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

Abstract

BackgroundThe associations of individual antiepileptic drugs (AEDs) with pregnancy duration and size at birth, and potential dose relations, are not well characterized.\n\nMethodsThis 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.\n\nResults6,720 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. 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 were 0.1 SDs smaller (-0.1 [-0.3 to 0.1]) in head circumference. Valproic acid-exposed infants had, on average, the same duration of gestation and birth weight z-score, but were 0.2 SDs smaller (-0.2 [-0.2 to -0.1]) in head circumference. More negative associations at the left tail of pregnancy duration and birth weight z-score, effect-measure modification, and dose-response relations were noted for some of the associations. Observed associations were generally of smaller magnitude than that of smoking, assessed as a potential confounder in the same models.\n\nConclusionsIn comparison with lamotrigine, valproic acid and carbamazepine had a more negative association with head circumference than other study AEDs.