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Previous Volume 360:1597-1605 April 16, 2009 Number 16 Next

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ABSTRACT

Background Fetal exposure of animals to antiepileptic drugs at doses lower than those required to produce congenital malformations can produce cognitive and behavioral abnormalities, but cognitive effects of fetal exposure of humans to antiepileptic drugs are uncertain.

Methods Between 1999 and 2004, we enrolled pregnant women with epilepsy who were taking a single antiepileptic agent (carbamazepine, lamotrigine, phenytoin, or valproate) in a prospective, observational, multicenter study in the United States and the United Kingdom. The primary analysis is a comparison of neurodevelopmental outcomes at the age of 6 years after exposure to different antiepileptic drugs in utero. This report focuses on a planned interim analysis of cognitive outcomes in 309 children at 3 years of age.

Results At 3 years of age, children who had been exposed to valproate in utero had significantly lower IQ scores than those who had been exposed to other antiepileptic drugs. After adjustment for maternal IQ, maternal age, antiepileptic-drug dose, gestational age at birth, and maternal preconception use of folate, the mean IQ was 101 for children exposed to lamotrigine, 99 for those exposed to phenytoin, 98 for those exposed to carbamazepine, and 92 for those exposed to valproate. On average, children exposed to valproate had an IQ score 9 points lower than the score of those exposed to lamotrigine (95% confidence interval [CI], 3.1 to 14.6; P=0.009), 7 points lower than the score of those exposed to phenytoin (95% CI, 0.2 to 14.0; P=0.04), and 6 points lower than the score of those exposed to carbamazepine (95% CI, 0.6 to 12.0; P=0.04). The association between valproate use and IQ was dose dependent. Children's IQs were significantly related to maternal IQs among children exposed to carbamazepine, lamotrigine, or phenytoin but not among those exposed to valproate.

Conclusions 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. This finding supports a recommendation that valproate not be used as a first-choice drug in women of childbearing potential.

Source Information

From Emory University, Atlanta (K.J.M., P.B.P., D.W.L.); the University of Liverpool, Merseyside, United Kingdom (G.A.B.); EMMES Corporation, Rockville, MD (N.B.); St. Mary's Hospital, Manchester, United Kingdom (J.C.-S.); the University of Texas Southwestern Medical Center, Dallas (D.T.C.-C.); the Medical College of Georgia, Augusta (M.C.); the University of Southern California, Los Angeles (L.A.K.); Rush University Medical Center, Chicago (A.K.); Riddle Health Care, Media, PA (J.D.L.); and the University of Cincinnati, Cincinnati (M.P.).

Address reprint requests to Dr. Meador at the Department of Neurology, Emory University, Woodruff Memorial Research Bldg., 101 Woodruff Cir., Suite 6000, Atlanta, GA 30322, or at kimford.meador{at}emory.edu.

Full Text of this Article

This article has been cited by other articles:

• Tomson, T. (2009). Which Drug for the Pregnant Woman with Epilepsy?. NEJM 360: 1667-1669 [Full Text]  
• (2009). In Utero Antiepileptic Drug Exposure and Childhood IQ. JWatch Neurology 2009: 1-1 [Full Text]