1. Objectives

To evaluate the effects of oral multiple-micronutrient supplementation during pregnancy on maternal, fetal and infant outcomes

2. How studies were identified

The following databases were searched in March 2015:

• Cochrane Pregnancy and Childbirth Group’s Trials Register

Reference lists were also searched and the authors directly contacted experts in the field.

3. Criteria for including studies in the review

3.1 Study type

Randomized controlled trials, including cluster-randomized trials

3.2 Study participants

Pregnant women at any stage of gestation at enrolment

(Studies that exclusively enrolled women with HIV or women at high risk of nutritional disorders for other reasons were excluded, and disaggregated data were used when studies included subgroups of such women)

3.3 Interventions

Oral multiple-micronutrient supplementation containing three micronutrients or more for any duration, compared to placebo, no supplementation or supplementation with two or less micronutrients

3.4 Primary outcomes

• Preterm birth (<37 weeks’ gestation)
• Small-for-gestational age
• Low birth weight (<2500 g)
• Perinatal mortality
• Stillbirths
• Neonatal mortality

3.5 Secondary outcomes

Secondary outcomes included maternal anaemia (third trimester haemoglobin < 110 g/L), maternal mortality, miscarriage (pregnancy loss before 28 weeks’ gestation), premature rupture of membranes, pre-eclampsia, mode of delivery: Caesarean section (post hoc outcome), macrosomia (post hoc outcome), placental abruption, very preterm birth (< 34 weeks’ gestation), neurodevelopmental delay (assessed using the Bayley Scale of Infant Development), nutritional status of children (stunting, wasting and underweight), cost of supplementation, side-effects, congenital anomalies (including neural tube defects), and maternal well-being or satisfaction

4. Main results

4.1 Included studies

Seventeen randomized controlled trials, enrolling 137,791 pregnant women, were included in this review.

• Seven of the trials were cluster-randomized; two further studies met inclusion criteria but did not contribute data to analyses
• Stage of gestation at enrolment ranged from early pregnancy to 36 weeks’ gestation, with supplementation being initiated at enrolment or soon thereafter.
• Supplementation ceased at delivery in ten trials and was continued up to 12 weeks after delivery in the remaining trials
• Fourteen trials compared multiple-micronutrient supplementation to supplementation with up to two micronutrients, and three trials assessed multiple-micronutrient supplements versus a placebo
• All trials used supplements of different composition; however, 14 studies included folic acid and iron in the supplement

4.2 Study settings

• Bangladesh (2 studies), Burkina Faso, China (2 studies), France, Guinea-Bissau, India, Indonesia (2 studies), Mexico, Nepal (2 studies), Niger, Pakistan, Tanzania, the United Kingdom (2 studies), and Zimbabwe
• Three of the 17 studies contributing data to the review were conducted in developed countries, of which one was conducted in a socially-deprived, multi-ethnic population in east London
• Studies were conducted in both rural and urban areas

4.3 Effect of interventions on outcomes

4.3.1 How the data were analysed

Two comparisons were made: i) multiple-micronutrient supplements with iron and folic acid versus iron with or without folic acid, and ii) multiple-micronutrient supplements versus placebo, no supplements, or supplements containing one or two micronutrients. Dichotomous data were summarized using risk ratios (RR) with corresponding 95% confidence intervals (CI), and for continuous data mean differences (MD) and 95% CI were generated. Data from cluster-randomized trials were adjusted for clustering. When substantial heterogeneity was detected, results were assessed using subgroup and sensitivity analyses, and where an overall summary was deemed meaningful, a random-effects model was used. In sensitivity analyses, trials judged to be of poor quality with regard to concealment of allocation or rate of attrition were excluded.

Subgroup analysis was conducted as follows:

• By timing of supplementation: before versus after 20 weeks’ gestation
• By dose of iron in the multiple-micronutrient supplement: 30 mg versus 60 mg
• By baseline nutritional status of the mother: body mass index (BMI) <20 kg/m2 versus ≥20 kg/m2, and height <154.9 cm versus ≥154.9 cm

4.3.2 Summary of effects

Multiple-micronutrient supplements with iron and folic acid versus iron, with or without folic acid
Primary outcomes
Women receiving multiple-micronutrient supplements with iron and folic acid had a 10% reduction in risk of delivering small-for-gestational age babies relative to those receiving iron alone, with or without folic acid (RR 0.90, 95% CI [0.83 to 0.97], p=0.0037; 14 trials). In addition, multiple-micronutrient treatment reduced the risk of low birth weight (RR 0.88, 95% CI [0.85 to 0.91], p<0.00001; 15 trials) and stillbirth (RR 0.91, 95% CI [0.85 to 0.98], p=0.012; 15 trials). For other primary outcomes, no differences between treatment and control groups were detected (preterm birth: RR 0.96, 95% CI [0.89 to 1.03], p=0.23, 15 trials; perinatal mortality RR 0.97, 95% CI [0.84 to 1.12], p=0.70, 12 studies; neonatal mortality: RR 0.98, 95% CI [0.90 to 1.07], p=0.66; 11 trials).

