Multiple-micronutrient supplementation for women during pregnancy

Abstract

Background: Multiple-micronutrient (MMN) deficiencies often coexist among women of reproductive age in low- and middle-income countries. They are exacerbated in pregnancy due to the increased demands of the developing fetus, leading to potentially adverse effects on the mother and baby. A consensus is yet to be reached regarding the replacement of iron and folic acid supplementation with MMNs. Since the last update of this Cochrane Review in 2017, evidence from several trials has become available. The findings of this review will be critical to inform policy on micronutrient supplementation in pregnancy.

Objectives: To evaluate the benefits of oral multiple-micronutrient supplementation during pregnancy on maternal, fetal and infant health outcomes.

Search methods: For this 2018 update, on 23 February 2018 we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP), and reference lists of retrieved studies. We also contacted experts in the field for additional and ongoing trials.

Selection criteria: All prospective randomised controlled trials evaluating MMN supplementation with iron and folic acid during pregnancy and its effects on pregnancy outcomes were eligible, irrespective of language or the publication status of the trials. We included cluster-randomised trials, but excluded quasi-randomised trials. Trial reports that were published as abstracts were eligible.

Data collection and analysis: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We assessed the quality of the evidence using the GRADE approach.

Main results: We identified 21 trials (involving 142,496 women) as eligible for inclusion in this review, but only 20 trials (involving 141,849 women) contributed data. Of these 20 trials, 19 were conducted in low- and middle-income countries and compared MMN supplements with iron and folic acid to iron, with or without folic acid. One trial conducted in the UK compared MMN supplementation with placebo. In total, eight trials were cluster-randomised.MMN with iron and folic acid versus iron, with or without folic acid (19 trials)MMN supplementation probably led to a slight reduction in preterm births (average risk ratio (RR) 0.95, 95% confidence interval (CI) 0.90 to 1.01; 18 trials, 91,425 participants; moderate-quality evidence), and babies considered small-for-gestational age (SGA) (average RR 0.92, 95% CI 0.88 to 0.97; 17 trials; 57,348 participants; moderate-quality evidence), though the CI for the pooled effect for preterm births just crossed the line of no effect. MMN reduced the number of newborn infants identified as low birthweight (LBW) (average RR 0.88, 95% CI 0.85 to 0.91; 18 trials, 68,801 participants; high-quality evidence). We did not observe any differences between groups for perinatal mortality (average RR 1.00, 95% CI 0.90 to 1.11; 15 trials, 63,922 participants; high-quality evidence). MMN supplementation led to slightly fewer stillbirths (average RR 0.95, 95% CI 0.86 to 1.04; 17 trials, 97,927 participants; high-quality evidence) but, again, the CI for the pooled effect just crossed the line of no effect. MMN supplementation did not have an important effect on neonatal mortality (average RR 1.00, 95% CI 0.89 to 1.12; 14 trials, 80,964 participants; high-quality evidence). We observed little or no difference between groups for the other maternal and pregnancy outcomes: maternal anaemia in the third trimester (average RR 1.04, 95% CI 0.94 to 1.15; 9 trials, 5912 participants), maternal mortality (average RR 1.06, 95% CI 0.72 to 1.54; 6 trials, 106,275 participants), miscarriage (average RR 0.99, 95% CI 0.94 to 1.04; 12 trials, 100,565 participants), delivery via a caesarean section (average RR 1.13, 95% CI 0.99 to 1.29; 5 trials, 12,836 participants), and congenital anomalies (average RR 1.34, 95% CI 0.25 to 7.12; 2 trials, 1958 participants). However, MMN supplementation probably led to a reduction in very preterm births (average RR 0.81, 95% CI 0.71 to 0.93; 4 trials, 37,701 participants). We were unable to assess a number of prespecified, clinically important outcomes due to insufficient or non-available data.When we assessed primary outcomes according to GRADE criteria, the quality of evidence for the review overall was moderate to high. We graded the following outcomes as high quality: LBW, perinatal mortality, stillbirth, and neonatal mortality. The outcomes of preterm birth and SGA we graded as moderate quality; both were downgraded for funnel plot asymmetry, indicating possible publication bias.We carried out sensitivity analyses excluding trials with high levels of sample attrition (> 20%). We found that results were consistent with the main analyses for all outcomes. We explored heterogeneity through subgroup analyses by maternal height, maternal body mass index (BMI), timing of supplementation, dose of iron, and MMN supplement formulation (UNIMMAP versus non-UNIMMAP). There was a greater reduction in preterm births for women with low BMI and among those who took non-UNIMMAP supplements. We also observed subgroup differences for maternal BMI and maternal height for SGA, indicating greater impact among women with greater BMI and height. Though we found that MMN supplementation made little or no difference to perinatal mortality, the analysis demonstrated substantial statistical heterogeneity. We explored this heterogeneity using subgroup analysis and found differences for timing of supplementation, whereby higher impact was observed with later initiation of supplementation. For all other subgroup analyses, the findings were inconclusive.MMN versus placebo (1 trial)A single trial in the UK found little or no important effect of MMN supplementation on preterm births, SGA, or LBW but did find a reduction in maternal anaemia in the third trimester (RR 0.66, 95% CI 0.51 to 0.85), when compared to placebo. This trial did not measure our other outcomes.

