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

Kimford J. Meador, Gus A. Baker, Nancy Browning, Jill Clayton-Smith, Deborah T. Combs-Cantrell, Morris Cohen, Laura A. Kalayjian, Andres M Kanner, Joyce D. Liporace, Page B. Pennell, Michael Privitera, David W. Loring

Research output: Contribution to journalArticle

536 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1597-1605
Number of pages9
JournalNew England Journal of Medicine
Volume360
Issue number16
DOIs
StatePublished - Apr 16 2009
Externally publishedYes

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Valproic Acid
Anticonvulsants
Cognition
Gestational Age
Carbamazepine
Phenytoin
Mothers
Confidence Intervals
Maternal Age
Folic Acid
Multicenter Studies
Observational Studies
Pregnant Women
Epilepsy
Parturition
lamotrigine
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Meador, K. J., Baker, G. A., Browning, N., Clayton-Smith, J., Combs-Cantrell, D. T., Cohen, M., ... Loring, D. W. (2009). Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. New England Journal of Medicine, 360(16), 1597-1605. https://doi.org/10.1056/NEJMoa0803531

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 M; Liporace, Joyce D.; Pennell, Page B.; Privitera, Michael; Loring, David W.

In: New England Journal of Medicine, Vol. 360, No. 16, 16.04.2009, p. 1597-1605.

Research output: Contribution to journalArticle

Meador, KJ, Baker, GA, Browning, N, Clayton-Smith, J, Combs-Cantrell, DT, Cohen, M, Kalayjian, LA, Kanner, AM, Liporace, JD, Pennell, PB, Privitera, M & Loring, DW 2009, 'Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs', New England Journal of Medicine, vol. 360, no. 16, pp. 1597-1605. https://doi.org/10.1056/NEJMoa0803531
Meador KJ, Baker GA, Browning N, Clayton-Smith J, Combs-Cantrell DT, Cohen M et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. New England Journal of Medicine. 2009 Apr 16;360(16):1597-1605. https://doi.org/10.1056/NEJMoa0803531
Meador, Kimford J. ; Baker, Gus A. ; Browning, Nancy ; Clayton-Smith, Jill ; Combs-Cantrell, Deborah T. ; Cohen, Morris ; Kalayjian, Laura A. ; Kanner, Andres M ; Liporace, Joyce D. ; Pennell, Page B. ; Privitera, Michael ; Loring, David W. / Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. In: New England Journal of Medicine. 2009 ; Vol. 360, No. 16. pp. 1597-1605.
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AU - Cohen, Morris

AU - Kalayjian, Laura A.

AU - Kanner, Andres M

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AU - Loring, David W.

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N2 - 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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