Lacosamide Use in Pregnancy Does Not Cause Major Teratogenic Effects

In women with epilepsy, no evidence of any significant embryogenic or teratogenic effects have been reported with the use of lacosamide, according to findings from an observational study published in Seizure: European Journal of Epilepsy.

In epilepsy, pregnancy presents a specific challenge as patients undergoing antiseizure medication (ASM) therapy and their clinicians must take into account the possibility of fetal side effects. Choosing an appropriate ASM for the long-term treatment of epilepsy can be difficult, requiring clinical experience. Newer ASMs have proven to improve tolerability and have had fewer interactions, but data in pregnancy remain limited for those agents introduced after 1989. Although most of the studies evaluating pregnancy outcomes among women with epilepsy are based on the use of ASM monotherapy, between 20% and 30% of patients with epilepsy require the treatment with polytherapy.

Researchers assessed the database from the German Embryotox Center of Clinical Teratology and Drug Safety, which provides users with risk evaluation on drug exposure during pregnancy, for newer ASMs licensed since 2005. At a patient’s initial consultation, maternal characteristics and drug exposures were recorded. Following this, data on the course and outcome of a particular pregnancy were established with the use of mailed questionnaires and/or structured telephone interviews occurring at approximately 8 weeks after a woman’s estimated due date.

Researchers of the present observational study evaluated the utilization of newer ASMs in pregnant women between January 2004 and April 2019. Newer ASMs were defined as “antiseizure medication with marketing authorization between 2005 and 2019 and included zonisamide, rufinamide, stiripentol, lacosamide, eslicarbazepine, retigabine, perampanel, and brivaracetam.”

The primary study outcomes regarding lacosamide-exposed pregnancies included loss of pregnancy and the occurrence of major birth defects.

Secondary outcomes comprised of neonatal and adverse events occurring throughout a pregnancy. All possible exposed pregnancies were reported within the initial year following the approval of lacosamide, brivaracetam, and eslicarbazepine.

Since lacosamide was the most often used newer ASM in the study cohort, this agent was selected for additional evaluation of pregnancy-related outcomes. From January 2008 to April 2019, a total of 171 information requests were received, with 55 prospectively ascertained and 10 retrospectively ascertained pregnancies with completed available follow-up ultimately selected for evaluation.

Researchers found that the median maternal age of the lacosamide-treated pregnant women was 30 years. Further, the median gestational age at the time of initial contact was 10 weeks postmenstruation. The median lacosamide dose administered was

300 mg/d (range, 200 to 387.5 mg/d). In all of the pregnant women, the treatment indication for lacosamide was epilepsy or seizures.

Regarding the women who were prospectively evaluated, at conception, only 11% (6 of 55) of them were receiving antiepileptic monotherapy, 60% (33 of 55) of them were receiving 2 ASMs, and 29% (16 of 55) of them were receiving ≥3 ASMs. In 52 of the 55 pregnancies, lacosamide therapy was initiated prior to conception.  Additionally, 3 of the 55 pregnancies terminated as spontaneous abortions, 1 was a stillbirth, and 8 pregnancies were terminated electively.

The estimated cumulative incidence of spontaneous abortions was 16.2% (95% CI, 4,7%-47.9%). Among the 43 pregnancies that were associated with live births, 1 of which was a pair of twins, lacosamide therapy throughout the pregnancy was needed in 81% (35 of 43) of the women, with the lacosamide dose increased among 3 of the participants.

Nongenetic major birth defects were reported in 2 of the pregnancies. Functional cardiac disorders were observed among 4 of the 36 neonates who were exposed to lacosamide until delivery. In fact, bradycardia, which was reported in 3 of the neonates, was deemed possibly associated with prenatal lacosamide exposure.

A key drawback of the current analysis is the missing or limited information available on the type of epilepsy, ASM plasma levels, and frequency of seizures. Further, the Embryotox cohort may not be representative of all pregnant women in Germany who were being treated with newer ASMs. Notably, the women enrolled in Embryotox appear to have a higher educational level than that of the general population of pregnant women in Germany.

Researchers highlighted that there is no evidence that lacosamide leads to substantial embryotoxic or teratogenic effects. “Further data are needed to support these findings and to examine a potential association between lacosamide exposure until delivery and neonatal bradycardia,” they noted. They concluded, “[F]or other increasingly used newer ASMs like brivaracetam and eslicarbazepine [,] studies on pregnancy outcome are needed to guide preconception counselling.”