HealthDay News — Prenatal exposure to valproate (Depacon) correlates with an increased risk of autism and autism spectrum disorders in children, study results indicate.

In utero exposure to the anti-epileptic drug was associated with a five-fold elevated risk of autism and three-fold elevated risk for autism spectrum disorder, Jakob Christensen, PhD, of Denmark’s Aarhus University Hospital, and colleagues reported in the Journal of the American Medical Association.

“For women of childbearing potential who use antiepileptic medications, these findings must be balanced against the treatment benefits for women who require valproate for epilepsy control,” the researchers wrote.

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The American Academy of Neurology currently cautions against using valproate in pregnancy whenever possible due to cognitive and physical birth defect problems for children exposed in utero. To further explore whether prenatal exposure to valproate correlates with autism risk in offspring, the researchers conducted a population-base study involving 655,615 children born from 1996 through 2006 in Denmark.

Autism spectrum disorders, including childhood autism, Asperger syndrome, atypical autism and other unspecified pervasive developmental disorders, were identified in 5,437 children through follow-up to a mean age of 8.8 years using national registries. Valporate exposure during pregnancy, determined by filled prescriptions, was identified in 508 children.

Compared with mothers who had used valporate but stopped at least 30 days before conception, the hazard ratios among children with prenatal exposure to the drug were 2.2-fold higher for ASD (95% CI 1.02-4.9) and 5.6-fold higher for childhood autism (95% CI: 1.7-18.1), the researchers found.

Of the cohort, 5,437 were identified with autism spectrum disorder, including 2,067 with childhood autism.

After 14 years of follow-up, the researchers found that the estimated absolute risk of autism spectrum disorder was 1.53 percent, and that of childhood autism was 0.48 percent. The absolute risks for the 508 children exposed to valproate were 4.42 percent for autism spectrum disorder (adjusted hazard ratio [aHR], 2.9) and 2.50 percent for childhood autism (aHR, 5.2).

The drug has an indication for manic and mixed episodes in bipolar disorder and for migraine prevention in addition to seizure control. 

When the cohort was restricted to the 6,584 children born to women with epilepsy, the absolute risk of autism spectrum disorder was 2.44% for those not exposed to valproate (n=6,152 children) vs. 4.15% for those exposed to valproate (n=432 children; aHR, 1.7)

For childhood autism, absolute risk for those exposed to valproate was 2.95% vs. 1.02% among all others in the cohort not exposed to the drug (aHR, 2.9).

“Because autism spectrum disorders are serious conditions with lifelong implications for affected children and their families, even a moderate increase in risk may have major health importance,” the researchers wrote, adding that children born to mothers who used volproate during pregnancy should be examined more carefully for ASD.

Study limitations included lack of data on valproate dosing, whether women actually took the pills that they picked up from the pharmacy, or if they used alcohol or took folic acid supplements during pregnancy. 

In an accompanying editorial, Kimford Meador, MD, and David Loring, PhD, both of Emory University in Atlanta, agreed that risk for autism and ASDs should be included in medication counseling for women who are prescribed volproate.

“Because approximately half of the pregnancies in the U.S. are unplanned, delaying discussions of treatment risks until a pregnancy is considered will leave a substantial number of children at unnecessary risk,” they warned. “Women of childbearing potential should be informed of the potential risks of fetal valproate exposure before valproate is prescribed.”


  1. Christensen J et al. JAMA. 2013; 309: 1696-1703.
  2. Meador KJ, Loring DW. JAMA. 2013; 309: 1730-1731.