Modifiers of the effect of maternal multiple micronutrient supplementation on stillbirth, birth outcomes, and infant mortality: a meta-analysis of individual patient data from 17 randomised trials in low-income and middle-income countries
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1090
A icles
Lance Glob Heal h 2017;
5: e1090–100
See Commen page e1050
Depa men o Global Heal h
and Popula ion (E R Smi h ScD,
W W Fawzi D PH,
C R Sud eld ScD), Depa men o
Nu i ion (A H Shanka
ScD),
Ha a d T.H. Chan School o
Public Heal h, Bos on, MA,
USA; Di ision o
Gas oen e ology, Hepa ology
and Nu i ion, Bos on
Child en’s Hospi al, Bos on,
MA, USA (E R Smi h); Summi
Ins i u e o De elopmen ,
Ma a am, Indonesia
(A H Shanka , R Agus ina PhD);
The JiVi A P ojec , Johns
Hopkins Uni e si y in
Bangladesh, Gaibandha,
Bangladesh (L S-F Wu
MHS,
H Ali MPH, P Ch is ian D PH,
K P Wes J D PH); Cen e o
Human Nu i ion, Depa men
o In e na ional Heal h, Johns
Hopkins Bloombe g School o
Public Heal h, Bal imo e, MD,
USA (L S-F Wu, H Ali, P Ch is ian,
K P Wes J ); Depa men o
Mic obiology and
Immunology, Muhimbili
Uni e si y o Heal h and Allied
Sciences, Da es Salaam,
Tanzania (S Aboud PhD,
W U assa PhD);
Depa men o
Nu i ion and Food Science,
Uni e si y o Ghana, Legon,
Acc a, Ghana
(S Adu-A a wuah
PhD);
Depa men o Nu i ion,
Facul y o Medicine,
Uni e si as Indonesia –
D . Cip o Mangunkusumo
Gene al Hospi al, Jaka a,
Indonesia (R Agus ina);
In e na ional Cen e o
Dia hoeal Diseases Resea ch
Bangladesh (ICDDR,B), Dhaka,
In oduc ion
Mic onu ien de iciencies a e common among women in
low-income and middle-income coun ies mainly due o
inadequa e die a y in ake and limi ed di e si y o ui s,
ege ables, animal p o ein, and o i ied oods.1 The
bu den and se e i y o mic onu ien de iciencies a e
exace ba ed du ing p egnancy because o inc eased
demands o bo h he mo he and he g owing e us.2 I is
Modi ie s o he e ec o ma e nal mul iple mic onu ien
supplemen a ion on s illbi h, bi h ou comes, and in an
mo ali y: a me a-analysis o indi idual pa ien da a
om 17 andomised ials in low-income and
middle-income coun ies
Emily R Smi h, Anu aj H Shanka , Lee S-F Wu, Said Aboud, Se h Adu-A a wuah, Hasmo Ali, Rina Agus ina, Shams A i een, Pe Asho n,
Zul iqa A Bhu a, Pa ul Ch is ian, Delanja han De akuma , Ka h yn G Dewey, Hen ik F iis, Exne ia Gomo, Piyush Gup a, Pe nille Kæs el,
Pa ick Kols e en, He mann Lanou, Kenne h Male a, Aissa Mamadoul aibou, Ge na d Msamanga, Da id Os in, La s-Åke Pe sson,
Usha Ramak ishnan, Juan A Ri e a, A jumand Riz i, H P S Sachde , Willy U assa, Kei h P Wes J , Noel Zag e, Lingxia Zeng, Zhonghai Zhu,
Wa aie W Fawzi, Ch is ophe R Sud eld
Summa y
Backg ound Mic onu ien de iciencies a e common among women in low-income and middle-income coun ies.
Da a om andomised ials sugges ha ma e nal mul iple mic onu ien supplemen a ion dec eases he isk o low
bi hweigh and po en ially imp o es o he in an heal h ou comes. Howe e , he e ogenei y ac oss s udies sugges s
in luence om e ec modi ie s. We aimed o iden i y indi idual-le el modi ie s o he e ec o mul iple mic onu ien
supplemen s on s illbi h, bi h ou comes, and in an mo ali y in low-income and middle-income coun ies.
Me hods This wo-s age me a-analysis o indi idual pa ien included da a om 17 andomised con olled ials done
in 14 low-income and middle-income coun ies, which compa ed mul iple mic onu ien supplemen s con aining
i on- olic acid e sus i on- olic acid alone in 112 953 p egnan women. We gene a ed s udy-speci ic es ima es and
pooled subg oup es ima es using ixed-e ec s models and assessed he e ogenei y be ween subg oups wi h he χ² es
o he e ogenei y. We did sensi i i y analyses using andom-e ec s models, s a i ying by i on- olic acid dose, and
explo ing indi idual s udy e ec .
Findings Mul iple mic onu ien supplemen s con aining i on- olic acid p o ided signi ican ly g ea e educ ions in
neona al mo ali y o emale neona es compa ed wi h male neona es han did i on- olic acid supplemen a ion alone
(RR 0·85, 95% CI 0·75–0·96 s 1·06, 0·95–1·17; p alue o in e ac ion 0·007). Mul iple mic onu ien supplemen s
esul ed in g ea e educ ions in low bi hweigh (RR 0·81, 95% CI 0·74–0·89; p alue o in e ac ion 0·049), small-
o -ges a ional-age bi hs (0·92, 0·87–0·97; p=0·03), and 6-mon h mo ali y (0·71, 0·60–0·86; p=0·04) in anaemic
p egnan women (haemoglobin <110g/L) as compa ed wi h non-anaemic p egnan women. Mul iple mic onu ien
supplemen s also had a g ea e e ec on p e e m bi hs among unde weigh p egnan women (BMI <18·5 kg/m²;
RR 0·84, 95% CI 0·78–0·91; p=0·01). Ini ia ion o mul iple mic onu ien supplemen s be o e 20 weeks ges a ion
p o ided g ea e educ ions in p e e m bi h (RR 0·89, 95% CI 0·85–0·93; p=0·03). Gene ally, he su i al and bi h
ou come e ec s o mul iple mic onu ien supplemen a ion we e g ea e wi h high adhe ence (≥95%) o
supplemen a ion. Mul iple mic onu ien supplemen s did no signi ican ly inc ease he isk o s illbi h o neona al,
6-mon h, o in an mo ali y, nei he o e all o in any o he 26 examined subg oups.
In e p e a ion An ena al mul iple mic onu ien supplemen s imp o ed su i al o emale neona es and p o ided
g ea e bi h-ou come bene i s o in an s bo n o unde nou ished and anaemic p egnan women. Ea ly ini ia ion in
p egnancy and high adhe ence o mul iple mic onu ien supplemen s also p o ided g ea e o e all bene i s. S udies
should now aim o elucida e he mechanisms accoun ing o di e ences in he e ec o an ena al mul iple
mic onu ien supplemen s on in an heal h by ma e nal nu i ion s a us and sex.
Funding None.
Copy igh © The Au ho (s). Published by Else ie L d. This is an Open Access a icle unde he CC BY 4.0 license.
