Maternal Malaria and Malnutrition (M3) initiative, a pooled birth cohort of 13 pregnancy studies in Africa and the Western Pacific

Ma e nal Mala ia and Malnu i ion (M3) ini ia i e, a pooled bi h coho o 13 p egnancy s udies in A ica and he Wes e n Pacific Holge W Unge , 1,2 Jo dan E Ca es, 3 Julie Gu man, 4 Vale ie B iand, 5,6 Nadine Fie e , 5,6 Innocen Valea, 7,8 Halidou Tin o, 7,8 Umbe o d’Alessand o, 9,10,11 Sa ah H Landis, 12 Se h Adu-A a wuah, 13 Ka h yn G Dewey, 14 Feiko Te Kuile, 15 S ephanie Dellicou , 15 Pe e Ouma, 16 Lau ence Slu ske , 4 Dianne J Te louw, 17 Simon Ka iuki, 16 John Ayisi, 16 Be na d Nahlen, 18 Meghna Desai, 4 Mwayi Madani sa, 19 Linda Kalilani-Phi i, 15,19 Pe Asho n, 20,21 Kenne h Male a, 19 I o Muelle , 22 Danielle S anisic, 23 Ch is en ze Schmiegelow, 24 John Lusingu, 24,25 Daniel Wes eich, 3 Anna Ma ia an Eijk, 15 S e en Meshnick, 3 S ephen Roge son 2 To ci e: Unge HW, Ca es JE, Gu man J, e al. Ma e nal Mala ia and Malnu i ion (M3) ini ia i e, a pooled bi h coho o 13 p egnancy s udies in A ica and he Wes e n Paci ic. BMJ Open 2016;6:e012697. doi:10.1136/bmjopen-2016- 012697 ▸P epublica ion his o y o his pape is a ailable online. To iew hese iles please isi he jou nal online (h p://dx.doi.o g/10.1136/ bmjopen-2016-012697). Recei ed 17 May 2016 Accep ed 8 No embe 2016 Fo numbe ed a ilia ions see end o a icle. Co espondence o P o esso S ephen Roge son; s [email p o ec ed] ABSTRACT Pu pose: The Ma e nal Mala ia and Malnu i ion (M3) ini ia i e has pooled oge he 13 s udies wi h he hope o imp o ing unde s anding o mala ia–nu i ion in e ac ions du ing p egnancy and o os e collabo a ion be ween nu i ionis s and mala iologis s. Pa icipan s: Da a we e pooled on 14 635 single on, li e bi h p egnancies om women who had pa icipa ed in 1 o 13 p egnancy s udies. The 13 s udies co e 8 coun ies in A ica and Papua New Guinea in he Wes e n Paci ic conduc ed om 1996 o 2015. Findings o da e: Da a a e a ailable a he ime o an ena al en olmen o women in o hei espec i e pa en s udy and a deli e y. The da a se comp ises essen ial da a such as mala ia in ec ion s a us, an h opome ic assessmen s o ma e nal nu i ional s a us, p esence o anaemia and bi h weigh , as well as addi ional a iables such ges a ional age a deli e y o a subse o women. Pa icipa ing s udies a e desc ibed in de ail wi h ega d o se ing and p ima y ou come measu es, and summa ised da a a e a ailable om each con ibu ing coho . Fu u e plans: This pooled bi h coho is he la ges p egnancy da a se o da e o pe mi a mo e de ini e e alua ion o he impac o plausible in e ac ions be ween poo nu i ional s a us and mala ia in ec ion in p egnan women on e al g ow h and ges a ional leng h. Gi en he cu en compa a i e lack o la ge p egnancy coho s in mala ia-endemic se ings, compila ion o sui able p egnancy coho s is likely o p o ide adequa e s a is ical powe o assess mala ia– nu i ion in e ac ions, and could poin owa ds se ings whe e such in e ac ions a e mos ele an . The M3 coho may hus help o iden i y p egnan women a high isk o ad e se ou comes who may bene i om ailo ed in ensi e an ena al ca e including nu i ional supplemen s and al e na i e o in ensi ied mala ia p e en ion egimens, and he se ings in which hese in e en ions would be mos e ec i e. INTRODUCTION I is es ima ed ha each yea o e 125 million p egnan women esiding in low-income and middle-income coun ies (LMICs) a e a isk o in ec ion wi h Plasmodium alcipa um and P. i ax. 1 Mala ia con ibu es o he high bu den o ma e nal mo bidi y and mo ali y in hese se ings and may a ec placen al de elopmen and e al g ow h. 2 Seques a ion o P. alcipa um pa asi es in he placen a has been associa ed wi h e al g ow h es ic ion (FGR) and low bi h weigh (LBW, <2500 g), hus con ibu ing o S eng hs and limi a ions o his s udy ▪This coho pools da a om 14 635 single on, li e bi h p egnancies in women who pa icipa ed in 1 o 13 p egnancy s udies in a eas wi h high bu dens o mala ia and unde nu i ion. ▪The Ma e nal Mala ia and Malnu i ion (M3) pooled da a se uses da a collec ed a i s an e- na al a endance and a ime o deli e y. ▪The da a se comp ises essen ial in o ma ion on mala ia in ec ion s a us, ma e nal an h opome ic indica o s o unde nu i ion, p esence o ma e - nal anaemia, neona al an h opome ics and ges- a ional age a deli e y, among o he s. ▪The main limi a ion is he he e ogenei y in a ail- abili y o ce ain a iables due o s udy design and da a collec ion di e ences be ween s udies. Unge HW, e al.BMJ Open 2016;6:e012697. doi:10.1136/bmjopen-2016-012697 1 Open Access Coho p o ile in an mo ali y and possibly long- e m heal h p o- blems. 