Researchers advise physicians to discuss the risks with women who have epilepsy and are of childbearing potential.
BALTIMORE—Fetal exposure to the antiepileptic drug (AED) valproate increases a child’s risk of autism and impairs his or her IQ until the age of 6, according to two studies presented at the 65th Annual Meeting of the American Epilepsy Society.
Children born to mothers on valproate monotherapy have a risk of childhood autism that is five times greater than that of children without prenatal exposure to the drug. In addition, children’s IQs are negatively associated with valproate dose, but not with carbamazepine, lamotrigine, or phenytoin.
Increased Risk of Autism
Previous research in animals and small studies involving humans have suggested that valproate treatment during pregnancy was associated with an increased risk of autism in the child.
To investigate this link, Jakob Christensen, PhD, a consultant neurologist at Aarhus University Hospital in Denmark, carried out a population-based cohort study. Using the Danish Civil Registration System, he identified 655,691 children born to 428,431 mothers between 1996 and 2006.
He looked to the Danish Prescription Register to identify women who had filled prescriptions for valproate from 30 days before the estimated date of conception to the day of birth.
Dr. Christensen also used the Danish Psychiatric Register to identify children diagnosed with an autism spectrum disorder and focused particularly on the subgroup that had been diagnosed with childhood autism. He and his colleagues then estimated the risk of autism in children born to mothers who used valproate during pregnancy and adjusted the risk estimates for parental psychiatric history, maternal age, and gender of the child.
Children born after prenatal exposure to valproate had more than twice the risk of an autism spectrum disorder than those without such exposure, according to the investigators. The risk of an autism spectrum disorder was 2.6 following valproate monotherapy and 2.5 following valproate polytherapy. The risk of childhood autism in children with prenatal exposure to valproate was 4.1 following valproate monotherapy and 6.8 following valproate polytherapy.
"Stopping any anticonvulsant medication poses a danger,” Dr. Christensen commented. “Women taking valproate who are contemplating pregnancy should consult with their doctors about the possibility of transitioning to another drug or reducing the dosage of their present medication when that isn’t possible.”
NeurodevelopmentalEffects of AEDs
Kimford Meador, MD, Director of the Emory Epilepsy Center and Professor of Neurology at Emory University in Atlanta, has directed the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study. His preliminary analysis indicated that fetal exposure to valproate impaired children’s IQ at age 3. Dr. Meador and his colleagues conducted a new analysis to determine whether valproate’s effects on IQ continued until age 6.
The NEAD study enrolled pregnant women with epilepsy on AED monotherapy from 1999 to 2004. It aims to examine the long-term neurodevelopmental effects of four common AEDs: carbamazepine, lamotrigine, phenytoin, and valproate. The primary outcome for Dr. Meador’s new analysis was IQ at age 6, as measured by the Differential Ability Scale (DAS). The team also performed a secondary analysis of verbal and nonverbal cluster scores from the DAS. The sample size was 310 children.
Dr. Meador found that child IQ was lower with valproate exposure than it was with exposure to any of the other AEDs. The adjusted mean IQ for children born after valproate exposure was 97. By contrast, the adjusted mean IQ for carbamazepine was 105, the adjusted mean IQ for lamotrigine was 108, and the adjusted mean IQ for phenytoin was 108. The verbal cluster score was less than the nonverbal cluster score for lamotrigine and valproate.
In children born after fetal exposure to valproate, the risks of low IQ and decreased verbal and nonverbal abilities are dose-dependent. However, “the dose-dependent effect is not seen with other AEDs on any of these factors,” said Dr. Meador.
Women of childbearing potential need to understand the risks that valproate entails, said Dr. Meador. “In my mind, it’s a very poor first choice for women of childbearing potential.
“The quandary is that there’s a subgroup of women with primary generalized epilepsy who will only respond to valproate,” he added. “Because it is not possible to predict which women are in this category, neurologists should treat them with another AED before trying valproate,” said Dr. Meador.
—Erik Greb
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