A icles
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Bangladesh (S A i een D PH);
Cen e o Child Heal h
Resea ch and Depa men o
Paedia ics, Uni e si y o
Tampe e School o Medicine
and Tampe e Uni e si y
Hospi al, Tampe e, Finland
(P Asho n PhD); Cen e o
Global Child Heal h, Hospi al
o Sick Child en, To on o, ON,
Canada (Z A Bhu a
PhD); Cen e
o Excellence in Women and
Child Heal h, The Aga Khan
Uni e si y, Ka achi, Pakis an
(Z A Bhu a, A Riz i MSC); UCL
Ins i u e o Global Heal h,
London, UK (D De akuma PhD,
D Os in PhD);
Depa men o
Nu i ion and P og am in
In e na ional and Communi y
Nu i ion, Uni e si y o
Cali o nia-Da is, Da is, CA,
USA (K G Dewey PhD);
Depa men o Nu i ion
Exe cise and Spo s, Uni e si y
o Copenhagen, Copenhagen,
Denma k (H F iis PhD,
P Kæs el PhD); College o Heal h
Sciences, Uni e si y o
Zimbabwe, Ha a e, Zimbabwe
(E Gomo PhD); Depa men o
Pedia ics, Uni e si y College o
Medical Sciences, Delhi, India
(P Gup a MD); Nu i ion and
Child Heal h Uni , Depa men
o Public Heal h, P ince
Leopold Ins i u e o T opical
Medicine, An we p, Belgium
(P Kols e en PhD); Facul y o
Bio-science enginee ing, Ghen
Uni e si y, Belgium
(P Kols e en); Ins i u de
Reche che en Sciences de la
San é, Minis y o Scien i ic
Resea ch and Inno a ion,
Ouagadougou, Bu kina Faso
(H Lanou MD); School o Public
Heal h and Family Medicine,
Uni e si y o Malawi College o
Medicine, Blan y e, Malawi
(K Male a PhD); Food and
Ag icul u e O ganiza ion o he
Uni ed Na ions, Lib e ille,
Gabon (A Mamadoul aibou MS);
Depa men o Communi y
Heal h, Muhimbili Uni e si y
o Heal h and Allied Sciences,
Da es Salaam, Tanzania
(G Msamanga
ScD); Depa men
o Women’s and Child en’s
Heal h, In e na ional Ma e nal
and Child Heal h, Uppsala
Uni e si y, Uppsala, Sweden
(L-Å Pe sson PhD); Hube
Depa men o Global Heal h,
Rollins School o Public Heal h,
Emo y Uni e si y, A lan a, USA
(U Ramak ishnan PhD);
Ins i u o Nacional de Salud
Publica, Cue na aca, Mexico
(J A Ri e a PhD); Pedia ic and
well es ablished ha i on-de iciency anaemia in p egnancy
can lead o dec eased bi hweigh , and insu icien ola e
concen a ions in he pe iconcep ional pe iod inc eases
he isk o neu al ube de ec s and o he ad e se
ou comes.3–5 De iciencies in o he mic onu ien s
including i amins A, B-complex, D, E, zinc, calcium,
coppe , magnesium, selenium, and iodine a e also
p e alen in low-income and middle-income coun ies and
can lead o poo p egnancy, e al g ow h, and child heal h
ou comes.3,6–8 As such, ma e nal mul iple mic onu ien
supplemen a ion including i on- olic acid is a po en ial
in e en ion o imp o e ma e nal and child heal h as
compa ed wi h i on- olic acid supplemen a ion alone.
The 2017 Coch ane Sys ema ic Re iew and me a-
analysis ha assessed he e ec o ma e nal mul iple
mic onu ien supplemen s in p egnancy on in an
mo ali y iden i ied 19 andomised con olled ials and
pooled da a om 17 o hese s udies.6 P o ision o
mul iple mic onu ien supplemen s in combina ion
wi h i on- olic acid du ing p egnancy educed he isk o
low bi hweigh (<2500 g; ela i e isk [RR] 0·88, 95% CI
0·85–0·91) and small- o -ges a ional-age bi hs (0·92,
0·86–0·98), bu had no signi ican e ec on pe ina al
(1·01, 0·91–1·13) and neona al mo ali y (1·06, 0·92–1·22)
as compa ed wi h i on- olic acid supplemen a ion alone.6
The e was mode a e he e ogenei y, as measu ed by I², o
he e ec o mul iple mic onu ien supplemen s on
some bi h ou comes ac oss published ials bu
subs an ial he e ogenei y o pe ina al mo ali y. A
p e iously published pooled analysis o 12 mul iple
mic onu ien supplemen s ials also indica ed he e ec
o mul iple mic onu ien supplemen s on bi hweigh
may be g ea e in p egnan women wi h highe BMI.9
In 2016, WHO e iewed hei an ena al ca e
ecommenda ions and acknowledged ha policy make s
in popula ions wi h a high p e alence o nu i ional
de iciencies migh wish o p o ide mul iple mic onu ien
supplemen s con aining i on and olic acid. Howe e ,
WHO did no uni e sally ecommend mul iple
mic onu ien supplemen s, no ing ha he e was
e idence o bene i bu also some e idence o ha m.10 The
exis ing da a also p ecluded de ini i e conclusions i any
subg oups expe ience g ea e bene i s o ha m due o
mul iple mic onu ien supplemen s.
In his s udy we aimed o elucida e indi idual-le el
e ec modi ie s ha migh al e he impac o ma e nal
mul iple mic onu ien supplemen s on s illbi h, bi h
ou comes, and in an mo ali y. We aimed o iden i y
subg oups o p egnan women and in an s who migh
expe ience g ea e bene i o ha m om mul iple
mic onu ien supplemen s and explo e he sou ces o
he he e ogenei y ac oss andomised ials.
Me hods
In his wo-s age me a-analysis o indi idual pa ien
da a, we iden i ied po en ial s udies o inclusion
Resea ch in con ex
E idence be o e his s udy
Mic onu ien de iciencies a e common in p egnan women in
low-income and middle-income coun ies. Howe e , deba e
pe sis s ega ding he cu en WHO ecommenda ion o
p o ide p egnan women wi h i on- olic acid supplemen a ion
alone, a he han mul iple mic onu ien supplemen s
con aining o he essen ial mic onu ien s in addi ion o
i on- olic acid du ing ou ine an ena al ca e. In he pas
wo decades, mo e han 20 andomised ials ha e examined
he e ec o mul iple mic onu ien supplemen s du ing
p egnancy, compa ed wi h i on- olic acid alone, on ma e nal
and child heal h ou comes. The 2017 Coch ane e iew and
me a-analysis es ablished ha p o ision o daily o al mul iple
mic onu ien supplemen s educed he isk o low bi hweigh
(<2500 g) and small- o -ges a ional-age bi hs, bu had no
o e all e ec on pe ina al and neona al mo ali y as compa ed
wi h i on- olic acid alone.