34 P. i ax has also been associa ed wi h ad e se p egnancy ou comes. 5 Mala ia du ing p egnancy may cause ma e nal anaemia, which i sel can ha e dele e i- ous e ec s on e al de elopmen . 2 Ma e nal unde nu i- ion is also common among p egnan women in hese se ings, 6–8 and unde nou ished women a e mo e likely o ha e g ow h- es ic ed e uses and babies wi h educed bi h weigh . 9 To da e, i emains unclea whe he he suscep ibili y o, and he impac o , mala ial in ec ion a e a ec ed by ma e nal nu i ional s a us. A small numbe o s udies sugges ha mac onu ien nu i ional s a us modifies he e ec s o mala ia in p eg- nancy, specifically he impac o P. alcipa um pa asi - aemia on e al g ow h and bi h weigh . 10–12 Al hough la gely o e looked, his may no be su p ising gi en ha bo h mac onu ien and mic onu ien nu i ional s a us a ec immune unc ion mo e b oadly. 13 14 As such, he e may be scope o design in e en ions ha p e en ad e se p egnancy ou comes by p o ec ing women and hei o sp ing om he dele e ious consequences o mala ia and unde nu i ion. This aligns wi h he 2015 Global S a egy o Women’s, Child en’s and Adolescen s’Heal h ecommenda ions o educe he isk o LBW and ma e nal anaemia h ough he p e en- ion and ea men o mala ia and h ough adequa e nu i ion du ing p egnancy. 15 16 The Mala ia in P egnancy Conso ium (MiPc), which ecei es unding om he Bill & Melinda Ga es Founda ion, b ings oge he scien is s whose aim is o educe he bu den and impac o mala ia in p egnancy in LMICs. 17 18 A he 2014 MiPc mee ing in New O leans, Louisiana, USA, Conso ium membe s iden i- fied he need o s udy he ela ionship be ween mac o- nu ien nu i ional s a us and mala ia in p egnancy, gi en he high p e alence o unde nu i ion in mala ia-endemic coun ies. The MiPc and o he mala ia esea che s ha e conduc ed a numbe o mala ia in p egnancy s udies (obse a ional s udies and andomised con olled ials (RCTs) o mala ia p e en- ion s a egies) and many had collec ed ma e nal an h opome ics and da a on anaemia. Simila ly, some ecen ials o nu i ional supplemen a ion du ing p eg- nancy collec ed mala iome ic indices. D awing on hese da a, he e is a unique oppo uni y o s udy he in e ac ion be ween unde nu i ion and mala ia, oge he wi h o he isk ac o s such as ma e nal anaemia. The Ma e nal Mala ia and Malnu i ion (M3) ini ia i e has pooled da a om 13 s udies wi h he hope o imp o ing he unde s anding o mala ia–nu i ion in e - ac ions and o os e collabo a ion be ween nu i ionis s and mala iologis s. Reduc ion o LBW and anaemia we e wo o he six global nu i ion a ge s o 2025 ag eed on a he 2012 Wo ld Heal h Assembly. 15 As o 2014, he Global Nu i ion Repo ound ha he e was li le p o- g ess owa ds his a ge . 19 Risk ac o s o , and in e en- ions o p e en , LBW a e all oo commonly s udied in isola ion and wi hou c oss-discipline collabo a ion. Topics o in e es o M3 include an e alua ion o whe he mac onu ien unde nu i ion modifies he impac o mala ia in ec ion du ing p egnancy; he in es- iga ion o po en ial in e en ions ha add ess bo h mala ia isk and nu i ional s a us du ing p egnancy; and he s udy o he ole o anaemia in ela ion o ad e se p egnancy ou comes. POOLED COHORT DESCRIPTION S udy popula ions The M3 ini ia i e comp ises 13 s udies (7 RCTs and 6 coho s udies) conduc ed among p egnan women in mala ia-endemic coun ies om 1996 o 2015. 10 20–32 S udies we e selec ed based on he a ailabili y o a p e- de e mined se o essen ial a iables o each woman, adequa e e hical clea ance and willingness o collabo a o s o sha e da a. Essen ial a iables included he assessmen o mala iome ic indices (ligh mic os- copy (LM), quan i a i e PCR (qPCR) and/o apid diag- nos ic es s (RDTs)) a en olmen /fi s an ena al ca e isi (ANC), assessmen o an h opome ic indica o s a en olmen (mid-uppe a m ci cum e ence (MUAC) and/o body mass index (BMI)), g a idi y, ype o mala ia p e en ion used and ma e nal age. Essen ial deli e y ou comes included bi h weigh and newbo n sex. Wi h bi h weigh being he p ima y ocus, we es ic ed inclusion o women who deli e ed li e single- on in an s wi hou congeni al abno mali ies, as p e i- ously ecommended. 