NTIEPILEPTIC DRUG EXPOsure during pregnancy has been associated with an increased risk for congenital malformations and delayed cognitive development in the offspring, 1-3 but little is known about the risk of other serious neuropsychiatric disorders. Autistic symptoms have been described in case series of children exposed in utero to valproic acid, 4-7 and it has been suggested that valproate given to animals during pregnancy may constitute an experimental model of autism. 8-10 Genes play a significant role in the risk of autism, and disease-related genes may be identified in up to 25% of children with autism. 11 However, a variety of environmental factors may increase the risk of autism, 12 and prenatal valproate exposure would be a modifiable environmental exposure. Autism spectrum disorders are characterized by social and communication difficulties and by stereotyped or repetitive behaviors and interests. 13 The autism spectrum disorders include childhood autism (autistic disorder), Asperger syndrome, atypical autism, and other or unspecified pervasive developmental disorders. We analyzed the risks associated with all autism spec-For editorial comment see p 1730.

Bial, Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, the Netherlands Epilepsy Foundation, and Stockholm County Council.

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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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BackgroundBoth the use of antidepressant medication during pregnancy and the prevalence of autism spectrum disorder have increased during recent years. A causal link has recently been suggested, but the association may be confounded by the underlying indication for antidepressant use. We investigated the association between maternal use of antidepressant medication in pregnancy and autism, controlling for potential confounding factors.MethodsWe identified all children born alive in Denmark 1996–2006 (n=668,468) and their parents in the Danish Civil Registration System. We obtained information on the mother’s prescriptions filled during pregnancy from the Danish National Prescription Registry, and on diagnoses of autism spectrum disorders in the children and diagnoses of psychiatric disorders in the parents from the Danish Psychiatric Central Register. In a cohort analysis, we estimated hazard ratios of autism spectrum disorders in children exposed to antidepressant medication during pregnancy compared with children who were not exposed, using Cox proportional hazards regression analysis. Furthermore, we estimated the risk for autism spectrum disorder in a sibling design.ResultsChildren exposed prenatally to antidepressants had an adjusted hazard ratio of 1.5 (95% confidence interval [CI] 1.2–1.9) for autism spectrum disorder compared with unexposed children. Restricting the analysis to children of women with a diagnosis of affective disorder, the adjusted hazard ratio was 1.2 (95% CI 0.7–2.1), and the risk was further reduced when exposed children were compared with their unexposed siblings (adjusted hazard ratio 1.1; 95% CI 0.5–2.3).ConclusionAfter controlling for important confounding factors, there was no significant association between prenatal exposure to antidepressant medication and autism spectrum disorders in the offspring.

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