The ecen ly upda ed 2016 WHO an ena al ca e
ecommenda ions acknowledged ha policy make s in
popula ions wi h a high p e alence o ma e nal nu i ional
de iciencies migh wish o p o ide mul iple mic onu ien
supplemen s. Howe e , WHO does no uni e sally ecommend
mul iple mic onu ien supplemen s, no ing: “The e is some
e idence o addi ional bene i o mul iple mic onu ien
supplemen s con aining 13–15 di e en mic onu ien s
(including i on and olic acid) o e i on and olic acid
supplemen s alone, bu he e is also some e idence o isk,
and some impo an gaps in he e idence”.
Added alue o his s udy
This s udy uses he mos de ailed app oach o analysing exis ing
ial da a on mul iple mic onu ien supplemen s. P e ious
me a-analyses iden i ied o e all bene i s o mul iple
mic onu ien supplemen s in e ms o bi h size, bu ou
indings show ha speci ic subg oups expe ience mo ali y
bene i s, no ably emale neona es. Women wi h indica o s o
malnu i ion du ing p egnancy who ook mul iple mic onu ien
supplemen s also had g ea e educ ions in low bi hweigh ,
p e e m, and small- o -ges a ional-age bi hs. We ound no
e idence ha mul iple mic onu ien supplemen s signi ican ly
inc eased he isk o s illbi h o neona al, 6-mon h, o in an
mo ali y, nei he o e all o in any o he 26 examined
subg oups.
Implica ions o he a ailable e idence
This no el analysis iden i ied subg oups o mo he s and in an s
ha migh bene i he mos om mul iple mic onu ien
supplemen s. This new e idence sugges s ha WHO migh
wish o e-e alua e he balance o bene i s and ha ms o
uni e sal mul iple mic onu ien supplemen a ion in hei
an ena al ca e ecommenda ions.
A icles
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1092
Clinical Epidemiology Uni ,
Si a am Bha ia Ins i u e o
Science and Resea ch,
New Delhi, India
(H P S Sachde FRCPCH); UNICEF
Regional O ice o Wes and
Cen al A ica, Daka , Senegal
(N Zag e PhD); and Depa men
o Epidemiology and
Bios a is ics, School o Public
Heal h, Xi’an Jiao ong
Uni e si y Heal h Science
Cen e , Xi’an, Shaanxi P o ince,
China (L Zeng PhD, Z Zhu MSc)
Co espondence o:
D Ch is ophe R Sud eld,
Depa men o Global Heal h and
Popula ion, Ha a d T.H. Chan
School o Public Heal h,
Bos on MA 02115, USA
[email p o ec ed]
h ough a e iew o ecen me a-analyses.6,11,12 We hen
upda ed his lis o po en ial s udies using he sea ch
s a egy employed by he 2015 Coch ane Re iew o
iden i y andomised con olled ials published up o
July 20, 2015.6 We also e iewed he e e ences o
included ials and sys ema ic e iews; he e we e no
language es ic ions.
Eligible s udies we e andomised con olled ials o
mul iple mic onu ien supplemen s o p egnan
women, con aining a leas h ee mic onu ien s; we e
done in low-income and middle-income coun ies as
de ined by he Wo ld Bank; included a con ol g oup ha
had ecei ed i on and olic acid supplemen s as pa o
he ial o as s anda d o ca e; whose au ho s p esen ed
da a on bi h ou comes, s illbi h, o in an mo ali y; and
whose au ho s ag eed o pa icipa e in his new indi idual
pa ien da a s udy. We excluded ials o ial g oups ha
used lipid-based mic onu ien supplemen s and
mic onu ien - o i ied powde s as hese p o ided
addi ional calo ies and nu ien s ha migh ha e
independen e ec s on ou comes o in e es .
All ou comes, subg oups, and s a is ical me hods we e
de ined a p io i. Ou comes o in e es included: s illbi h,
ea ly neona al (≤7 days age), neona al (≤28 days age),
6-mon h (≤180 days age), and in an (≤365 days age)
mo ali y. Bi h ou comes included: bi hweigh , e y low
bi hweigh (<2000 g), low bi hweigh (<2500 g), ea ly
p e e m (<34 weeks ges a ion), p e e m (<37 weeks
ges a ion), small- o -ges a ional-age (<10 h pe cen ile o
weigh - o -ges a ional-age and sex as de ined by Oken13
and In e g ow h14 s anda ds), and la ge- o -ges a ional-
age (>90 h pe cen ile as de ined by Oken13 and
In e g ow h14 s anda ds). Bi hs ha occu ed be o e
33 weeks o a e week 43 we e excluded om
In e g ow h14 analyses because small- o -ges a ional-age
and la ge- o -ges a ional-age cu o s we e no de ined o
hese ges a ional ages a he ime o analysis.
We assessed he e ec o mul iple mic onu ien
supplemen s on all ou comes wi hin he ollowing
subg oups selec ed based on biological plausibili y and
inclusion in p e ious me a-analyses: ges a ional age a
andomisa ion ( imes e s and <20 weeks s ≥20 weeks),
pa i y (1 child s ≥2 child en), ma e nal age (<18 yea s s
≥18 yea s and <20 yea s s ≥20 yea s), ma e nal
unde weigh a andomisa ion (BMI <18·5 kg/m² s
≥18·5 kg/m²), ma e nal anaemia a andomisa ion
(<110 g/L s ≥110 g/L), ma e nal s a u e (<150 cm s
≥150 cm), ma e nal educa ion (none s ≥1 yea ), in an sex
(male s emale), and adhe ence o ial egimen
(≥95% s <95%). We examined he e ec o mul iple
mic onu ien supplemen s on s illbi h and mo ali y
ou comes by he p esence o a skilled bi h a endan a
deli e y (yes s no).
We con ac ed p incipal in es iga o s o each s udy and
in i ed hem o pa icipa e in his s udy. Eigh ials
p o ided indi idual-le el da a o he Ha a d T.H. Chan
in es iga o s (ERS and CRS) and nine independen ly
conduc ed he subg oup analyses in acco dance wi h he
s udy p o ocol and using he same s a is ical analysis
code. We calcula ed non-pa ame ic ela i e isk o mean
di e ence es ima es and co esponding 95% CIs o
indi idually andomised ials. We calcula ed es ima es
and 95% CIs o clus e andomised ials using me hods
consis en wi h he p ima y published pape .
We pooled s udy-speci ic ela i e isk and mean
di e ence es ima es using ixed e ec s models using
STATA e sion 14 METAN command. We excluded ials
which did no con ibu e a leas one subjec o all s a a
wi hin a subg oup analysis. He e ogenei y wi hin s a a
was quan i ied using he I² es s a is ic and
co esponding p alue, while he e ogenei y be ween
subg oups was assessed wi h he χ² es o he e ogenei y.
We quali a i ely assessed s udy quali y using he Child
Heal h Epidemiology Re e ence G oup s anda ds.15 As a
sensi i i y analysis o indi idual subg oup e ec s, we
gene a ed pooled subg oup es ima es using andom-
e ec s models; we also examined o e all and subg oup
e ec s sepa a ely o ials using he same dose o i on in
he mul iple mic onu ien supplemen s and compa ison
g oup and again o he ials using a lowe dose i on in
he mul iple mic onu ien supplemen s g oup han he
compa ison g oup. In addi ion, we did an in luence
analysis o signi ican esul s whe eby we p esen ed
pooled es ima es omi ing each s udy, one a a ime
(appendix pp 218–220).16 To assess publica ion bias and
small s udy e ec s we isually inspec ed unnel-plo s
(appendix pp 221–224). All indi idual ials we e
app o ed by hei espec i e e hics commi ees. The
pooling s udy p o ocol was app o ed by he
Ha a d T. H. Chan School o Public Heal h IRB
(15-2969).
