Trends in antiepileptic drug use in pregnancy from 2000–2018 and pregnancy outcome of levetiracetam exposed pregnancies.

Introduction Several antiepileptic drugs are not suitable for use in pregnancy due to their developmental toxicity. So far, there is no evidence of teratogenic effects after levetiracetam (LEV) use, but data on the risks of spontaneous abortion and major birth defects are still limited, especially for the dual therapy of LEV and lamotrigine (LTG).

Material and Methods Trends in antiepileptic drug (AED) use at conception and treatment indications were analyzed in 3,763 prospectively ascertained pregnancies between 2000 and 2018. Changes in AED treatment over time were evaluated in pregnancies of women with epilepsy (n=1,506). LEV exposed pregnancies (n=364) were compared to an unexposed control cohort (n=729). In a sensitivity analysis the subgroup with LEV monotherapy (n=221) was compared to LTG monotherapy in women with epilepsy (n=469). In addition, pregnancy outcomes of women treated with the dual therapy of LEV and LTG were evaluated separately. Objectives for evaluation of pregnancy outcomes were rates of major birth defects and spontaneous abortions as well as effects on preterm birth and neonatal characteristics.

Results There was an increase in women using AEDs for non-epilepsy indications from 19% in 2000 to 39% in 2018. In women with epilepsy, analysis of treatment pattern over time showed a shift from non-recommended teratogenic AEDs like Valproate to recommended AEDs, especially for LEV.

For LEV exposed pregnancies the risk for spontaneous abortions or for major birth defects was neither significantly increased compared to the control group nor after comparison of the LEV and LTG monotherapy cohorts. There was no evidence of an increased risk for preterm birth after LEV use in pregnancy. However, birth weights of male neonates was significantly lower in the LEV monotherapy cohort than in the LTG monotherapy cohort [SDS difference adj. – 0.26 (95% CI -0.49 to -0.04)]. The rate of major birth defects in infants exposed to the dual therapy with LEV and LTG was unexpectedly high (7.7%). Moreover, there was a significantly increased risk of spontaneous abortions after dual therapy with LEV and LTG compared with the control cohort [HR adj. 3.01 (95% KI 1.43–6.33) and the LTG monotherapy cohort (HR adj. 2.75 (95% KI 1.07–7.05)].

Discussion This first analysis of treatment pattern in AED exposed pregnancies in Germany confirms a trend also observed in other countries towards less teratogenic and newer AEDs. We could confirm the results of previous studies that the antiepileptic LEV is suitable for use in pregnancy. However, the lower birth weight of male LEV-exposed neonates and the increased rates of major birth defects and spontaneous abortions associated with the dual therapy of LEV and LTG require further investigation.

This work was funded by the German Federal Institute for Drugs and Medical Devices (BfArM).

Publication History

Article published online:
26 November 2021