33 We included 14 635 single on, li e bi h p egnancies om women who had pa icipa ed in 1 o 13 p egnancy s udies ( able 1) conduc ed in se en coun ies in A ica and one in he Wes e n Pacific(figu e 1, able 1). O he se en RCTs, ou assessed he e ec i eness o di e - en pha macological mala ia p e en ion egimens, 27–30 one addi ionally e alua ed nu i ional supplemen a- ion, 21 one was designed solely o assess he e ec i eness o nu i ional supplemen a ion 22 and one measu ed he impac o insec icide- ea ed bed ne s (ITNs) on bi h weigh . 25 The six p ospec i e coho s udies we e all designed o assess isk ac o s and consequences o mala ia in ec ion and/o an imala ial ea men du ing p egnancy in di e en loca ions and among di e en s udy popula ions. 10 20 23 26 31 32 Fo 10 o he 13 s udies, p egnan women we e iden i- fied and ec ui ed a one o hei sel -ini ia ed ANC, usually he booking isi 10 20 22 27–32 bu some imes a a subsequen isi . 26 The EMEP s udy en olled women ea ly in p egnancy, bu a subse o hese same women we e also en olled in a c oss-sec ional s udy a deli e y, he in e mi en p e en i e ea men in p egnancy (IPTp)-MON s udy. 23 24 The Asembo Bay ITN coho (Kenya) iden ified p egnan women h ough mon hly communi y census, and he FSP/MISAME (Bu kina Faso) s udy ec ui ed h ough a communi y-based ne wo k o home isi o s. 21 25 Th ee s udies excluded 2Unge HW, e al.BMJ Open 2016;6:e012697. doi:10.1136/bmjopen-2016-012697 Open Access Table 1 Cha ac e is ics o he 13 indi idual s udies included in he M3 ini ia i e Coun ies S udy name Design Pe iod Median GA (IQR)* Mala ia p e en ion† Nu i ional in e en ion N‡n§ Benin STOPPAM I 20 Coho 2008–2010 17 (14–20) IPT-SP None 1037 791 BF FSP/MISAME 21 34 RCT 2006–2008 16 (11–21) IPT-SP(2), IPT-SP(3) MMS, FFS 1296 1020 DRC ECHO 10 Coho 2005–2006 19 (17–21) IPT-SP None 182 164 Ghana iLiNS-DYAD 22 RCT 2009–2012 17 (15–20) IPT-SP LNS, MMN, IFA 1320 1068 Kenya EMEP and IPTp-MON 23 24 Coho ¶ 2011–2013 23 (16–30) IPTp-SP None 1453 473¶ Kenya ITN 25 RCT 1996–1999 24 (20–30) IPT-SP s a ed du ing s udy None 911 711 Kenya Kisumu coho 26 Coho 1996–2001 36 (34–37) IPT-SP s a ed du ing s udy None 3155 3388** Kenya STOPMIP 27 RCT 2012–2015 23 (20–26) IPT-SP, IPT-DHA-PQ, IST-DHA-PQ None 1546 1203 Malawi ISTp 28 RCT 2011–2013 21 (19–23) IPT-SP, IST-DP None 1873 1602 Malawi LAIS 29 RCT 2003–2006 20 (18–23) IPT-SP(2), IPT-SP(4) IPT-SPAZ None 1320 1190 PNG IPTp s udy 30 RCT 2009–2013 22 (19–25) IPT-SPAZ; Single dose SP and CQ None 2793 1943 PNG Sek coho 31 Coho 2005–2007 25 (22–28) Single dose SP and weekly CQ None 470 293 Tanzania STOPPAM II 32 Coho 2008–2010 19 (15–21) IPT-SP None 995 789 *Median (IQR): ges a ional age a en olmen assessed by e al biome y, o symphysis-pubis undal heigh when ul asound una ailable. †I RCT, desc ibes he in e en ion, i coho , desc ibes he na ional policy du ing he s udy pe iod. ‡N, en olled in pa en s udy. §n, li e bi h p egnancies ha me inclusion c i e ia o M3. ¶The EMEP s udy was a p ospec i e coho s udy wi h some o e lapping en olmen wi h he c oss-sec ional s udy IPTp-MON. One hund ed and ele en p egnancies we e en olled in EMEP and IPTp-MON; in o ma ion on mala ia in ec ion a deli e y was ob ained o he subse o women in IPTp-MON. **Includes addi ional women om a subs udy no included in he pa en s udy which o he wise me inclusion c i e ia o he pooled da a. BF, Bu kina Faso; CQ, chlo oquine; DHA-PQ, dihyd oa emisinin-pipe aquine; DRC, Democ a ic Republic o he Congo; FFS, o i ied ood supplemen a ion; IFA, i on and olic acid supplemen a ion; IPTp, in e mi en p e en i e ea men in p egnancy; IST, in e mi en sc eening o mala ia in ec ion; ISTp, in e mi en sc eening o mala ia in ec ion in p egnancy; ITN, insec icide- ea ed bed ne ; LNS, lipid-based nu ien supplemen a ion; M3, Ma e nal Malnu i ion and Mala ia; MMS, mul iple mic onu ien s supplemen a ion; PNG, Papua New Guinea; RCT, andomised con olled ial; SP, sulphadoxine-py ime hamine; SPAZ, SP and azi h omycin; STOPPAM, S a egies To P e en P egnancy Associa ed Mala ia. Unge HW, e al.BMJ Open 2016;6:e012697. doi:10.1136/bmjopen-2016-012697 3 Open Access HIV-in ec ed p egnan women, 22 27 28 h ee s udies did no assess HIV s a us 21 30 31 and he emaining se en s udies included bo h HIV-in ec ed and HIV-nega i e p egnan women. 