Iron-Folic Acid Plus Micronutrients Cut Low Birthweight Risk

clinical-trial PMID: 30873598

Quick Summary: Research shows that taking a mix of vitamins and minerals, including iron and folic acid, during pregnancy can significantly lower the risk of babies being born with low birth weight. This is especially helpful in low- and middle-income countries.

What The Research Found

This study looked at many smaller studies to see how well different supplements work during pregnancy. The main finding? Taking a supplement with iron, folic acid, and other nutrients can:

Lower the chances of having a baby with low birth weight.

Reduce the risk of babies being smaller than expected for their gestational age.

Possibly reduce the risk of premature births.

The study found no significant differences in the number of stillbirths or deaths around the time of birth.

Study Details

Who was studied: Over 140,000 pregnant women from around the world, mostly in low- and middle-income countries.

How long: The studies followed the women throughout their pregnancies.

What they took: Some women took a supplement with iron, folic acid, and other vitamins and minerals. Others took just iron and folic acid.

What This Means For You

If you're pregnant, especially in a low- or middle-income country, talking to your doctor about a supplement that includes iron, folic acid, and other nutrients could be beneficial. It may help your baby grow and develop properly. Always follow your doctor's advice on the best supplements for you.

Study Limitations

Most of the studies were done in low- and middle-income countries, so the results might not be exactly the same for everyone.

The study couldn't fully assess all outcomes due to lack of data.

Some of the studies had some issues, like not all women taking the supplements as directed.

Key Findings

This Cochrane Review (2019) analyzed 20 randomized trials (141,849 women) comparing multiple-micronutrient (MMN) supplements containing iron and folic acid versus standard iron±folic acid during pregnancy. MMN supplementation significantly reduced low birthweight (LBW) infants (average RR 0.88, 95% CI 0.85–0.91; 18 trials, 68,801 participants; high-quality evidence). It probably reduced small-for-gestational-age (SGA) infants (RR 0.92, 95% CI 0.88–0.97; 17 trials; moderate-quality evidence) and very preterm births (RR 0.81, 95% CI 0.71–0.93; 4 trials), though the effect on overall preterm birth (RR 0.95, 95% CI 0.90–1.01) and stillbirths (RR 0.95, 95% CI 0.86–1.04) was borderline non-significant. No meaningful differences were observed for perinatal mortality (RR 1.00, 95% CI 0.90–1.11), neonatal mortality, maternal anemia (third trimester), or maternal mortality.

Study Design

This systematic review and meta-analysis included 20 randomized controlled trials (19 cluster-randomized), primarily conducted in low- and middle-income countries (LMICs; 19 trials). One trial was from the UK. Total participants numbered 141,849 pregnant women. Trials compared MMN supplements (containing iron and folic acid) against standard iron supplementation, with or without folic acid. The primary outcomes assessed were maternal, fetal, and infant health outcomes, analyzed using GRADE to assess evidence quality.

Dosage & Administration

The MMN formulations varied across trials but universally included iron (doses ranged from 40–66 mg elemental iron) and folic acid (typically 400 µg), plus other micronutrients. The UNIMMAP formulation (a standardized MMN blend developed by international agencies) was used in some trials, while others used non-UNIMMAP formulations. Supplements were administered orally, daily, starting at various gestational ages (subgroup analysis examined timing effects).

Results & Efficacy

MMN supplementation significantly reduced LBW by 12% (RR 0.88, 95% CI 0.85–0.91; p<0.001) with high-quality evidence. SGA was reduced by 8% (RR 0.92, 95% CI 0.88–0.97; p=0.001), graded as moderate-quality evidence. Very preterm birth (<32 weeks) decreased by 19% (RR 0.81, 95% CI 0.71–0.93). The reduction in overall preterm birth (<37 weeks) was non-significant (RR 0.95, 95% CI 0.90–1.01; CI crossed 1.0). Stillbirths showed a non-significant 5% reduction (RR 0.95, 95% CI 0.86–1.04). No significant effects were found for mortality outcomes or most maternal outcomes.

Limitations

Evidence quality was downgraded for preterm birth and SGA due to funnel plot asymmetry suggesting publication bias. Substantial unexplained heterogeneity existed for perinatal mortality. Most trials were in LMICs, limiting generalizability to high-income settings (only one UK trial). Insufficient data prevented analysis of several prespecified outcomes. Sample attrition exceeded 20% in some trials, though sensitivity analyses confirmed robustness. Subgroup analyses (e.g., by BMI, supplement timing) showed inconsistent results, requiring further investigation.

Clinical Relevance

For pregnant women in LMICs, replacing standard iron-folic acid with MMN supplements containing iron may meaningfully reduce LBW and SGA infants, key risk factors for infant mortality and developmental issues. The lack of mortality benefit and borderline effects on preterm birth/stillbirth indicate MMN is not a panacea but offers specific advantages for fetal growth. Clinicians in LMIC settings should consider MMN as a potentially superior alternative to iron-folic acid alone for improving birth weight outcomes, though context-specific implementation and monitoring are essential. Results do not support routine MMN use in high-income countries based on this evidence.