per tablet of 20 mg Cost is US$0.034 per tablet of 250(mean public-sector price in 2007 mg (mean public-sector price inacross countries in sub-Saharan 2007 across countries in sub-Africa). 11 Saharan Africa). 11Antihypertensives require someonewith prescriptive authority as thechoice of type of antihypertensiveand dosing can be complex.Prescription occurs at a health carefacility.Antihypertensives requiresomeone with prescriptiveauthority as the choice of type ofantihypertensive and dosing canbe complex. Prescription occurs ata health care facility.Page 67 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012SupplyInformationSustainablebusiness modelsTECHNOLOGY/SOLUTIONHydralazine Labetalol Nifedipine MethyldopaAntihypertensives address multiple Antihypertensives addressAntihypertensives address multiple Antihypertensives addressmarkets, which strengthens the multiple markets, whichmarkets, which strengthens the multiple markets, whichsustainability of this technology. strengthens the sustainability of sustainability of this technology. strengthens the sustainability ofHowever, antihypertensives are this technology. However,However, antihypertensives are this technology. However,commodity products, and,antihypertensives are commodity commodity products, and,antihypertensives are commoditytherefore, are priced with slim products, and, therefore, are therefore, are priced with slim products, and, therefore, aremargins, especially due to the large priced with slim margins,margins, especially due to the large priced with slim margins,number of manufacturers.especially due to the large number number of manufacturers.especially due to the large numberof manufacturers.of manufacturers.DemandInformationExisting demandAttractivenessPrice sensitivityPolicyenvironmentTECHNOLOGY/SOLUTIONHydralazine Labeltolol Nifedipine MethyldopaMarket size driven by number of Market size driven by number of Market size driven by number of Market size driven by number ofadults with hypertension (not just adults with hypertension (not just adults with hypertension (not just adults with hypertension (not justpregnant and postpartum women pregnant and postpartum women pregnant and postpartum women pregnant and postpartum womenwith chronic hypertension,with chronic hypertension,with chronic hypertension,with chronic hypertension,gestational hypertension, severe gestational hypertension, severe gestational hypertension, severe gestational hypertension, severepreeclampsia and eclampsia). preeclampsia and eclampsia). preeclampsia and eclampsia). preeclampsia and eclampsia).Adverse drug events (ADEs), manyof which are dose related such asdizziness, headaches, constipation,low energy, or sedation. Whilethese may be seen as minor, theycan greatly interfere with normalfunctioning, which many patientsfind unacceptable.To be evaluated. Would beinteresting to see how price affectsthe choice of whichantihypertensive providers use.As mentioned above, guidelines(WHO, NICE, midwifery education)differ widely causing confusion forproviders.ADEs, many of which are doserelated such as dizziness,headaches, constipation, lowenergy, or sedation. While thesemay be seen as minor, they cangreatly interfere with normalfunctioning, which many patientsfind unacceptable.To be evaluated. Would beinteresting to see how price affectsthe choice of whichantihypertensive providers use.As mentioned above, guidelines(WHO, NICE, midwifery education)differ widely causing confusion forproviders.ADEs, many of which are doserelated such as dizziness,headaches, constipation, lowenergy, or sedation. While thesemay be seen as minor, they cangreatly interfere with normalfunctioning, which many patientsfind unacceptable.To be evaluated. Would beinteresting to see how price affectsthe choice of whichantihypertensive providers use.As mentioned above, guidelines(WHO, NICE, midwifery education)differ widely causing confusion forproviders.ADEs, many of which are doserelated such as dizziness,headaches, constipation, lowenergy, or sedation. While thesemay be seen as minor, they cangreatly interfere with normalfunctioning, which many patientsfind unacceptable.To be evaluated. Would beinteresting to see how price affectsthe choice of whichantihypertensive providers use.As mentioned above, guidelines(WHO, NICE, midwifery education)differ widely causing confusion forproviders.Page 68 of 70

PREECLAMPSIA/ECLAMPSIAHealthTech—February 2012DemandInformationDonors/stakeholdersPre- and post-salessupportNeed for demandcreationTECHNOLOGY/SOLUTIONHydralazine Labeltolol Nifedipine MethyldopaWHO has set guidelines; the Gates WHO has set guidelines; the Gates WHO has set guidelines; the Gates WHO has set guidelines; the GatesFoundation has funded research Foundation has funded research Foundation has funded research Foundation has funded researchconducted by PRE-EMPT for conducted by PRE-EMPT forconducted by PRE-EMPT forconducted by PRE-EMPT forevaluating alternative approaches evaluating alternative approaches evaluating alternative approaches evaluating alternative approachessuch as two-drug therapy and such as two-drug therapy and such as two-drug therapy and such as two-drug therapy andpropranolol.propranolol.propranolol.propranolol.There is a need for clear protocolsand how to address stock-outs.Dosing is complicated. Doses needto be increased until thetherapeutic level is reached. If theBP is not well controlled with oneantihypertensive, either a secondone is added or the drug ischanged.There is an inadequacy ofproviders’ explanations to patientsof the importance of treatinghypertension, which often isasymptomatic; expected sideeffects and how to manage andtake this drug.Demand creation should be wellintegrated into training programssuch as by PRONTO International.There is a need for clear protocolsand how to address stock-outs.Dosing is complicated. Doses needto be increased until thetherapeutic level is reached. If theBP is not well controlled with oneantihypertensive, either a secondone is added or the drug is changed.There is an inadequacy of providers’explanations to patients of theimportance of treatinghypertension, which often isasymptomatic; expected sideeffects and how to manage andtake this drugDemand creation should be wellintegrated into training programssuch as by PRONTO International.There is a need for clear protocolsand how to address stock-outs.Dosing is complicated. Doses needto be increased until thetherapeutic level is reached. If theBP is not well controlled with oneantihypertensive, either a secondone is added or the drug is changed.There is an inadequacy of providers’explanations to patients of theimportance of treatinghypertension, which often isasymptomatic; expected sideeffects and how to manage andtake this drugDemand creation should be wellintegrated into training programssuch as by PRONTO International.There is a need for clear protocolsand how to address stock-outs.Dosing is complicated. Doses needto be increased until thetherapeutic level is reached. If theBP is not well controlled with oneantihypertensive, either a secondone is added or the drug ischanged.There is an inadequacy ofproviders’ explanations to patientsof the importance of treatinghypertension, which often isasymptomatic; expected sideeffects and how to manage andtake this drugDemand creation should be wellintegrated into training programssuch as by PRONTO International.Page 69 of 70

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