Valproic Acid Monotherapy in Pregnancy and Major Congenital Malformations
Open accessAbstract
BACKGROUND: The use of valproic acid in the first trimester of pregnancy is associated with an increased risk of spina bifida, but data on the risks of other congenital malformations are limited. METHODS: We first combined data from eight published cohort studies (1565 pregnancies in which the women were exposed to valproic acid, among which 118 major malformations were observed) and identified 14 malformations that were significantly more common among the offspring of women who had received valproic acid during the first trimester. We then assessed the associations between use of valproic acid during the first trimester and these 14 malformations by performing a case-control study with the use of the European Surveillance of Congenital Anomalies (EUROCAT) antiepileptic-study database, which is derived from population-based congenital-anomaly registries. Registrations (i.e., pregnancy outcomes with malformations included in EUROCAT) with any of these 14 malformations were compared with two control groups, one consisting of infants with malformations not previously linked to valproic acid use (control group 1), and one consisting of infants with chromosomal abnormalities (control group 2). The data set included 98,075 live births, stillbirths, or terminations with malformations among 3.8 million births in 14 European countries from 1995 through 2005. RESULTS: Exposure to valproic acid monotherapy was recorded for a total of 180 registrations, with 122 registrations in the case group, 45 in control group 1, and 13 in control group 2. As compared with no use of an antiepileptic drug during the first trimester (control group 1), use of valproic acid monotherapy was associated with significantly increased risks for 6 of the 14 malformations under consideration; the adjusted odds ratios were as follows: spina bifida, 12.7 (95% confidence interval [CI], 7.7 to 20.7); atrial septal defect, 2.5 (95% CI, 1.4 to 4.4); cleft palate, 5.2 (95% CI, 2.8 to 9.9); hypospadias, 4.8 (95% CI, 2.9 to 8.1); polydactyly, 2.2 (95% CI, 1.0 to 4.5); and craniosynostosis, 6.8 (95% CI, 1.8 to 18.8). Results for exposure to valproic acid were similar to results for exposure to other antiepileptic drugs. CONCLUSIONS: The use of valproic acid monotherapy in the first trimester was associated with significantly increased risks of several congenital malformations, as compared with no use of antiepileptic drugs or with use of other antiepileptic drugs.
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Divalproex 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 [529]
The Results report an increased risk of spina bifida, a neural tube defect, after first-trimester exposure to valproic acid monotherapy. The Discussion estimates the absolute risk at approximately 0.6%, not the claimed figure of up to 5%; the paper does not provide a 5% estimate for neural tube defects. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDivalproex 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 [529]
The Discussion reports increased risks of several congenital malformations after first-trimester valproic acid exposure. But it does not support the claim that their incidences are generally higher than that of spina bifida: its estimated absolute risk is 0.6% for spina bifida, while four of the five other listed malformations have lower estimates; only hypospadias is higher, at 0.7%. (LLM, conf=0.87)
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 [529]
The Discussion (page not available in our copy) reports that children exposed to valproic acid in utero were more likely to have impaired cognitive function at age 3 than children exposed to other antiepileptic drugs. It does not quantify the impairment as an average loss of nine IQ points or describe its degree as striking; the paper's own study examined congenital malformations, not cognitive outcomes. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAnimal models demonstrate that exposure to valproate impacts short- and long-term neurodevelopmental trajectories, interfering with neural migration pathways at critical points during embryonic development, and potentially contributing to neural tube defects.
“Animal models demonstrate that exposure to valproate impacts both short- and long-term neurodevelopmental trajectories, interfering with neural migration pathways at critical points during embryonic development, and potentially contributing to neural tube defects [126, 127].”
From The contribution of environmental exposure to the etiology of autism spectrum disorder (2019) · cites this paper as [126]
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- Authors
- Jentink, J., Loane, M. A., Dolk, H., Barisic, I., Garne, E., Morris, J. K., & de Jong-van den Berg, L. T. W.
- Affiliations
- University of Groningen (NL)
- University of Ulster (GB)
- Lillebaelt Hospital (DK)
- Queen Mary University of London (GB)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2010-06-10
- Volume
- 362
- Issue
- 23
- Pages
- 2185-2193
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2048937347
- Cited by
- 587
- References
- 28
- Citations by year
- 2026: 18 · 2025: 28 · 2024: 35 · 2023: 36 · 2022: 36 · 2021: 31 · 2020: 33 · 2019: 32 · 2018: 34 · 2017: 34 · 2016: 41 · 2015: 51 · 2014: 35 · 2013: 46 · 2012: 50
- FWCI
- 41.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- IRIS (submittedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- GlaxoSmithKline
- Ulster University
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Pregnancy and Medication Impact
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Keywords
- valproic acid, antiepileptic drugs, first trimester exposure, congenital malformations, spina bifida, atrial septal defect, cleft palate, hypospadias, polydactyly, congenital heart disease, EUROCAT, pregnancy outcomes, drug safety in pregnancy, case-control study
- MeSH terms
- Abnormalities, Drug-Induced, Anticonvulsants, Female, Humans, Infant, Newborn, Male, Pregnancy, Pregnancy Complications, Pregnancy Trimester, First, Prenatal Exposure Delayed Effects, Risk Factors, Valproic Acid, Cohort Studies, Prevalence, Case-Control Studies
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