Gestational Exposure to Valproate and Autism Spectrum Disorder or Attention-Deficit/Hyperactivity Disorder in...

Area of Science:

• Neurodevelopmental disorders
• Pregnancy and childbirth
• Pharmacology

Background:

• Valproate is a medication with known risks during pregnancy, including major congenital malformations.
• Previous research has not comprehensively evaluated the association between gestational valproate exposure and the risks of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD).

Purpose of the Study:

• To conduct a meta-analysis examining the risk of ASD and ADHD in children following gestational exposure to valproate.
• To assess trimester-specific risks and the impact of valproate dosage on these outcomes.

Main Methods:

• A systematic literature search was performed across MEDLINE, Embase, and Scopus databases.
• Eight cohort studies comprising over 6 million children were included.
• Random effects models were used to pool hazard ratios (HRs) and 95% confidence intervals (CIs) for ASD and ADHD risks.

Main Results:

• Gestational valproate exposure was linked to a significant increase in ASD risk (aHR, 3.10) and a modest increase in ADHD risk (aHR, 1.62).
• High-dose valproate (> 1.0 g/day) exposure substantially elevated ASD risk (aHR, 6.32).
• Increased ASD risk was also observed in monotherapy and discordant sibling pair analyses.

Conclusions:

• Gestational valproate exposure is associated with increased risks of ASD and ADHD.
• The risk of ASD is dose-dependent, with higher risks observed at doses ≥ 1000 mg/day.
• Findings support strong recommendations against valproate use in women of childbearing potential, particularly during pregnancy.