Effect of folate intake on health outcomes in pregnancy: a systematic review and meta-analysis on birth weight, placental weight and length of gestation

Healthy pregnant women; randomized controlled trials; multi-country settings (Europe, South America, Asia, Africa); includes one adolescent participant; blinding adequacy varied (adequate in one trial).

Oral folate supplementation started in the second trimester; folic acid or 5-methyltetrahydrofolate (5-MTHF); daily doses from 0.25 mg to 5 mg; duration 12–22 weeks; often co-administered with iron; one trial included 5-MTHF vs placebo and 5-MTHF with fish oil vs fish oil.

Birth weight increased with higher total folate intake; a two-fold increase in folate intake corresponds to about 2% higher birth weight (β = 0.03; 95% CI 0.01-0.05; P = 0.001). No significant effects on placental weight (β = 0.04; 95% CI 0.00-0.09; P = 0.08) or length of gestation (β = 0.00; 95% CI -0.01 to 0.01; P = 0.77). Conclusion: Increased folate intake after the first trimester is associated with a modest rise in birth weight, with no evidence of effects on placental weight or gestational length. More high-quality randomized trials focusing on outcomes after the first trimester are needed.

Most trials were conducted decades ago and had high risk of bias; inconsistent reporting of randomization and blinding; heterogeneity in supplement form, gestational age at start, dose, and duration; small sample sizes; potential confounders underreported; insufficient data for subgroup analyses; underpowered for outcomes like SGA and preterm birth.