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PLoS One. 2019 Aug 5;14(8):e0214180. doi: 10.1371/journal.pone.0214180. eCollection 2019.

Relation of in-utero exposure to antiepileptic drugs to pregnancy duration and size at birth.

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RTI Health Solutions, Barcelona, Spain.
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.
Division of Maternal-Fetal Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
RTI Health Solutions, Waltham, Massachusetts, United States of America.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States of America.



The associations of individual antiepileptic drugs (AEDs) with pregnancy duration and size at birth, and potential dose relations, are not well characterized.


This cohort study used nationwide Swedish register data (1996-2013). Adjusting for smoking, epilepsy and other AED indications, we used linear and quantile regression to explore associations with pregnancy duration, and birth weight, length, and head circumference (the last three operationalized as z-scores). We used logistic regression for preterm delivery, small for gestational age, and microcephaly. Lamotrigine was the reference drug.


6,720 infants were exposed to AEDs in utero; AED exposure increased over the study period. Relative to lamotrigine-exposed infants, carbamazepine-exposed infants were born, on average, 1.3 days earlier (mean [95% confidence interval]: -1.3 [-2.3 to -0.3]); were 0.1 standard deviations (SDs) lighter (-0.1 [-0.2 to 0.0]); and had a head circumference that was 0.2 SDs smaller (-0.2 [-0.3 to -0.1]). Pregabalin-exposed infants were born, on average, 1.1 days earlier (-1.1 [-3.0 to 0.8]); were 0.1 SDs lighter (-0.1 [-0.3 to 0.0]); and had the same head circumference as lamotrigine-exposed infants. Levetiracetam-exposed infants were born, on average, 0.5 days earlier (-0.5 [-2.6 to 1.6]); were 0.1 SDs lighter (-0.1 [-0.3 to 0.0]); and had a head circumference 0.1 SDs smaller (-0.1 [-0.3 to 0.1]). Valproic acid-exposed infants had, on average, the same duration of gestation and birth weight z-score as lamotrigine-exposed infants, but had a head circumference 0.2 SDs smaller (-0.2 [-0.2 to -0.1]). Associations between carbamazepine exposure and pregnancy duration and between valproic acid exposure and pregnancy duration and birth weight z-score were more negative at the left than at the right tails of the outcome distributions. Effect-measure modification and dose-response relations were noted for some of the associations.


Relative to lamotrigine, valproic acid and carbamazepine were associated with smaller head circumference.

Conflict of interest statement

We have read the journal’s policy and the authors of this manuscript have the following competing interests: AVM, KJR, and EP work for RTI Health Solutions, a unit of RTI International. RTI International is an independent, nonprofit organization that conducts work for government, public, and private organizations including pharmaceutical companies; this project was internally funded. Other authors have declared that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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