Levetiracetam use and pregnancy outcome

Abstract

Prenatal exposure to levetiracetam (LEV) has been shown to cause skeletal abnormalities and growth retardation in animal studies, but the teratogenicity of this new antiepileptic drug in humans is still unknown. We detected no malformations in a series of 11 pregnancies with LEV exposure, although it was striking that three cases had a low birth weight. There may be an association between maternal LEV use and reduced birth weight, but too few cases have been monitored so far. We recommend that the outcomes of all pregnancies exposed to LEV should be carefully registered.

Introduction

Maternal antiepileptic drug use is associated with an increased frequency of adverse pregnancy outcome including congenital malformations [1]. However, continuation of medication during pregnancy is often necessary to prevent seizures which would be harmful to mother and fetus. Recently, some new antiepileptic drugs (AEDs) have been launched, promising better antiepileptic properties and fewer side effects; however, the teratogenicity of this new generation of AEDs in humans is still unknown. The same holds true for levetiracetam (LEV), which has been registered for treatment of partial epilepsy and seems to be effective in idiopathic generalized epilepsy as well [2]. It is used mostly as adjunctive therapy in doses of 1000–3000 mg/day. The drug is chemically unrelated to existing AEDs and precisely how it prevents seizures is unknown.

In animal studies, LEV showed developmental toxicity at doses similar to or greater than human therapeutic doses [3], [4], [5]. In rats and rabbits, treatment with ≥350 and ≥600 mg/kg/day, respectively, was associated with an increase in embryo-fetal mortality, minor skeletal abnormalities and growth retardation [3], [4], [5]. In a mouse model of teratogenicity, no gross external malformations were observed in offspring prenatally exposed to LEV and its major metabolite in humans, 2-pyrrolidinine N-butyric acid (PBA), at doses up to 2000 mg/kg/day, except for cleft palate in two fetuses exposed to LEV 1200 mg/kg/day [3]. In both the LEV and PBA groups, at doses ≥600 mg/kg/day fetal weights were reduced and the overall frequency of skeletal abnormalities, specifically of hypoplastic phalanges, was increased. These skeletal abnormalities were not actual malformations but they are well-recognized indicators of perturbations in fetal growth and development; therefore, they point towards LEV affecting prenatal growth. Furthermore, LEV treatment at 600 mg/kg/day caused a 15% reduction in maternal weight gain associated with the delayed fetal growth.

Few data are available on the teratogenicity of LEV in humans. Long [6] reported a normal pregnancy outcome for three cases treated with monotherapy of 750–3000 mg LEV daily. Birth weights were within the normal range. During safety trials, 23 women became pregnant while taking 1000–4000 mg LEV/day in mono- or poly-therapy [7]. Pregnancy outcomes were: eight healthy children (including one set of twins), one child with syndactyly between second and third toes, and one child with a tetralogy of fallot (both exposed to LEV in polytherapy), one prematurely delivered child with abnormal heart rhythm, one ectopic pregnancy, seven spontaneous abortions, three voluntary abortions (no details given about fetal malformations) and two unknown outcome. No data were published on the birth weights.

Since there is evidence that LEV has adverse developmental effects in animals, careful monitoring of human pregnancy outcome with maternal LEV use is of great importance. Here we present the outcome of 11 well-documented pregnancies in 10 women on LEV treatment.