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

• Published in: JAMA : the journal of the American Medical Association 2013-04, Vol.309 (16), p.1696-1703
• Main Authors: Christensen, Jakob, Grønborg, Therese Koops, Sørensen, Merete Juul, Schendel, Diana, Parner, Erik Thorlund, Pedersen, Lars Henning, Vestergaard, Mogens
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Anticonvulsants - adverse effects; Anticonvulsants - therapeutic use; Anticonvulsants. Antiepileptics. Antiparkinson agents; Autistic Disorder - epidemiology; Biological and medical sciences; Child; Child clinical studies; Child Development Disorders, Pervasive - epidemiology; Child, Preschool; Denmark - epidemiology; Developmental disorders; Epilepsy - drug therapy; Female; Follow-Up Studies; General aspects; Humans; Incidence; Infantile autism; Male; Maternal Age; Medical sciences; Mental Disorders - epidemiology; Neuropharmacology; Pharmacology. Drug treatments; Pregnancy; Pregnancy Complications - drug therapy; Prenatal Exposure Delayed Effects; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Registries - statistics & numerical data; Risk; Valproic Acid - adverse effects; Valproic Acid - therapeutic use; Young Adult
• ISSN: 0098-7484; 1538-3598
• DOI: 10.1001/jama.2013.2270

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 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% (95% CI, 1.30%-4.81%) for childhood autism (adjusted HR, 5.2 [95% CI, 2.7-10.0]). When restricting the cohort to the 6584 children born to women with epilepsy, the absolute risk of autism spectrum disorder among 432 children exposed to valproate was 4.15% (95% CI, 2.20%-7.81%) (adjusted HR, 1.7 [95% CI, 0.9-3.2]), and the absolute risk of childhood autism was 2.95% (95% CI, 1.42%-6.11%) (adjusted HR, 2.9 [95% CI, 1.4-6.0]) vs 2.44% (95% CI, 1.88%-3.16%) for aut