WebMD Medical News
Louise Chang, MD
April 15, 2009 -- Women with epilepsy who took the drug valproate (Depakote) during pregnancy gave birth to children whose IQ at age 3 averaged up to 9 points lower than the scores of children exposed to other epilepsy drugs, according to a new study.
"Valproate exposure to the unborn child is associated with a lower IQ, which is not explained by any of the other factors [influencing IQ], such as mother's IQ, mother's age, or epilepsy type," says Kimford J. Meador, MD, the study's lead author and professor of neurology at Emory University in Atlanta.
The average IQ of children born to women who took valproate was 92 -- 8 below the 100 that is considered average -- and the scores of those exposed to other epilepsy drugs ranged from 98 to 101, he tells WebMD.
The implications go beyond the use of the drugs in women of childbearing age who have epilepsy, Meador tells WebMD, because the drug is also commonly prescribed for migraine headaches and bipolar disorder.
In response to the study, published in Wednesday's New England Journal of Medicine, a spokesperson for Abbott, which makes valproate, said the drug may be the only effective medication for some women.
Meador and his colleagues enrolled pregnant women with epilepsy who received care at 25 epilepsy centers in the U.S. and the United Kingdom from late 1999 to early 2004.
About 3 million people in the U.S. have some form of epilepsy, according to the Epilepsy Foundation of America, and experience seizures, which are brief disturbances of electrical activity in the brain. About 25,000 babies are born annually in the U.S. to mothers who have epilepsy.
The researchers gathered information about the type of epilepsy drug taken, the dose, compliance with the medication, the mother's IQ, her age at delivery, race or ethnicity, type of epilepsy, and lifestyle habits such as the use of alcohol, tobacco, and other drugs during pregnancy.
The women in the study took one of four drugs: valproate (Depakote), lamotrigine (Lamictal), carbamazepine (Tegretol), or phenytoin (Dilantin).
Although the association between epilepsy drugs and birth defects has long been known -- with valproate found to have risks of birth defects two to four times as high as other epilepsy drugs -- the potential link between the drugs and cognitive functioning in the children has been studied much less, Meador says.
His team followed the children for six years to assess intelligence, with the current report focusing on the interim test results on the 309 children at age 3.
Children born to mothers who took valproate had the lowest average IQ, Meador's team found, even after adjusting for other factors that might influence IQ, such as a mother's IQ, her age at delivery, or the type of epilepsy.
The average IQs were:
"An average IQ is 100," Meador says, "and below 70 is mentally retarded."
Exactly how valproate lowers IQ is not known, Meador says. "We think the effect may be similar to babies exposed to alcohol in utero," he says, with both substances causing damage of brain cells.
When they looked more closely at the doses of valproate, the researchers found that children born to women who took less than 1,000 milligrams a day of valproate had higher IQs than those who took more than 1,000 milligrams. Those exposed to high doses had an average IQ of 87, and those exposed to lower doses had an average IQ of 97, they found.
Although the researchers found the lower doses of valproate associated with less risk, Meador says he can't pinpoint a "safe" dose.
Even so, the study finding "supports a recommendation that valproate not be used as a first-choice drug in women of childbearing potential," the authors conclude in the report. They reached that conclusion, Meador says, despite the fact that some women with epilepsy respond better to valproate than to other drugs.
Women should not stop any epilepsy drug without consulting their physician, Meador warns.
After reviewing the study, Abbott, the Chicago-based pharmaceutical company that makes Depakote, issued this statement: "For many women, Depakote may be the only effective medicine to control their seizures, but it is important that physicians and patients have a candid conversation about the risks of treatment versus the benefits of treatment."
The label on Depakote alerts users and physicians to the risks of the drug during pregnancy, says Raquel Powers, an Abbott spokeswoman.
Even before the study linking valproate with lower IQs in children of mothers with epilepsy, it was not a "first-choice" drug for women of childbearing age because of the risk of birth defects, writes Torbjorn Tomson, MD, of the Karolinska Institutet in Stockholm, who authored an editorial to accompany the study.
His advice: "Discussion of the risks of valproate should be balanced with consideration of the risks of uncontrolled seizures."
"This study gives us information to make an informed decision to avoid valproate in women of childbearing age," says Page Pennell, MD, an associate professor of neurology at Emory University and chair of the national professional advisory board for the Epilepsy Foundation of America, based in Landover, MD. Pennell is also a co-author on the paper.
Speaking to WebMD on behalf of the Epilepsy Foundation, Pennell says that the foundation advises women to talk to their doctor about the risk of various medicines vs. the risk of seizures. "Get on the safest medication for pregnancy," she says.
Currently, guidelines from the American Academy of Neurology and other organizations don't differentiate among epilepsy drugs in terms of risks of birth defects, the authors note in the report..
But new, more specific guidelines are expected to be issued soon from the American Academy of Neurology, say Meador and Pennell.
SOURCES:Kimford J. Meador, MD, professor of neurology, Emory University, Atlanta.Meador, J. New England Journal of Medicine, April 16, 2009, vol 360: pp 1597-1605.Tomson, T. New England Journal of Medicine, April 16, 2009, vol 360: p 1667.Page Pennell, MD, associate professor of neurology, Emory University, Atlanta; chair of the national professional advisory board, Epilepsy Foundation of America, Landover, Md.Raquel Powers, spokeswoman, Abbott.
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