Protocol for the Redefining Maternal Anemia in Pregnancy and Postpartum (ReMAPP) study: A multisite, international, population-based cohort study to establish global hemoglobin thresholds for maternal anemia

Protocol for the Redefining Maternal Anemia in Pregnancy and Postpartum (ReMAPP) study: A multisite, international, population-based cohort study to establish global hemoglobin thresholds for maternal anemia | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Protocol for the Redefining Maternal Anemia in Pregnancy and Postpartum (ReMAPP) study: A multisite, international, population-based cohort study to establish global hemoglobin thresholds for maternal anemia View ORCID Profile Zahra Hoodbhoy , Aneeta Hotwani , View ORCID Profile Fyezah Jehan , Amna Khan , View ORCID Profile Imran Nisar , Nida Yazdani , Santosh Joseph Benjamin , Anne George Cherian , View ORCID Profile Venkata Raghava Mohan , Sunitha Varghese , Balakrishnan Vijayalekshmi , Blair J. Wylie , Leena Chatterjee , Arjun Dang , R Venketeshwar , View ORCID Profile Sasha G. Baumann , Christopher Mores , Qing Pan , View ORCID Profile Emily R. Smith , View ORCID Profile Christopher R. Sudfeld , View ORCID Profile Victor Akelo , □Winnie K. Mwebia , Kephas Otieno , Gregory Ouma , Harun Owuor , Joyce Were , Dennis Adu-Gyasi , Veronica Agyemang , Kwaku Poku Asante , Sam Newton , Charlotte Tawiah , Arun Singh Jadaun , Sarmila Mazumder , View ORCID Profile Neeraj Sharma , Lynda G. Ugwu , Amma Benneh-Akwasi Kuma , Bethany Freeman , Margaret P. Kasaro , Felistas M. Mbewe , Humphrey Mwape , View ORCID Profile Rachel S. Resop , M. Bridget Spelke doi: https://doi.org/10.1101/2024.11.06.24316823 Zahra Hoodbhoy 1 Department of Paediatrics and Child Health, Aga Khan University , Karachi, Pakistan Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Zahra Hoodbhoy Aneeta Hotwani 1 Department of Paediatrics and Child Health, Aga Khan University , Karachi, Pakistan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Fyezah Jehan 1 Department of Paediatrics and Child Health, Aga Khan University , Karachi, Pakistan Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Fyezah Jehan Amna Khan 1 Department of Paediatrics and Child Health, Aga Khan University , Karachi, Pakistan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Imran Nisar 1 Department of Paediatrics and Child Health, Aga Khan University , Karachi, Pakistan Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Imran Nisar Nida Yazdani 1 Department of Paediatrics and Child Health, Aga Khan University , Karachi, Pakistan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Santosh Joseph Benjamin 2 Christian Medical College Vellore , Vellore, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site Anne George Cherian 2 Christian Medical College Vellore , Vellore, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site Venkata Raghava Mohan 2 Christian Medical College Vellore , Vellore, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Venkata Raghava Mohan Sunitha Varghese 2 Christian Medical College Vellore , Vellore, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site Balakrishnan Vijayalekshmi 2 Christian Medical College Vellore , Vellore, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site Blair J. Wylie 3 Department of Obstetrics and Gynecology, Columbia University Medical Center , NY, United States Find this author on Google Scholar Find this author on PubMed Search for this author on this site Leena Chatterjee 4 Dr. Dangs Lab , New Delhi, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site Arjun Dang 4 Dr. Dangs Lab , New Delhi, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site R Venketeshwar 4 Dr. Dangs Lab , New Delhi, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sasha G. Baumann 5 Department of Global Health, George Washington University , Washington, DC, United States Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Sasha G. Baumann Christopher Mores 5 Department of Global Health, George Washington University , Washington, DC, United States Find this author on Google Scholar Find this author on PubMed Search for this author on this site Qing Pan 5 Department of Global Health, George Washington University , Washington, DC, United States Find this author on Google Scholar Find this author on PubMed Search for this author on this site Emily R. Smith 5 Department of Global Health, George Washington University , Washington, DC, United States Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Emily R. Smith For correspondence: kwakupoku.asante{at}kintampo-hrc.org emilysmith{at}gwu.edu Christopher R. Sudfeld 6 Department of Global Health, Harvard T.H. Chan