Prenatal Valproate Exposure and Risk of Autism Spectrum Disorders and Childhood Autism

Abstract

Exposure to antiepileptic drugs during pregnancy increases the risk of congenital malformations and delayed cognitive development in offspring. This population-based study was performed to determine whether prenatal exposure to valproate led to an increased risk of autism in the children. Data were extracted from Danish national registers for children born in 1996 to 2006 and for those exposed to valproate during pregnancy and subsequently diagnosed with autism spectrum disorders (ASDs), including childhood autism, Asperger syndrome, atypical autism, and other/unspecified pervasive developmental disorders. The estimated daily antiepileptic drug dose was divided into high (>750 mg/d) and low (≥750 mg/d) levels. The primary outcome was the hazard ratio of ASD and childhood autism after exposure to valproate during pregnancy, as determined by Cox regression. The secondary outcome was the risk of autism following valproate exposure after accounting for maternal epilepsy before birth. Of 655,615 births, 5437 children had a diagnosis of ASD, including 2067 with childhood autism. The mean age of the children at the end of follow-up was 8.84 years. Of 2644 children exposed to antiepileptic drugs during pregnancy, 508 were exposed to valproate. In all children, the absolute risks for ASD and childhood autism were 1.53% (95% confidence interval [CI], 1.47%–1.58%) and 0.48% (95% CI, 0.46%–0.51%), respectively. Valproate use during pregnancy was associated with absolute risks of 4.42% (95% CI, 2.59%–7.46%) for ASD and 2.50% (95% CI, 1.30%–4.81%) for childhood autism. The adjusted hazard ratio (aHR) for ASD was 2.9 (95% CI, 1.7–4.9), and for childhood autism it was 5.2 (95% CI, 2.7–10.0). Risks were similar for children of women who used high valproate doses (aHR 2.5; 95%CI, 1.03–6.1 for ASD; 4.3; 95%CI, 1.4–13.4 for childhood autism) compared with those for children of women who used low doses (aHR, 3.2; 95% CI, 1.7–6.2 and 5.4; 95% CI, 2.4–12.1, respectively). For other antiepileptic drugs, no increased risk of ASD or childhood autism was found. For women of childbearing age who use antiepileptic drugs, these findings must be considered against the benefits for those who need valproate to control epilepsy. The less than 5% absolute risk of ASD should be considered when counseling patients about use of valproate during pregnancy.