10 20 23 25 26 29 32 The p edominan mala ia species obse ed in all s udies was P. alcipa um. The wo s udies in Papua New Guinea (PNG) also epo ed P. i ax in ec ions. 30 31 Some s udies de ec ed P. o ale and P. mala iae in ec ions bu p e alence was e y low (<1%). S udies no di e en- ia ing be ween species (n=4) we e conduc ed in a eas whe e P. alcipa um is he p incipal mala ia species, and P. i ax is hough o be la gely absen . 20–22 25 Ele en s udies epo ed high and pe ennial mala ia ansmis- sion, while wo s udies epo ed medium- o-high pe en- nial mala ia ansmission. 22 30 Measu emen s Women in all s udies had a leas wo s udy isi s, a en ol- men and deli e y, bu he equency and iming o ollow-up isi s du ing p egnancy a ied by s udy. Gi en logis ical and compu a ional in ensi y equi ed in pooling longi udinal measu es and subs an ial he e ogenei y in e- quency and iming o measu emen s, only da a a en ol- men and a deli e y we e pooled om e e y s udy. Tables 2 and 3show a ailable en olmen and deli e y measu emen s o each included coho . Measu emen s included bo h hose a iables deemed essen ial o he main analyses on mala ia, anaemia and malnu i ion, and hose a iables deemed op ional bu in o ma i e. A ew measu emen s, specifically mala ia in ec ion diagnos ics, malnu i ion an h opome ics and anaemia diagnos ics wa an u he discussion. Mala ia in ec ion a en olmen A en olmen , mala ia in ec ion was diagnosed by exam- ina ion o pe iphe al blood. 35 Pa asi aemia was assessed using one o mo e o he h ee ollowing app oaches: LM examina ion o a Giemsa-s ained blood smea , qPCR and RDTs ( able 2). In all bu wo s udies, mala ia a en olmen was ou inely diagnosed by LM. In he FSP/ MISAME s udy in Bu kina Faso, LM was only pe o med i a woman p esen ed wi h symp oms consis en wi h mala ia, ha is, e e o his o y o e e . 21 In he iLiNS-DYAD Ghana s udy, mala ia was only diagnosed using an RDT. 22 RDTs de ec ci cula ing a ge mala ia an igens and a e inc easingly used in mala ia-endemic a eas when mic oscopy is no eadily a ailable. 35 36 Howe e , pe sis ence o ci cula ing a ge an igens a e pa asi e clea ance can lead o alse-posi i e es esul s. 35 Sensi i i y o qPCR is much highe han LM and RDTs, bu he ole o submic oscopic in ec ions de ec ed by qPCR alone in causing ad e se ou comes has no been clea ly de e mined. 37 38 Mala ia in ec ion a deli e y In addi ion o pe iphe al blood diagnos ics a deli e y, some s udies also assessed placen al mala ia in ec ion a deli e y ( able 3). Placen al mala ia was diagnosed by LM o a placen al blood smea , qPCR and/o placen al his ology. 39 Th ee c i e ia a e used o classi y placen al mala ia by his ology: p esence o in ec ed e y h ocy es; haemozoin in monocy es/mac ophages and haemozoin in fib in deposi s. 40 Placen al his ology is conside ed he diagnos ic e e ence s anda d o placen al in ec ion. MUAC and BMI Ma e nal mac onu ien nu i ional s a us was assessed by measu emen o women’s MUAC and/o BMI a en olmen . MUAC, he ci cum e ence o he uppe a m, assessed a he mid-poin be ween he elbow and he ip o he shoulde , is equen ly used as a b oad indica o o ma e nal p o ein ese es, a s o es and mac onu i- en nu i ional s a us. 41 MUAC was measu ed in 10 o he 13 s udies, which included 61% o ou o al s udy popula ion ( able 2). Weigh and heigh ( o de i e BMI) we e addi ionally measu ed in nine o hese s udies as well as in he h ee s udies whe e MUAC was una ailable ( able 2). While nei he measu emen is pe ec , MUAC Figu e 1 Geog aphical loca ions whe e he 13 pa en s udies we e conduc ed: Benin, Bu kina Faso, Democ a ic Republic o he Congo, Ghana, Kenya, Malawi, Papua New Guinea and Tanzania. 4Unge HW, e al.BMJ Open 2016;6:e012697. doi:10.1136/bmjopen-2016-012697 Open Access Table 2 Key measu es a en olmen ac oss he 13 s udies included in he M3 ini ia i e Va iable STOPPAM-Benin FSP/ MISAME-BF ECHO-DRC iLiNS-DYAD-Ghana EMEP and IPTp-MON-Kenya ITN-Kenya Kisumu- Kenya STOPMIP-Kenya ISTp-Malawi LAIS-Malawi IPTp-PNG Sek-PNG STOPPAM-Tanzania Essen ial a iables Mala ia LM X X* X X X X X X X X X X PCR XX XX RDT X†X‡X§ X§ X† An h opome ics MUAC X* X X X X* X¶ X X X X Weigh X X X X X X X X X X X X X Heigh X X X X X X X X X X X X G a idi y X X X X X X X X X X X X X Anaemia** Haemoglobin X X X X X X X X X X X X Haema oc i X Op ional a iables Ges a ional age Ul asound X X X X X* X X X* X Fundal heigh X X* X X X* X X X X X X X X Age X X X X X X X X X X X X X Smoking (Y/N) X X X XXXX HIV X X X X X* X X X X X Residence ( u al/u ban) XXXXXXXXXXXX Bed ne owne ship X X