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WASHINGTON, DC—One-quarter of children who were exposed to valproate in utero had a major birth defect, reduced IQ, or both of those adverse outcomes, according to research presented at the 67th Annual Meeting of the American Academy of Neurology.
This finding, based on a reanalysis of data from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, adds to researchers’ understanding of how dangerous valproate can be to a developing fetus, said Kimford Meador, MD, Professor of Neurology and Neurosciences at Stanford University and Clinical Director of Stanford Comprehensive Epilepsy Center in California.
“I don’t think we have even yet captured all the risks that are there,” he said. He stressed that valproate, which also is used to treat depression and migraine, is a poor choice in a woman who plans a pregnancy and should not be used unless absolutely necessary in any woman of childbearing age who maintains her fertility.
The Effects of AEDs During Pregnancy
From 1999 to 2004, the NEAD study enrolled pregnant women with epilepsy who were on antiepileptic drug (AED) monotherapy (ie, valproate, phenytoin, carbamazepine, or lamotrigine) and tracked the outcomes in 311 children. The AEDs examined in the study were the most commonly prescribed therapies when the study began. Prior analyses of the NEAD study have shown that valproate is linked to major congenital malformations and lower IQ in toddlers and 6-year-olds. In another study, the drug was linked to an increased risk of autism spectrum disorders and autism.
The new analysis examined the risk of either a negative physical or cognitive outcome, or a combination of both, in the entire NEAD group. Verbal IQ also was examined because it had been an area of concern in previous analyses. Because maternal IQ is the major predictor of child IQ in the general population, the analysis looked at how many children had an IQ more than one standard deviation (about 15 points) lower than their mother’s IQ.
Of the children exposed to valproate, seven of 69 (10%) had a major congenital malformation, and 12 of 58 children (21%) had a decreased IQ, compared with the mother. About 25% (17 of 69 children) had one or both of these problems. All of the outcomes were significantly worse than those seen with carbamazepine (birth defect, 5%; low IQ, 11%; either or both, 10%); lamotrigine (birth defect, 1%; low IQ, 12%; either or both, 12%); and phenytoin (birth defect, 7%; low IQ, 6%; either or both, 13%).
The investigators also examined cognitive measures such as verbal and nonverbal IQ, General Memory Index, Behavior Rating of Inventory of Executive Function, and NEPSY Executive Index. “Whatever cognitive measure we employed, we saw a greater negative effect as the valproate dose increased,” Dr. Meador said. “At what level the dose confers no risk is unclear, though, because it’s hard to adjust for genetic risk factors and the individual drug absorption levels, among other things.”
Risk Seen at Low Doses
A study published in the January 27 issue of Neurology found that exposure to even a low dose of the drug—less than 800 mg daily—was associated with impaired verbal abilities. It’s not clear how valproate exerts its deleterious effects, Dr. Meador noted. “It may damage the developing brain by causing neuronal death, or causing dysfunction in the surviving cells. This risk of adverse drug-induced effects on the immature brain doesn’t go away immediately when the baby comes out of the womb,” he observed. “It’s a complicated area to study, too, because we don’t normally expose neonates to antiepileptic drugs unless they are already having seizures.”
Researchers made an unexpected finding in their analysis of the NEAD study data, Dr. Meador said. “We were collecting information on periconceptual folate as a confounding factor. There was a very robust positive effect of about a 6-point IQ gain in those children, compared to those whose mothers didn’t take folate at time of conception.
“This is consistent with the idea that periconceptual folate may not only be important for reducing fetal malformations, but may also have a positive effect on cognitive abilities,” Dr. Meador said. “So, I recommend that all women of childbearing age should be taking folate.”
An extension of the NEAD study, the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study, aims to answer further questions about how to care for women with epilepsy in anticipation of and during pregnancy.
—Michele G. Sullivan