Role o he unding sou ce
The e was no unding sou ce o his s udy. The
co esponding au ho had ull access o all he da a in he
s udy and had inal esponsibili y o he decision o
submi o publica ion.
Resul s
We iden i ied 19 andomised con olled ials ha me
ou inclusion c i e ia, 17 o which we e included in his
me a-analysis.17–33 Two we e no included; one s udy
declined o pa icipa e and one could no loca e he
p ima y da a.34,35 Table 1 p o ides a summa y o ials
included in he me a-analysis. The ials included
112 953 p egnan women and s udy-speci ic sample size
anged om 20022 o 44 567,31 wi h wo s udies
con ibu ing mo e han wo- hi ds o o al pa icipan s.26,31
Eigh ials used he Uni ed Na ions mul iple
mic onu ien p epa a ion (UNIMMAP; mul iple
mic onu ien supplemen s o mula ions in appendix
p 1).20,21,23,26–30 All ials used mul iple mic onu ien
supplemen s p epa a ions ha included a leas eigh
mic onu ien s in addi ion o i on- olic acid. The
See Online o appendix
A icles
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p e alence o e ec modi ie s and cumula i e incidence
o s udy ou comes by ial a e p esen ed in he appendix
(pp 3, 4). All ials we e g aded low o mode a e isk o
bias (appendix p 2). Funnel plo s did no p o ide clea
e idence o publica ion bias o small s udy e ec s
(appendix pp 221–224).
Figu e 1 p esen s subg oup-speci ic pooled e ec sizes
o he ollowing ou comes: s illbi h, neona al mo ali y,
in an mo ali y, low bi hweigh , p e e m, and small- o -
ges a ional-age bi hs as pe he Oken s anda d. Fo es
plo s o all subg oup me a-analyses a e p esen ed in he
appendix (pp 5–205). Table 2 p esen s he e ec o
ma e nal mul iple mic onu ien supplemen s on
s illbi h, neona al mo ali y, mo ali y o 6 mon hs, and
in an mo ali y s a i ied by po en ial e ec modi ie s.
We did no iden i y any ac o s ha signi ican ly modi ied
he e ec o mul iple mic onu ien supplemen s on
s illbi h. In me a-analyses including all li ebi hs, he e
was no o e all e ec o mul iple mic onu ien
supplemen s on mo ali y a any imepoin ; howe e ,
he e we e se e al subg oups o which mul iple
mic onu ien supplemen s p o ided signi ican su i al
bene i s. We ound sex modi ied he e ec o mul iple
mic onu ien supplemen s on su i al in he ea ly
neona al, neona al, and in an pe iods (p alues o
he e ogenei y: 0·047, 0·007, 0·04; able 2; appendix p 23).
Mul iple mic onu ien supplemen s signi ican ly
educed he isk o neona al mo ali y by 15% among
emales (95% CI 4–25) wi h a simila magni ude o
educ ion o ea ly neona al, 6 mon hs, and in an
mo ali y. Signi ican mo ali y bene i s o mul iple
mic onu ien supplemen s o emales we e also ound
a all imepoin s in andom e ec s sensi i i y analyses
(appendix p 206). Mul iple mic onu ien supplemen s
p o ided signi ican ly g ea e 6-mon h mo ali y
educ ion among anaemic p egnan women as compa ed
wi h non-anaemic p egnan women (RR 0·71, 95% CI
0·60–0·86 s 0·93, 0·78–1·11; p alue o he e ogenei y
0·04). Ma e nal adhe ence o he in e en ion also
modi ied he e ec o mul iple mic onu ien
supplemen s on in an mo ali y, wi h su i al bene i s
o in an s bo n o women wi h highe han 95%
adhe ence o he supplemen s ( able 2). No subg oup had
signi ican ly inc eased isk o s illbi h o neona al,
6 mon h, o in an mo ali y in bo h ixed and andom
e ec s me a-analyses ( able 2 and appendix p 206).
Among all li ebi hs, mul iple mic onu ien
supplemen s signi ican ly educed he isk o e y low
Loca ion Yea s o s udy S udy
design
Pa icipan s S udy popula ion
Fawzi,24 1998 Da es Salaam, Tanzania 1995–1997 RCT 1075 HIV-in ec ed p egnan women 12–27 weeks ges a ion
Ch is ian,17 2003 Sa lahi, Nepal 1998–2001 cRCT 4926 P egnan women
Ramak ishnan,18
2003
Cue na aca, Mexico 1997–2000 RCT 873 P egnan women <13 weeks ges a ion
F iis,19 2004 Ha a e, Zimbabwe 1996–1997 RCT 1669 P egnan women 22–36 weeks ges a ion including
725 HIV-in ec ed women
Kaes el,20 2005 Bissau, Guinea-Bissau 2001–02 RCT 2100 P egnan women <37 weeks ges a ion
Os in,21 2005 Dhanusha and Maho a i
Dis ic s, Nepal
2002–04 RCT 1200 Single on p egnan women be ween 12–20 weeks
ges a ion
Gup a,22 2007 Eas Delhi, India 2002–03 RCT 200 P egnan women wi h BMI <18·5 kg/m², 24–32 weeks
ges a ion
Zag e,23 2007 Ma adi, Nige 2004–06 cRCT 2902 P egnan women <28 weeks ges a ion
Fawzi,25 2007 Da es Salaam, Tanzania 2001–04 RCT 8468 HIV-unin ec ed p egnan women o 12–27 weeks
ges a ion
Shanka ,26 2008 Lombok island, Indonesia 2001–04 cRCT 31 290 P egnan women (34% i s , 43% second, and 23% hi d
imes e )
Zeng,27 2008 Shaanxi P o ince, China 2002–06 cRCT 3811 P egnan women ( olic acid-only g oup excluded)
Robe oid,28 2008 Hounde heal h dis ic ,
Bu kina Faso
2004–06 RCT 1426 P egnan women
Bhu a,29 2009 Bilal colony, Ka achi, Ko Diji,
Sindh, Pakis an
2002–04 cRCT 2378 P egnan women <16 weeks ges a ion
Pe sson,30 2012 Ma lab, Bangladesh 2001–03 RCT 4436 P egnan women be ween 6–8 weeks ges a ion
Wes ,31 2014 Gaibandha and Rangpu ,
Bangladesh
2007–12 cRCT 44 567 P egnan women (79% <13 weeks ges a ion)
Asho n,32 2015 Mangochi Dis ic , Malawi 2011–13 RCT 929 P egnan women <20 weeks ges a ion (excluding
lipid-based nu ien supplemen g oup)
Adu-A a wuah,34
2015
Somanya-Kpong, Ghana 2009–11 RCT 703 P egnan women <20 weeks ges a ion (excluding
lipid-based nu ien supplemen g oup)
RCT= andomised con ol ial. cRCT=clus e andomised con ol ial.
