Malaria, malnutrition, and birthweight: A meta-analysis using individual participant data

RESEARCH ARTICLE Mala ia, malnu i ion, and bi hweigh : A me a-analysis using indi idual pa icipan da a Jo dan E. Ca es 1 *, Holge W. Unge 2,3 , Vale ie B iand 4 , Nadine Fie e 4 , Innocen Valea 5,6 , Halidou Tin o 5,6 , Umbe o D’Alessand o 7 , Sa ah H. Landis 8 , Se h Adu-A a wuah 9 , Ka h yn G. Dewey 10 , Feiko O. e Kuile 11 , Meghna Desai 12 , S ephanie Dellicou 11 , Pe e Ouma 13 , Julie Gu man 12 , Ma ina Oneko 13 , Lau ence Slu ske 14 , Dianne J. Te louw 11,15 , Simon Ka iuki 13 , John Ayisi 13 , Mwayiwawo Madani sa 11,16 , Vic o Mwapasa 16 , Pe Asho n 17 , Kenne h Male a 16 , I o Muelle 18 , Danielle S anisic 19 , Ch is en ze Schmiegelow 20 , John P. A. Lusingu 20,21 , Anna Ma ia an Eijk 11 , Melissa Bause man 22,23 , Linda Adai 23 , S ephen R. Cole 1 , Daniel Wes eich 1‡ , S e en Meshnick 1‡ , S ephen Roge son 3‡ 1Depa men o Epidemiology, UNC-Chapel Hill, Chapel Hill, No h Ca olina, Uni ed S a es o Ame ica, 2Depa men o Obs e ics and Gynaecology, Edinbu gh Royal In i ma y, Edinbu gh, Uni ed Kingdom, 3Depa men o Medicine a he Dohe y Ins i u e, The Uni e si y o Melbou ne, Pa k ille, Vic o ia, Aus alia, 4UMR216-MERIT, F ench Na ional Resea ch Ins i u e o Sus ainable De elopmen (IRD), Pa is Desca es Uni e si y, Pa is, F ance, 5Uni e de Reche che Clinique de Nano o, Ins i u de Reche che en Sciences de la San e ´-DRO, Bobo-Dioulasso, Bu kina Faso, 6Depa emen de Reche che Clinique, Cen e Mu az, Bobo- Dioulasso, Bu kina Faso, 7Medical Resea ch Council Uni , The Gambia; London School o Hygiene and T opical Medicine, London, Uni ed Kingdom, 8Wo ldwide Epidemiology, GlaxoSmi hKline, Uxb idge, Uni ed Kingdom, 9Depa men o Nu i ion and Food Science, Uni e si y o Ghana, Legon, Acc a, Ghana, 10 Depa men o Nu i ion, Uni e si y o Cali o nia, Da is, Cali o nia, Uni ed S a es o Ame ica, 11 Depa men o Clinical Sciences, Li e pool School o T opical Medicine, Li e pool, Uni ed Kingdom, 12 Mala ia B anch, Di ision o Pa asi ic Diseases and Mala ia, Cen e o Global Heal h, Cen e s o Disease Con ol and P e en ion, A lan a, Geo gia, Uni ed S a es o Ame ica, 13 Kenya Medical Resea ch Ins i u e (KEMRI)/ Cen e o Global Heal h Resea ch, Kisumu, Kenya, 14 Mala ia and Neglec ed T opical Diseases, Cen e o Mala ia Con ol and Elimina ion, PATH, Sea le, Washing on, Uni ed S a es o Ame ica, 15 Malawi-Li e pool-Wellcome T us Clinical Resea ch P og amme, Blan y e, Malawi, 16 School o Public Heal h and Family Medicine, College o Medicine, Uni e si y o Malawi, Blan y e, Malawi, 17 Cen e o Child Heal h Resea ch Uni e si y o Tampe e School o Medicine and Tampe e Uni e si y Hospi al, Tampe e, Finland, 18 Wal e and Eliza Hall Ins i u e, Pa k ille, Vic o ia, Aus alia, 19 Ins i u e o Glycomics, G i i h Uni e si y, Gold Coas , Queensland, Aus alia, 20 Cen e o Medical Pa asi ology, Depa . O Immunology and Mic obiology, Facul y o Heal h Science, Uni e si y o Copenhagen, Copenhagen, Denma k, 21 Na ional Ins i u e o Medical Resea ch, Tanga Cen e, Tanga, Tanzania, 22 Depa men o Pedia ics, Di ision o Neona al-Pe ina al Medicine, School o Medicine, UNC-Chapel Hill, Chapel Hill, No h Ca olina, Uni ed S a es o Ame ica, 23 Depa men o Nu i ion, UNC-Chapel Hill, Chapel Hill, No h Ca olina, Uni ed S a es o Ame ica ‡These au ho s a e join senio au ho s on his wo k. *[email p o ec ed]om Abs ac Backg ound Fou s udies p e iously indica ed ha he e ec o mala ia in ec ion du ing p egnancy on he isk o low bi hweigh (LBW; <2,500 g) may depend upon ma e nal nu i ional s a us. We in es iga ed his dependence u he using a la ge, di e se s udy popula ion. PLOS Medicine | h ps://doi.o g/10.1371/jou nal.pmed.1002373 Augus 8, 2017 1 / 20 a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 OPEN ACCESS Ci a ion: Ca es JE, Unge HW, B iand V, Fie e N, Valea I, Tin o H, e al. (2017) Mala ia, malnu i ion, and bi hweigh : A me a-analysis using indi idual pa icipan da a. PLoS Med 14(8): e1002373. h ps://doi.o g/10.1371/jou nal.pmed.1002373 Academic Edi o : Lo enz on Seidlein, Mahidol- Ox o d T opical Medicine Resea ch Uni , THAILAND Recei ed: Ma ch 6, 2017 Accep ed: July 11, 2017 Published: Augus 8, 2017 Copy igh : This is an open access a icle, ee o all copy igh , and may be eely ep oduced, dis ibu ed, ansmi ed, modi ied, buil upon, o o he wise used by anyone o any law ul pu pose. The wo k is made a ailable unde he C ea i e Commons CC0 public domain dedica ion. Da a A ailabili y S a emen : Da a a e a ailable om he WWARN da a eposi o y (h p://www. wwa n.o g/wo king- oge he /sha ing-da a/ accessing-da a) o esea che s who mee he c i e ia o access o con iden ial da a. Funding: JC was unded by he Na ional Ins i u e o Alle gy and In ec ious Diseases a he Na ional Ins i u es o Heal h (P e-doc o al T aining in In ec ious Disease Epidemiology g an #5 T32 AI070114). The STOPPAM p ojec , "S a egies To P e en P egnancy-Associa ed Mala ia," was Me hods and indings We e alua