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

  • 2026-05
  • American journal of obstetrics & gynecology MFM 8(5)
    • Daniele Vinti
    • Alexander Fiore
    • Gianfranco Fornelli
    • Marco Reschini
    • Paola Viganò
    • Edgardo Somigliana
    • Noemi Salmeri

Study Design

Type
Meta-Analysis
Sample size
n = 5,144
Population
nonpregnant women of reproductive age
Methods
systematic review and meta-analysis of three RCTs comparing high-dose (4-5 mg/day) versus standard-dose (0.4 mg/day) folic acid supplementation

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.

Research Insights

  • Vitamin B9→Improved Pregnancy Rate

    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).

    Effect
    Beneficial
    Effect size
    Small
    Dose
    4-5 mg/day (high dose) vs 0.4 mg/day (standard dose)
  • Vitamin B9→Increased Pregnancy Rate

    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)

    Effect
    Beneficial
    Effect size
    Small
    Dose
    4-5 mg/day (high-dose) vs 0.4 mg/day (standard-dose)
  • Vitamin B9→Reduced Miscarriage Risk

    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).

    Effect
    Neutral
    Effect size
    Small
    Dose
    4-5 mg/day (high dose) vs 0.4 mg/day (standard dose)
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