Table 1: Cha ac e is ics o ials included in he me a-analysis
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Figu e: The e ec o mul iple
mic onu ien supplemen s
con aining i on- olic acid
compa ed wi h i on- olic
acid alone on (A) s illbi h,
(B) neona al mo ali y,
(C) in an mo ali y,
(D) low bi hweigh ,
(E) p e e m bi h, and
(F) small- o -ges a ional-age
as de ined by he Oken
s anda d,13 s a i ied by
modi ie s o in e es
A S illbi h B Neona al mo ali y C In an mo ali y
In an sex
Male
Female
Ges a ional age a en olmen
<20 weeks
≥20 weeks
Ma e nal adhe ence o egimen
<95% adhe ence
≥95% adhe ence
Ma e nal age
<20 yea s
≥20 yea s
Pa i y
Fi s bi h
Second+ bi h
Ma e nal unde weigh a en olmen
BMI <18·5 kg/m²
BMI ≥18·5 kg/m²
Ma e nal s a u e
Heigh <150 cm
Heigh ≥150 cm
Ma e nal haemoglobin a en olmen
Anaemic (haemoglobin >110 g/L)
Non-anaemic (haemoglobin ≥110 g/L)
Ma e nal educa ion
None
≥1 yea o mal educa ion
Skilled bi h a endan
Yes
No
O e all
10·5 1·50·751·25 10·5 1·50·751·25 10·5 1·50·751·25
D Low bi hweigh E P e e m bi h F Small- o -ges a ional age
In an sex
Male
Female
Ges a ional age a en olmen
<20 weeks
≥20 weeks
Ma e nal adhe ence o egimen
<95% adhe ence
≥95% adhe ence
Ma e nal age
<20 yea s
≥20 yea s
Pa i y
Fi s bi h
Second+ bi h
Ma e nal unde weigh a en olmen
BMI <18·5 kg/m²
BMI ≥18·5 kg/m²
Ma e nal s a u e
Heigh <150 cm
Heigh ≥150 cm
Ma e nal haemoglobin a en olmen
Anaemic (haemoglobin >110 g/L)
Non-anaemic (haemoglobin ≥110 g/L)
Ma e nal educa ion
None
≥1 yea o mal educa ion
O e all
Pooled ela i e isk wi h 95% CI
10·6 1·2
0·7 0·8 0·9 1·1 0·90·6 1·20·7 0·8 1·11 10·6 1·20·7 0·8 0·9 1·1
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S illbi h Neona al mo ali y (≤28 days) 6-mon h mo ali y (≤180 days) In an mo ali y (≤365 days)
n Rela i e isk
(95% CI)
p alue
he e ogenei y
n Rela i e isk
(95% CI)
p alue
he e ogenei y
n Rela i e isk
(95% CI)
p alue
he e ogenei y
n Rela i e isk
(95% CI)
p alue
he e ogenei y
O e all, ixed
e ec s
16 0·92 (0·86–0·99) ·· 12 0·98 (0·90–1·05) ·· 9 0·93 (0·85–1·00) ·· 8 0·97 (0·88–1·06) ··
O e all, andom
e ec s
16 0·97 (0·85–1·11) ·· 12 0·99 (0·89–1·09) ·· 9 0·93 (0·86–1·00) ·· 8 0·97 (0·88–1·06) ··
In an sex 16 ·· 0·88 12 ·· 0·007 9 ·· 0·06 8 ·· 0·04
Male ·· 0·92 (0·82–1·03) ·· ·· 1·06 (0·95–1·17) ·· ·· 0·98 (0·89–1·09) ·· ·· 1·05 (0·93–1·18) ··
Female ·· 0·91 (0·80–1·03) ·· ·· 0·85 (0·75–0·96) ·· ·· 0·85 (0·75–0·95) ·· ·· 0·87 (0·77–0·99) ··
Ges a ional age
a en olmen
10 0·05 10 0·60 7 0·10 7 0·57
<20 weeks .. 0·97 (0·89–1·06) .. .. 0·99 (0·90–1·09) .. .. 0·96 (0·87–1·05) .. .. 0·98 (0·89–1·07) ..
≥20 weeks ·· 0·81 (0·70–0·95) ·· ·· 0·94 (0·81–1·10) ·· ·· 0·82 (0·69–0·96) ·· ·· 0·89 (0·64–1·23) ··
Ma e nal
adhe ence o
egimen
11 0·96 9 0·05 6 0·11 5 0·02
<95%
Adhe ence
·· 0·92 (0·83–1·01) ·· ·· 1·05 (0·94–1·17) ·· ·· 0·98 (0·88–1·09) ·· ·· 1·06 (0·94–1·20) ··
≥95%
Adhe ence
·· 0·92 (0·85–0·99) .. ·· 0·88 (0·77–1·01) .. ·· 0·85 (0·74–0·97) ·· ·· 0·85 (0·74–0·97) ..
Ma e nal age 16 0·26 9 0·51 8 0·68 8 0·87
< 20 yea s ·· 0·99 (0·85–1·16) ·· ·· 0·95 (0·83–1·10) ·· ·· 0·96 (0·84–1·09) ·· ·· 0·98 (0·86–1·13) ··
≥ 20 yea s ·· 0·90 (0·83–0·97) ·· ·· 1·01 (0·92–1·12) ·· ·· 0·92 (0·84–1·02) ·· ·· 0·97 (0·87–1·09) ··
Pa i y 15 0·06 12 0·26 9 0·76 8 0·87
Fi s bi h ·· 1·01 (0·90–1·14) ·· ·· 0·93 (0·83–1·04) ·· ·· 0·94 (0·84–1·04) ·· ·· 0·97 (0·85–1·10) ··
≥ Second
bi h
·· 0·88 (0·80–0·96) ·· ·· 1·02 (0·91–1·14) ·· ·· 0·92 (0·82–1·02) ·· ·· 0·96 (0·85–1·08) ··
Ma e nal BMI
a en olmen
12 0·53 11 0·61 8 0·60 7 0·95
<18·5 kg/m² ·· 0·90 (0·78–1·04) ·· ·· 1·01 (0·86–1·20) ·· ·· 0·96 (0·83–1·12) ·· ·· 0·97 (0·84–1·13) ··
≥18·5 kg/m² ·· 0·95 (0·87–1·04) ·· ·· 0·96 (0·88–1·06) ·· ·· 0·92 (0·84–1·01) ·· ·· 0·98 (0·88–1·09) ··
Ma e nal heigh 14 0·38 10 0·98 7 0·84 6 0·58
<150 cm ·· 0·96 (0·86–1·08) ·· ·· 0·97 (0·86–1·08) ·· ·· 0·92 (0·83–1·02) ·· ·· 0·98 (0·87–1·11) ··
≥150 cm ·· 0·90 (0·81–1·00) ·· ·· 0·96 (0·86–1·08) ·· ·· 0·91 (0·81–1·02) ·· ·· 0·93 (0·81–1·06) ··
Ma e nal
haemoglobin a
en olmen
13 0·16 10 0·54 8 0·04 7 0·95
Anaemic
(haemoglobin
<110 g/L)
·· 0·79 (0·66–0·94) ·· ·· 0·87 (0·73–1·03) ·· ·· 0·71 (0·60–0·86) ·· ·· 1·00 (0·73–1·30) ··
Non-anaemic
(haemoglobin
≥110 g/L)
·· 0·94 (0·79–1·12) ·· ·· 0·94 (0·79–1·11) ·· ·· 0·93 (0·78–1·11) ·· ·· 1·01 (0·79–1·30) ··
Ma e nal
educa ion
14 0·62 12 0·02 8 0·22 7 0·24
None ·· 0·95 (0·83–1·09) ·· ·· 1·13 (0·97–1·31) ·· ·· 0·99 (0·86–1·13) ·· ·· 1·02 (0·88–1·18) ··
≥1 yea
o mal
educa ion
·· 0·91 (0·84–1·00) ·· ·· 0·92 (0·83–1·01) ·· ·· 0·89 (0·81–0·98) ·· ·· 0·92 (0·82–1·02) ··
Skilled bi h
a endan
10 0·09 10 0·23 7 0·01 6 0·006
Yes ·· 0·87 (0·78–0·97) ·· ·· 1·00 (0·91–1·11) ·· ·· 1·00 (0·90–1·11) ·· ·· 1·06 (0·95–1·20) ··
No ·· 1·01 (0·88–1·15) ·· ·· 0·91 (0·80–1·03) ·· ·· 0·82 (0·74–0·92) ·· ·· 0·82 (0·71–0·95) ··
n=numbe o s udies included in subg oup analysis.
