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

Abstract

Micro nutrient deficiencies are common among women in low-income and middle-income countries.Data from randomized trials suggest that maternal multiple micro nutrient supplementation decreases the risk of low birth weight 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 micro nutrient supplements on stillbirth, birth outcomes, and infant mortality in low-income and middle-income countries.This two-stage meta-analysis of individual patient included data from 17 randomized controlled trials done in 14 low-income and middle-income countries, which compared multiple micro nutrient 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 χ² test for heterogeneity. We did sensitivity analyses using random-effects models, stratifying by iron-folic acid dose, and exploring individual study effect.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 micro nutrient supplements resulted in greater reductions in low birth weight (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-anemic pregnant women. Multiple micro nutrient supplements also had a greater effect on preterm births among underweight pregnant women (BMI <18·5 kg/m²; RR 0·84, 95% CI 0·78–0·91; p=0·01). Initiation of multiple micro nutrient 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 micro nutrient supplementation were greater with high adherence (≥95%) to supplementation. Multiple micro nutrient 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. Antenatal multiple micro nutrient 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 micro nutrient supplements also provided greater overall benefits. Studies should now aim to elucidate the mechanisms accounting for differences in the effect of antenatal multiple micro nutrient supplements on infant health by maternal nutrition status and sex.