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Comparative Study
. 2009 Apr 16;360(16):1597-605.
doi: 10.1056/NEJMoa0803531.

Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs

Kimford J Meador  1 , Gus A Baker, Nancy Browning, Jill Clayton-Smith, Deborah T Combs-Cantrell, Morris Cohen, Laura A Kalayjian, Andres Kanner, Joyce D Liporace, Page B Pennell, Michael Privitera, David W Loring; NEAD Study Group
Collaborators, Affiliations
Comparative Study

Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs

Kimford J Meador et al. N Engl J Med. .

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.

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Conflict of interest statement

Dr. Meador reports receiving research support from the McKnight Brain Institute, the MCG Foundation, GlaxoSmithKline, Eisai Medical Research, Myriad Pharmaceuticals, Marinus Pharmaceuticals, NeuroPace, SAM Technology, and UCB Pharma and serving on the professional advisory board of the Epilepsy Foundation. Dr. Baker reports serving on paid advisory boards for UCB Pharma; receiving lecture fees from Pfizer, UCB Pharma, and Janssen; receiving grant support from Sanofi-Aventis and Pfizer; and serving as an expert witness in litigation related to neurodevelopmental effects of antiepileptic drugs. Dr. Clayton-Smith reports serving as an expert witness in litigation related to neurodevelopmental effects of antiepileptic drugs. Dr. Combs-Cantrell reports receiving lecture fees from GlaxoWellcome. Dr. Kalayjian reports receiving lecture fees from GlaxoSmithKline and Ortho-McNeil and grant support from Marinus Pharmaceuticals. Dr. Kanner reports receiving lecture fees from GlaxoSmithKline, Ortho-McNeil, Pfizer, and UCB Pharma; advisory-board fees from GlaxoSmithKline, Ortho-McNeil, Valeant Pharmaceuticals, and UCB Pharma; and grant support from GlaxoSmithKline and Novartis. Dr. Liporace reports serving on the professional board of the Epilepsy Foundation of Eastern Pennsylvania. Dr. Pennell reports serving on the Keppra Pregnancy Registry Expert Panel (UCB Pharma) and receiving grant support from UCB Pharma, Marinus Pharmaceuticals, and GlaxoSmithKline. Dr. Privitera reports receiving consulting and advisory-board fees from Ortho-McNeil, UCB Pharma, Johnson & Johnson, and the National EpiFellows Foundation; lecture fees from Ortho-McNeil, Pfizer, GlaxoSmithKline, Janssen, and UCB Pharma; and grant support from UCB Pharma, Ortho-McNeil, and the American Epilepsy Society. Dr. Loring reports receiving consulting fees from UCB Pharma, NeuroPace, and Sanofi-Aventis and grant support from Myriad Pharmaceuticals, SAM Technology, and Novartis. No other potential conflict of interest relevant to this article was reported.

Figures

Figure 1
Figure 1. IQ Scores of Children Who Were Exposed to Antiepileptic Drugs In Utero, According to Drug and Dose
The means (black squares) and 95% confidence intervals (horizontal lines) are given for the children’s IQ as a function of antiepileptic drug and dose. The children’s IQs were adjusted for factors in the primary model, except dose. Low doses are below the median for each antiepileptic drug, and high doses are equal to or above the median. The median doses were 750 mg per day for carbamazepine, 433 mg per day for lamotrigine, 398 mg per day for phenytoin, and 1000 mg per day for valproate. The vertical line is the mean IQ for all children, and the size of the black squares is proportional to the sample size.
Figure 2
Figure 2. IQ Scores of Children Who Were Exposed to Antiepileptic Drugs In Utero, According to Drug and Type of Maternal Epilepsy
The means (black squares) and 95% confidence intervals (horizontal lines) are given for the children’s IQ as a function of antiepileptic drug and type of maternal epilepsy. The children’s IQs were adjusted for factors in the primary model. The vertical line is the mean IQ for all children, and the size of the black squares is proportional to the sample size.
Figure 3
Figure 3. Relationship between Child and Maternal IQ According to Antiepileptic Drug
Child IQ at 3 years of age and maternal IQ are significantly correlated for all antiepileptic drugs except valproate. The data are from an intention-to-treat sample of 309 children. IQ was imputed for 77 children.
See this image and copyright information in PMC

Comment in

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