WASHINGTON – One-quarter of valproate-exposed children in an ongoing study had a major birth defect or reduced IQ, Dr. Kimford Meador reported at the annual meeting of the American Academy of Neurology.
The findings reconfirm just how dangerous the antiepileptic drug can be to a developing fetus, especially when viewed along with findings of increased risk associated with even low valproate doses, said Dr. Meador of Stanford (Calif.) University.
Dr. Kimford J. Meador
“I don’t think we have even yet captured all the risks that are there,” he said. In addition, he stressed that valproate is a poor choice in a woman who plans a pregnancy, and it should not be used, unless absolutely necessary, in any woman of childbearing age who maintains her fertility.
The drug also is commonly employed to treat depression and migraine, he added.
The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study assessed neurodevelopmental outcomes in 311 children whose mothers took valproate, phenytoin, carbamazepine, or lamotrigine for epilepsy during pregnancy. These drugs were chosen because they were the most commonly prescribed when the study began.
Analyses in the prior Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study have shown that valproate is linked to major congenital malformations and lower IQ in toddlers (N. Engl. J. Med. 2009;360:1597-605) and 6-year-olds (Lancet Neurol. 2013;12:244-52). In another study, the drug has also been linked to an increased risk of autism spectrum disorders and autism (hazard ratios of 3.0 and 5.2, respectively).
The new analysis examined the risk of either a negative physical or cognitive outcome, or a combination of both, among the entire NEAD group. The individual domain of verbal IQ also was examined because it was an area of particular concern in the 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 less than one standard deviation lower than their mother’s IQ – about 15 points.
Of the children exposed to valproate, 7 of 69 children had some kind of a major congenital malformation, and 12 of 58 children had a decreased IQ, compared with the mother. A full 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 a variety of cognitive measures: 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 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.”
However, a recent U.K. study showed an increased risk of both outcomes among children who were exposed to even a very low dose of the drug – below 800 mg daily (Neurology 2015;84:382-90).
It’s not clear how valproate might exert 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 antiepileptics unless they are already having seizures.”
There was also an “unexpected” finding in the analysis, Dr. Meador said. “We were collecting information on periconceptional 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.”
Dr. Meador has received personal compensation for activities on behalf of the Epilepsy Study Consortium with Eisai, NeuroPace, Novartis, Supernus, UCB Pharma, Upsher-Smith Laboratories, and Vivus Pharmaceuticals as a consultant. He has received research support from Pfizer and UCB Pharma.
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This article was updated May 5, 2015.