X X X X X X X* A ailable in o ma ion indica ed wi h X, missing da a >10% indica ed by *, and sys ema ically missing da a indica ed wi h g ey highligh ing. †The STOPPAM Benin and Tanzania s udies p ima ily used he Pa asc een RDT (Zephy Biomedical Sys ems, Goa, India), which de ec s Plasmodium alcipa um HRP-2 and pLDH. ‡The iLiNS-DYAD-Ghana s udy used he Clea iew Mala ia Combo RDT (B i ish Biocell In e na ional, Dundee, UK), which de ec s HRP-2 and plasmodium aldolase. §Women andomised o he ISTp a ms o he STOPMIP-Kenya and ISTp-Malawi s udies we e es ed wi h a Fi s Response Mala ia Ag. (pLDH/HRP2) Combo RDT (P emie Medical Co po a ion, India). ¶Ma e nal MUAC measu ed a deli e y. **Nine s udies measu ed haemoglobin using a HemoCue haemoglobinome e (Hemocue, Angelholm, Sweden), 20–22 26–31 one s udy elied on haemoglobin measu es om a local labo a o y (unknown make), 23 one s udy used Sysmex hema ological analyse (Kobe, Japan) 32 and one s udy collec ed capilla y blood ( inge s ick) specimens o de e mina ion o haema oc i o haemoglobin le els using a s anda dised cha . 10 In he ITN-Kenya s udy, haemoglobin was measu ed using a HemoCue haemoglobinome e (Hemocue, Angelholm, Sweden) be o e 1997, and om 1997 onwa ds capilla y blood ( inge s ick) specimens we e collec ed o de e mina ion o haema oc i le els, which we e di ided by a ac o o h ee and p esen ed as haemoglobin alues o consis ency wi h he 1996 da a. BF, Bu kina Faso; DRC, Democ a ic Republic o he Congo; HRP-2, his idine p o ein-2; 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 in p egnancy; ITN, insec icide- ea ed bed ne s; LM, ligh mic oscopy; M3, Ma e nal Malnu i ion and Mala ia; MUAC, mid-uppe a m ci cum e ence; N, no; pLDH, Plasmodium lac a e dehyd ogenase; PNG, Papua New Guinea; RDT, apid diagnos ic es ; STOPPAM, S a egies To P e en P egnancy Associa ed Mala ia; Y, yes. Unge HW, e al.BMJ Open 2016;6:e012697. doi:10.1136/bmjopen-2016-012697 5 Open Access Table 3 Key measu es a deli e y ac oss he 13 s udies included in he M3 Ini ia i e Va iable STOPPAM -Benin FSP/MISAME-BF ECHO-DRC iLiNS-DYAD -Ghana EMEP and IPTp-MON-Kenya ITN-Kenya Kisumu-Kenya STOPMIP -Kenya ISTp-Malawi LAIS-Malawi IPTp-PNG Sek-PNG STOPPAM -Tanzania Essen ial a iables Mala ia—pe iphe al LM X* X* X X*,†X X X X X* X X X PCR X* X X Mala ia—placen al LM X* X* X*,†X X X X X* X* X* PCR X X X* X* X* His ology X X X X* X* IPTp doses ecei ed X X* X X X X* X X X Bi h weigh X X X X X X X X X X X X X In an sex X X X X X X X X X X X X X Op ional a iables Ges a ional age By ul asound X X X X X* X X X* X Neona al an h opome ics Abdomen ci cum e ence X* X XX Ches ci cum e ence X X Head ci cum e ence X X X X X X X X X X X C own heel leng h X X X X X X X X Timing o an h opome ics X X X X X X X X X X X X A ailable in o ma ion indica ed wi h X, missing da a >10% indica ed by *, and sys ema ically missing da a indica ed wi h g ey highligh ing. †Fo he EMEP/IPTp-MON s udy, only women co-en olled in he IPTp-MON s udy (n=111) had mala ia diagnos ics a deli e y. BF, Bu kina Faso; DRC, Democ a ic Republic o he Congo; 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 in p egnancy; ITN, insec icide- ea ed bed ne s; LM, ligh mic oscopy; M3, Ma e nal Malnu i ion and Mala ia; PNG, Papua New Guinea; STOPPAM, S a egies To P e en P egnancy Associa ed Mala ia. 6Unge HW, e al.BMJ Open 2016;6:e012697. doi:10.1136/bmjopen-2016-012697 Open Access and BMI a e easy and low-cos nu i ional assessmen s ha can be unde aken in low- esou ce se ings, and a e clinically ele an . 42 Anaemia a en olmen Mos women had haemoglobin measu emen s pe - o med a fi s ANC, and mos ecei ed ou ine i on/ ola e supplemen s, al hough in o ma ion on hei use was no ou inely collec ed. The dosage o ola e supple- men a ion (0.4–5 mg) a ied by s udy si e. FINDINGS TO DATE Findings om each indi idual s udy emphasise how pooling hese da a has he po en ial o gene a e impo - an in o ma ion on mala ia–nu i ion in e ac ions in p egnancy. The ECHO s udy in he Democ a ic Republic o he Congo (DRC) was he fi s s udy o epo an in e ac ion be ween mala ia and malnu i ion on he isk o FGR. 10 In his s udy, he isk o FGR was 2–8 imes highe among women wi h e idence o malnu i ion. In his s udy, he magni ude o he di e ence in e ec sizes depended on he measu emen o malnu i ion (BMI s MUAC s sho s a u e s weigh gain) and he meas- u emen o mala ia (c oss-sec ional s cumula i e); howe e , wi h all measu emen s o malnu i ion and mala ia, he pa e n and di ec ionali y o he modifica- ion was consis en . This s udy, oge he wi h a small numbe o ollow-up s udies, p o ided he necessa y p e- limina y da a o he M3 ini ia i e. 712 Two pa icipa ing s udies p o ided e idence ega ding nu i ional in e en ions du ing p egnancy. The FSP/ MISAME in Bu kina Faso s udy concluded ha mul iple mic onu ien - o ified ood supplemen a ion inc eased mean bi h weigh , and ha his e ec was mos p o- nounced among women who we e anaemic o unde - nou ished ea ly in hei p egnancy. 