Gestational Exposure to Valproate and Autism Spectrum Disorder or Attention-Deficit/Hyperactivity Disorder in Offspring: Systematic Review and Meta-Analysis.

Introduction: Gestational exposure to valproate has been associated with a wide range of adverse pregnancy outcomes, including major congenital malformations in offspring. However, to date, no meta-analysis has comprehensively examined the risk of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) in children gestationally exposed to valproate.

Methods: We searched MEDLINE, Embase, and Scopus from inception until 15 May 2024 for relevant English-language articles. Primary outcomes of interest were the risk of ASD and ADHD, two independent primary outcomes, in children exposed to valproate anytime during pregnancy relative to unexposed children. Secondary outcomes were trimester-wise analyses of risk. We used a random effects model to pool the overall and trimester-wise hazard ratios (HRs) and obtained 95% confidence intervals (CIs), separately for the risks of ASD and ADHD. Study quality was assessed using the Joanna Briggs Institute (JBI) critical appraisal checklist.

Results: Eight cohort studies (pooled N = 6,033,300) met our search criteria. Anytime gestational exposure to valproate was associated with a large increase in the risk of ASD (adjusted HR [aHR], 3.10; 95% confidence interval [CI], 2.24-4.28; N = 1,841,198) and a modest increase in the risk of ADHD (aHR, 1.62; 95% CI, 1.30-2.01; N = 24,295). The findings in sensitivity analyses for both outcomes were generally consistent with those of the main analyses. Notably, anytime gestational exposure to high-dose valproate (> 1.0 to 1.1 g/day) was associated with a substantially elevated risk of ASD (aHR, 6.32; 95% CI, 3.12-12.80, N = 1,719,825). Likewise, in monotherapy (aHR, 4.21; 95% CI, 2.97-5.95; N = 1,745,253) and discordant sibling pair (aHR, 6.42; 95% CI, 2.02-20.42; N = 1133) analyses, the risk of ASD was substantially elevated.

Conclusion: Gestational exposure to valproate was associated with an increased risk of ASD and ADHD; the risks for ASD were greater at doses ≥ 1000 mg/day. These findings add to the literature that strongly discourages the use of valproate by women of childbearing age, especially during pregnancy.