Children exposed to valproate in utero have significantly lower IQs at age 3 than do children exposed to other antiepileptics during gestation, according to findings from the interim analysis of a large international study.
The drug previously had been associated with a higher rate of birth defects in children exposed prenatally. The combination of findings strengthens a recommendation to avoid valproate as a first-line antiepileptic in women who may bear children, Dr. Kimford J. Meador said in an interview.
“Valproate poses a special risk for both congenital malformations and for cognitive impairment,” said Dr. Meador, principal investigator in the Neurodevelopmental Effects of Antiepileptics Drugs (NEAD) study. “Since there are other therapeutic options, it would seem prudent to try those first. At a minimum, it is critical that physicians inform women of this risk when prescribing valproate so that they may make an informed choice.”
NEAD is an ongoing study of 309 children, including three sets of twins, born in either the United States or the United Kingdom from 1999 to 2004, whose mothers were taking a single antiepileptic drug (AED): carbamazepine, lamotrigine, phenytoin, or valproate. The children are being followed to age 6. Dr. Meador, professor of neurology at Emory University, Atlanta, and his associates reported the results of a planned 3-year interim analysis in the New England Journal of Medicine (2009;360:1597–605).
All of the 303 women in the study were taking the drugs for a seizure disorder. Their mean age at delivery was 30 years. Most women were well controlled on their AED, with about 80% having no seizures during their pregnancy.
Most of the children in the study (258) underwent cognitive assessment at either 2 or 3 years of age, or at both ages. Of these, 73 (28%) had been exposed to carbamazepine, 84 (32%) to lamotrigine, 48 (19%) to phenytoin, and 53 (21%) to valproate. Cognitive testing consisted of the Bayley Scales of Infant Development and the Differential Ability Scales.
IQ scores were adjusted for factors that could significantly affect cognitive development, some of which were maternal IQ; age at delivery; education; type of epilepsy; seizure frequency; socioeconomic status; the use of folate, alcohol, tobacco, and drugs; obstetrical complications; gestational age; birth weight; and breastfeeding.
Children exposed to valproate had the lowest mean IQs of any of the exposure groups (92)—significantly lower than those of any other treatment group. The mean IQ in those exposed to carbamazepine was 98; to lamotrigine, 101; and to phenytoin, 99. These did not vary significantly from one another.
The association of valproate with reduced IQ held after adjustment for the confounders in both a linear regression and subgroup analysis, the investigators said. They also examined whether the IQ scores were related to AED dosage. In this analysis, only valproate maintained a significant dose-response relationship.
Additionally, higher maternal IQs were associated with higher child IQs in all of the treatment groups except valproate.
The results are consistent with several European studies that have found poor cognitive outcomes in children exposed to the drug prenatally, the investigators said. The drug also has been found to increase the rate of congenital malformations, compared with other AEDs. A recent meta-analysis found the rate to be as many as 11% of births.
Unfortunately, Dr. Meador and his colleagues wrote, women whose seizures are well controlled on valproate may be placed on the horns of a dilemma when trying to balance gestational safety with seizure control.
“For some patients, valproate is the only medication that adequately controls seizures. Such women should be informed of the potential risks associated with the use of this medication in pregnancy. If a woman taking valproate is already pregnant, it's critical that she not stop valproate without consultation with her physician, since stopping an antiepileptic drug could lead to seizures and serious consequences for both the woman and her fetus.”
“One other important point is that less than half of the prescriptions for valproate are for seizures or epilepsy. The majority are for pain or psychiatric indications. I believe that the women taking valproate for other indications are at the same risk as our women with epilepsy,” he said in the interview.
The study was supported by grants from the United Kingdom Epilepsy Research Foundation and the National Institute of Neurological Disorders and Stroke. Dr. Meador reported receiving research support from GlaxoSmithKline, Myriad Pharmaceuticals, Marinus Pharmaceuticals, UCB Pharmaceuticals, and several other companies and foundations.