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Women who take valproate (Depacon) during pregnancy may increase the risk of childhood autism and its spectrum disorders in their children, a population-based study showed.

In utero exposure to the 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 found.

The absolute risks were 2.5% and 4.4%, respectively, and remained significantly elevated after adjustment for parents' epilepsy and psychiatric disease, the group reported in the April 24 issue of the Journal of the American Medical Association.

"For women of childbearing potential who use anti-epileptic medications, these findings must be balanced against the treatment benefits for women who require valproate for epilepsy control," they concluded.

But "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," they added.

The American Academy of Neurology recommends avoiding valproate in pregnancy whenever possible due to cognitive and physical birth defect problems for children exposed in utero.

The additional risk of autism and spectrum disorders needs to be included in counseling for women now too, Kimford Meador, MD, and David Loring, PhD, both of Emory University in Atlanta, recommended in an accompanying editorial.

"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."

The study included all 655,615 children born in Denmark from 1996 through 2006. National registries indicated autism spectrum disorder diagnoses -- childhood autism, Asperger syndrome, atypical autism, and other or unspecified pervasive developmental disorders -- in 5,437 children through follow-up to a mean age of 8.8 years.

Filled valproate prescriptions suggested exposure during pregnancy in 508 children.

After adjusting for parental age at conception and psychiatric history, gestational age, sex, congenital malformations, and other potentially confounding factors, the risks for valproate-exposed children remained elevated.

Compared with those whose mothers had used the drug but stopped at least 30 days before conception, the hazard ratios were:

• 2.2-fold higher risk of autism spectrum disorder (95% CI 1.02 to 4.9)
• 5.6-fold higher risk of childhood autism (95% CI 1.7 to 18.1)

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

When looking only at children of mothers with epilepsy (432 of 508), the risk of autism was 2.9 times higher with valproate exposure, with an absolute risk of 2.95% versus 1.02% among all others in the cohort not exposed to the drug.

Autism spectrum disorder was also 70% elevated in that analysis, but not statistically significant.

The risk for kids exposed to valproate during gestation also appeared elevated if the mother wasn't taking it for epilepsy, but the numbers were small.

This finding suggested a true biological effect of the drug rather than the underlying condition, possibly via alteration of neurotransmitter functioning involved in cell migration and differentiation, neuronal apoptosis, or synaptic plasticity.

But the smaller impact in the maternal epilepsy group than overall indicated some confounding, Christensen's group noted.

"We cannot exclude the possibility that children of women who used valproate during pregnancy may be examined more carefully for autism spectrum disorders, because valproate has been associated with adverse effects," they acknowledged.

Exposure during the first trimester when organs are forming and other aspects of timing didn't appear to influence the autism risk with valproate.

That may not have been very reliable, though, since the timing was based on when women filled the prescription not when they took the pills, and because few women took the drug solely in later pregnancy.

The study lacked data on the dose of valproate, whether women actually took the pills that they picked up from the pharmacy, or their alcohol and folic acid supplement use in pregnancy.

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