ed he in e ac ion be ween ma e nal mala ia in ec ion and ma e nal an h opo- me ic s a us on he isk o LBW using pooled da a om 14,633 p egnancies om 13 s udies (6 coho s udies and 7 andomized con olled ials) conduc ed in A ica and he Wes e n Paci ic om 1996–2015. S udies we e iden i ied by he Ma e nal Mala ia and Malnu i ion (M3) ini ia i e using a con enience sampling app oach and we e eligible o pooling gi en adequa e e hical app o al and a ailabili y o essen ial a iables. S udy-speci ic adjus ed e ec es ima es we e calcula ed using in e se p obabili y o ea men -weigh ed linea and log-binomial eg ession models and pooled using a andom-e ec s model. The adjus ed isk o deli e ing a baby wi h LBW was 8.8% among women wi h mala ia in ec ion a an ena- al en ollmen compa ed o 7.7% among unin ec ed women (adjus ed isk a io [aRR] 1.14 [95% con idence in e al (CI): 0.91, 1.42]; N= 13,613), 10.5% among women wi h mala ia in ec ion a deli e y compa ed o 7.9% among unin ec ed women (aRR 1.32 [95% CI: 1.08, 1.62]; N= 11,826), and 15.3% among women wi h low mid-uppe a m ci cum e ence (MUAC <23 cm) a en ollmen compa ed o 9.5% among women wi h MUAC 23 cm (aRR 1.60 [95% CI: 1.36, 1.87]; N= 9,008). The isk o deli e ing a baby wi h LBW was 17.8% among women wi h bo h mala ia in ec ion and low MUAC a en ollmen compa ed o 8.4% among unin ec ed women wi h MUAC 23 cm (join aRR 2.13 [95% CI: 1.21, 3.73]; N= 8,152). The e was no e idence o syne gism (i.e., excess isk due o in e ac ion) be ween mala ia in ec ion and MUAC on he mul iplica i e (p= 0.5) o addi i e scale (p= 0.9). Resul s we e simila using body mass index (BMI) as an an h opome ic indica o o nu i ional s a us. Me a- eg ession esul s indica ed ha he e may be mul iplica i e in e - ac ion be ween mala ia in ec ion a en ollmen and low MUAC wi hin s udies conduc ed in A ica; howe e , his inding was no consis en on he addi i e scale, when accoun ing o mul iple compa isons, o when using o he de ini ions o mala ia and malnu i ion. The majo limi a ions o he s udy included a ailabili y o only 2 c oss-sec ional measu emen s o mala ia and he limi ed a ailabili y o ul asound-based p egnancy da ing o assess impac s on p e e m bi h and e al g ow h in all s udies. Conclusions P egnan women wi h malnu i ion and mala ia in ec ion a e a inc eased isk o LBW com- pa ed o women wi h only 1 isk ac o o none, bu mala ia and malnu i ion do no ac syne gis ically. Au ho summa y Why was his s udy done? • Mo e han 125 million p egnan women a e a isk o mala ia in p egnancy annually, p oducing de imen al e ec s on ma e nal, newbo n, and in an heal h. • Ma e nal unde nu i ion is es ima ed o be esponsible o 800,000 newbo n dea hs annually. Mala ia, malnu i ion, and bi hweigh PLOS Medicine | h ps://doi.o g/10.1371/jou nal.pmed.1002373 Augus 8, 2017 2 / 20 suppo ed by he Eu opean Union’s Se en h F amewo k P og amme (EU FP7); STOPPAM con ac numbe : 200889. STOPPAM I (Benin) and STOPPAM II (Tanzania). The FSP/MISAME s udy (Bu kina Faso) was unded by Nu i ion Thi d Wo ld, The Belgium Minis y o De elopmen , Flemish In e uni e si y Council, and F ench Minis y o De elopmen . The ECHO s udy (Democ a ic Republic o he Congo) was unded by he Depa men o Epidemiology, Uni e si y o No h Ca olina Chapel Hill, UNC Gillings School o Global Public Heal h. The iLiNS-DYAD (Ghana) ial was unded by a g an o he Uni e si y o Cali o nia, Da is om he Bill & Melinda Ga es Founda ion. EMEP was pa ly suppo ed by he Mala ia in P egnancy (MiP) Conso ium, which is unded h ough a g an om he Bill & Melinda Ga es Founda ion o he Li e pool School o T opical Medicine, UK and pa ly by he US Cen e s o Disease Con ol and P e en ion (CDC), Di ision o Pa asi ic Diseases and Mala ia h ough a coope a i e ag eemen wi h Kenya Medical Resea ch Ins i u e (KEMRI), Cen e o Global Heal h Resea ch (CGHR), Kisumu, Kenya. The IPTp-MON s udy (Kenya) was pa ly suppo ed by he MiP Conso ium, which is unded h ough a g an om he Bill & Melinda Ga es Founda ion o he Li e pool School o T opical Medicine, UK and pa ly suppo ed by he CDC. The ITN p ojec (Kenya) was unded by he US Agency o In e na ional De elopmen . The Special Heal h Suppo Fund om he Royal Ne he lands Embassy (Nai obi, Kenya) p o ided addi ional suppo o he s udy o he impac o ITN in p egnancy. The Kisumu s udy (Kenya) was unded by US Agency o In e na ional De elopmen (g an s AOT0483-PH1-2171 and HRN-A-00-04- 00010-02) and he Ne he lands Founda ion o he Ad ancemen o T opical Resea ch. The STOPMIP s udy (Kenya) was unded by he Mala ia in P egnancy (MiP) Conso ium, which is unded h ough a g an om he Bill & Melinda Ga es Founda ion o he Li e pool School o T opical Medicine, UK. The ISTp s udy (Malawi) was pa ly suppo ed by he Mala ia in P egnancy (MiP) Conso ium, which is unded h ough a g an om he Bill & Melinda Ga es Founda ion o he Li e pool School o T opical Medicine, UK and pa ly unded by he Eu opean and De eloping Coun ies Clinical T ials Pa ne ship (EDCTP). The