School of Public Health , Cambridge, MA, United States Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Christopher R. Sudfeld Victor Akelo 7 Kenya Medical Research Institute , Kisumu, Kenya 8 Department of Clinical Sciences, Liverpool School of Tropical Medicine , Liverpool, England Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Victor Akelo □Winnie K. Mwebia 8 Department of Clinical Sciences, Liverpool School of Tropical Medicine , Liverpool, England Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kephas Otieno 8 Department of Clinical Sciences, Liverpool School of Tropical Medicine , Liverpool, England Find this author on Google Scholar Find this author on PubMed Search for this author on this site Gregory Ouma 8 Department of Clinical Sciences, Liverpool School of Tropical Medicine , Liverpool, England Find this author on Google Scholar Find this author on PubMed Search for this author on this site Harun Owuor 8 Department of Clinical Sciences, Liverpool School of Tropical Medicine , Liverpool, England Find this author on Google Scholar Find this author on PubMed Search for this author on this site Joyce Were 8 Department of Clinical Sciences, Liverpool School of Tropical Medicine , Liverpool, England Find this author on Google Scholar Find this author on PubMed Search for this author on this site Dennis Adu-Gyasi 9 Kintampo Health Research Centre, Research and Development Division, Ghana Health Service, Kintampo North Municipality, Bono East Region , Ghana Find this author on Google Scholar Find this author on PubMed Search for this author on this site Veronica Agyemang 9 Kintampo Health Research Centre, Research and Development Division, Ghana Health Service, Kintampo North Municipality, Bono East Region , Ghana Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kwaku Poku Asante 9 Kintampo Health Research Centre, Research and Development Division, Ghana Health Service, Kintampo North Municipality, Bono East Region , Ghana Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: kwakupoku.asante{at}kintampo-hrc.org emilysmith{at}gwu.edu Sam Newton 9 Kintampo Health Research Centre, Research and Development Division, Ghana Health Service, Kintampo North Municipality, Bono East Region , Ghana Find this author on Google Scholar Find this author on PubMed Search for this author on this site Charlotte Tawiah 9 Kintampo Health Research Centre, Research and Development Division, Ghana Health Service, Kintampo North Municipality, Bono East Region , Ghana Find this author on Google Scholar Find this author on PubMed Search for this author on this site Arun Singh Jadaun 10 Society for Applied Studies , New Delhi, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sarmila Mazumder 10 Society for Applied Studies , New Delhi, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site Neeraj Sharma 10 Society for Applied Studies , New Delhi, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Neeraj Sharma Lynda G. Ugwu 11 Department of Maternal-Fetal Medicine, University of Alabama at Birmingham School of Medicine , Birmingham, AL, United States Find this author on Google Scholar Find this author on PubMed Search for this author on this site Amma Benneh-Akwasi Kuma 12 Department of Hematology, College of Health Sciences, University of Ghana , Accra, Ghana Find this author on Google Scholar Find this author on PubMed Search for this author on this site Bethany Freeman 13 Department of Obstetrics and Gynecology, School of Medicine, University of North Carolina , Chapel Hill, NC Find this author on Google Scholar Find this author on PubMed Search for this author on this site Margaret P. Kasaro 13 Department of Obstetrics and Gynecology, School of Medicine, University of North Carolina , Chapel Hill, NC 14 University of North Carolina—Global Projects Zambia , Lusaka, Zambia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Felistas M. Mbewe 14 University of North Carolina—Global Projects Zambia , Lusaka, Zambia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Humphrey Mwape 14 University of North Carolina—Global Projects Zambia , Lusaka, Zambia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Rachel S. Resop 14 University of North Carolina—Global Projects Zambia , Lusaka, Zambia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Rachel S. Resop M. Bridget Spelke 13 Department of Obstetrics and Gynecology, School of Medicine, University of North Carolina , Chapel Hill, NC 14 University of North Carolina—Global Projects Zambia , Lusaka, Zambia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Abstract Full Text Info/History Metrics Data/Code Preview PDF ABSTRACT Background Anemia affects one in three