Children exposed to valproate in utero have significantly lower IQs at age 3 years 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 on 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 neurology of Emory University, Atlanta, and his associates reported 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 of the 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.
IQ scores were adjusted for factors that could significantly affect cognitive development.
Children exposed to valproate had a mean IQ of 92, the lowest any of the exposure groups and 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.
In this analysis, only valproate maintained a significant dose-response relationship. In addition, 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 findings of both physical and cognitive problems with prenatal exposure show that the drug probably is not safe for use at any time during pregnancy, said Dr. Michael Privitera, director of the Cincinnati Epilepsy Center and another of the NEAD investigators.
“The neural tube defects [with which valproate is associated] occur during the first trimester, so there has been a question whether we might be able to use valproate later in pregnancy. This study shows that the answer is no, because cognitive development in the fetus occurs during the third trimester,” Dr. Privitera said in an interview.
“For some patients, valproate is the only medication that adequately controls seizures,” Dr. Meador and his colleagues wrote. “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.”
The risk of adverse fetal outcomes holds true for any woman who takes the drug during pregnancy, regardless of the indication, Dr. Meador said in the interview. “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.”