34 The iLiNS-DYAD ial in Ghana ound modes o e all inc eases in bi h weigh wi h he p o ision o lipid-based nu ien supple- men s compa ed wi h i on and olic acid supplemen a- ion, bu showed ha he in e en ion may be mos e ec i e when gi en o p imipa ous women. 22 While nu i ional assessmen was no he p ima y aim o he emaining s udies, he IPTp RCT in PNG and he S a egies To P e en P egnancy Associa ed Mala ia (STOPPAM) coho s udy in Benin epo ed associa ions be ween low ma e nal an h opome ics and bi h weigh . 20 43 O he s udies la gely ocused on mala ia p e en ion. In he la e 90s, he Kisumu coho s udy ound ha implemen a ion o wo doses o IPT-sulphadoxine- py ime hamine (SP) hal ed he p e alence o placen al mala ia in ec ion. In ano he s udy conduc ed concu - en ly in Kenya (Asembo Bay s udy) use o ITNs was associa ed wi h a ma ked educ ion in placen al mala ia and LBW, bu (as expec ed) wi h no appa en impac on nu i ional s a us. 25 The LAIS s udy, conduc ed in Malawi om 2003 o 2006, ound ha adding azi h omy- cin o wo cou ses o mon hly SP (SPAZ) was be e a educing mala ia a deli e y, LBW and p e e m bi h han mon hly SP o wo doses o SP. 29 44 45 SPAZ was also supe io when compa ed wi h he s anda d mala ia p e en ion egimen used in PNG (SP plus chlo o- quine), 30 whe e placen al in ec ion is an impo an isk ac o o LBW. 31 The EMEP coho s udy ound ha use o a emisinin combina ion ea men s du ing he fi s imes e was no associa ed wi h inc eased isk o misca iage. 23 The IPTp-MON s udy ound ha wi h inc easing esis ance, he e ficacy o IPTp-SP in clea ing exis ing in ec ions o p e en ing new ones is comp o- mised; howe e , whe e he sex uple mu an is a e, i emains associa ed wi h imp o emen s in bi h weigh and ma e nal haemoglobin. 24 The STOPPAM coho s udies conduc ed in Benin and Tanzania p o ided obse a ional da a on he e ec s and po en ial limi a ions o wo-dose IPTp-SP. Specifically, he STOPPAM-Benin s udy ound ha a sub- s an ial p opo ion o women acqui ed mala ia in ec- ions la e in p egnancy, some imes a e he second IPTp dose had been gi en. 20 The STOPPAM-Tanzania s udy also ound ha mala ia in ec ions in he fi s o second imes e we e associa ed wi h al e ed e al g ow h ha migh no be de ec able un il he hi d i- mes e . 32 T ial da a om he FSP/MISAME s udy u he co obo a ed hese obse a ional s udies; he FSP/ MISAME s udy ound ha mala ia in ec ion du ing he fi s imes e was associa ed wi h highe isk o LBW and ha addi ional doses o IPTp migh be mo e e ec - i e. 21 46 These s udies, along wi h o he s, ha e high- ligh ed he impo ance o ea ly and equen mala ia p e en ion o imp o e bi h ou comes, and IPT-SP is now ou inely gi en mon hly un il deli e y. 47 48 The in e mi en sc eening o mala ia in ec ion (ISTp) Malawi s udy assessed ano he mala ia p e en- ion s a egy by compa ing IPTp-SP wi h ISTp a ANC isi s using RDTs and ea ing in ec ed women wi h dihyd oa emisinin-pipe aquine (DHA-PQ). 28 The STOPMIP Kenya s udy also assessed ISTp wi h DHA-PQ, compa ing i o IPTp wi h DHA-PQ as well as IPTp-SP. Analyses om bo h s udies sugges ha ISTp-DHA-PQ is no supe io o he exis ing s a egy o IPTp-SP, al hough IPTp-DHA-PQ was mo e e ec i e han bo h ISTp-DP and IPTp-SP. 27 FUTURE PLANS We plan o assess whe he ma e nal mac onu ien nu i- ional s a us, as assessed by MUAC, BMI and ma e nal heigh , al e s he isk o educed bi h weigh ha is associa ed wi h mala ia in ec ion du ing p egnancy. Among women who unde wen a da ing ul asound scan in ea ly p egnancy, analyses will be pe o med using p e e m bi h and small- o -ges a ional age as end poin s in addi ion o LBW. To in o m policy decisions, we u he plan o use ad anced epidemiological me hods Unge HW, e al.BMJ Open 2016;6:e012697. doi:10.1136/bmjopen-2016-012697 7 Open Access o s ochas ically model he impac ha plausible a