pregnant women worldwide, with the greatest burden in South Asia and sub-Saharan Africa. During pregnancy, anemia has been linked to an increased risk of adverse maternal and neonatal health outcomes. Despite widespread recognition that anemia can complicate pregnancy, critical gaps persist in our understanding of the specific causes of maternal anemia and the cutoffs used to diagnose anemia in each trimester and in the postpartum period. Methods and analysis The Redefining Maternal Anemia in Pregnancy and Postpartum (ReMAPP) study is a multisite, prospective, cohort study nested within the Pregnancy Risk, Infant Surveillance, and Measurement Alliance (PRISMA) Maternal and Newborn Health study. Research sites are located in Kenya, Ghana, Zambia, India, and Pakistan. Participants are up to 12,000 pregnant women who provide serial venous blood samples for hemoglobin assessment at five time points: at <20 weeks, 20 weeks, 28 weeks, and 36 weeks gestation and at six weeks postpartum. We will use two analytical approaches to estimate hemoglobin thresholds for defining anemia: (1) clinical decision limits for cutoffs in each trimester and at six weeks postpartum based on associations of hemoglobin levels with adverse maternal, fetal, and neonatal health outcomes and (2) reference limits for gestational-week-specific cutoffs and at six weeks postpartum for mild, moderate, and severe anemia based on tail statistical percentiles of hemoglobin values in a reference (i.e., clinically healthy) subpopulation. We will also conduct biomarker-intensive testing among a sub-sample of participants in each trimester to explore underlying contributing factors of maternal anemia. Ethics and dissemination The study received local and national ethical approvals from all participating institutions. Findings from multisite analyses will be published among open-access, peer-reviewed journals and disseminated with local, national, and international partners. Registration ClinicalTrials.gov (ID: PRISMA-MNH 2022; NCT05904145 ) Strengths and limitations Novel study design to allow multiple analytical approaches (clinical decision limits and reference limits) in the same population to establish hemoglobin thresholds. Use of gold standard methods and external quality assurance programs to ensure harmonized hemoglobin measurement across sites. Inclusion of biomarker-intensive study arm to examine the etiology of anemia among pregnant women. All data is contributed by populations historically underrepresented in research in low- and middle-income countries. INTRODUCTION Anemia is a common health condition characterized by low blood hemoglobin concentration and/or low red blood cell count. Women, particularly those who are pregnant and lactating, are physiologically at a higher risk than men of being anemic [ 1 , 2 ]. An estimated 36% of pregnant women globally are anemic, with the highest prevalence in South Asia (48%) and West and Central Africa (52%) [ 3 ]. Although there are many causes of anemia, iron deficiency is estimated to account for roughly half of anemia cases in women [ 4 ]. Other contributing causes of anemia include infectious diseases (e.g., hookworm, malaria, schistosomiasis, HIV), gynecologic conditions (e.g., abnormal uterine bleeding, hemorrhage, uterine fibroids), other micronutrient deficiencies (e.g. folate, vitamin B12), thyroid dysfunction, chronic kidney disease, hemoglobinopathies like sickle cell disease or thalassemia, and environmental exposures such as lead or arsenic [ 1 , 2 , 5 – 8 ]. Importantly, causes of anemia vary widely by geography, life stage, and age. During pregnancy, abnormal hemoglobin levels are linked to an increased risk of adverse maternal, fetal and neonatal health outcomes. Specifically, maternal anemia (i.e. low hemoglobin) can increase risk of postpartum hemorrhage, preeclampsia, maternal mortality, postpartum maternal depression, preterm delivery, low birth weight, small for gestational age, stillbirth, neonatal mortality, and poor infant brain structural development [ 9 – 13 ]. The likelihood of these outcomes depends on the case severity, gestational timing onset and duration of anemia [ 11 , 12 ]. Multiple studies have also observed an association between high hemoglobin concentration and pregnancy complications, though there are no standard thresholds to define excess hemoglobin [ 11 , 14 – 16 ]. In a systematic review and meta-analysis by Young et al. (2023), hemoglobin levels greater than 13.0 g/dL during pregnancy were associated with increased risk of small-for-gestational-age, stillbirth, (very) low birth weight, preterm birth, gestational diabetes, preeclampsia, and maternal