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

Date Published: August 5, 2019

Publisher: Public Library of Science

Author(s): Andrea V. Margulis, Sonia Hernandez-Diaz, Thomas McElrath, Kenneth J. Rothman, Estel Plana, Catarina Almqvist, Brian M. D’Onofrio, Anna Sara Oberg, Umberto Simeoni.


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.

Partial Text

Epilepsy and antiepileptic drugs (AEDs) have been associated with adverse pregnancy, fetal, and neonatal outcomes [1]. AEDs differ in their risk for congenital malformations [2–4], and some associations have been found to be dose dependent [4–6]. Newer AEDs are generally considered safer than the older drugs, with the possible exception of topiramate [7]. Antiepileptic drugs also differ in the magnitude of their associations with adverse neurodevelopmental outcomes in the offspring, which also appear to be dose dependent [8–10]. The exploration of indication and dose is important because some AEDs have several indications, confounding by indication has been a concern, and AED doses are often higher in epilepsy than in other conditions [11].

In this population-based, comparative safety cohort study involving 6,720 infants exposed to AEDs in pregnancy in Sweden during 1996–2013, we observed an increase in AED use in pregnancy over time and an evolution in preference from older to newer AEDs. With the possible exception of pregabalin, maternal characteristics were comparable across users of individual AEDs, except for the indications or uses for each drug: in the extremes, levetiracetam was used almost exclusively in women with an epilepsy diagnosis, and pregabalin was used mostly in women with chronic pain or psychiatric diagnoses. These diagnoses, which may have acted as confounders despite the comparative safety design, were controlled in the analyses. Analyses comparing individual AEDs to lamotrigine showed generally small associations (e.g., mean changes in duration of pregnancy smaller than 3 days, changes in z-scores mostly up to 0.2 SDs), which were generally milder than those observed for smoking or diabetes. Below, we contextualize our findings within what was previously known about the associations between the study AEDs and size at birth, congenital malformations and cognitive outcomes.

We observed that commonly used AEDs have distinct safety profiles regarding duration of pregnancy and size at birth. In comparison with lamotrigine, valproic acid and carbamazepine had a more negative association with head circumference than other study AEDs, suggesting that fetal head size in exposed pregnancies should be monitored. To put our results in perspective, we note that the adverse effects of AEDs on the outcomes studied were generally smaller than those of smoking. Although no mean effect was observed, associations between valproic acid and the endpoints duration of pregnancy and birth weight for gestational age in the left tail of the distributions were toward shorter pregnancies and smaller infants.