LAIS s udy was suppo ed by g an s om he Academy o Finland (g an s 79787 and 207010), he Founda ion o Pedia ic Resea ch in Finland, and he Medical Resea ch Fund o Tampe e Uni e si y Hospi al. Azi h omycin and i s placebo we e p o ided ee o cha ge by P ize Inc (New Yo k, New Yo k), which also p o ided unding o • P io e idence om 4 small s udies indica ed ha he ha m ul impac o mala ia on e al g ow h and bi hweigh (BW) may depend upon he mac onu ien nu i ional s a- us o he mo he . • I mala ia and ma e nal unde nu i ion ha e syne gis ic nega i e impac s on p egnancy ou comes, in e en ions a ge ed o high- isk women migh p o ide subs an ial public bene i . • The p esen s udy p o ides a obus assessmen o po en ial mala ia–nu i ion in e ac- ions in p egnancy and o e comes size and me hodological limi a ions o ea lie explo - a o y s udies. Wha did he esea che s do and ind? • We p esen a la ge, pooled analysis o indi idual pa icipan da a om 13 s udies con- duc ed in sub-Saha an A ica and he Wes e n Paci ic in es iga ing he in e ac ion be ween ma e nal mala ia in ec ion and malnu i ion on he isk o low bi hweigh (LBW) and educed mean BW. • The indings sugges ha women who a e bo h in ec ed wi h mala ia and malnou ished a e a g ea e isk o LBW han hei unin ec ed, well-nou ished coun e pa s. • Howe e , he s udy ound no conclusi e e idence o in e ac ion be ween he 2, i.e., he impac o mala ia on BW was independen o he mac onu ien nu i ional s a us o he mo he . • Subg oup analyses did ind ha s udies conduc ed jus in A ica had sligh e idence o in e ac ion, bu his was no consis en h oughou all analyses. Wha do hese indings mean? • Al hough he e was no o e all e idence o mala ia–nu i ion in e ac ions, mo e han 1 in 3 p egnan women su e ed om mala ia and/o unde nu i ion, emphasizing he impo ance o join app oaches o dec ease ma e nal mala ia and imp o e nu i ion o minimize ad e se p egnancy ou comes. In oduc ion Annually, o e 20 million in an s a e bo n low bi hweigh (LBW; <2,500 g), p edominan ly in low- and middle-income coun ies (LMICs) [1]. LBW can ha e nega i e impac s on neona- al mo ali y and childhood neu ological, me abolic, and physical de elopmen [2]. The Wo ld Heal h O ganiza ion (WHO) has se a Global Nu i ion Ta ge o 30% educ ion in LBW by 2025 [1]. One p e en able cause o LBW in LMICs is ma e nal mala ia in ec ion [2,3]. I s p e alence emains high, despi e a ge ed mala ia p e en ion p og ams [2]. Annually, 125 million p eg- nan women a e a isk o mala ia [4]. The p edominan species, Plasmodium alcipa um, Mala ia, malnu i ion, and bi hweigh PLOS Medicine | h ps://doi.o g/10.1371/jou nal.pmed.1002373 Augus 8, 2017 3 / 20 he polyme ase chain eac ion es ing o he sexually ansmi ed in ec ions. The IPTp s udy (Papua New Guinea [PNG]) was unded by he MiP Conso ium, h ough a g an om he Bill & Melinda Ga es Founda ion (46099); he P eg ax Conso ium, h ough a g an om he EU FP7- 2007-HEALTH (PREGVAX 201588) and he Spanish Go e nmen (EUROSALUD 2008 P og amme); and P ize Inc., h ough an in es iga o -ini ia ed esea ch g an (WS394663). The Sek s udy (PNG) was suppo ed by AusAID (g an o PNG Ins i u e o Medical Resea ch [IMR]), he Na ional Heal h and Medical Resea ch Council o Aus alia; Aus alian Resea ch Council; Wellcome T us ; and Ve e ans A ai s Resea ch Se ice. The Wal e and Eliza Hall Ins i u e is suppo ed by he NHMRC In as uc u e o Resea ch Ins i u es Suppo Scheme and Vic o ian S a e Go e nmen Ope a ional In as uc u e Suppo . The unde s had no ole in s udy design, da a collec ion and analysis, decision o publish, o p epa a ion o he manusc ip . Compe ing in e es s: The au ho s o his manusc ip ha e he ollowing compe ing in e es s: SHL is is a ull- ime employee o GlaxoSmi hKline and holds sha es in GlaxoSmi hKline. SR is a membe o he Edi o ial Boa d o PLOS Medicine. Abb e ia ions: aRR, adjus ed isk a io; BMI, body mass index; BW, bi hweigh ; CI, con idence in e al; DRC, Democ a ic Republic o he Congo; EMM, e ec measu e modi ica ion; FGR, e al g ow h es ic ion; HIV, human immunode iciency i us; IPTp, in e mi en p e en i e ea men in p egnancy; IPTW, in e se p obabili y o ea men weigh s; LBW, low bi hweigh ; LM, ligh mic oscopy; LMIC, low- and middle-income coun ies; M3, Ma e nal Mala ia and Malnu i ion; MiPc, Mala ia in P egnancy Conso ium; MUAC, mid-uppe a m ci cum e ence; PCR, polyme ase chain eac ion; PEI, popula ion e ec s in e al; PNG, Papua New Guinea; RDT, apid diagnos ic es ; RR, isk a io; SGA, small o ges a ional age; SP, sul adoxine-py ime hamine; WHO, Wo ld Heal h O ganiza ion. seques e s in he placen a, causing LBW h ough e al g ow h es ic ion (FGR) and p e e m deli e y [2]. P io es ima es om A ica sugges ha mala ia in ec ion doubles he isk o LBW [2,4]. The p e en ion o mala ia in ec ion du ing p egnancy emains a public heal h p io i y. Ano he modi iable isk ac o o impai ed e al g ow h is ma e nal malnu i ion, speci i- cally unde nu i ion [5]. Up o 20% o A ican women o ep oduc i e age a