mortality [ 17 ]. A growing body of evidence over the last decade suggests that the hemoglobin cutoffs used to diagnose anemia during pregnancy and the postpartum period should be reevaluated in consideration of data from low- and middle-income countries (LMICs) [ 11 , 18 – 20 ]. In 2017, a World Health Organization (WHO) technical consultation concluded that the current hemoglobin thresholds used in pregnancy were not supported by sufficient data, not proven to be linked to health outcomes, not representative of diverse geographies and ethnicities, and not necessarily applicable in the context of common gene mutations that affect hemoglobin function [ 21 ]. Although WHO released revised anemia definitions in 2024, the use of trimester-specific cutoffs during pregnancy and of non-pregnant adult cutoffs in the immediate postpartum period to diagnose anemia are not well-evidenced [ 22 ]. Similarly—given that causes of anemia are varied in severity, multifactorial, and regionally distinct—further research is needed to understand how anemia etiology differs for pregnant women, given that most research to date has focused on non-pregnant women [ 23 ]. Correct anemia identification carries significance not only for its prevention, diagnosis, and treatment at the individual level, but also for tracking progress toward global anemia reduction targets. Hemoglobin thresholds to diagnose anemia in pregnancy at all gestational ages were first established by the World Health Organization (WHO) in 1959 as <10.0 g/dL, then adapted in 1968 to <11.0 g/dL [ 24 , 25 ]. These definitions of anemia were based on a ‘normal range’ of hemoglobin values; wherein below the 2.5th percentile (−2 standard deviations (SDs) from the mean) is considered low hemoglobin (i.e. anemia) and above the 97.5th percentile (+2 SDs from the mean) is high hemoglobin. Data informing the ‘normal range’ was largely derived from four published studies in high-income countries (Norway, England, Wales, United States) with small sample sizes, not all of which included women [ 26 – 29 ]. In 1989, the Centers for Disease Control (CDC) set thresholds based on studies in Europe and the United States for each trimester: <11.0 g/dL in the first and third trimesters and <10.5 g/dL in the second trimester [ 30 ]. The WHO introduced thresholds for anemia severity in pregnant women in 2011, adopted the CDC trimester-specific thresholds in 2016, and added trimester-specific severity cutoffs in 2024 ( Table 1 ) [ 22 , 31 , 32 ]. Notably, the WHO guidelines released in 2024 excluded data from LMICs in the pooled analysis that informed the update, citing that the unknown effect of infection and inflammation on hemoglobin coupled with their high prevalence in these settings precluded their inclusion [ 22 ]. View this table: View inline View popup Download powerpoint Table 1. WHO (2024) thresholds for anemia for non-pregnant and pregnant women We designed the Redefining Maternal Anemia in Pregnancy and Postpartum (ReMAPP) study to establish hemoglobin cutoffs using multiple analytical approaches for the diagnosis of anemia during pregnancy and within 42 days postpartum in LMIC populations. The specific aims are threefold: (1) to determine trimester-specific and postpartum hemoglobin thresholds for anemia diagnosis based on statistically significant increased risks of adverse maternal, fetal, and newborn health outcomes (i.e. decision limits); (2) to estimate gestational-week-specific and six-week postpartum hemoglobin thresholds for mild, moderate, and severe anemia diagnosis using the 5th and 2.5th statistical percentiles among a clinically healthy subpopulation (i.e. reference limits); (3) to describe the underlying contributing factors of anemia (i.e. etiology) in pregnancy in Ghana, Kenya, Zambia, Pakistan, and India. MATERIALS AND METHODS Study design ReMAPP is a prospective cohort study in five countries. It is embedded within the Pregnancy Risk, Infant Surveillance, and Measurement Alliance (PRISMA) Maternal and Newborn Health study: a longitudinal, open cohort study that seeks to evaluate pregnancy risk and health and development for women and infants [ 33 ]. The population for ReMAPP is nested in the PRISMA study cohort. Enrollment for ReMAPP was initiated on a rolling basis by site and began between September 2022 and December 2023 (22 September 2022 in Pakistan, 15 December 2022 in Zambia, 28 December 2022 in Ghana, 14 April 2023 in Kenya, 20 June 2023 in India (Vellore), and 12 December 2023 in India (Hodal). Enrollment is expected to be completed by June 2025. As illustrated in Figure 1 , further selection will be done from the primary cohort of enrolled