ge ed an imala ial and nu i ional in e en ions du ing p eg- nancy could ha e on he numbe o babies bo n LBW in mala ia endemic a eas. 49–51 Addi ional u u e analyses include, bu a e no limi ed o, he ollowing: he impac o anaemia on LBW; he in e ac ion be ween anaemia and mala ia wi h ega d o inc easing he isk o LBW; he media ion o he e ec o mala ia h ough anaemia on LBW; and he use ulness and ag eemen o MUAC e sus BMI o p edic ad e se bi h ou comes. Sho ma e nal s a u e, po en ially indica i e o s un ing and educed adolescen ca ch-up g ow h (ch onic unde nu- i ion), has also been associa ed wi h inc eased isks o ad e se bi h ou comes and will be explo ed using his pooled da a se . 52 Finally, we will assess a o emen ioned ela ionships and e ec s among p egnan women wi h HIV, a pa ien coho known o be a inc eased isk o ad e se ou comes due o mala ia and malnu i ion. 53 STRENGTHS AND LIMITATIONS This pooled bi h coho holds p omise as he la ges p eg- nancy da a se o da e o add ess ques ions ega ding mala ia and nu i ion ha a e o g ea impo ance o ma e nal and in an heal h. P io esea ch on his opic has been limi ed by insu ficien s a is ical powe o examine he in e ac ion be ween mala ia and malnu i- ion. The pooled M3 o e s he oppo uni y o o e come his limi a ion by inc easing s a is ical powe and p ecision, which is pa icula ly aluable o conduc ing subg oup ana- lyses and in es iga ing in e ac ions. The subs an ial size o he pooled da a se also acili a es he applica ion o igo - ous me hodological app oaches o sys ema ically missing da a, such as mul iple impu a ion by chained equa ions, s anda disa ion, la en a iable me hods o ans o ma ion o measu emen s o c ea e commensu a e measu es. 54 55 A ailabili y o indi idual-le el da a, a he han agg ega e da a om each s udy, allows defini ions o exposu es and ou comes o be ha monised. Indi idual-le el in o ma ion on mala ia and malnu i ion u he enables implemen a- ion o complex modelling o assess a ge ed an imala ial and nu i ional in e en ions du ing p egnancy. The di e - si y o s udy popula ions included in he M3 coho , o example, wi h espec o loca ion, e hnici y, mala ia ans- mission in ensi y, mala ia and nu i ion in e en ions, heal h in as uc u e and HIV p e alence, could p o ide impo an da a wi h ega d o gene alisabili y o ou find- ings. Specifically, his le el o popula ion di e si y, coupled wi h a ailabili y o da a on mul iple isk ac o s o LBW and g ea e s a is ical powe o assess subg oup e ec s, may allow he iden ifica ion o high- isk women who could benefi mos om mo e in ensi e an ena al ca e, nu i- ional supplemen s and al e na i e mala ia p e en ion egi- mens, and o he se ings in which hese in e en ions would be mos e ec i e. The main limi a ions o he pooled da a se a e ela ed o missing da a and he e ogenei y o he col- lec ed da a. Fi s , in o ma ion ha was collec ed by all s udies a ied, leading o sys ema ically missing da a on a numbe o impo an a iables ( ables 2 and 3). The limi ed a ailabili y o accu a ely measu ed ges a ional age hinde s he abili y o conduc p e e m bi h and small- o -ges a ional age analyses o he en i e da a se ( able 3), bu should allow o meaning ul subanalyses. Second, exclusion o misca iages and s illbi hs may cause selec ion bias (le unca ion) o some analyses, gi en he possibili y o di e en ial a es o ea ly p eg- nancy losses in ela ion o in ec ion and nu i ional s a us. 56 We will assess his po en ial bias using da a on misca iages and s illbi hs ex ac ed om a subse o s udies. 21 23 27 28 Thi d, po en ial con ounde s such as concomi an helmin h in ec ion and mic onu ien defi- ciencies we e no measu ed in pa icipan s udies. 57 58 Fou h, while MUAC only modes ly changes h oughou p egnancy, BMI ends o inc ease wi h ges a ional age: ges a ional age-adjus ed BMI may be one app oach o add ess his p oblem. Fi h, while we ha e in o ma ion on HIV s a us o a majo i y o s udies, in o ma ion on use o an i e o i al he apy (ART) was no ex ac ed, and secula changes o e ime ega ding use and e fi- cacy o ARTs could influence he compa abili y o esul s ac oss s udies ha en olled HIV-in ec ed women. Finally, since he in en ion was o concen a e on a eas o mode a e- o-high P. alcipa um ansmission, we did no include any s udies ep esen ing o he mala ia-a ec ed egions such as Cen al/Sou h Ame ica and India. COLLABORATION The in es iga o s welcome collabo a