Valproate use during pregnancy increases risk of autism

Prenatal exposure to valproate significantly increased the risk of autism spectrum disorder and childhood autism in the offspring of mothers who took the anti-epileptic agent, according to a study published in the April 24 issue of the Journal of the American Medical Association.

Danish researchers identified all children born in Denmark over a 10-year period, starting in January 1996, from the Danish Civil Registration System. They were able to determine which children were exposed to antiepileptic drugs within 30 days of conception, based on information of filled prescriptions in the Danish Prescription Register. Children were followed from birth until emigration, diagnosis of autism spectrum disorder or autism, death, or the end of the study.

Jakob Christensen, PhD, and colleagues identified more than 668,000 children during the study and excluded about 12,800 due to errors in gestational age, missing information of the mother, adopted children, children who emigrated, and those who died during the first year of life and more than 1 year after birth. The study included more than 655,000 children born to approximately 428,000 women. The mean age of children at the end of follow-up was 8.84 years (range: 4-14 years).

During the 10-year study, 5,437 children were diagnosed with autism spectrum disorder. More than 2,000 were diagnosed with childhood autism, the researchers noted.

Of the 2,644 children who were exposed to antiepileptic medications during pregnancy, 508 had been exposed to valproate. During this study period (1996-2006), the use of antiepileptic drugs was stable, but the use of valproate decreased and the use of lamotrigine increased.

The researchers found a higher absolute risk of 4.42% (95% CI, 2.59%-7.46%) for autism spectrum disorder and an absolute risk of 2.50% (95% CI, 1.30%-4.81%) for childhood autism among children whose mothers had taken valproate. The absolute risk among all children at 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.

“We also found higher risks of autism spectrum disorder (adjusted HR, 2.2 [95% CI, 1.02-4.9]) and childhood autism (adjusted HR, 5.6 [95% CI, 1.7-18.1]) among children of women who used valproate during pregnancy compared with children of women who were previous users of valproate but who stopped at least 30 days before conception,” the authors wrote.

Valproate is indicated for the treatment of epilepsy, manic disorders associated with bipolar disease, and for the prevention of migraine headaches. In this study researchers did not have access to medical records to determine if mothers were being treated for epilepsy or another condition.