participants to identify a clinically ‘healthy’ analytical subcohort and cross-sectional sub-samples for etiology assessment. Data from the primary cohort, analytical subcohort, and cross-sectional sample will be used to achieve aims one, two, and three, respectively. Download figure Open in new tab Figure 1. Nested ReMAPP study design with estimated 12,000 pregnancies in study cohort (n=1,650 to 2,000 each site) Study setting This study focuses on countries in South Asia and sub-Saharan Africa with high anemia prevalence [ 34 ]. There are six research sites: Kintampo, Ghana; Kisumu and Siaya, Kenya; Lusaka, Zambia; Karachi, Pakistan; Vellore, India; and Hodal, India. Each site has identified and mapped geographic catchment areas, which have at least 1500 deliveries per year. Eligibility criteria and recruitment Participants eligible for the ReMAPP study are pregnant women who live within the catchment area, are <45 years and meet country-specific minimum age requirements (Ghana: 15 years of age; Kenya: 18 years of age or emancipated minors; Pakistan: 15 years of age or emancipated minors; Zambia: 15 years of age; India: 18 years of age), have a viable intrauterine pregnancy, are less than 20 weeks gestation as verified via ultrasound, intend to stay in the study area until six weeks post-delivery, and who provide informed consent. Participant selection and sampling All participants enrolled in the PRISMA study will be invited to participate in the ReMAPP study if they meet eligibility criteria. Enrollment will continue until the target sample size (n=1650 to 2000 per site) is achieved. These participants will form the ReMAPP primary cohort, and will undergo serial hemoglobin testing by complete blood count and be followed up at regular study visits through one year postpartum. Upon enrollment, all ReMAPP participants will undergo screening based on predetermined criteria to obtain sociodemographic information, obstetric history, vital signs, anthropometric measurements, and laboratory results. If a participant meets the 21 screening criteria ( Box 1 ), they will be included in the clinically ‘healthy’ analytical subcohort. Selected participants may also be excluded from the final ‘healthy’ analytical subcohort if any of the following occur during follow-up: multiple pregnancies previously not identified, severe conditions not initially evident including cancer, HIV, tuberculosis, or malaria, or severe pregnancy-related conditions requiring hospital admission including severe preeclampsia/eclampsia. Box 1. Screening criteria for clinically healthy subcohort Aged 18 to 34 years Gestational age at enrollment 18.5 and 23cm Height ≥150 cm Singleton pregnancy Systolic blood pressure <140 mmHg and diastolic blood pressure 15 mcg/L adjusted for inflammation [ 35 ]) No subclinical inflammation (CRP≤5 mg/L and/or AGP≤1 g/L) No hemoglobinopathies (SS, SC, SE, EE, CC, SD-Punjab, Sβthal, Eβthal, Cβthal, CD-Punjab, ED-Punjab, D-D-Punjab, D-Punjabβthal, Thalassemia major, Thalassemia intermedia, or Alpha thalassemia) Normal glucose-6-phosphate dehydrogenase (≥6.1 U/g Hb) No reported previous low birth weight delivery No reported previous stillbirth No reported previous unplanned cesarean delivery No reported cigarette smoking, tobacco chewing, or betel nut use No reported alcohol consumption during pregnancy No current malaria infection (per rapid diagnostic test) No current Hepatitis B virus infection (per rapid diagnostic test) No current Hepatitis C virus infection (per rapid diagnostic test) No known history or current chronic disease (cancer, kidney disease, or cardiac condition) No known history or current HIV Among the participants screened, a cross-sectional sample of up to 300 participants (100 per trimester, both anemic and nonanemic) per site will be selected to undergo biomarker-intensive testing. Any method of population-representative sampling may be used within each trimester stratum, provided that selection occurs over the same time period to eliminate time bias. Follow-up procedures and data collection Data will be collected using a harmonized set of forms developed for the PRISMA study [ 33 ]. Beyond the routine PRISMA study visit procedures, ReMAPP participants will provide biological specimens to undergo additional laboratory testing ( Table 2 ). For hemoglobin, the primary measure of interest, participants will be serially assessed at less than 20 weeks, at 20 weeks, 28 weeks, and 36 weeks gestation and at six weeks postpartum by complete blood count using a venous blood sample and a five-part differential automated hematology analyzer. Additional testing will be done at enrollment, as a part of