e unde nou ished [5–7]. Ma e nal p o ein-ene gy- a (mac onu ien ) and mic onu ien ese es and die a y consump ion in luence e al g ow h. Mic onu ien de iciencies a e di icul and cos ly o assess; he e o e, an h opome ics a e commonly used as sensi i e bu nonspeci ic indica o s o p o ein ese es, a s o es, and malnu i ion mo e b oadly [7]. Recen e idence indica es ha he ela ionship be ween mala ia in ec ion and LBW may depend upon he mo he ’s nu i ional s a us [8]. S udies in Papua New Guinea (PNG) and Benin ound inconsis en e idence o modi ica ion o he mala ia in ec ion–LBW ela ionship by ma e nal an h opome ic s a us, bu s udies om Kenya and he Democ a ic Republic o he Congo (DRC) epo ed signi ican modi ica ion [9–12]. No ably, in he DRC, he isk o FGR associa ed wi h mala ia in ec ion was 2 o 8 imes highe among malnou ished women [11]. Mala ia in ec ion and malnu i ion may ac along simila physiological pa hways by a ec ing placen al de elopmen and nu ien ans e [2,4,5]. To da e, wo k on his po en ial in e ac ion has been limi ed o 4 s udies, wi h only 1,318 p egnan women om A ica and 1,369 p egnan women om PNG. No only we e hese s udies somewha inconsis en in hei indings, bu hei in e p e a ion is hinde ed by ela- i ely small sample sizes, and hei indings may no be gene alizable o o he mala ia-endemic coun ies. The objec i e o his s udy was o in es iga e he pu a i e in e ac ion be ween ma e nal mala ia in ec ion and malnu i ion in ela ion o bi hweigh (BW) using a la ge, pooled da ase o 14,633 li e bi h p egnancies om women pa icipa ing in 13 s udies con- duc ed in mul iple LMICs. We hypo hesized ha he e would be a syne gis ic in e ac ion, such ha he obse ed join e ec o being bo h in ec ed wi h mala ia and malnou ished would be g ea e han expec ed i conside ing each exposu e independen ly. Me hods S udy popula ion We used da a om 14,633 single on li e bi h p egnancies om women pa icipa ing in 13 s udies conduc ed om 1996 o 2015 in 8 A ican coun ies and he Wes e n Paci ic (PNG) as pa o he Ma e nal Mala ia and Malnu i ion (M3) ini ia i e [9,11,13–24]. The M3 ini ia i e has been desc ibed in de ail p e iously [25]. B ie ly, he M3 ini ia i e is a collabo a ion wi h he Mala ia in P egnancy Conso ium (MiPc) and a ilia ed mala ia and nu i ion esea che s who ag eed o pool esou ces o imp o e he unde s anding o mala ia–nu i ion in e ac ions. A con enience sampling app oach was aken o ob ain eligible s udies iden i ied by esea che s wi hin he MiPc, and inclusion o s udies o he indi idual pa icipan da a me a-analysis s opped 1 Janua y 2016. S udies we e eligible i hey we e an obse a ional s udy o andom- ized con olled ial conduc ed be ween 1996 and 2015 en olling p egnan women du ing p egnancy wi h ollow-up h ough deli e y and hey me he ollowing c i e ia: e hical app o al allowed o seconda y analyses and da a sha ing, mala ia was endemic in he a ea wi h medium o high ansmission, assessmen o mala iome ic indices (ligh mic oscopy [LM] and/o apid diagnos ic es s [RDT]) a en ollmen / i s an ena al ca e isi (ANC), assessmen o an h opome ic indica o s a en ollmen (mid-uppe a m ci cum e ence [MUAC] and/o body mass index [BMI]), and assessmen o in an weigh wi hin 24 hou s pos pa um o wi hin 7 days o bi h i iming o weigh measu emen da a was a ailable. Da a Mala ia, malnu i ion, and bi hweigh PLOS Medicine | h ps://doi.o g/10.1371/jou nal.pmed.1002373 Augus 8, 2017 4 / 20 was sha ed by each indi idual s udy using a s anda dized da a ans e ile. Pa icipa ing s ud- ies had been unde aken o a ange o objec i es, including in es iga ion o he mechanisms leading o LBW as a esul o mala ia, e alua ion o an imala ial in e en ions du ing p eg- nancy such as in e mi en p e en i e he apy du ing p egnancy (IPTp) o insec icide- ea ed bed ne s (ITN), o he assessmen o he po en ial o nu i ional supplemen a ion du ing p eg- nancy o imp o e bi h ou comes (S1 Table). All s udies ecei ed app o al by hei local e hics boa d and ob ained in o med consen om all pa icipan s. The p ospec i e p o ocol o he IPD analysis is included in he supplemen al ex (S2 Tex ). Ou comes and exposu es The main ou come measu e was BW, analyzed bo h con inuously and dicho omized a 2,500 g ams (LBW) [1]. Ten s udies used digi al scales o weigh newbo ns, 2 s udies used sp ing o digi al scales, and 1 s udy used a hanging weighing scale (S2 Table). Weigh s measu ed a e 24 hou s (13% o weigh s) we e adjus ed using a cubic eg ession model o accoun o weigh changes in he i s week o li e [26]. Among 9 s udies wi h ul asound-da ed ges a ional age, we conside ed 2 seconda y ou comes: small o ges a ional age (SGA; a BW less han he 10 h pe cen ile o he INTERGROWTH-21 s e e ence) and p e e m bi h (PTB; ges a ional age less han 37 weeks) [27]. Diagnos ics o mala ia we e collec ed a s udy en ollmen and a deli e y. Fo he in e ac- ion analyses, we chose o ocus on mala ia in ec ion a en ollmen ins ead o a deli e y o 2 easons. Fi s , om a public heal h pe spec i