Valproate linked to high birth defect rates

Roughly 20 percent of epileptic women who take the antiseizure drug valproate during pregnancy will have a fetus with a serious adverse outcome, almost twice the rate associated with the next most problematic antiepileptic drug, new research shows.

Several years ago, the American Academy of Neurology and other groups issued guidelines for treating epileptic women during pregnancy. Since antiepileptic drugs, in general, have been linked to adverse fetal outcomes, the strategy was to optimize treatment before conception, using a single antiepileptic drug if possible, at the lowest effective dose. These guidelines did not, however, differentiate between the various drugs for their potential to cause birth defects.

At the time the guidelines came out, "there were no data comparing the adverse fetal effects of the different antiepileptic drugs," lead author Dr. Kimford J. Meador, from the University of Florida in Gainesville, told Reuters Health. "In the last two years, however, seven studies have come out, all showing an increased risk with valproate."

The initial focus of the current study wasn't to look at the rate of birth defects and fetal deaths associated with antiepileptic drugs, Meador noted. "We wanted to look at the impact of these drugs on neurodevelopmental later in life." They were only monitoring the children until they became old enough to complete the tests. "Then the early effects came to light."

The study, which is reported in the journal of Neurology, involved 333 pregnant women who were drawn from 25 epilepsy centers across the US and UK between October 1999 and February 2004. All of the women were receiving antiepileptic therapy with a single drug, including carbamazepine in 110, lamotrigine in 98, phenytoin in 56 and valproate in 69.

The rate of serious adverse outcomes, which included congential malformation and fetal death, was 20.3 percent for valproate, 10.7 percent for phenytoin, 8.2 percent for carbamazepine, and 1.0 percent for lamotrigine.

Valproate use was associated with two fetal deaths and 12 congenital malformations, including skull deformities, heart structural abnormalities, kidney swelling due to backup of urine; and cleft palate, a birth defect in which the mouth or lip tissues don't properly form during development; and several others.

My personal view is that valproate should not be used as the first therapy in pregnant women, Meador said.

However, for women who fail to response to other antiepileptic drugs and must use valproate, "their doctor should emphasize that despite the increased risk of adverse outcomes, the majority of pregnant women who take the drug have normal, healthy babies."

Meador said the neurodevelopmental results of the study are now coming in and he hopes to present them at an upcoming meeting.

SOURCE: Neurology, August 8, 2006.