the screening laboratory tests for the clinically ‘healthy’ subcohort. Biomarker-intensive testing will be done for the sample of 300 participants (100 per trimester), either during their enrollment visit (gestational age less than 14 weeks), 20- week, or 32-week ANC visit. Methods and timing of laboratory assessments will be standardized across sites to ensure comparability and quality. View this table: View inline View popup Table 2. Laboratory tests for the ReMAPP study Quality assurance for laboratory tests Each site laboratory will adhere to the Laboratory Quality Assurance and Quality Control Standard Operating Procedures manual developed specifically for this study. For full blood count measurement, all participating labs will be enrolled onto the United Kingdom National External Quality Assurance Scheme for Hematology for monthly quality assurance [ 36 ]. For full blood count and all other analytes, the College of American Pathologists’ External Quality Assessment Program is required [ 37 ]. Sample size estimates Each site will enroll 1,650 to 2,000 participants in the ReMAPP study, to achieve an overall study sample of 12,000 participants across the six sites. The sample size was selected assuming that about 30% (n=600) will meet the eligibility criteria for the ‘healthy’ subcohort. This sample size will also capture sufficient cases of the primary maternal and newborn outcomes of interest, based on previous regional prevalence estimates, in order to conduct a pooled decision limits analysis with at least 90% power to estimate association between anemia and each outcome. Our power speculation is based on the distribution of hemoglobin values in pregnancy by gestational age presented in the INTERGROWTH-21 st study [ 18 ]. For the ‘healthy’ analytical subcohort, a sample size of 600 participants per site allows for single-site estimation of hemoglobin thresholds for any maternal anemia (i.e., 5th percentile) and severe maternal anemia (i.e., 2.5th percentile). As illustrated in Figure 2 , there will be sufficient precision to distinguish between these two percentiles without overlapping 95% confidence intervals. If sites are unable to identify 600 participants for the healthy cohort, a minimum sample size of 300 participants will be sufficient for single-site hemoglobin threshold estimation. Download figure Open in new tab Figure 2. Visualization of sample size estimates with thresholds for any (i.e. 5th percentile) and severe maternal anemia (i.e. 2.5th percentile) at n = 300, 400, 500, 600 For the cross-sectional sample, n=300 was determined to minimize the burden of additional specimen collection while allowing for exploratory pooled analyses of anemia etiology. The calculation is based on the following assumptions: one third of the participants have a certain contributing factor (e.g., the prevalence of vitamin A insufficiency); 30% of participants without the factor have anemia; and 50% with the factor have anemia. At the two-sided significance level of 95% and 80% statistical power, we can detect a prevalence ratio of 1.7 with a sample size of between 240 and 270 [ 38 ]. We inflated the sample to 300 to account for the fact that some contributing factors are less prevalent in certain study sites. Participant and public involvement Participants will be collaboratively involved at multiple phases of the study. During initial protocol workshops, investigators carefully evaluated the additional burden of study participation; for this reason, the size of the biomarker-intensive sample was kept to a minimum and invasive blood draws limited to select visit timepoints. As a part of the translation and validation process for questionnaires to measure fatigue, patients’ experiences were centered and informed scale validation procedures. Participants’ health priorities and experiences will also be explored in corresponding qualitative research about maternal morbidity. Upon completion of the study, we intend to share the main findings with participants and community members via appropriate local dissemination methods. Finally, we will ensure that participants’ contributions to this research are acknowledged in any subsequent reports, presentations, and publications. Ethical and safety considerations This protocol, the informed consent documents and any subsequent modifications will be reviewed and approved by the relevant institutional review board (IRB) and ethics review committee (ERC) responsible for oversight of the study at each site. IRB approvals for this research were received from the following ERCs in each country: Ghana (Ghana Health Service ERC (FWA No. 000200025) and the Kintampo Health