There have long been concerns regarding the use of the anticonvulsant valproate (Depakote, VPA) during pregnancy. First trimester use of valproate has been associated with a 3-5% risk of neural tube defects, as well as an increased risk of other malformations affecting the heart and other organ systems. Multiple reports have also indicated that in utero exposure to valproate may also negatively affect cognitive development.
Last year, we reviewed data collected from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, a prospective, observational, multicenter study which has followed women with epilepsy taking antiepileptic agents (carbamazepine, lamotrigine, phenytoin, or valproate) during pregnancy. Initial reports from the NEAD study have shown lower IQs and increased risk of marked intellectual impairment among valproate-exposed children evaluated at six years of age. New data from the NEAD study indicates that valproate exposure may also increase the risk of autism spectrum disorders (ASD).
In the most recent NEAD report, a cohort of women with epilepsy (n=201) and a control group of women without epilepsy (n=214) were followed prospectively, and their children (n=415) were evaluated at 6 years of age. Diagnosis of a neurodevelopmental disorder was made by a blinded rater independently of the research team.
The researchers found that the risk of neurodevelopmental disorders was higher in children exposed to valproate monotherapy (6/50, 12.0%; adjusted OR 6.05, 95% CI 1.65 to 24.53, p=0.007) compared with control children (4/214; 1.87%). This risk was also elevated in those exposed to polytherapy with VPA (3/20, 15.0%; aOR 9.97, 95% CI 1.82 to 49.40, p=0.005). Autistic spectrum disorder was the most frequent diagnosis. No significant increase was found among children exposed to carbamazepine (1/50) or lamotrigine (2/30).
The NEAD study has many strengths, including its prospective design, blinded cognitive assessments, the use of standardized measures, and detailed monitoring of multiple potential confounding factors. While other studies must be carried out to confirm this finding, this report, in combination with earlier studies, indicates that certain antiepileptic drugs, specifically valproate, may present an undesirable reproductive safety profile. Not only does exposure to valproic acid during pregnancy carry a significant teratogenic risk, a growing number of studies have demonstrated that valproate exposure is associated with significant long term effects on cognitive functioning.
Ruta Nonacs, MD PhD
Bromley RL, Mawer GE, Briggs M, et al. The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs.J Neurol Neurosurg Psychiatry. 2013 Jan 31.