Authors' conclusions: Our findings suggest a positive impact of MMN supplementation with iron and folic acid on several birth outcomes. MMN supplementation in pregnancy led to a reduction in babies considered LBW, and probably led to a reduction in babies considered SGA. In addition, MMN probably reduced preterm births. No important benefits or harms of MMN supplementation were found for mortality outcomes (stillbirths, perinatal and neonatal mortality). These findings may provide some basis to guide the replacement of iron and folic acid supplements with MMN supplements for pregnant women residing in low- and middle-income countries.

Conflict of interest statement

Emily Keats: none

Batool A Haider: none

Emily Tam: none

Zulfiqar A Bhutta was the principal investigator of the UNIMAPP trial conducted in Pakistan (Bhutta 2009a). He was not involved in the screening and data extraction for this paper, which was conducted by other review authors acknowledged above. Dr Bhutta is also the recipient of a grant from the Bill & Melinda Gates Foundation to undertake an individual participant data analysis of nutrition interventions in adolescents and women during pregnancy.

Figures

1

Study flow diagram

2

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

3

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study

4

Funnel plot of comparison 1. Multiple micronutrients vs control, outcome: 1.3 Low birthweight

5

Funnel plot of comparison 1. Multiple micronutrients vs control, outcome: 1.4 Perinatal mortality

6

Funnel plot of comparison 1. Multiple micronutrients vs control, outcome: 1.5 Stillbirths

7

Funnel plot of comparison 1. Multiple micronutrients vs control, outcome: 1.6 Neonatal mortality

8

Funnel plot of comparison 1. Multiple micronutrients vs control, outcome: 1.1 Preterm births

9

Funnel plot of comparison 1. Multiple micronutrients vs control, outcome: 1.2 Small‐for‐gestational age

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Funnel plot of comparison 1. Multiple micronutrients vs control, outcome: 1.9 Miscarriage (loss before 28 weeks)

1.1. Analysis

Comparison 1 Multiple micronutrients vs control, Outcome 1 Preterm births.

1.2. Analysis

Comparison 1 Multiple micronutrients vs control, Outcome 2 Small‐for‐gestational age.

1.3. Analysis

Comparison 1 Multiple micronutrients vs control, Outcome 3 Low birthweight.

1.4. Analysis

Comparison 1 Multiple micronutrients vs control, Outcome 4 Perinatal mortality.

1.5. Analysis

Comparison 1 Multiple micronutrients vs control, Outcome 5 Stillbirths.

1.6. Analysis

Comparison 1 Multiple micronutrients vs control, Outcome 6 Neonatal mortality.

1.7. Analysis

Comparison 1 Multiple micronutrients vs control, Outcome 7 Maternal anaemia (third trimester Hb

1.8. Analysis

Comparison 1 Multiple micronutrients vs control, Outcome 8 Maternal mortality.

1.9. Analysis

Comparison 1 Multiple micronutrients vs control, Outcome 9 Miscarriage (loss before 28 weeks).

1.10. Analysis

Comparison 1 Multiple micronutrients vs control, Outcome 10 Mode of delivery: caesarean section.

1.11. Analysis

Comparison 1 Multiple micronutrients vs control, Outcome 11 Congenital anomalies.

1.12. Analysis

Comparison 1 Multiple micronutrients vs control, Outcome 12 Very preterm birth (before 34 weeks of gestation).

2.1. Analysis

Comparison 2 Subgroup analysis for primary outcomes (MMN with iron and folic acid vs iron with or without folic acid)), Outcome 1 Preterm births: mean maternal BMI.

2.2. Analysis

Comparison 2 Subgroup analysis for primary outcomes (MMN with iron and folic acid vs iron with or without folic acid)), Outcome 2 Preterm births: mean maternal height.

2.3. Analysis

Comparison 2 Subgroup analysis for primary outcomes (MMN with iron and folic acid vs iron with or without folic acid)), Outcome 3 Preterm births: timing of supplementation.

