Valproate in Pregnancy Problematic, Carbamazepine Another Concern

Allison Gandey

December 18, 2009

December 18, 2009 (Boston, Massachusetts) — New evidence confirms the dose-related effect of fetal valproate exposure on cognitive development. It also suggests that carbamazepine affects verbal abilities. The new pregnancy data were presented here at the American Epilepsy Society 63rd Annual Scientific Conference.

"The main message to neurologists or other clinicians is that valproate poses the greatest threat to ultimate cognition in the unborn child compared to other antiepileptic drugs," lead investigator Kimford Meador, MD, from Emory University in Atlanta, Georgia, told Medscape Neurology. "This effect is worse for verbal abilities and is dose dependent."

Dr. Kimford Meador presenting at the pediatric highlights session.

Dr. Meador urges caution in interpreting the results for carbamazepine. "This was not seen in other studies," he noted. "We still have a lot of unanswered questions, and additional research is critically needed."

Valproate and carbamazepine are antiepileptic drugs that are also prescribed for psychiatric indications.

The new results are based on 3-year cognitive outcomes from the Neurodevelopmental Effects of Antiepileptic Drugs study. The ongoing prospective, multicenter study is based in the United States and the United Kingdom. It is designed to determine the long-term neurodevelopmental effects of 4 commonly used antiepileptic drugs: valproate, carbamazepine, lamotrigine, and phenytoin.

Investigators compared the cognitive outcomes of 234 children. They evaluated the children's expressive language skills, receptive language skills, visuomotor-construction ability, and nonverbal intellectual ability. They found that children who were exposed to valproate had cognitive deficits.

Table. Effects of In Utero Valproate Exposure at 3 Years of Age

Cognitive Outcome R Value P Value
Expressive language −0.40 <.007
Receptive language −0.45 <.002
Visuomotor-construction −0.39 <.007
Nonverbal −0.34 <.02

The researchers found that child performance was also negatively associated with carbamazepine dose for expressive language (r = −.36, P < .005) and receptive language (r = −0.32, P < .01).

"This raises concerns that higher carbamazepine doses during pregnancy may adversely affect a child’s language ability," Dr. Meador said at the meeting. "Additional research is needed to confirm this finding."

Investigators observed no dose effects for lamotrigine and phenytoin.

No dose effects for lamotrigine and phenytoin.

First results linking valproate exposure to impaired IQ in children were presented at last year's epilepsy society meeting and published in April in the New England Journal of Medicine (2009;360:1597-1605).

Session moderator Paul Van Ness, MD, from Southwestern Medical Center, in Dallas, Texas, called this an important, practice-changing study. "Valproate is a great drug. It works and it's inexpensive, but we now know there are other potentially safer options for women who may become pregnant," he said.

In an accompanying New England Journal of Medicine editorial, Torbjörn Tomson, MD, from the Karolinska Institutet, in Stockholm, Sweden, noted, "Although the study by Meador and colleagues is the largest study of this question to date, the numbers of children exposed to individual antiepileptic drugs are still small, and additional studies are needed to confirm the results and refine risk assessments."

Dr. Meador and his team are working to publish these latest findings and plan to continue following up the children in their study.

The study was funded by the National Institute of Neurological Disorders and Stroke and the UK Epilepsy Research Foundation. The researchers have disclosed no relevant financial relationships.

American Epilepsy Society (AES) 63rd Annual Scientific Conference: Abstract 2.180. Presented December 7, 2009.

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