While it is widely recognized that valproate is a teratogen, its impact on fetal neurodevelopment and the subsequent risk of neurobehavioral disorders is less widely discussed.
Multiple studies have shown that exposure to valproic acid during pregnancy is associated with an increased risk of autism spectrum disorder. In addition, gestational exposure has been linked to lower IQ and a higher likelihood of learning disabilities, particularly an increased risk of intellectual disability.
An excellent systematic review and meta-analysis was recently published by Chittaranjan Andrade and colleagues and provides further compelling evidence against the use of valproic acid in women of childbearing age:
Systematic Review and Meta-Analysis
A total of eight cohort studies, including over 6 million pregnancies, met the inclusion criteria. Six studies were retrospective and two were prospective. The countries represented included the United States (n = 3), Denmark (n = 2), United Kingdom (n = 1), France (n = 1), and Pakistan (n = 1).
Risk of Autism Spectrum Disorder
Exposure to valproate at any point in pregnancy was strongly associated with increased risk of ASD in offspring:
- Any exposure during pregnancy: Adjusted hazards ratio (aHR) 3.10 (95% CI, 2.24–4.28; N = 1,841,198)
- High-dose valproate (?1000 mg/day): aHR 6.32 (95% CI, 3.12–12.80)
- Valproate Monotherapy: aHR 4.21 (95% CI, 2.97–5.95; N = 1,745,253)
- Third trimester exposure: aHR 3.04 (95% CI, 1.98–4.66; 2 studies)
Importantly, in discordant sibling analyses (a design that minimizes genetic and environmental confounding by comparing risk in exposed vs. unexposed siblings), the risk of ASD remained strikingly high:
- Discordant sibling exposure: aHR 6.42 (95% CI, 2.02–20.42; N = 1133)
Risk of Attention-Deficit/Hyperactivity Disorder
Findings for prenatal exposure to valproic acid and risk for ADHD were more modest:
- Any exposure during pregnancy: aHR 1.62 (95% CI, 1.30–2.01; N = 24,295)
- High-dose valproate: nonsignificant increase (unadjusted RR, 7.69; 95% CI 0.17–358.36; 1 study; n = 241)
Clinical Implications
This is the first meta-analysis examining neurodevelopmental outcomes following in utero exposure to valproate. While the results are not surprising and have been noted in previous studies; the magnitude of the risks associated with valproate exposure is striking and highlights the need for vigilance surrounding the use of valproate. In addition, it must be emphasized that the risks associated with valproate are not limited to the first trimester. Although exposure to valproate later in pregnancy may not be associated with teratogenic risk, there continues to be a significant risk of adverse neurodevelopmental outcomes. The findings indicate that:
- Prenatal exposure to valproate is associated with a substantial elevation in ASD risk (aHR, 3.10).
- There is a modest increase in ADHD risk (aHR, 1.62).
- High-dose valproate exposure further magnifies ASD risk (aHR, 6.32).
- Risk for ASD is the highest with third trimester exposure to valproate (aHR 3.04).
- Dose-dependency and sibling analysis results support a causal role for valproate in these outcomes.
Although the use of valproate in pregnancy has declined in several countries over the past decade, prescribing patterns remain inconsistent worldwide. Valproate is still commonly prescribed to women of childbearing age — even during pregnancy– in certain regions.
Given the accumulating evidence of adverse neurodevelopmental outcomes, valproate should be avoided in this population whenever clinically feasible.
Ruta Nonacs, MD PhD
Reference:
Andrade C, Varadharajan N, Bascarane S, Kale A, Gnanadhas J, Menon V. Gestational Exposure to Valproate and Autism Spectrum Disorder or Attention-Deficit/Hyperactivity Disorder in Offspring: Systematic Review and Meta-Analysis. Acta Psychiatr Scand. 2025 Jun;151(6):668-679
