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

Abstract

Importance-Valproate is used for the treatment of epilepsy and other neuropsychological disorders and may be the only treatment option for women of childbearing potential. However, prenatal exposure to valproate may increase the risk of autism.Objective-To determine whether prenatal exposure to valproate is associated with an increased risk of autism in offspring.Design, Setting, and Participants-Population-based study of all children born alive in Denmark from 1996 to 2006. National registers were used to identify children exposed to valproate during pregnancy and diagnosed with autism spectrum disorders (childhood autism [autistic disorder], Asperger syndrome, atypical autism, and other or unspecified pervasive developmental disorders). We analyzed the risks associated with all autism spectrum disorders as well as childhood autism. Data were analyzed by Cox regression adjusting for potential Corresponding Author: Jakob Christensen, PhD, Department of Neurology, Aarhus University Hospital, Norrebrogade 44, DK-8000 Aarhus C, Denmark (jakob @farm.au.dk). Author Contributions: Dr Christensen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Online-Only Material: eTables 1-6 and Author Video Interview are available at http://www.jama.com. Conflict of Interest Disclosures:All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Christensen reported receiving honoraria for serving on the scientific advisory boards of UCB Nordic and Eisai AB; receiving lecture honoraria from UCB Nordic and Eisai AB; and receiving travel funding from UCB Nordic. Dr Parner reported receiving grants from Autism Speaks and the National Institutes of Health. No other authors reported disclosures. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author Manuscript confounders (maternal age at conception, paternal age at conception, parental psychiatric history, gestational age, birth weight, sex, congenital malformations, and parity). Children were followed up from birth until the day of autism spectrum disorder diagnosis, death, emigration, or December 31, 2010, whichever came first.Main Outcomes and Measures-Absolute risk (cumulative incidence) and the hazard ratio (HR) of autism spectrum disorder and childhood autism in children after exposure to valproate in pregnancy.Results-Of 655 615 children born from 1996 through 2006, 5437 were identified with autism spectrum disorder, including 2067 with childhood autism. The mean age of the children at end of follow-up was 8.84 years (range, 4-14; median, 8.85). The estimated absolute risk after 14 years of follow-up was 1.53% (95% CI, 1.47%-1.58%) for autism spectrum disorder and 0.48% (95% CI, 0.46%-0.51%) for childhood autism. Overall, the 508 children exposed to valproate had an absolute risk of 4.42% (95% CI, 2.59%-7.46%) for autism spectrum disorder (adjusted HR, 2.9 [95% CI, 1.7-4.9]) and an absolute risk of 2.50% (9...

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