Prenatal exposure to antiseizure medications and risk of autism spectrum disorder in offspring: an integrated pharmacovigilance and two-sample mendelian randomization study

Abstract

Background: Evidence suggests that prenatal exposure to antiseizure medications (ASMs) may be associated with an increased risk of autism spectrum disorder (ASD) in offspring. However, the risks attributable to specific ASMs and the underlying biological mechanisms remain incompletely characterized.

Objective: This study aimed to systematically assess ASMs-ASD associations and explore potential causal pathways through an integrated approach combining pharmacovigilance data and Mendelian randomization (MR) analyses.

Methods: Disproportionality analyses were performed using three major pharmacovigilance databases: FDA Adverse Event Reporting System (FAERS, Q1 2004-Q1 2025), the European Medicines Agency EudraVigilance (inception-April 2025), and the United Kingdom Medicines and Healthcare Products Regulatory Agency (inception-May 2025). Signals identified in FAERS were further investigated using two-sample MR analyses from brain and blood tissues.

Results: Valproate (VPA) demonstrated the strongest and most consistent pharmacovigilance signal for ASD across all databases. Additional signals were observed for carbamazepine (CBZ), lamotrigine (LTG), and oxcarbazepine. Drug-target MR supported a potential protective role of ALDH5A1 (targeted by VPA), while CHRNA4 (targeted by CBZ) and HTR2A (targeted by LTG) were associated with increased ASD risk in offspring.

Conclusion: This integrated study extended prior evidence linking prenatal exposure to specific ASMs, particularly VPA, CBZ and LTG, with an elevated risk and potential signaling pathways of ASD in offspring. The findings underscored the importance of cautious ASM selection during pregnancy, prioritizing agents with a favorable risk-benefit profile at the minimum effective dose. Large, prospective, multicenter studies are warranted to validate these associations and to establish potential dose-response relationships.

Keywords: Antiseizure Medications; Autism Spectrum Disorder; Mendelian Randomization; Pharmacovigilance; Prenatal Exposure.