Antiepileptic Drug Linked to Risk of Impaired Cognitive Development

CINCINNATI—A study co-authored by a University of Cincinnati (UC) physician and published in the New England Journal of Medicine links a drug commonly used to treat epilepsy with increased risk of impaired cognitive development in children.

The study, published in the Journal’s April 16, 2009, edition, includes a recommendation that the antiepileptic drug valproate (marketed under the brand name Depakote in the United States) not be used as a first choice drug in women of child-bearing age. Approximately 25,000 children are born in the United States each year to mothers with epilepsy.

Michael Privitera, MD, a professor in UC’s neurology department, was one of the co-authors of the study. The lead author was Kimford Meador, MD, of Emory University in Atlanta. All are members of the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study Group.

The study, funded by the National Institutes of Health (NIH) and conducted at multiple sites in the United States and the United Kingdom, assessed the effect of several drugs on cognitive function of 309 children whose mothers received the drugs during pregnancy. Carbamazepine, lamotrigine and phenytoin were studied in addition to valproate.

At 3 years of age, the study found, children who had been exposed to valproate in the womb had significantly lower IQ scores than those who had been exposed to the other antiepileptic drugs. After adjustment for maternal IQ, age at delivery, dosage level and other factors, the mean IQ for children exposed to valproate was 92. Other scores were 101 for children exposed to lamotrigine, 99 for phenytoin and 98 for carbamazepine.
 
Additionally, the association between valproate use and IQ was found to be dose dependent—the stronger the dose, the greater the cognitive impairment. And children’s IQs were significantly related to their mothers’ IQs among children exposed to carbamazepine, lamotrigine and phenytoin, but not among those exposed to valproate.

“We’ve known for years that women who receive antiepileptic drugs during pregnancy, in general, are at higher risk of physical malformations in their children,” says Privitera. “There has been some speculation that there are cognitive deficits too, but previous studies have not been designed well enough to be able to interpret that.”

This study, Privitera says, addressed that problem by enrolling women receiving antiepileptic drugs during pregnancy, testing their IQs, and then testing their children’s IQs over several years. The children will continue to be tested at three-year intervals.

Privitera points out that while physical malformations generally are caused by problems in the first trimester of pregnancy, cognitive development is primarily impacted during the third trimester. “So now we have to worry about the drug’s effects during the later part of pregnancy as well,” he says.

Using another drug besides valproate isn’t always as simple as it sounds, Privitera says. “Some people respond to one drug and not others,” he says, “so there are some women who only respond to valproate.” And it’s dangerous to forgo antiepileptic drugs during pregnancy, because uncontrolled seizures can harm the unborn child as well as the mother.

The challenge in cases of women who respond only to valproate, Privitera says, is to identify the minimally effective dose that will keep seizures from happening. Additionally, the patient should understand the potential risks and benefits and weigh them with her physician.

An accompanying editorial by Torbjorn Tomson, MD, of the Karolinska Institute in Stockholm, echoes that advice, saying that discussion of the study’s findings should be included in pre-pregnancy counseling. Tomson also says potential adverse fetal effects should be considered in antiepileptic drug selection for all women with epilepsy who are of child-bearing age.

Privitera stresses that it’s important for all women of child-bearing age to take folic acid, which reduces the risk of neural tube defects such as spina bifida. Folic acid is a B vitamin found mostly in leafy green vegetables, orange juice and enriched grains.

“No matter what medication they’re receiving, women with epilepsy should work closely with their doctors in planning pregnancy and be closely monitored during pregnancy to minimize the risk of mother and child,” Privitera says.