Cognitive Function at 3 Years of Age after Fetal Exposure to Antiepileptic Drugs
Open accessAbstract
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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Divalproex during pregnancy is associated with even higher incidences of other congenital abnormalities.
“Divalproex should be avoided during pregnancy due to elevated risk of neural tube defects (up to 5%), even higher incidences of other congenital abnormalities, and evidence of striking degrees of neurodevelopmental delay in children at 3 years of age and loss of an average of nine IQ points.529, 530, 531”
From Canadian Network for Mood and Anxiety Treatments ( <scp>CANMAT</scp> ) and International Society for Bipolar Disorders ( <scp>ISBD</scp> ) 2018 guidelines for the management of patients with bipolar disorder (2018) · cites this paper as [530]
The Discussion reports that prenatal valproate exposure is associated with increased congenital malformations and cites an overall malformation incidence of 10.7%. It does not give a separate incidence for abnormalities other than neural tube defects, so it does not establish the claimed comparison for those abnormalities specifically. (LLM, conf=0.83)
Experimental — accuracy not yet measuredDivalproex during pregnancy is associated with elevated risk of neural tube defects up to 5%.
“Divalproex should be avoided during pregnancy due to elevated risk of neural tube defects (up to 5%), even higher incidences of other congenital abnormalities, and evidence of striking degrees of neurodevelopmental delay in children at 3 years of age and loss of an average of nine IQ points.529, 530, 531”
From Canadian Network for Mood and Anxiety Treatments ( <scp>CANMAT</scp> ) and International Society for Bipolar Disorders ( <scp>ISBD</scp> ) 2018 guidelines for the management of patients with bipolar disorder (2018) · cites this paper as [530]
The Discussion reports an increased risk of congenital malformations after prenatal valproate exposure, citing a 10.7% incidence for malformations overall. It does not identify neural tube defects or give a risk of up to 5% for them (searched: neural tube defects, spina bifida, 5%). (LLM, conf=0.86)
Experimental — accuracy not yet measuredDivalproex exposure is associated with striking degrees of neurodevelopmental delay in children at 3 years of age and loss of an average of nine IQ points.
“Divalproex should be avoided during pregnancy due to elevated risk of neural tube defects (up to 5%), even higher incidences of other congenital abnormalities, and evidence of striking degrees of neurodevelopmental delay in children at 3 years of age and loss of an average of nine IQ points.529, 530, 531”
From Canadian Network for Mood and Anxiety Treatments ( <scp>CANMAT</scp> ) and International Society for Bipolar Disorders ( <scp>ISBD</scp> ) 2018 guidelines for the management of patients with bipolar disorder (2018) · cites this paper as [530]
The Results report that children exposed to valproate in utero had an average IQ nine points lower than children exposed to lamotrigine at age 3; the difference was six or seven points relative to the other drugs studied. The Discussion associates valproate with increased risk of cognitive impairment, but does not characterize the study's findings as striking degrees of neurodevelopmental delay. (LLM, conf=0.86)
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References 40 · Cited by 812
Research works printed but not linked: 3
- [4]Finnell RH Nau H Yerby MS Levy RH Mattson RH Meldrum BS General principles: teratogenicity of antiepileptic drugs Antiepileptic drugs 4 New York Raven Press 1995 209 30
- [6]Practice parameter: management issues for women with epilepsy (summary statement) — report of the Quality Standards Subcommittee of the American Academy of Neurology Neurology 1998 51 944 8 9781510
- [15]Nelson H Willison J National adult reading test (NART) Oxford, England NFER–Nelson Publishing 1991
- Authors
- Meador, K. J., Baker, G. A., Browning, N., Clayton-Smith, J., Combs-Cantrell, D. T., Cohen, M., Kalayjian, L. A., Kanner, A., Liporace, J. D., Pennell, P. B., Privitera, M., & Loring, D. W.
- Affiliations
- Emory University (US)
- University of Liverpool (GB)
- Emmes (United States) (US)
- Augusta University (US)
- University of Southern California (US)
- Rush University Medical Center (US)
- Riddle Hospital (US)
- University of Cincinnati (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2009-04-16
- Volume
- 360
- Issue
- 16
- Pages
- 1597-1605
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC2737185
- OpenAlex
- W2148147266
- Cited by
- 812
- References
- 40
- Citations by year
- 2026: 10 · 2025: 36 · 2024: 33 · 2023: 33 · 2022: 40 · 2021: 33 · 2020: 34 · 2019: 45 · 2018: 46 · 2017: 34 · 2016: 39 · 2015: 50 · 2014: 46 · 2013: 63 · 2012: 87
- FWCI
- 79.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Wellcome Trust
- National Institutes of Health (UL1TR000454)
- National Institute of Neurological Disorders and Stroke (R01NS038455, R01NS050659)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Prenatal Substance Exposure Effects
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Keywords
- valproic acid, lamotrigine, phenytoin, carbamazepine, prenatal drug exposure, neurodevelopmental outcomes, IQ, cognitive function, maternal epilepsy, dose-dependent effects, maternal IQ, folic acid supplementation, congenital malformations, autism spectrum disorder risk
- MeSH terms
- Lamotrigine, Adult, Anticonvulsants, Carbamazepine, Developmental Disabilities, Child, Preschool, Cognition, Dose-Response Relationship, Drug, Epilepsy, Female, Humans, Intelligence, Intelligence Tests, Neuropsychological Tests, Phenytoin, Pregnancy, Pregnancy Complications, Prenatal Exposure Delayed Effects, Prospective Studies, Regression Analysis, Triazines, Valproic Acid
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