Table 2: The e ec o ma e nal mul iple mic onu ien supplemen s on s illbi h, neona al mo ali y, mo ali y o 6 mon hs, and in an mo ali y, s a i ied by po en ial e ec
modi ie s
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bi hweigh , low bi hweigh , ea ly p e e m, p e e m, and
small- o -ges a ional-age bi hs (Oken o In e g ow h
s anda ds; able 3 and appendix p 80, p 122). We also ound
mul iple mic onu ien supplemen s signi ican ly
inc eased he isk o being bo n la ge- o -ges a ional-age
by he In e g ow h s anda d (RR 1·11, 95% CI 1·04–1·19;
appendix p 150). The e was no e idence ha in an sex
modi ied he e ec o mul iple mic onu ien supplemen s
Low bi hweigh (<2500 g) P e e m (<37 weeks) Small- o -ges a ional-age* La ge- o -ges a ional-age*
n Rela i e isk (95%
CI)
p alue
he e ogenei y
n Rela i e isk
(95% CI)
p alue
he e ogenei y
n Rela i e isk
(95% CI)
p alue
he e ogenei y
n Rela i e isk
(95% CI)
p alue
he e ogenei y
O e all, ixed
e ec s
17 0·88 (0·85–0·90) ·· 16 0·92 (0·88–0·95) ·· 16 0·97 (0·96–0·99) ·· 13 1·05 (0·95–1·15) ··
O e all, andom
e ec s
17 0·86 (0·81–0·92) ·· 16 0·93 (0·87–0·98) ·· 16 0·94 (0·90–0·98) ·· 13 1·04 (0·92–1·18) ··
In an sex 17 ·· 0·48 15 ·· 0·63 15 ·· 0·62 12 ·· 0·18
Male ·· 0·87 (0·83–0·91) ·· ·· 0·93 (0·88–0·97) ·· ·· 0·97 (0·95–1·00) ·· ·· 1·11 (0·98–1·25) ··
Female ·· 0·89 (0·86–0·92) ·· ·· 0·91 (0·86–0·96) ·· ·· 0·98 (0·96–1·01) ·· ·· 0·98 (0·86–1·12) ··
Ges a ional age
a en olmen
13 0·32 11 0·03 12 0·004 8 0·09
<20 weeks ·· 0·88 (0·86–0·91) ·· ·· 0·89 (0·85–0·93) ·· ·· 0·99 (0·97–1·01) ·· ·· 0·99 (0·86–1·13) ··
≥20 weeks ·· 0·84 (0·77–0·92) ·· ·· 1·00 (0·94–1·08) ·· ·· 0·91 (0·86–0·96) ·· ·· 1·18 (1·02–1·37) ··
Ma e nal
adhe ence o
egimen
12 0·61 10 0·62 11 0·43 8 0·88
<95%
Adhe ence
·· 0·89 (0·85–0·92) ·· ·· 0·93 (0·88–0·97) ·· ·· 0·98 (0·96–1·01) ·· ·· 1·03 (0·90–1·18) ··
≥95%
Adhe ence
·· 0·87 (0·84–0·91) ·· ·· 0·90 (0·85–0·96) ·· ·· 0·97 (0·94–1·00) ·· ·· 1·05 (0·90–1·22) ··
Ma e nal age 15 0·85 15 0·82 16 0·70 11 0·51
<20 yea s ·· 0·90 (0·86–0·93) ·· ·· 0·92 (0·87–0·98) ·· ·· 0·98 (0·95–1·00) ·· ·· 0·98 (0·79–1·22) ··
≥20 yea s ·· 0·90 (0·88–0·92) ·· ·· 0·92 (0·88–0·96) ·· ·· 0·97 (0·94–0·99) ·· ·· 1·06 (0·96–1·18) ··
Pa i y 16 0·88 14 0·63 15 0·94 10 0·09
Fi s bi h ·· 0·88 (0·85–0·92) ·· ·· 0·91 (0·86–0·96) ·· ·· 0·98 (0·95–1·00) ·· ·· 0·94 (0·78–1·12) ··
≥ Second
bi h
·· 0·88 (0·85–0·92) ·· ·· 0·92 (0·88–0·97) ·· ·· 0·97 (0·95–1·00) ·· ·· 1·12 (1·00–1·25) ··
Ma e nal BMI a
en olmen
16 0·80 13 0·01 16 0·20 8 0·045
<18·5 kg/m2·· 0·88 (0·84–0·91) ·· ·· 0·84 (0·78–0·91) ·· ·· 1·00 (0·96–1·03) ·· ·· 0·77 (0·57–1·05) ··
≥18·5 kg/m2·· 0·88 (0·85–0·92) ·· ·· 0·94 (0·90–0·98) ·· ·· 0·97 (0·95–0·99) ·· ·· 1·08 (0·97–1·21) ··
Ma e nal heigh 16 0·16 15 0·58 16 0·27 10 0·17
<150 cm ·· 0·90 (0·87–0·93) ·· ·· 0·91 (0·86–0·96) ·· ·· 0·99 (0·96–1·01) ·· ·· 0·93 (0·78–1·12) ··
≥150 cm ·· 0·86 (0·82–0·90) ·· ·· 0·92 (0·88–0·97) ·· ·· 0·97 (0·96–0·99) ·· ·· 1·09 (0·97–1·22) ··
Ma e nal
hemoglobin a
en olmen
14 0·049 12 0·05 13 0·03 9 0·09
Anaemic
(haemoglobin
<110 g/L)
·· 0·81 (0·74–0·89) ·· ·· 0·98 (0·91–1·05) ·· ·· 0·92 (0·87–0·97) ·· ·· 1·25 (1·06–1·49) ··
Non-anaemic
(haemoglobin
≥110 g/L)
·· 0·91 (0·85–0·98) ·· ·· 0·88 (0·81–0·95) ·· ·· 0·99 (0·95–1·03) ·· ·· 0·99 (0·80–1·22) ··
Ma e nal
educa ion
16 0·75 14 0·64 15 0·049 9 0·75
None ·· 0·88 (0·84–0·93) ·· ·· 0·92 (0·87–0·98) ·· ·· 1·00 (0·97–1·03) ·· ·· 1·07 (0·88–1·29) ··
≥1 yea
o mal
educa ion
·· 0·87 (0·84–0·91) ·· ·· 0·90 (0·87–0·95) ·· ·· 0·96 (0·94–0·98) ·· ·· 1·03 (0·92–1·16) ··
n=numbe o s udies included in subg oup analysis. *As de ined by he Oken s anda d.13
Table 3: The e ec o ma e nal mul iple mic onu ien supplemen s on low bi hweigh , p e e m bi h, small- o -ges a ional-age bi h, and la ge- o -ges a ional-age bi h, s a i ied by
po en ial e ec modi ie s
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on low bi hweigh , p ema u i y, o small- o -ges a ional-
age bi hs. Mul iple mic onu ien supplemen s had a
g ea e e ec on educing he isk o low bi hweigh
(RR 0·81; 95% CI 0·74–0·89) and small- o -ges a ional-age
by Oken s anda d (0·92, 0·87–0·97) in anaemic p egnan
women e sus non-anaemic p egnan women (p alues
o he e ogenei y 0·049 and 0·03, espec i ely; able 3).