e, i he e was in e ac ion a he ime o s udy en ollmen , his migh help in o m u u e in e en ions ha could be implemen ed du ing an ena al ca e. Second, i has been hypo hesized ha mala ia in ec ion and malnu i ion may ac along simila physiological pa hways o al e e al g ow h by dec easing ma e nal– e al oxy- gen ans e and educing u e oplacen al blood low; 2 mechanisms ha would be al e ed ea - lie in p egnancy e sus a deli e y. A s udy en ollmen , we de ined mala ia based on LM examina ion o a Giemsa-s ained pe iphe al blood smea o a RDT o mala ia an igen [28]. A deli e y, we de ined mala ia based on pe iphe al o placen al LM o placen al his ology (ac i e o pas in ec ion). Gi en he unce ain impac o submic oscopic in ec ions on LBW and he a ia ion in he a ailabili y o polyme ase chain eac ion (PCR) diagnos ics ac oss s udies, we excluded PCR esul s [29]. In sensi i i y analyses, we explo ed al e na i e de ini- ions o mala ia, including any PCR esul s and “any mala ia,” de ined as a posi i e LM, RDT, o PCR a en ollmen , deli e y, o du ing p egnancy (in 5 s udies wi h epea mala ia diagnos- ics h oughou p egnancy). The p ima y measu e o ma e nal malnu i ion was low MUAC a en ollmen , dicho o- mized a 23 cm [7]. MUAC changes li le o e p egnancy, making i a use ul measu e o mal- nu i ion [7]. Since some s udies did no measu e MUAC, we used BMI as a seconda y measu e o malnu i ion. Acco ding o WHO, a p ep egnancy BMI <18.5 kg/m 2 is p edic i e o ad e se bi h ou comes [30]. BMI a en ollmen was used o es ima e p ep egnancy BMI by adjus ing ma e nal weigh measu ed in he second/ hi d imes e s using a cubic eg ession model o accoun o ges a ional weigh gain [30]. Low adjus ed-BMI was de ined as alues unde 18.5 kg/m 2 . As he co ela ion be ween BMI and MUAC is no pe ec , indica o s we e analyzed sepa a ely [7]. The eason o dicho omizing MUAC and BMI was 2- old. Fi s , cu - o s a e endo sed by WHO, a e clinically easie o use, and a e commonly used in he cu en li e a u e o de ine unde nu i ion [7]. Second, while con inuous exposu es can be assessed in in e ac ion models, in e p e a ion is di icul , as he in e ac ion es ima es a y acco ding o he le els o he exposu es being compa ed and can a y in di ec ionali y as well [31]. Mala ia, malnu i ion, and bi hweigh PLOS Medicine | h ps://doi.o g/10.1371/jou nal.pmed.1002373 Augus 8, 2017 5 / 20 Risk o bias assessmen We de eloped a checklis o s udy cha ac e is ics o each o he included indi idual s udies o assess he isk o bias o he main e alua ion o he in e ac ion be ween mala ia in ec ion and ma e nal malnu i ion on BW. C i e ia we e speci ic o he esea ch ques ion and we e in o med by he Newcas le-O awa Scale, Downs and Black ins umen , and he Me a-Analysis o Obse a ional S udies in Epidemiology checklis [32–34]. Fo each included s udy, we e al- ua ed he indi idual s udy publica ions o con ac ed indi idual s udy collabo a o s o iden i y he ollowing i ems o ca ego ize s udies as being ei he a lowe o highe isk o bias: pa ici- pan e en ion a e (<75% e sus 75%), measu emen o impo an con ounde s (ma e nal age, g a idi y, u al e sus u ban esidence, HIV in ec ion, and anemia a en ollmen ), clea ly desc ibed measu emen o mala ia pa asi emia, measu emen o MUAC and/o BMI, >80% o BWs measu ed using elec onic scale wi h known p ecision 20 g, and >80% BWs mea- su ed wi hin 24 hou s. S udies we e de ined as a lowe isk o bias i e e y i em was de e - mined o be a a lowe isk o bias. S a is ical analysis We analyzed ma e nal mala ia in ec ion and malnu i ion as cop ima y exposu es and assessed malnu i ion as a modi ie o he mala ia–LBW ela ionship. While e ec measu e modi ica ion (EMM) assesses how he e ec o 1 exposu e a ies ac oss s a a o ano he a i- able, in e ac ion analyses assess he join e ec s o 2 exposu es [35]. We pe o med bo h in e - ac ion and EMM analyses; howe e , in he con ex o his wo k, in e ac ion is p e e able o EMM because in e en ions o bo h mala ia in ec ion and malnu i ion migh p e en LBW. The e a e 2 commonly employed app oaches o handling indi idual pooled da a, a 1-s age and a 2-s age app oach, al hough he e is no consensus as o which app oach is p e e able [36–38]. We employed a 2-s age app oach, as i is gene ally conside ed mo e easily in e p e - able and allows he in es iga o o isually p esen o es plo s and quan i y s a is ical he e oge- nei y [36]. We examined he consis ency o esul s wi h a 1-s age app oach, i ing a gene alized mixed model wi h andom in e cep s and slopes. S udy-speci ic isk a ios (RRs) and mean BW di e ences we e calcula ed using linea and log-binomial eg ession models con olling o con ounding using in e se p obabili y o ea men weigh s (IPTW) unca ed a he 1s and 99 h pe cen iles. A minimally su icien se o con ounde s was iden i ied using a di ec ed acyclic g aph based upon backg ound knowledge o co a ia e ela ionships [39]. We iden i ied con ounde s o bo h mala ia in ec ion and malnu i ion ela i e o LBW since we we e