Research Center Institutional Ethics Committee, FWA No. 00011103), Kenya (KEMRI Scientific and Ethics Review Unit, 04-10-358- 4166), Zambia (University of Zambia Biomedical Research Ethics Committee, IRB00001131 of IORG0000774 and UNC Biomedical IRB 356795), India (Office of Research, Christian Medical College, Vellore, India Ethics Committee, IRB14553), India (Ethics Review Committee, Society for Applied Studies, New Delhi, SAS/ERC/ReMAPP Study/2022; Department of Health Research, EC/NEW/INST/2022/DL/0140), Pakistan (National Institutes of Health - Health Research Institute, National Bioethics Committee Ref: No.4-87/NBC-962/23/593 and Aga Khan University Ethics Review Committee, 2022-7197-21350), and the United States (Columbia University IRB IRB- AAAU7504; The George Washington University IRB NCR224396; Harvard University IRB IRB- 23-1093). The rights and safety of all study participants will be protected. Written informed consent, assent and parental consent will be sought from all study participants as appropriate prior to enrollment. Site-specific unique identification numbers will be issued to participants instead of names to protect their identity. A limited data set will be stored in a secure cloud server where only trained study staff will have credentials for access. Study participants with abnormal biochemical results will be referred for further clinical assessment and management according to study-specific standard operating procedures. ANALYTICAL PLAN Aim 1: Establishing hemoglobin clinical decision limits based on adverse outcomes Aim 1 will establish trimester-specific and postpartum hemoglobin clinical decision limits for any anemia based on associations with adverse maternal, fetal, and infant outcomes ( Table 3 ). For this analysis, hemoglobin and outcome data points from all participants will be pooled. Nonparametric relationships between risks of adverse events and hemoglobin levels will be plotted using real data [ 39 ]. A series of candidate thresholds in hemoglobin values will be considered and disease risks before and after each threshold will be compared. Thresholds with clinically meaningful differences in the disease risks and statistically sound significance levels will be selected. Clinical decision limits for overall adverse events will be reported, as well as disease-specific clinical decision limits. View this table: View inline View popup Table 3. Primary and secondary health outcomes for establishing decision limits Aim 2: Establishing hemoglobin reference limits among a healthy population Aim 2 will establish gestational-age-specific hemoglobin reference limits for any, mild, moderate, or severe anemia in a reference population (i.e., clinically ‘healthy’ subcohort) during pregnancy and within 42 days postpartum [ 42 , 43 ]. This analysis will include hemoglobin data points from all participants eligible for the clinically ‘healthy’ subcohort. Fractional polynomial regression (FPR) will be used to model and visualize the hemoglobin changing curves of different percentiles against gestational age [ 18 ]. Sensitivity analysis of the percentile curves predicted by FPR models will be performed excluding one site at a time. If the hemoglobin distributions are similar across sites and between-site between is less than within-site variance, we will pool the data; if not, analyses will remain stratified by site. Hemoglobin levels below the 5th or 2.5th percentiles at the corresponding time points during pregnancy are typically considered abnormally low and likely indicative of anemia. Therefore, the reference limits are defined as tail percentiles of hemoglobin levels in the reference population. Tail percentiles, such as 5th or 2.5th percentiles, will be modeled as a smooth polynomial function of gestational weeks using hemoglobin levels. With the final validated model, we will estimate the 2.5th, 5th, 95th, and 97.5th percentiles predicted from the FPR curves at specific gestational timepoints from 14 to 40 weeks and postpartum. Aim 3: Describing the etiology of anemia in pregnancy Aim 3 will describe the underlying contributing factors of anemia in pregnancy among a sample of up to 1,800 participants (up to 300 per site), with approximately equal numbers in each trimester. Analyses will be performed on pooled, regional, and site-specific data to identify shared and unique risk factors for anemia. We will quantify the association between contributing factors and anemia (defined using the WHO cutoffs and study-established reference and decision limit thresholds) by calculating relative risks from a generalized linear log-binomial model with robust standard errors. If these models