TY - JOUR

T1 - Modifiers of the effect of maternal multiple micronutrient supplementation on stillbirth, birth outcomes, and infant mortality

T2 - a meta-analysis of individual patient data from 17 randomised trials in low-income and middle-income countries

AU - Smith, Emily R

AU - Shankar, Anuraj H

AU - Wu, Lee S-F

AU - Aboud, Said

AU - Adu-Afarwuah, Seth

AU - Ali, Hasmot

AU - Agustina, Rina

AU - Arifeen, Shams

AU - Ashorn, Per

AU - Bhutta, Zulfiqar A

AU - Christian, Parul

AU - Devakumar, Delanjathan

AU - Dewey, Kathryn G

AU - Friis, Henrik

AU - Gomo, Exnevia

AU - Gupta, Piyush

AU - Kæstel, Pernille

AU - Kolsteren, Patrick

AU - Lanou, Hermann

AU - Maleta, Kenneth

AU - Mamadoultaibou, Aissa

AU - Msamanga, Gernard

AU - Osrin, David

AU - Persson, Lars-Åke

AU - Ramakrishnan, Usha

AU - Rivera, Juan A

AU - Rizvi, Arjumand

AU - Sachdev, H P S

AU - Urassa, Willy

AU - West, Keith P

AU - Zagre, Noel

AU - Zeng, Lingxia

AU - Zhu, Zhonghai

AU - Fawzi, Wafaie W

AU - Sudfeld, Christopher R

N1 - CURIS 2017 NEXS 272

PY - 2017

Y1 - 2017

N2 - BACKGROUND: Micronutrient deficiencies are common among women in low-income and middle-income countries. Data from randomised trials suggest that maternal multiple micronutrient supplementation decreases the risk of low birthweight and potentially improves other infant health outcomes. However, heterogeneity across studies suggests influence from effect modifiers. We aimed to identify individual-level modifiers of the effect of multiple micronutrient supplements on stillbirth, birth outcomes, and infant mortality in low-income and middle-income countries.METHODS: This two-stage meta-analysis of individual patient included data from 17 randomised controlled trials done in 14 low-income and middle-income countries, which compared multiple micronutrient supplements containing iron-folic acid versus iron-folic acid alone in 112 953 pregnant women. We generated study-specific estimates and pooled subgroup estimates using fixed-effects models and assessed heterogeneity between subgroups with the χ(2) test for heterogeneity. We did sensitivity analyses using random-effects models, stratifying by iron-folic acid dose, and exploring individual study effect.FINDINGS: Multiple micronutrient supplements containing iron-folic acid provided significantly greater reductions in neonatal mortality for female neonates compared with male neonates than did iron-folic acid supplementation alone (RR 0·85, 95% CI 0·75-0·96 vs 1·06, 0·95-1·17; p value for interaction 0·007). Multiple micronutrient supplements resulted in greater reductions in low birthweight (RR 0·81, 95% CI 0·74-0·89; p value for interaction 0·049), small-for-gestational-age births (0·92, 0·87-0·97; p=0·03), and 6-month mortality (0·71, 0·60-0·86; p=0·04) in anaemic pregnant women (haemoglobin <110g/L) as compared with non-anaemic pregnant women. Multiple micronutrient supplements also had a greater effect on preterm births among underweight pregnant women (BMI <18·5 kg/m(2); RR 0·84, 95% CI 0·78-0·91; p=0·01). Initiation of multiple micronutrient supplements before 20 weeks gestation provided greater reductions in preterm birth (RR 0·89, 95% CI 0·85-0·93; p=0·03). Generally, the survival and birth outcome effects of multiple micronutrient supplementation were greater with high adherence (≥95%) to supplementation. Multiple micronutrient supplements did not significantly increase the risk of stillbirth or neonatal, 6-month, or infant mortality, neither overall or in any of the 26 examined subgroups.INTERPRETATION: Antenatal multiple micronutrient supplements improved survival for female neonates and provided greater birth-outcome benefits for infants born to undernourished and anaemic pregnant women. Early initiation in pregnancy and high adherence to multiple micronutrient supplements also provided greater overall benefits. Studies should now aim to elucidate the mechanisms accounting for differences in the effect of antenatal multiple micronutrient supplements on infant health by maternal nutrition status and sex.FUNDING: None.

AB - BACKGROUND: Micronutrient deficiencies are common among women in low-income and middle-income countries. Data from randomised trials suggest that maternal multiple micronutrient supplementation decreases the risk of low birthweight and potentially improves other infant health outcomes. However, heterogeneity across studies suggests influence from effect modifiers. We aimed to identify individual-level modifiers of the effect of multiple micronutrient supplements on stillbirth, birth outcomes, and infant mortality in low-income and middle-income countries.METHODS: This two-stage meta-analysis of individual patient included data from 17 randomised controlled trials done in 14 low-income and middle-income countries, which compared multiple micronutrient supplements containing iron-folic acid versus iron-folic acid alone in 112 953 pregnant women. We generated study-specific estimates and pooled subgroup estimates using fixed-effects models and assessed heterogeneity between subgroups with the χ(2) test for heterogeneity. We did sensitivity analyses using random-effects models, stratifying by iron-folic acid dose, and exploring individual study effect.FINDINGS: Multiple micronutrient supplements containing iron-folic acid provided significantly greater reductions in neonatal mortality for female neonates compared with male neonates than did iron-folic acid supplementation alone (RR 0·85, 95% CI 0·75-0·96 vs 1·06, 0·95-1·17; p value for interaction 0·007). Multiple micronutrient supplements resulted in greater reductions in low birthweight (RR 0·81, 95% CI 0·74-0·89; p value for interaction 0·049), small-for-gestational-age births (0·92, 0·87-0·97; p=0·03), and 6-month mortality (0·71, 0·60-0·86; p=0·04) in anaemic pregnant women (haemoglobin <110g/L) as compared with non-anaemic pregnant women. Multiple micronutrient supplements also had a greater effect on preterm births among underweight pregnant women (BMI <18·5 kg/m(2); RR 0·84, 95% CI 0·78-0·91; p=0·01). Initiation of multiple micronutrient supplements before 20 weeks gestation provided greater reductions in preterm birth (RR 0·89, 95% CI 0·85-0·93; p=0·03). Generally, the survival and birth outcome effects of multiple micronutrient supplementation were greater with high adherence (≥95%) to supplementation. Multiple micronutrient supplements did not significantly increase the risk of stillbirth or neonatal, 6-month, or infant mortality, neither overall or in any of the 26 examined subgroups.INTERPRETATION: Antenatal multiple micronutrient supplements improved survival for female neonates and provided greater birth-outcome benefits for infants born to undernourished and anaemic pregnant women. Early initiation in pregnancy and high adherence to multiple micronutrient supplements also provided greater overall benefits. Studies should now aim to elucidate the mechanisms accounting for differences in the effect of antenatal multiple micronutrient supplements on infant health by maternal nutrition status and sex.FUNDING: None.

KW - Journal Article

U2 - 10.1016/S2214-109X(17)30371-6

DO - 10.1016/S2214-109X(17)30371-6

M3 - Journal article

C2 - 29025632

VL - 5

SP - e1090-e1100

JO - The Lancet Global Health

JF - The Lancet Global Health

SN - 2214-109X

IS - 11

ER -