analyzing hem as cop ima y exposu es. Con ounde s o he ela ionship be ween mala ia in ec ion a en ollmen and LBW included ma e nal age, g a idi y, u al e sus u ban esidence, malnu i ion (MUAC when a ailable, o he wise BMI), and HIV in ec ion. Because mala ia in ec ion is a cause o anemia, he la e was conside ed a media o and no a con- ounde . We explo ed modi ica ion o he e ec o mala ia in ec ion a en ollmen on LBW by ma e nal g a idi y and doses o in e mi en p e en i e he apy (IPTp) ecei ed. When assess- ing mala ia in ec ion a deli e y, anemia a en ollmen and he numbe o IPTp doses we e conside ed addi ional con ounde s. Con ounde s o he malnu i ion–LBW ela ionship included ma e nal age, g a idi y, u al e sus u ban esidence, anemia a en ollmen , and HIV in ec ion. Pa ially missing da a we e impu ed using mul i a ia e no mal mul iple impu a ion (S1 Tex ) [40]. We calcula ed in e ac ion es ima es using a p oduc e m in he mul iplica i e and addi i e model o LBW and he addi i e model o mean BW [35]. These es ima es e lec whe he he e ec o exposu e o bo h mala ia in ec ion and malnu i ion exceeds he p oduc (o sum) o he e ec s o each exposu e conside ed sepa a ely, de ined as syne gy. A p oduc Mala ia, malnu i ion, and bi hweigh PLOS Medicine | h ps://doi.o g/10.1371/jou nal.pmed.1002373 Augus 8, 2017 6 / 20 e m g ea e han 1 on he mul iplica i e scale o g ea e han 0 on he addi i e scale is indica- i e o syne gis ic in e ac ion be ween mala ia in ec ion and malnu i ion. S udy-speci ic es ima es we e pooled using De Simonian and Lai d es ic ed maximum likelihood me hod andom-e ec s models [41]. When τ 2 , he es ima ed a iance o he an- dom-e ec s dis ibu ion, was g ea e han 0, we calcula ed 95% popula ion e ec s in e als (PEI), which inco po a e he es ima ed a iance be ween s udies [41]. I τ 2 equaled 0, he an- dom-e ec s model was in e p e ed as a ixed-e ec s model. We decided a p io i o e alua e he modi ica ion o he esul s by ime pe iod (be o e e sus a e 2008) due o changes in an i- mala ial ecommenda ions, s udy ype ( ial/coho ), loca ion (A ica/Wes e n Paci ic), and he s udy-le el p e alence o mala ia in ec ion a s udy en ollmen and deli e y based on he indi idual s udy da a, using me a- eg ession. We u he decided pos hoc o conduc a sensi- i i y analysis o he in e ac ion analyses es ic ed o adolescen women. Resul s Using a con enience sample app oach, a o al o 18 s udies we e conside ed o inclusion by he ime o ou inclusion cu o da e (1 Janua y 2016), o which 13 we e included in he pooled analysis (Fig 1). We excluded 5 s udies: 2 s udies did no assess mala ia a an ena al en ollmen [42,43], 1 s udy had da a ha we e no ye a ailable o inclusion [44], 1 ec ui ed women com- pa a i ely la e in p egnancy [10], and 1 had no di ec ly measu ed he numbe o sul adoxine- py ime hamine (SP) doses gi en o IPTp [45]. Following he cu o da e, 5 u he s udies we e iden i ied, o which 4 could be eligible wi h a collec i e sample size o 3,528 p egnan women (S3 Table) [46–50]. S udy popula ion cha ac e is ics Twen y- i e pe cen o he pooled da ase comp ised adolescen women aged 19 o younge . The imes e a en ollmen , anemia p e alence, g a idi y dis ibu ion, a ea o esidence, and HIV p e alence a ied ac oss s udies (Tables 1and 2). The p e alence o mala ia in ec ion a en ollmen , mala ia in ec ion a deli e y, low MUAC, and join mala ia in ec ion a en oll- men and low MUAC also a ied by s udy (Fig 2 and S5 Fig). Among 8,152 women wi h bo h measu emen s, only 2% had bo h low MUAC and mala ia in ec ion a en ollmen . The p e a- lence o mala ia in ec ion among women wi h low MUAC was 16%, compa ed o 12% among well-nou ished women (p= 0.0005). The p e alence o low BMI a ied ac oss s udies and was di e en om, al hough co ela ed wi h, he p e alence o low MUAC (χ 2 p<0.0001; S1 Fig). The join p e alence o mala ia in ec ion a en ollmen and low BMI was also 2%. O all 14,633 women, 35% we e in ec ed wi h mala ia a ei he en ollmen o deli e y o had low MUAC o BMI. The p e alence o LBW was 9% ( ange 5% o 15% among s udies). Among 9 s udies wi h ul asound-da ed ges a ional age, he p e alence o SGA was 19% ( ange 13% o 25%), and he p e alence o PTB was 11% ( ange 3% o 20%). Fi e o he hi een included s udies we e judged o be a a lowe isk o bias o he assess- men o in e ac ion be ween mala ia in ec ion and ma e nal malnu i ion on BW (S4 Table). Among he 8 o he s udies, 3 had a <75% e en ion a e o he p ima y ou come, 5 did no measu e a leas 80% o BWs wi h an elec onic scale wi h known p ecision 20 g, and 3 did no measu e a leas 80% o BWs wi hin 24 hou s. Independen e ec s o mala ia in ec ion and malnu i ion The pooled IPTW-adjus ed isk a io (aRR) o he e ec o mala ia in ec ion a en ollmen on LBW was 1.14 (95% CI: 0.91, 1.42; 95% τ 2 = 0.05 [95% CI: 0.00, 0.25]; PEI: 0.72, 1.80), and he mean BW di e ence was −55 g (95% CI: −79, −30; τ 2 = 0 [95% CI: 0.00, 1,610]) (Fig 3a). The Mala ia, malnu i ion, and bi hweigh PLOS Medicine | h