fail to converge, we will use modified Poisson estimates, which produce valid but less efficient estimates of the log-binomial model. We will run separate models for proximal, medial, and distal risk factors ( Figure 3 ). Distal risk factors will be included as potential confounders to proximal and medial models. We will estimate the population attributable risk fraction using prevalence of the exposure/risk factor and the relative risk of anemia in the exposed versus unexposed group. Partial population attributable risk will be calculated by fitting multivariate models with log link for anemia adjusting for multiple risk factors. For contributing factors significantly associated with risks of anemia, we will further report the change in continuous hemoglobin concentrations associated with the factor. Download figure Open in new tab Figure 3. Risk factors of maternal anemia Dissemination plan The data generated in the course of the study will be reviewed on a regular basis for quality per our established Data Quality Assurance and Quality Control Standard Operating Procedures monthly. Following the end of the study, meetings will be organized at each study site to share results with community members, local authorities, and study participants. Findings will also be shared with local and international stakeholders, including the Bill & Melinda Gates Foundation, WHO, CDC, United States Agency for International Development, and Ministries of Health in each participating country. Abstracts will be developed for dissemination through both local and international scientific conferences and publication in peer-reviewed journals. Data Availability No datasets were generated or analysed during the current study. All relevant data from this study will be made available upon study completion. AUTHORS’ CONTRIBUTIONS Conceptualization: VA, KPA, AGC, ZH, FJ, MPK, SM, VRM, CM, IN, QP, ERS, MBS, and CRS. Funding acquisition: KPA, CT, SN, VA, SJB, IN, MPK, MBS, ERS, CM, and SM. Design of methodology: KPA, CT, ABAK, ERS, QP, LGU, CRS, and BJW. Project administration: VA, DAG, SGB, BF, ASJ, AK, FMM, HM, KO, RSR, WKM, GO, HO, NS, BV, SV, ZAW, JW, and NY. Provision of study materials: VA, DAG, LC, AD, AH, HM, KO, RR, RV, and BV. Supervision: VA, KPA, SJB, ZH, FJ, ASJ, MPK, SM, VRM, CM, WKM, SN, IN, QP, NS, ERS, MBS, CRS, CT, and LGU. Visualization: SGB, QP, and ERS. Writing—original draft preparation: VA, KPA, SGB, QP, and ERS. Writing—review and editing: VA, VA, KPA, SGB, SJB, LC, AGC, AD, DAG, AH, BF, ZH, ASJ, FJ, ABAK, AK, MPK, CM, VRM, HM, SM, IM, FMM, WKM, SN, GO, KO, HO, QP, RSR, NS, ERS, MBS, CRS, CT, LGU, BV, RV, SV, BJW, JW, NY. FUNDING STATEMENT This work was supported by Bill and Melinda Gates Foundation grant number [INV-002220 and INV-037626 to KPA, CTA, and SN; INV-003601 to VA; INV-043092 to SB; INV-005776 to IN and ZH; INV-057218 to MPK; K01TW012426 NIH/FIC to MBS; INV-041999 and INV-031954 to ERS; INV-060797 to CM; and INV-057223 to SM]. The funders provided input on the design of the study but had no role in the decision to publish or preparation of the manuscript. COMPETING INTERESTS STATEMENT The authors declare no competing interests. ACKNOWLEDGEMENTS This study would not be possible without the support of the Bill & Melinda Gates Foundation, specifically from Laura Lamberti and Sun-Eun Lee. The study design greatly benefited from the expertise of the ReMAPP Technical Advisory Group members, who were generous with their time and expertise: Lisa Rogers, Maria Elena Jefferds, Denish Moorthy, Melissa Fox Young, Nicholas Kassebaum, Eric Ohuma, and Bosede Afolabi. 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Bridget Spelke medRxiv 2024.11.06.24316823; doi: https://doi.org/10.1101/2024.11.06.24316823 Share This Article: Copy Citation Tools Protocol for the Redefining Maternal Anemia in Pregnancy and Postpartum (ReMAPP) study: A multisite, international, population-based cohort study to establish global hemoglobin thresholds for maternal anemia Zahra Hoodbhoy , Aneeta Hotwani , Fyezah Jehan , Amna Khan , Imran Nisar , Nida Yazdani , Santosh Joseph Benjamin , Anne George Cherian , Venkata Raghava Mohan , Sunitha Varghese , Balakrishnan Vijayalekshmi , Blair J. Wylie , Leena Chatterjee , Arjun Dang , R Venketeshwar , Sasha G. Baumann , Christopher Mores , Qing Pan , Emily R. Smith , Christopher R. Sudfeld , Victor Akelo , □Winnie K. Mwebia , Kephas Otieno , Gregory Ouma , Harun Owuor , Joyce Were , Dennis Adu-Gyasi , Veronica Agyemang , Kwaku Poku Asante , Sam Newton , Charlotte Tawiah , Arun Singh Jadaun , Sarmila Mazumder , Neeraj Sharma , Lynda G. 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