Teratogenicity of the newer antiepileptic drugs – the Australian experience

Abstract

Data on the use in pregnancy of the new antiepileptic drugs (AED) are limited. We analysed data collected by the Australian Pregnancy Register to provide information on their relative teratogenicity. The database containing pregnancy outcomes from 1317 women with epilepsy (WWE) was examined for three widely used new AED in monotherapy in the first trimester – lamotrigine, levetiracetam and topiramate. This was compared with outcomes of pregnant WWE on monotherapy with three traditional AED, and with untreated women. The incidence of malformations associated with lamotrigine monotherapy was 12/231 (5.2%), with topiramate 1/31 (3.2%) and with levetiracetam 0/22 (0%). This compares with rates of 1/35 (2.9%) for phenytoin, 35/215 (16.3%) for valproate (VPA), 19/301 (6.3%) for carbamazepine and 6/116 (5.2%) for untreated women. There was no evidence of dose-dependent risks of foetal malformation, except with VPA monotherapy. We conclude that the new AED appear no more teratogenic than traditional drugs in monotherapy.

Introduction

In the last decade of the 20th century, more than 10 new antiepileptic drugs (AED) were introduced, often known as the second generation, in contrast to the traditional agents, some of which have been available since the 1940s. These new AED possess some novel characteristics, fueling expectations that they may be more suitable for managing difficult-to-treat epilepsy syndromes, more easily tolerable than the older agents, and undergo fewer interactions. Their favorable pharmacokinetic profiles may render them suitable for use in polytherapy and in special situations such as in pregnant women with epilepsy (WWE).1, 2, 3 However, there are also the important issues of the possible teratogenic effects of these newer AED when taken in pregnancy, how they compare with the older generation of AED in this regard, and whether such effects may extend to both the physical and the cognitive development of the infant.

Recent action by the US Food and Drug Administration (FDA) in issuing a warning of an increased risk of harelip and facial cleft abnormalities associated with use of topiramate in pregnancy, and that this AED is increasingly used as a migraine prophylactic as well as an antiepileptic agent and so may be taken by growing numbers of women early in pregnancy, has prompted an analysis of the data in the Australian Register of Antiepileptic Drugs in Pregnancy to try to assess the degree of foetal hazard associated with exposure to this, and the other newer, AED.⁴