ps://doi.o g/10.1371/jou nal.pmed.1002373 Augus 8, 2017 7 / 20 e ec o mala ia in ec ion a deli e y was mo e p onounced: aRR, 1.32 (95% CI: 1.08, 1.62; τ 2 = 0.04 [95% CI: 0.00, 0.39]; 95% PEI: 0.91, 1.91) (Fig 3b). When conside ing SGA and PTB as seconda y ou comes, esul s we e simila o mala ia in ec ion a en ollmen and a enua ed o mala ia in ec ion a deli e y (S5 Table). The e ec o mala ia in ec ion a en ollmen was a enua ed among hose wi h mo e han 1 IPTp dose e sus 1 o 0 doses (aRR 0.98 e sus 1.22) and was sligh ly s onge among p imi/secundig a id e sus mul ig a ida women (aRR 1.19 e sus 1.14). A sligh ly s onge e ec o mala ia in ec ion was seen among women en olled in s udies conduc ed p io o 2008, in A ica, o wi h mala ia in ec ion p e alence a o abo e he median (S2 Fig). The aRR o he e ec o low MUAC on LBW was 1.60 (95% CI: 1.36, 1.87; τ 2 = 0 [95% CI: 0.00, 0.05]); he mean BW di e ence was −142 g (95% CI: −171, −113; τ 2 = 0 [95% CI: 0, 100] (Fig 4a). Resul s we e simila o low BMI: aRR, 1.49 (95% CI: 1.26, 1.76; τ 2 = 0 [95% CI: 0.00, 0.16]); mean BW di e ence −133 g (95% CI: −158, −108; τ 2 = 0 [95% CI: 0.00, 0.00]) (Fig 4b). The e was no modi ica ion by s udy cha ac e is ics on he malnu i ion–LBW ela ionship (S3 Fig). Simila bu weake ends we e obse ed when SGA was used as he ou come among Fig 1. Flow diag am o s udies included in he indi idual pa icipan me a-analysis o he in e ac ion be ween mala ia in ec ion and ma e nal malnu i ion on bi hweigh . M3, Ma e nal Mala ia and Malnu i ion Ini ia i e. h ps://doi.o g/10.1371/jou nal.pmed.1002373.g001 Mala ia, malnu i ion, and bi hweigh PLOS Medicine | h ps://doi.o g/10.1371/jou nal.pmed.1002373 Augus 8, 2017 8 / 20 he s udies wi h ul asound da a, bu low MUAC o low BMI we e signi ican ly associa ed wi h an inc eased isk o PTB (S5 Table). In e ac ion and EMM The join aRR o bo h mala ia in ec ion a en ollmen and low MUAC was 2.13 (95% CI: 1.21, 3.73; τ 2 = 0.25 [95% CI: 0.00, 1.82]; 95% PEI: 0.80, 5.67), and he mean BW di e ence was Table 1. The cha ac e is ics o women included in he Ma e nal Mala ia and Malnu i ion (M3) ini ia i e om he ollowing 6 ou o 13 M3 s udies: Kisumu-Kenya, IPTp-PNG, ISTp-Malawi, STOPMIP-Kenya, LAIS-Malawi, and iLiNS-Ghana. Kisumu-Kenya (N= 3,388) IPTp-PNG (N= 1,943) ISTp-Malawi (N= 1,602) STOPMIP-Kenya (N= 1,203) LAIS-Malawi (N= 1,190) iLiNS-Ghana (N= 1,068) S udy en ollmen (yea s) 1996–2001 2009–2013 2011–2013 2012–2015 2003–2006 2009–2012 Ma e nal age 20 (18–24) 24 (20–28) 21 (18–26) 22 (19–27) 24 (20–29) 26 (22–30) G a idi y 1 (P imi-) 1,656 (49) 966 (50) 542 (34) 403 (34) 267 (22) 349 (33) 2 (Secundi-) 748 (22) 494 (21) 448 (28) 237 (20) 213 (18) 351 (33) 3+ (Mul i-) 984 (29) 573 (29) 612 (38) 563 (47) 710 (60) 368 (34) T imes e * 1 0 (0) 72 (4) 0 (0) 21 (2) 0 (0) 103 (10) 2 0 (0) 1,780 (92) 1,585 (99) 991 (82) 1,190 (100) 881 (82) 3 3,388 (100) 91 (5) 17 (1) 191 (16) 0 (0) 81 (8) Missing GA 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 3 (0) Anemic † Yes 2,548 (75) 1,348 (69) 533 (33) 591 (49) 459 (39) 305 (29) No 808 (24) 512 (26) 1,069 (67) 612 (51) 731 (61) 763 (71) Missing 32 (1) 83 (4) 0 (0) 0 (0) 0 (0) 0 (0) HIV Yes 810 (24) – 0 (0) 0 (0) 144 (12) 0 (0) No 2,560 (76) – 1,602 (100) 1,203 (100) 931 (78) 1,059 (99) Missing 18 (1) 1,943 (100) 0 (0) 0 (0) 115 (10) 9 (1) A ea o Residence Ru al 722 (21) 1,185 (61) 1,590 (99) 1027 (85) 1,190 (100) 0 (0) U ban 2,666 (77) 758 (39) 10 (1) 169 (14) 0 (0) 1,068 (100) Missing 0 (0) 0 (0) 2 (0) 7 (1) 0 (0) 0 (0) IPTp doses 0 (0–0) 1 (1–3) 4 (3–4) ‡ 2 (1–3) ‡ 4 (2–4) – Bed ne owne ship Yes – 1,798 (93) 327 (20) 681 (57) 877 (74) – No – 145 (7) 1,275 (80) 522 (43) 313 (26) – Missing 3,388 (100) 0 (0) 0 (0) 0 (0) 0 (0) 1,068 (100) Ca ego ical a iables a e exp essed as N (%) and con inuous a iables a e exp essed as median (IQR). A dash indica es in o ma ion on pa icula ac o was no assessed in pa en s udy. *Based on ul asound i measu ed, o he wise based on Balla d’s sco e o symphysis-pubis undal heigh (SFH). When using SFH, o adjus o misclassi ica ion in he i s imes e , a undal heigh <7 cm was de ined as i s imes e , while SFH <28 cm was de ined as second imes e , and SFH 28 cm was de ined as hi d imes e . † Anemic = hemoglobin <11 g/dL o enous blood, i a ailable, o hema oc i <33% in he i s and hi d imes e s and less han 10.5 g/dL and 32%, espec i ely, o he second imes e . ‡ Excluding women andomized o he in e mi en sc eening and ea men g oup. GA, ges a ional age; iLiNS, In e na ional Lipid-Based Nu ien Supplemen s; IPTp, in e mi en p e en i e ea men in p egnancy; ISTp, in e mi en sc eening o mala ia in ec ion du ing p egnancy; LAIS, Lungwena An ena al In e en ion S udy; M3, Ma e nal Mala ia and Malnu i ion; PNG, Papua New Guinea; STOPMIP, s a egies o p e en mala ia in ec ion du ing p egnancy. h ps://doi.o g/10.1371/jou nal.pmed.1002373. 