Adverse events associated with single-ingredient folic acid in pregnancy: A descriptive analysis of the United States Food and Drug Administration Adverse Event Reporting System (2004–2025)

Abstract

Background

Folic acid supplementation is widely recommended during pregnancy to prevent neural tube defects, with substantial evidence supporting its safety and efficacy. However, because adverse event (AE) reporting for dietary supplements is not mandatory, rare but serious AEs may go unrecognized.

Aim

This study aimed to investigate potential AEs associated with prenatal folic acid supplementation by analyzing reports from the United States Food and Drug Administration Adverse Event Reporting System between the first quarter of 2004 and the first quarter of 2025.

Methods

Pregnant women who reported AEs following folic acid supplementation were identified, and both AE categories and individual events were analyzed.

Summary

Among 3866 pregnant women reporting AEs, folic acid supplementation was identified as the primary suspect in 40 cases. Of these, 8 cases occurred at the recommended dose (0.4 mg/day), including 3 cases of pregnancy termination and loss; 9 cases occurred at above the recommended dose (>0.4 mg/day), and 23 cases had unknown dosage information. These cases included pregnancy termination and loss, congenital anomalies and developmental disorders, prematurity and low birth weight, and pregnancy complications. While folic acid supplementation remains essential for prenatal care and is considered safe at the recommended dose, the identification of rare but serious AEs even at this dose underscores the need for ongoing surveillance. Limitations of spontaneous reporting systems, such as underreporting and incomplete data—including missing dosage in many cases—may result in underestimation of the true incidence of AEs. Enhanced pharmacovigilance and prospective studies are warranted.