SAN DIEGO — In utero exposure to valproate is associated with a greater risk of cognitive impairment in offspring, compared with exposure to other commonly used antiepileptic medications, Dr. Kimford J. Meador reported at the annual meetings of the American Epilepsy Society and the Canadian League Against Epilepsy.
“Further studies are needed to investigate additional [antiepileptic] drugs that have not been studied and determine if the effects we see here continue,” said Dr. Meador, a neurologist who directs the epilepsy program in the department of neurology at the University of Florida, Gainesville.
The findings come from a preliminary analysis of cognitive data from the ongoing Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study, a 25-center trial in the United States and England that is funded by the National Institute of Neurological Disorders and Stroke. The long-term goal of NEAD is to examine children born to mothers with epilepsy at 6 years of age to see if differential neuropsychological effects are associated with in utero exposure to the four most commonly prescribed antiepileptic medications.
Dr. Meador and his associates performed neuropsychological testing on 2-year-old children born to mothers with partial or primary generalized epilepsy who were on antiepileptic monotherapy with carbamazepine, lamotrigine, phenytoin, or valproate. Subsequent testing was performed when the children were aged 3.5, 4, and 6 years.
The researchers administered the mental scale of the Bayley Scales of Infant Development and analyzed the children's Mental Developmental Index (MDI) scores while controlling for maternal IQ.
At the meeting, Dr. Meador presented 2-year data on 185 children in the study. During pregnancy, 48 of the children were exposed to carbamazepine, 66 to lamotrigine, 42 to phenytoin, and 29 to valproate.
The mean MDI scores were 93 in children exposed to carbamazepine, 97 in those exposed to lamotrigine, 91 in those exposed to phenytoin, and 86 in those exposed to valproate. An MDI score of 100 represents the mean score in a normal population.
Almost one-quarter of children exposed to valproate (24%) had MDIs of less than 70, compared with 12% of those exposed to carbamazepine, 11% of those exposed to lamotrigine, and 12% of those exposed to phenytoin.
The apparent adverse effect of valproate was related to anticonvulsant blood level. “This is true whether we analyzed it for blood levels across the entire pregnancy or for just the third trimester,” Dr. Meador noted. The pattern also held true after the researchers controlled for confounding factors, including seizure frequency, maternal age, history of alcohol use during pregnancy, and gestational age.