ion o u u e p o- jec s and in i e p oposals o addi ional analyses. Fu he de ails can be ob ained by con ac ing SR (s o- [email p o ec ed]) and HWU (hwunge @doc o s. o g.uk). Au ho a ilia ions 1 Depa men o Obs e ics and Gynaecology, Edinbu gh Royal In i ma y, Edinbu gh, UK 2 Depa 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 3 Depa men o Epidemiology, UNC-Chapel Hill, Chapel Hill, No h Ca olina, USA 4 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, USA 5 Ins i u de Reche che pou le Dé eloppemen (IRD), Mè e e en an ace aux in ec ions opicales (UMR216), Pa is, F ance 6 COMUE So bonne Pa is Ci é, Facul é de Pha macie, Uni e si é Pa is Desca es, Pa is, F ance 7 Uni e de Reche che Clinique de Nano o, Ins i u de Reche che en Sciences de la San é-DRO, Bobo-Dioulasso, Bu kina Faso 8 Depa emen de Reche che Clinique, Cen e Mu az, Bobo-Dioulasso, Bu kina Faso 9 Medical Resea ch Council Uni , The Gambia 10 London School o Hygiene and T opical Medicine, UK 11 Ins i u e o T opical Medicine, An we p, Belgium 12 Wo ldwide Epidemiology, GlaxoSmi hKline, Uxb idge, UK 13 Depa men o Nu i ion and Food Science, Uni e si y o Ghana, Legon, Acc a, Ghana 14 Depa men o Nu i ion, Uni e si y o Cali o nia, Da is, Cali o nia, USA 15 Depa men o Clinical Sciences, Li e pool School o T opical Medicine, Li e pool, UK 8Unge HW, e al.BMJ Open 2016;6:e012697. doi:10.1136/bmjopen-2016-012697 Open Access 16 Kenya Medical Resea ch Ins i u e (KEMRI)/Cen e o Global Heal h Resea ch, Kisumu, Kenya 17 Malawi-Li e pool-Wellcome T us Clinical Resea ch P og amme Li e pool School o T opical Medicine, Li e pool, UK 18 P esiden ’s Mala ia Ini ia i e, Washing on DC, USA 19 School o Public Heal h and Family Medicine, College o Medicine, Uni e si y o Malawi, Blan y e, Malawi 20 Tampe e Cen e o Child Heal h Resea ch, Tampe e, Finland 21 Depa men o Pedia ics, Uni e si y o Tampe e and Tampe e Uni e si y Hospi al, Tampe e, Finland 22 Wal e and Eliza Hall Ins i u e, Pa k ille, Vic o ia, Aus alia 23 Ins i u e o Glycomics, G i i h Uni e si y, Gold Coas , Queensland, Aus alia 24 Facul y o Heal h Science, Depa men o Immunology and Mic obiology, Cen e o Medical Pa asi ology, Uni e si y o Copenhagen, Copenhagen, Denma k 25 Na ional Ins i u e o Medical Resea ch, Tanga Cen e, Tanga, Tanzania Con ibu o s HWU and SR we e in ol ed in he concep ion o his s udy. HWU, JG, VB, NF, IV, HT, Ud’A, SHL, SA-A, KGD, FTK, SD, PO, LS, DJT, SK, JA, BN, MD, MM, LK-P, PA, KM, IM, DS, CS, JL, AM E, SM and SR we e in ol ed in design and supe ision o da a collec ion o he pa en s udies. JEC and HWU d a ed he wo k. All he au ho s c i ically e ised his a icle and app o ed he inal manusc ip as submi ed. Funding The STOPPAM p ojec , ‘S a egies To P e en P egnancy Associa ed Mala ia’was 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 (46099) 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 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 numbe 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 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 numbe 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 (New Yo k, New Yo k, USA), which also p o ided unding o he PCR 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 , 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 . JEC 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). Compe ing in e es s None decla ed. P o enance and pee e iew No commissioned; ex e nally pee e iewed. Da a sha ing s a emen Resea che s can eques da a use by con ac ing SR (s oge @unimelb.edu.au) and HWU ([email p o ec ed]k). Open Access This is an Open Access a icle dis ibu ed in acco dance wi h he e ms o he C ea i e Commons A ibu ion (CC BY 4.0) license, which pe mi s o he s o dis ibu e, emix, adap and build upon his wo k, o comme cial use, p o ided he o iginal wo k is p ope ly ci ed. See: h p:// c ea i ecommons.o g/licenses/by/4.0/ REFERENCES 1. Dellicou S, Ta em AJ, Gue a CA, e al. Quan i ying he numbe o p egnancies a isk o Mala ia in 2007: a demog aphic s udy. PLoS Med 2010;7:e1000221. 2. Umbe s AJ, Ai ken EH, Roge son SJ. Mala ia in p egnancy: small babies, big p oblem. T ends Pa asi ol 2011;27:168–75. 3. Ba dají A, Sigauque B, Sanz S, e al. Impac o mala ia a he end o p egnancy on in an mo ali y and mo bidi y. J In ec Dis 2011;203:691–9. 4. Ba ke DJ, Gluckman PD, God ey KM, e al. 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