Children Exposed In Utero to Valproate Have Cognitive Deficits

Allison Gandey

December 15, 2010

December 15, 2010 — Children exposed to valproate in utero are more likely to have cognitive deficits that persist for years, report researchers. The new results, from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, again support standing recommendations that women should avoid taking valproate during pregnancy.

"In my opinion, valproate is a poor first choice drug in women of childbearing potential," lead investigator Kimford Meador, MD, from Emory University in Atlanta, Georgia, told Medscape Medical News.

Presenting new results at the American Epilepsy Society 64th Annual Meeting, Dr. Meador showed the cognitive deficits persist at the age of 4.5 years. "The results are unchanged from our age 3 years results published in the New England Journal of Medicine in 2009," he said (2009;360:1597-1605).

Cognitive function at 4.5 years of age.

Guidelines on pregnancy in epilepsy developed by the American Academy of Neurology and the American Epilepsy Society released in 2009 already suggest valproate should be avoided during pregnancy if possible.

The NEAD study is an ongoing, prospective, observational, multicenter analysis in the United States and United Kingdom. Investigators enrolled pregnant women with epilepsy receiving antiepileptic drug monotherapy. The purpose of the study is to determine whether long-term neurodevelopmental effects on offspring exist across 4 commonly used drugs — valproate, carbamazepine, lamotrigine, and phenytoin.

This planned interim analysis includes 209 children, but the study will continue until the children are 6 years of age.

Dr. Meador and his team found that children exposed to valproate had a lower intelligence quotient at the age of 4.5 years (P = .04). They also report that IQ was negatively associated with valproate dose (r = −0.33, P = .04). The associations for the other antiepileptic drugs were not significant.

Maternal intelligence was associated with child IQ for children exposed to carbamazepine (r = 0.57, P < .001), lamotrigine (r = 0.35, P = .003), and phenytoin (r = 0.56, P < .001) but not valproate.

These results are preliminary, Dr. Meador pointed out to Medscape Medical News. "We have not completed all analyses on the age 4 data, which will be completed and submitted for publication in a month or 2."

Dr. Meador says the final results for children 6 years of age will be ready next year. "We are also assessing other cognitive and behavioral outcomes beyond IQ," he said. "Much work remains to be done in this area."

More Maladaptive Behavior

In another presentation at the meeting in San Antonio, Texas, researchers showed that children exposed to valproate in the womb had a higher incidence of maladaptive behavior.

The group led by NEAD investigator Gus Baker, PhD, from University of Liverpool in Merseyside, United Kingdom, reported this was also the case for children exposed to polytherapy.

The study of 272 children found those exposed to valproate or multiple antiepileptic drugs scored significantly higher for conduct difficulties in comparison to control children (P = .023 or P = .012).

In a separate presentation at the meeting by a different group, investigators found that 94% of healthcare professionals in their survey were able to correctly identify that valproate substantially increases the risk for major congenital malformations. However, only 55% were aware this drug crosses the placenta.

Knowledge Gaps

The team, led by Nathalie Jette, MD, from the University of Calgary in Alberta, Canada, developed a questionnaire to assess the current level of knowledge of women's issues related to pregnancy and used it to survey 33 neurologists and neurology residents.

Most respondents were not epileptologists and only followed up patients with epilepsy while they were on the inpatient neurology ward service.

Dr. Jette reports that just 40% of physicians knew there was good evidence of a dose-response relationship between valproate and the risk for major congenital malformations. And only 6% were aware of a similar relationship for lamotrigine.

A quarter of physicians knew that women should be seizure free for 9 months before conception to ensure a high likelihood of a seizure-free pregnancy.

"More knowledge translation efforts are required to increase physician knowledge of issues related to pregnancy for women with epilepsy," her team concluded. "Steps need to be taken to address this knowledge gap."

The NEAD study was funded by the National Institute of Neurological Disorders and Stroke. The researchers in all 3 studies discussed in this report have disclosed no relevant financial relationships.

American Epilepsy Society (AES) 64th Annual Meeting: Clinical platform session C.07, Poster 1.297, Poster 3.327. Presented December 4 and 6, 2010.

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