2.4. Analysis

Comparison 2 Subgroup analysis for primary outcomes (MMN with iron and folic acid vs iron with or without folic acid)), Outcome 4 Preterm births: dose of iron.

2.5. Analysis

Comparison 2 Subgroup analysis for primary outcomes (MMN with iron and folic acid vs iron with or without folic acid)), Outcome 5 Preterm births: MMN supplement formulation.

2.6. Analysis

Comparison 2 Subgroup analysis for primary outcomes (MMN with iron and folic acid vs iron with or without folic acid)), Outcome 6 Small‐for‐gestational age: mean maternal BMI.

2.7. Analysis

Comparison 2 Subgroup analysis for primary outcomes (MMN with iron and folic acid vs iron with or without folic acid)), Outcome 7 Small‐for‐gestational age: mean maternal height.

2.8. Analysis

Comparison 2 Subgroup analysis for primary outcomes (MMN with iron and folic acid vs iron with or without folic acid)), Outcome 8 Small‐for‐gestational age: timing of supplementation.

2.9. Analysis

Comparison 2 Subgroup analysis for primary outcomes (MMN with iron and folic acid vs iron with or without folic acid)), Outcome 9 Small‐for‐gestational age: dose of iron.

2.10. Analysis

Comparison 2 Subgroup analysis for primary outcomes (MMN with iron and folic acid vs iron with or without folic acid)), Outcome 10 Small‐for‐gestational age: MMN supplement formulation.

2.11. Analysis

Comparison 2 Subgroup analysis for primary outcomes (MMN with iron and folic acid vs iron with or without folic acid)), Outcome 11 Perinatal mortality: mean maternal BMI.

2.12. Analysis

Comparison 2 Subgroup analysis for primary outcomes (MMN with iron and folic acid vs iron with or without folic acid)), Outcome 12 Perinatal mortality: mean maternal height.

2.13. Analysis

Comparison 2 Subgroup analysis for primary outcomes (MMN with iron and folic acid vs iron with or without folic acid)), Outcome 13 Perinatal mortality: timing of supplementation.

2.14. Analysis

Comparison 2 Subgroup analysis for primary outcomes (MMN with iron and folic acid vs iron with or without folic acid)), Outcome 14 Perinatal mortality: dose of iron.

2.15. Analysis

Comparison 2 Subgroup analysis for primary outcomes (MMN with iron and folic acid vs iron with or without folic acid)), Outcome 15 Perinatal mortality: MMN supplement formulation.

3.1. Analysis

Comparison 3 Sensitivity analysis (all trials) excluding trials with > 20% loss to follow up, Outcome 1 Preterm births.

3.2. Analysis

Comparison 3 Sensitivity analysis (all trials) excluding trials with > 20% loss to follow up, Outcome 2 Small‐for‐gestational age.

3.3. Analysis

Comparison 3 Sensitivity analysis (all trials) excluding trials with > 20% loss to follow up, Outcome 3 Low birthweight.

3.4. Analysis

Comparison 3 Sensitivity analysis (all trials) excluding trials with > 20% loss to follow up, Outcome 4 Perinatal mortality.

3.5. Analysis

Comparison 3 Sensitivity analysis (all trials) excluding trials with > 20% loss to follow up, Outcome 5 Stillbirths.

3.6. Analysis

Comparison 3 Sensitivity analysis (all trials) excluding trials with > 20% loss to follow up, Outcome 6 Neonatal mortality.

3.7. Analysis

Comparison 3 Sensitivity analysis (all trials) excluding trials with > 20% loss to follow up, Outcome 7 Maternal anaemia (third trimester Hb

3.8. Analysis

Comparison 3 Sensitivity analysis (all trials) excluding trials with > 20% loss to follow up, Outcome 8 Miscarriage (loss before 28 weeks).

3.9. Analysis

Comparison 3 Sensitivity analysis (all trials) excluding trials with > 20% loss to follow up, Outcome 9 Maternal mortality.

3.10. Analysis

Comparison 3 Sensitivity analysis (all trials) excluding trials with > 20% loss to follow up, Outcome 10 Very preterm birth (before 34 weeks of gestation).

3.11. Analysis

Comparison 3 Sensitivity analysis (all trials) excluding trials with > 20% loss to follow up, Outcome 11 Congenital anomalies.

3.12. Analysis

Comparison 3 Sensitivity analysis (all trials) excluding trials with > 20% loss to follow up, Outcome 12 Neurodevelopmental outcome: BSID scores.

3.13. Analysis

Comparison 3 Sensitivity analysis (all trials) excluding trials with > 20% loss to follow up, Outcome 13 Mode of delivery: caesarean section.