Risk of Adverse Pregnancy Outcomes Associated with Sodium Valproate(VPA): A Disproportionality Analysis Using the FDA Adverse Event Reporting System (FAERS)

Abstract Background: Valproate(VPA) is widely used for treating epilepsy, bipolar disorder, and migraines. However, its use during pregnancy raises concerns due to potential adverse events (AEs) on fetal development. Previous studies have linked VPA to neural tube defects, cardiac malformations, and cognitive impairments in offspring. Despite these risks, some pregnant women continue VPA therapy due to medical necessity, highlighting the need for a comprehensive evaluation of its AEs. This study aims to systematically assess AEs with VPA use during pregnancy from the FDA Adverse Event Reporting System (FAERS) database. Methods: We utilized the Standardized MedDRA Query to detect AEs associated with pregnancy. Disproportionality analyses were conducted to pinpoint AEs related to VPA, employing metrics including the Reporting Odds Ratios (ROR), Proportional Reporting Ratios (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and the Empirical Bayesian Geometric Mean (EBGM) to ascertain the associations. Results: The significantly reported adverse signals in SOCs were Social circumstances, Ear and labyrinth disorders, Congenital, familial and genetic disorders, Psychiatric disorders, Nervous system disorders, and Eye disorders. The five strongest signals for VPA-related included Physical disability(n=345, ROR 387.63,PRR 380.87,IC025 5.15,EBGM 46.55), Foetal anticonvulsant syndrome (n=387, ROR 217.87,PRR 213.62,IC025 5.06,EBGM 42.55),Tension(n=216, ROR453.25,PRR 448.30,IC025 5.01,EBGM 47.40),Social problem(n=212, ROR370.64,PRR 366.67,IC025 4.98,EBGM 46.33), and Deformit(n=340, ROR157.44,PRR 154.75,IC025 4.94,EBGM 39.61). An in-depth analysis of AEs in fetus found that the five strongest signals for VPA-related to the fetus included Foetal anticonvulsant syndrome (n=387, ROR 217.87,PRR 213.62,IC025 5.06,EBGM 42.55), Neural tube defect (n=218, ROR 42.679,PRR 42.21,IC025 4.19,EBGM 23.72), Spina bifida (n=347, ROR 22.12,PRR 21.74,IC025 3.73,EBGM 15.62), Dysmorphism (n=270, ROR 20.69,PRR 20.42,IC025 3.63,EBGM 14.94), Congenital cardiovascular anomaly (n=141, ROR 19.59,PRR 19.46,IC0253.44,EBGM14.42). Additionally, Autism spectrum disorder, Congenital nose malformation, Foot deformity, Neurodevelopmental disorder are high intensity signal. Conclusion: VPA use in pregnancy demonstrates robust pharmacovigilance signals for teratogenic outcomes. These findings corroborate clinical warnings, urging strict avoidance of VPA in pregnancy when possible. Risk-benefit assessments and alternative therapies are critical for necessitated cases, alongside vigilant prenatal monitoring. Further research is needed to confirm causality and explore underlying mechanisms.