High versus standard dose folic acid supplementation for miscarriage prevention: systematic review and meta-analysis of randomized controlled trials

Objectives: To assess whether high-dose folic acid supplementation (4-5 mg/day), initiated before conception, reduces the risk of miscarriage and improves pregnancy rates compared to standard-dose supplementation (0.4 mg/day). Data sources: A comprehensive search was conducted in PubMed, Embase, Scopus, the Cochrane Library, and ClinicalTrials.gov from inception through May 16, 2025. Study eligibility criteria: Eligible studies were randomized controlled trials (RCTs) comparing high-dose (4-5 mg/day) versus standard-dose (0.4 mg/day) folic acid supplementation in nonpregnant women of reproductive age, with no restrictions on language or publication date. Methods: The primary outcome was miscarriage; the secondary outcome was clinical pregnancy. Data were pooled using random-effects meta-analysis models and reported as risk ratios (RRs) with 95% confidence intervals (CIs). Risk of bias, study trustworthiness, and certainty of evidence were assessed using the RoB 2.0 tool, OGEIG criteria, and the GRADE framework, respectively. Results: Three RCTs (n=5144) were included. Among these, 1488 women became pregnant during the study period and were included in the primary analysis of miscarriage risk. In this population, high-dose folic acid supplementation was associated with a statistically significant reduction in miscarriage risk (RR 0.73; 95% CI: 0.56-0.94; I2=0%). An additional intention-to-treat (ITT) analysis, which included all randomized participants regardless of pregnancy status, showed a nonsignificant reduction in miscarriage risk (RR 0.79; 95% CI: 0.61-1.04). Moreover, the pregnancy rate was significantly higher in the high-dose group compared to the standard-dose group (RR 1.10; 95% CI: 1.02-1.18). The certainty of evidence was rated as low to moderate. Conclusion: High-dose folic acid supplementation (4 mg/day) may reduce the risk of miscarriage and increase pregnancy rates in women trying to conceive. These findings may support consideration of revising current recommended dosage of folic acid in women trying to conceive. However, large-scale RCTs are needed to confirm these results. El resumen está disponible en Español al final del artículo.