Ma e nal BMI modi ied he e ec o mul iple mic onu ien
supplemen s on se e al bi h ou comes. Mul iple
mic onu ien supplemen s educed he isk o being bo n
ea ly p e e m and p e e m wi h g ea e magni ude among
p egnan women wi h a BMI lowe han 18·5 kg/m²
compa ed wi h non-unde weigh p egnan women
( able 3, appendix p 86). Ma e nal BMI also modi ied he
isk o ha ing a la ge- o -ges a ional-age bi h based on he
Oken s anda d (p alue o he e ogenei y 0·045); wi h non-
unde weigh women (BMI ≥18·5 kg/m²) ha ing a g ea e
inc ease in isk o la ge- o -ges a ional-age bi h ( able 4).
Ges a ional age a mul iple mic onu ien supplemen s
ini ia ion modi ied he e ec o supplemen a ion. Women
ini ia ing mul iple mic onu ien supplemen s be o e
20 weeks ges a ion had g ea e educ ions in he isk o
p e e m bi h (RR 0·89, 95% CI 0·85–0·93; p alue o
he e ogenei y 0·03; able 3). Howe e , mul iple
mic onu ien supplemen s p o ided g ea e educ ions
in he isk o small- o -ges a ional-age bi h in women
ini ia ing supplemen a ion a e 20 weeks (RR 0·91,
95% CI 0·86–0·96; p alue he e ogenei y 0·004; able 3).
Mul iple mic onu ien supplemen s ini ia ion be o e o
a e 20 weeks ges a ion con e ed simila bene i s in
educing he isk o low bi hweigh ( able 3).
As a sensi i i y analysis, we s a i ied s udies by whe he
o no hey used he same dose o i on in he mul iple
mic onu ien supplemen s and i on- olic acid g oups.
The appendix p o ides o e all es ima es (appendix p 208)
and subg oup es ima es (appendix pp 209–217) o he
e ec o mul iple mic onu ien supplemen s o ials
using he same dose o i on in he mul iple mic onu ien
supplemen s and i on- olic acid alone g oups e sus ials
using a lowe dose i on in he mul iple mic onu ien
supplemen s g oup han he i on- olic acid alone g oup
(all used ≤30 mg i on o mul iple mic onu ien
supplemen s and 60 mg i on o i on- olic acid alone).
Among ials using he same dose o i on in bo h g oups,
he bene i s o mul iple mic onu ien supplemen s we e
consis en wi h he p ima y analysis. By con as , some
subg oups gi en mul iple mic onu ien supplemen s
wi h low dose i on (≤30 mg) had highe s illbi h and
neona al mo ali y han i on- olic acid alone wi h 60 mg
i on. Speci ically, mul iple mic onu ien supplemen s
con aining a lowe dose o i on han he i on- olic acid
compa ison g oup we e associa ed wi h an inc eased
s illbi h a e among i s p egnancies, ea ly neona al
mo ali y in women who ini ia ed supplemen a ion
be o e 20 weeks ges a ion, ea ly neona al and neona al
mo ali y in women wi h <95% adhe ence, and ea ly
neona al mo ali y o mul ig a idae.
Discussion
Ou indings show ha p egnan women who ake
an ena al mul iple mic onu ien supplemen s including
i on- olic acid ha e a lowe isk o ha ing a baby wi h low
bi hweigh , a p e e m bi h, o ha ing a small- o -
ges a ional-age baby. Fu he mo e, we iden i ied se e al
ac o s ha modi ied he e ec o mul iple mic onu ien
supplemen s on in an su i al and bi h ou comes.
The e ec o mul iple mic onu ien supplemen s on
su i al was modi ied by in an sex. Mul iple mic o-
nu ien supplemen s consis en ly educed mo ali y by
abou 15% in emales du ing he i s yea o li e, bu we
did no eco d signi ican bene i s in males. The
biological mechanisms leading o hese sex di e ences
a e no clea . Wes and colleagues31 and Lee and
colleagues36 ha e p e iously p oposed ha sex di e ences
in he mo ali y e ec o mul iple mic onu ien
supplemen s could be explained by di e ences in bi h
size by sex. Males ha e g ea e leng h, head
ci cum e ence, and bi hweigh on a e age han emales,
and inc eased bi h size due o mul iple mic onu ien
supplemen s migh lead o g ea e bi h complica ions in
males.37 Howe e , we no ed no sex di e ences in he
e ec o mul iple mic onu ien supplemen s on
s illbi h, which sugges s ha e ec modi ica ion by sex
migh ope a e h ough o he mechanisms o a y wi h
he popula ion con ex . The bu den o in ec ions and
leading causes o mo ali y ha e been shown o a y by
in an sex;38,39 addi ional in o ma ion abou he causes
and iming o dea hs wi hin ials migh help cla i y why
mul iple mic onu ien supplemen s seem o be mo e
bene icial o emale in an s. Ne e heless, we do no
ecommend p og ammes conside ing implemen a ion
o mul iple mic onu ien supplemen s a ge only
p egnan women ca ying emale e uses as bo h male
and emale neona es expe ience bi hweigh bene i s and
small posi i e su i al bene i s a e possible in males.