Additional subgroup analysis of primary outcomes
Substantial heterogeneity was detected in the analyses for preterm birth, small-for-gestational age, and perinatal mortality. While multiple-micronutrient supplementation reduced the number of preterm births among women with a mean maternal BMI of <20 kg/m2 (RR 0.85, 95% CI [0.80 to 0.90], 4 trials), there was no effect among women with a BMI ≥20 kg/m2 (RR 1.01, 95% CI [0.96 to 1.07], 11 studies; p<0.00001 for subgroup differences). The opposite was found for small-for-gestational age, where women with a mean maternal BMI ≥20 kg/m2 receiving multiple-micronutrient treatment were at a significantly reduced risk (RR 0.85, 95% CI [0.79 to 0.91], 10 studies), while women with a mean maternal BMI <20 kg/m2 were not (RR 0.99, 95% CI [0.97 to 1.01], 4 studies; p<0.01 for subgroup differences). Maternal height also affected the treatment effect for small-for-gestational age, with women ≥154.9 cm having a statistically significant 18% reduction in risk versus those <154.9 cm having no reduction in risk (RR 0.82, 95% CI [0.76 to 0.89], 6 trials; versus RR 0.99, 95% CI [0.97 to 1.01], 8 trials; p<0.01 for subgroup differences). The effect size was greatest for small-for-gestational age in studies comparing multiple-micronutrient supplements containing 30 mg of iron to a control of 60 mg of iron (RR 0.85, 95% CI [0.76 to 0.96]; 6 studies), while it was non-significant when the amount of iron (30 mg or 60 mg) was identical in multiple-micronutrient and control groups (p<0.02 for subgroup differences). No other analyses showed evidence of a significant difference between subgroups, and sensitivity analyses did not show any meaningful differences in effects.

Secondary outcomes
No statistically significant differences were observed between those receiving multiple-micronutrients and those receiving iron with or without folic acid for maternal anaemia in the third trimester (RR 0.97, 95% CI [0.86 to 1.10], p=0.66; 5 trials), miscarriages (RR 0.89, 95% CI [0.78 to 1.01], p=0.063; 8 studies), Caesarean section delivery (RR 1.03, 95% CI [0.75 to 1.43], p=0.85; 4 trials), or maternal mortality (RR 0.97, 95% CI [0.63 to 1.48]; 3 trials). No other pre-specified secondary analysed could be assessed in pooled analysis due to insufficient data.

Multiple-micronutrient supplements versus placebo, no supplements, or supplements containing one or two micronutrients
In one trial of multiple-micronutrient supplements versus placebo, no statistically significant difference in the risk of pre-eclampsia was observed between treatment and control groups (RR 0.67, 95% CI [0.12 to 3.74], p=0.65). In another trial of 402 women in which multiple-micronutrient supplements were compared to advice to take folic acid alone, women in the multiple-micronutrient group were at reduced risk of anaemia in the third trimester (RR 0.46, 95% CI [0.29 to 0.73], p=0.00097), but no significant differences were detected for the outcomes preterm birth (RR 1.10, 95% CI [0.41 to 2.95], p=0.85), small-for-gestational age (RR 0.93, 95% CI [0.53 to 1.63], p=0.80) or low birth weight (RR 1.63, 95% CI [0.66 to 4.03], p=0.29).

5. Additional author observations*

For the comparison of multiple-micronutrients with iron and folic acid versus iron with or without folic acid, the overall quality of the evidence for the primary outcomes preterm birth, low birth weight, perinatal mortality, stillbirth and neonatal mortality was judged to be high. The outcome small-for-gestational age was graded as being of moderate quality due to potential publication bias and funnel plot asymmetry. Most of the included trials were conducted in low- and middle-income countries, and therefore the findings are of most relevance in these settings.

Overall, multiple-micronutrient supplementation with iron and folic acid versus supplementation with iron with or without folic acid showed clear reductions in the risk of small-for-gestational age birth, low birth weight and stillbirth. While no increased risk of neonatal mortality was observed with multiple-micronutrient supplementation in this review, in the previous version a significantly increased risk was found among populations where the majority of births took place at home, and no effect was seen where the majority of births took place in health facilities. Therefore, the authors recommend the use of multiple-micronutrient supplements in pregnancy principally in settings where facility-based births and skilled care during childbirth can be provided. Future efforts should focus on the inclusion of multiple-micronutrient supplementation in standard maternal and antenatal care programs in developing countries where micronutrient deficiencies are common.

Future efforts should focus on the inclusion of multiple-micronutrient supplementation in standard maternal and antenatal care programs in developing countries where micronutrient deficiencies are common.