Valproate Anti-Epilepsy Drug In Pregnancy Linked To Lower IQ In Children

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Main Category: Epilepsy
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Article Date: 16 Apr 2009 - 2:00 PDT

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A study found that children born to women who took the anti-epilepsy drug valproate while pregnant tended to score significantly lower in IQ tests by an average of 6 to 9 points at age 3 than children born to mothers who took other anti-epilepsy drugs. The researchers said the findings support the recommendation that women of childbearing age should not be offered this drug as a first choice.

The study is published online in the 16 April issue of the New England Journal of Medicine, NEJM, and is the work of scientists from Emory University, Atlanta, Georgia, USA, the University of Liverpool, Merseyside, UK, and other research centres in the US and the UK. The lead and corresponding author is Dr Kimford J Meador, professor of neurology at the Emory University School of Medicine.

Studies have shown that when animal fetuses are exposed to antiepileptic drugs at doses below those that lead to birth defects, they can end up with cognitive and behavioural abnormalities. However, the effect on human IQ of being exposed to such drugs while in the womb are uncertain, wrote the authors in their background information.

Valproate is an anti-epilepsy drug that is also prescribed for bipolar disorder and migraine headaches. It is marketed under the brand name Depakote (by Abbott Laboratories in the US, and by Pfizer in the UK), and last year the US Food and Drug Administration approved a generic version.

The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study is following more than 300 children in the UK and the US who were born to mothers with epilepsy who were taking one of four single anti-epileptic drugs (carbamazepine, lamotrigine, phenytoin, or valproate) while they were pregnant. Enrollment started in 1999 and finished in 2004, and took place at 25 centers in the UK and the US.

Overall, NEAD will follow the neurodevelopment of children born to the women until they reach the age of 6, but the present study focuses on cognitive tests done when they were 3 years old.

The results showed that:

• 3 year old children exposed to valproate in the womb had significantly lower IQ scores than those who had been exposed to any of the other three anti-epileptic drugs.


• The mean IQ was 92 for children exposed to valproate, 98 for those exposed to carbamazepine, 99 for those exposed to phenytoin, and 101 for those exposed to lamotrigine.


• These results include adjustments for the mother's IQ, the dose of the drug, duration of pregnancy, and the mother's consumption of folate during pregnancy.


• The IQ scores of children exposed to valproate were on average between 6 and 9 points lower than those exposed to any of the other three drugs.


• The average was 9 points lower than that of those exposed to lamotrigine (95 per cent confidence interval [CI] ranging from 3.1 to 14.6, P=0.009), 7 points lower than that of those exposed to phenytoin (95% CI 0.2-14.0, P=0.04), and 6 points lower than that of those exposed to carbamazepine (95% CI 0.6-12.0, P=0.04).


• The link between valproate exposure and the toddlers' IQ depended on the dose used by their mothers in pregnancy.


• Children's IQ was significantly linked to their mother's IQ for all the drugs except valproate.

The authors concluded that:

"In utero exposure to valproate, as compared with other commonly used antiepileptic drugs, is associated with an increased risk of impaired cognitive function at 3 years of age."

They suggested that this finding supports:

"A recommendation that valproate not be used as a first-choice drug in women of childbearing potential."

The NEAD study had previously discovered that exposure to valproate also raised the risk of physical birth defects, said the researchers in a separate statement to the press.

Meador said that:

"There are clear risks associated with valproate, and physicians have an obligation to inform women about them."

About 15 per cent of patients with primary generalized epilepsy respond only to valproate, but this is not the case for other forms of epilepsy, he explained:

"Valproate still has an important role in treating epilepsy, because some patients' seizures can only be controlled with valproate. However, we are recommending that women with epilepsy try another drug first," said Meador.

Pregnant women currently taking valproate should not stop without talking to their doctor, so as to avoid the risk of serious seizures, cautioned Meador.

The effect on children's IQ appears to depend on the dose taken by the mother, so perhaps the risk can be lowered by lowering the dose, or using a sustained release version, he added.

"Cognitive Function at 3 Years of Age after Fetal Exposure to Antiepileptic Drugs."
Meador, Kimford J., Baker, Gus A., Browning, Nancy, Clayton-Smith, Jill, Combs-Cantrell, Deborah T., Cohen, Morris, Kalayjian, Laura A., Kanner, Andres, Liporace, Joyce D., Pennell, Page B., Privitera, Michael, Loring, David W., the NEAD Study Group. N Engl J Med 2009 360: 1597-1605.
Published online 16 April 2009.

Sources: NEJM, Emory University.

Written by: Catharine Paddock, PhD


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