Safety of Valproic Acid Use in Pregnant Women: A Systematic Review and Meta-Analysis.

OBJECTIVE

To evaluate valproic acid (VPA) safety in pregnancy versus other antiepileptic drugs (AEDs), focusing on fetal malformation risks.

METHODS

A literature search was conducted across PUBMED, MEDLINE, EMBASE, and Web of Science databases. Two researchers independently screened studies, extracted data, assessed quality, and analyzed VPA safety.

RESULTS

This meta-analysis of 25 safety studies showed that compared with other AEDs, VPA's teratogenic risks were as follows: combined major congenital malformations (RR = 2.36, 95% CI: 2.17-2.56), neural tube defects (RR = 6.54, 95% CI: 4.51-9.47), congenital heart defects (RR = 2.53, 95% CI: 2.16-2.96), cleft lip and/or palate (RR = 4.31, 95% CI: 3.06-6.08), genitourinary anomalies (RR = 3.32, 95% CI: 2.67-4.14), and musculoskeletal anomalies (RR = 2.88, 95% CI: 1.98-4.19). Additional analyses stratified by calendar era yielded consistent results, with the corresponding RR values for the above malformations being 2.43 (95% CI: 2.13-2.77), 6.64 (95% CI: 4.50-9.79), 2.64 (95% CI: 2.14-3.26), 4.27 (95% CI: 2.98-6.12), 3.45 (95% CI: 2.76-4.31), and 2.99 (95% CI: 2.00-4.46), indicating a higher risk of multiple malformations with VPA.

CONCLUSION

VPA monotherapy significantly increases teratogenic risk, especially for neural tube defects and cleft lip/palate. Newer AEDs with lower risk profiles are preferred for epilepsy treatment during pregnancy. If VPA use is unavoidable, low doses and blood concentration monitoring are recommended to mitigate risk.