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

Full 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. 2009 Massachusetts Medical Society

Author information

Author/s: Meador, Kimford J (KJ); Baker, Gus A (GA); Browning, Nancy (N); Clayton-Smith, Jill (J); Combs-Cantrell, Deborah T (DT); Cohen, Morris (M); Kalayjian, Laura A (LA); Kanner, Andres (A); Liporace, Joyce D (JD); Pennell, Page B (PB); Privitera, Michael (M); Loring, David W (DW); NEAD Study Group;

Affiliation: Department of Neurology, Emory University, Woodruff Memorial Research Bldg., 101 Woodruff Cir., Suite 6000, Atlanta, GA 30322, USA. kimford.meador(-atsign-)emory.edu

Grants: R01 NS038455-08 (Agency:NINDS NIH HHS) ; R01NS038455 (Agency:NINDS NIH HHS) ; R01NS050659 (Agency:NINDS NIH HHS)

Journal and publication information

Publication Type: Comparative Study; Journal Article; Multicenter Study; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: The New England journal of medicine (N Engl J Med), published in United States. (Language: eng)

Reference: 2009-Apr; vol 360 (issue 16) : pp 1597-605

Dates: Created 2009/04/16; Completed 2009/04/20; Revised 2009/10/01;

PMID: 19369666, status: MEDLINE (last retrieval date: 10/1/2009, IMS Date: 01 Oct 2009 00:00:00)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

Comments and Corrections

CommentIn: Evid Based Med. 2009 Oct;14(5):153. (PMID: 19794028)

CommentIn: N Engl J Med. 2009 Apr 16;360(16):1667-9. (PMID: 19369673)

CommentIn: N Engl J Med. 2009 Aug 6;361(6):629; author reply 629-30. (PMID: 19657130)

External Links for this article
(including full text providers, if available):

Click Electronic Full-text Provider Links to see options for finding the electronic full text links to this article. Note there may be a subscription or fee required for access to the full text. See our FAQ for information on finding FREE full text articles.

This article may also be located in paper journal collections available in many libraries. Use the Journal and Publication Information above to find the full article.

MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Adult
Anticonvulsants - adverse effects
Carbamazepine - adverse effects
Child, Preschool
Cognition - drug effects
Developmental Disabilities - chemically induced; diagnosis
Dose-Response Relationship, Drug
Epilepsy - drug therapy
Female
Humans
Intelligence - drug effects

Intelligence - drug effects
Intelligence Tests
Neuropsychological Tests
Phenytoin - adverse effects
Pregnancy
Pregnancy Complications - drug therapy
Prenatal Exposure Delayed Effects - chemically induced; diagnosis
Prospective Studies
Regression Analysis
Triazines - adverse effects
Valproic Acid - adverse effects

Associated Chemicals: Anticonvulsants (0) ; Triazines (0) ; Carbamazepine (298-46-4) ; Phenytoin (57-41-0) ; lamotrigine (84057-84-1) ; Valproic Acid (99-66-1)

These are the highest related articles currently in the database: