Abstract
BACKGROUND: Iron-Folic Acid (IFA) supplementation during pregnancy is widely recommended to prevent maternal anemia and improve birth outcomes. However, the optimal formulation, dose, and frequency of IFA supplementation remain uncertain. This systematic review and meta-analysis aimed to evaluate the effect of different IFA formulations, doses, and frequencies on pregnancy and neonatal outcomes compared to Multiple Micronutrients (MMN) among pregnant women. METHODS: A comprehensive literature search was conducted across PubMed, Google Scholar, Cochrane Library, Scopus, and TRIP databases to identify pertinent studies published up to December 31st, 2023. Outcome measures includes preterm birth (PTB), stillbirths, low birth weight (LBW), small for gestational age (SGA), miscarriage rate (MR), neonatal mortality, and perinatal mortality. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated, and the quality of evidence was assessed using GRADEpro. RESULTS: Among 20 studies comparing IFA to MMN, our analysis showed a significant increased risk with LBW (RR: 1.07, 95% CI: 1.01 to 1.13, p = 0.02, I(2) = 24%) associated with IFA and MMN and elevated risk of stillbirth (RR: 1.08, 95% CI: 1.00 to 1.17, p = 0.05, I(2) = 19%), SGA (RR: 1.03, 95% CI: 0.99 to 1.06) compared to IFA with MMN. However, non-significant risk of PTB (RR: 0.84, 95% CI: 0.38 to 1.84) and MR (RR: 1.04, 95% CI: 0.92 to 1.16, p = 0.54) was observed with IFA as compared to MMN. Neonatal mortality and perinatal mortality also did not significantly differ between the two groups. Certain formulations and doses showed trend of risk, particularly in relation to stillbirth and SGA. CONCLUSIONS: Our findings emphasize the importance of carefully considering the potential risks and benefits of IFA supplementation in pregnancy, and suggest the need for further research to elucidate the underlying mechanisms driving these associations and to optimize supplementation strategies for maternal and neonatal health. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12884-025-08292-7.