001 Mala ia, malnu i ion, and bi hweigh PLOS Medicine | h ps://doi.o g/10.1371/jou nal.pmed.1002373 Augus 8, 2017 9 / 20 S3 Table. Cha ac e is ics o s udies no included in he Ma e nal Mala ia and Malnu i ion (M3) ini ia i e coho . (DOCX) S4 Table. Assessmen o isk o bias o he 13 s udies included in he indi idual pa ici- pan da a me a-analysis. (DOCX) S5 Table. The independen and join e ec s o mala ia in ec ion a en ollmen , mala ia in ec ion a deli e y, low mid-uppe a m ci cum e ence (MUAC), and low body mass index (BMI) on he isk o small o ges a ional age (SGA) and isk o p e e m bi h among a subse o 9 s udies om he Ma e nal Mala ia and Malnu i ion (M3) ini ia i e. (DOCX) S6 Table. Selec sensi i i y analysis esul s o he mul iplica i e in e ac ion e ec s o mala ia and malnu i ion on isk o ad e se bi h ou comes among he 13 s udies in he Ma e nal Mala ia and Malnu i ion (M3) ini ia i e. Sensi i i y analyses a ied he de ini- ions o mala ia, malnu i ion, he ou come o in e es , and he app oach aken in pooling s udy esul s. (DOCX) S7 Table. PRISMA 2009 checklis . (DOC) S8 Table. Indi idual pa icipan da a checklis . (DOCX) S1 Tex . Mul iple impu a ion. (DOCX) S2 Tex . P o ocol o he indi idual pa icipan da a p ojec . W i en 17 No embe 2014. (DOCX) S1 Fig. P e alence o low mid-uppe a m ci cum e ence (MUAC <23cm) compa ed o p e alence o low body mass index (BMI <18.5 kg/m 2 ) among he 13 s udies in he Ma e - nal Mala ia and Malnu i ion (M3) ini ia i e. (DOCX) S2 Fig. Me a- eg ession esul s o he e ec s o mala ia in ec ion a en ollmen and deli - e y on isk o low bi hweigh (LBW) and mean bi hweigh (BW) by ime pe iod, s udy ype, loca ion, and mala ia p e alence. Median mala ia p e alence ac oss s udies was 17% a en ollmen and 15% a deli e y. RCT = andomized con ol ial. (DOCX) S3 Fig. Me a- eg ession esul s o he e ec s o malnu i ion a en ollmen , (a) low mid- uppe a m ci cum e ence (MUAC <23 cm) and (b) low BMI (BMI <18.5 kg/m 2 ), on isk o low bi hweigh (LBW) and mean bi hweigh (BW) by ime pe iod, s udy ype, loca- ion, and mala ia p e alence. Median mala ia p e alence ac oss s udies was 17% a en oll- men and 15% a deli e y. RCT = andomized con ol ial. (DOCX) S4 Fig. Me a- eg ession esul s o he mul iplica i e and addi i e in e ac ion e ec s o mala ia a en ollmen o deli e y and low mid-uppe a m ci cum e ence (MUAC <23 cm) on isk o low bi hweigh (LBW) and mean bi hweigh (BW) by ime pe iod, s udy Mala ia, malnu i ion, and bi hweigh PLOS Medicine | h ps://doi.o g/10.1371/jou nal.pmed.1002373 Augus 8, 2017 16 / 20 ype, loca ion, and mala ia p e alence. Median mala ia p e alence ac oss s udies was 17% a en ollmen and 15% a deli e y. (DOCX) S5 Fig. P e alence o mala ia in ec ion a deli e y among he 13 s udies in he Ma e nal Mala ia and Malnu i ion (M3) ini ia i e. (DOCX) Acknowledgmen s The indings and conclusions p esen ed in his manusc ip a e hose o he au ho s and do no necessa ily e lec he o icial posi ion o he U.S. Cen e s o Disease Con ol and P e en ion o he Na ional Ins i u es o Heal h. Au ho Con ibu ions Concep ualiza ion: Jo dan E. Ca es, Holge W. Unge , S e en Meshnick, S ephen Roge son. Da a cu a ion: Holge W. Unge , Vale ie B iand, Nadine Fie e , Innocen Valea, Halidou Tin o, Umbe o D’Alessand o, Sa ah H. Landis, Se h Adu-A a wuah, Ka h yn G. Dewey, Feiko O. e Kuile, Meghna Desai, S ephanie Dellicou , Pe e Ouma, Julie Gu man, Ma ina Oneko, Lau ence Slu ske , Dianne J. Te louw, Simon Ka iuki, John Ayisi, Mwayiwawo Madani sa, Vic o Mwapasa, Pe Asho n, Kenne h Male a, I o Muelle , Danielle S anisic, Ch is en ze Schmiegelow, John P. A. Lusingu, Anna Ma ia an Eijk, S e en Meshnick, S e- phen Roge son. Fo mal analysis: Jo dan E. Ca es. In es iga ion: Jo dan E. Ca es. Me hodology: Jo dan E. Ca es, Holge W. Unge , Melissa Bause man, Linda Adai , S ephen R. Cole, Daniel Wes eich, S e en Meshnick, S ephen Roge son. P ojec adminis a ion: Holge W. Unge , Vale ie B iand, Nadine Fie e , Innocen Valea, Halidou Tin o, Umbe o D’Alessand o, Sa ah H. Landis, Se h Adu-A a wuah, Ka h yn G. Dewey, Feiko O. e Kuile, Meghna Desai, S ephanie Dellicou , Pe e Ouma, Julie Gu man, Ma ina Oneko, Lau ence Slu ske , Dianne J. Te louw, Simon Ka iuki, John Ayisi, Mwayi- wawo Madani sa, Vic o Mwapasa, Pe Asho n, Kenne h Male a, I o Muelle , Danielle S a- nisic, Ch is en ze Schmiegelow, John P. A. Lusingu, Anna Ma ia an Eijk, S e en Meshnick, S ephen Roge son. Supe ision: Holge W. Unge , Daniel Wes eich, S e en Meshnick. Visualiza ion: Jo dan E. Ca es. W i ing – o iginal d a : Jo dan E. Ca es. W i ing – e iew & edi ing: Jo dan E. Ca es, Holge W. Unge , Vale ie B iand, Nadine Fie e , Innocen Valea, Halidou Tin o, Umbe o D’Alessand o, Sa ah H. Landis, Se h Adu-A a - wuah, Ka h yn G. Dewey, Feiko O. e Kuile, Meghna Desai, S ephanie Dellicou , Pe e Ouma, Julie Gu man, Ma ina Oneko, Lau ence Slu ske , Dianne J. Te louw, Simon Ka - iuki, John Ayisi, Mwayiwawo Madani sa, Vic o Mwapasa, Pe Asho n, Kenne h Male a, I o Muelle , Danielle S anisic, Ch is en ze Schmiegelow, John P. A. 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