Mul iple mic onu ien supplemen s had a bigge e ec
on bi h ou comes in women wi h poo nu i ional s a us,
as indica ed by anaemia o low BMI, a he s a o
supplemen a ion, as ini ially epo ed in he SUMMIT
s udy.26 Anaemic women had g ea e educ ions in he
isk o low bi hweigh , small- o -ges a ional-age bi h,
and mo ali y o 6 mon hs han non-anaemic p egnan
women. The e ec o mul iple mic onu ien supplemen s
on p e e m bi h was also g ea e o p egnan women
who had a BMI o lowe han 18·5 kg/m² a he s a o
supplemen a ion. These indings sugges ha i on- olic
acid alone is likely an insu icien in e en ion o
anaemic p egnan women and jus i ies con inued ocus
on anaemia and low BMI as key e ec modi ie s o
nu i ion in e en ions in p egnancy. A ecen mul iple
mic onu ien supplemen s ial34 done in China among
non-anaemic and mildly anaemic women (no included
in ou me a-analysis) ound no e ec o mul iple
mic onu ien supplemen s on pe ina al mo ali y and a
non-signi ican 10% educ ion in low bi hweigh . These
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indings a e consis en wi h ou non-anaemic subg oup
esul s, which showed no e ec o mul iple mic onu ien
supplemen s on ea ly neona al, neona al, o in an
mo ali y and an 8% educ ion in low bi hweigh .
Due o he clus e ing o p o ein-ene gy and
mic onu ien de iciencies, we canno di ec ly examine
whe he imp o emen in ma e nal haemoglobin s a us
media ed a g ea e e ec o mul iple mic onu ien
supplemen s on low bi hweigh in anaemic women.
Anaemia migh be a p oxy o de iciencies o
mic onu ien s included in mul iple mic onu ien
supplemen s, as well as nume ous o he ac o s including
ma e nal in ec ion.40,41 Findings o a p e ious me a-
analysis showed ha mul iple mic onu ien supplemen s
(which included i on) had a simila e ec on haemoglobin
and anaemia han i on alone o i on wi h olic acid.42
No ably, some ials included in ou me a-analysis and he
anaemia me a-analysis used highe dose i on in he
con ol g oup han he mul iple mic onu ien supple-
men s a m, which migh ha e a enua ed he
haemoglobin, mo ali y, and bi h ou come e ec s o
mul iple mic onu ien supplemen s, pa icula ly in
anaemic p egnan women.20,21,27–29,32,33,35,42 Despi e his, we
s ill ind a la ge e ec o mul iple mic onu ien
supplemen s among anaemic han o non-anaemic
p egnan women. The e a e se e al haemoglobin
independen pa hways by which mul iple mic onu ien
supplemen s migh imp o e bi h ou comes,5 including
educ ions in ma e nal and e al in lamma ion,43
imp o emen s in oxida i e me abolism and placen al
unc ion,44,45 and al e ed ma e nal endoc ine e ec s.46
Al hough he biological mechanisms h ough which
mul iple mic onu ien supplemen s p o ides bene i s a e
unclea , ou me a-analysis indica es ha he popula ion-
le el bene i s o bi h ou comes a e likely o be g ea e in
se ings wi h high a es o ma e nal nu i ional
de iciencies. I is also impo an o no e ha in he
MINIMa ial women who ecei ed bo h ea ly ood
supplemen a ion and mul iple mic onu ien supple-
men s had he lowes a e o in an mo ali y;30 combined
mac onu ien and mic onu ien in e en ions migh
p oduce e en g ea e e ec s in se ings wi h high a es o
ma e nal malnu i ion.
We did no iden i y any subg oup ha expe ienced
signi ican ly ele a ed isk o s illbi h o mo ali y a any
imepoin in he p ima y analysis. Mul iple mic onu ien
supplemen s ial epo s ha e aised conce ns ha
inc eased bi h size due o mul iple mic onu ien
supplemen s may inc ease he isk o cephalopel ic
disp opo ion and neona al asphyxia, pa icula ly among
women o small s a u e.17,31 We ound ha mul iple
mic onu ien supplemen s indeed inc eased he isk o
la ge- o -ges a ional-age bi hs (as de ined by he
In e g ow h s anda d14), which could hypo he ically
inc ease he isk o ma e nal- e al disp opo ion and
ela ed bi h complica ions. Howe e , we ound no
indica ion ha mo he s who ook mul iple mic onu ien
supplemen s and whose heigh was less han 150 cm had
inc eased isk o s illbi h o mo ali y a any imepoin .
As such, al e na i e in e p e a ions o mechanisms o
explain no o e all e ec o mul iple mic onu ien
supplemen s on mo ali y should be explo ed.
We also p o ide e idence ha i on dosage in luences
he obse ed e ec o mul iple mic onu ien
supplemen s on s illbi h and mo ali y. Speci ically, he
sensi i i y analyses e ealed bene i s and no signi ican
ha m ul e ec s o e all o in any subg oup among ials
ha used he same dose o i on in he mul iple
mic onu ien supplemen s and i on- olic acid alone
a ms. By con as , he sensi i i y analyses also ound ha
mul iple mic onu ien supplemen s wi h low dose i on
(<30 mg) esul s in a highe obse ed s illbi h and
mo ali y in some subg oups when compa ed o i on-
olic acid alone wi h 60 mg i on. The mos ecen
Coch ane Re iew ound simila e ec modi ica ion by
i on dose on pe ina al mo ali y.6 Fu he mo e, he WHO
an ena al ca e guidelines no ed he po en ial o ha m ul
e ec s o mul iple mic onu ien supplemen s on
neona al mo ali y among a subg oup analysis in which
5 ou o 6 ials used low dose i on (≤30 mg) in he
mul iple mic onu ien supplemen s g oup and 60 mg
i on in he i on- olic acid alone g oup.10 Taken oge he
wi h p e ious analyses, ou da a sugges ha bo h i on
and mul iple mic onu ien s ha e bene icial e ec s and
ha mul iple mic onu ien s oge he wi h i on- olic acid
p o ide e en g ea e bene i s han i on- olic acid alone.
Acco dingly, coun ies and p og ammes conside ing
implemen a ion o mul iple mic onu ien supplemen s
should use a o mula ion wi h an i on dose simila o
wha hey cu en ly use; o example, mul iple
mic onu ien supplemen s ha con ains 60 mg i on
should be conside ed in se ings whe e 60 mg i on- olic
acid is cu en ly implemen ed.
No wi hs anding he la ge sample size and consis ency
o ou indings, he e a e se e al limi a ions o ou me a-
analysis. Fi s , because o he numbe o subg oup
analyses we did, he e is an inc eased isk o ype 1 e o s
inhe en o he numbe o he e ogenei y es s p esen ed.
Howe e , ou indings as a whole exceed hose ha
would be expec ed by chance; 13 o 70 es s o
he e ogenei y o mo ali y ou comes we e signi ican
(p obabili y o occu ing by chance alone <0·01%).
The e is also low p obabili y o inding 26 o
146 subg oups had signi ican su i al bene i s (<0·01%)
and ha no subg oups had inc eased mo ali y isk
(2·5%) i we cons uc a hypo hesis assuming he e was
no ue e ec o mul iple mic onu ien supplemen s on
mo ali y in any subg oup. Second, as p e iously
discussed, some ials used a highe dose o i on in he
con ol g oup as compa ed wi h he mul iple
mic onu ien supplemen s g oup, and ou sensi i i y
analysis sugges s ha inclusion o hese ials esul ed
in a enua ion o he e ec o mul iple mic onu ien
supplemen a ion because he i on- olic acid alone g oup