Clinical Commentary Teratogenicity of antiepileptic drugs: role of drug metabolism and pharmacogenomics Many neurologists were surprised by the report by Morrow et al. of a dose-dependent association of the use of lamotrigine (LTG) during pregnancy with major congenital malformations (MCM) (1). The UK Epilepsy and Pregnancy Register data reported by Morrow et al. were based on 3607 cases. Of those, 647 cases involved LTG use as monotherapy and the MCM rate was 3.2%, roughly half that for valproic acid (VPA) at 6.2% based on 715 monotherapy cases. Those treated with two or more AEDs sustained a rate of 6.0% while a rate of 3.7% was seen when all patients treated with a single AED were considered. The Ôno AEDÕ group in the registry had an MCM rate of 3.5%. This rate agrees overall with that reported by Cunnington et al. of 2.9% from the Interna- tional Lamotrigine Pregnancy Registry (2). There has been a general perception of the relative safety of using this antiepileptic drug (AED) for man- aging pregnancy in women with epilepsy compared with other AEDs (2, 3). The unexpected finding in the report by Morrow et al. (1) was that the MCM rate for LTG for a daily dose exceeding 200 mg was 5.4% while the rates for <100 and 100–200 mg/day were 1.3% and 1.9%, respectively, supporting an overall rate of 3.2%. This dose– response relationship suggests a mechanistic basis, hinting at an interaction between the chemistry of LTG, and the biology of how maternal and fetal tissues may interact with this medication based on a number of genetic endowments. Much of the discussion on this topic has relied on the pregnancy registries in Europe and North America. Variations in the results could reflect differences in the number of pregnancies available for study as well as dilution by the differences in the genetic make-up of the population studied. The lack of resolution in these epidemiologically Acta Neurol Scand 2007: 116: 65–71 DOI: 10.1111/j.1600-0404.2007.00830.x Copyright Ó 2007 The Author Journal compilation Ó 2007 Blackwell Munksgaard ACTA NEUROLOGICA SCANDINAVICA Sankar R. Teratogenicity of antiepileptic drugs: role of drug metabolism and pharmacogenomics. Acta Neurol Scand 2007: 116: 65–71. Ó 2007 The Author Journal compilation Ó 2007 Blackwell Munksgaard. The approach to clinical decision-making pertaining to the use of antiepileptic drugs (AEDs) during pregnancy has relied on previous accumulated experience and, since the 1990s, on data from pregnancy registries. The limitations of this process are that no information regarding the chemical attributes of the AED under consideration, nor the role of a number of enzyme systems that are known to interact with foreign compounds to modify their potential for harm, are included. The role of the hepatic mixed function oxidase system may be especially important in conferring teratogenic risk. However, systems such as epoxide hydrolase, glutathione reductase, superoxide dismutase and other toxin-scavenging systems may be important modifiers that lower the risk. Knowledge is also accumulating on the interactions of AEDs with molecular targets such as histone deacetylase and peroxisome proliferator-activated receptors that may play important roles in teratogenesis. While our knowledge of these factors are incomplete, progress can be achieved by beginning to include these concepts in our discussion on the topic and by promoting research that may improve our ability to individualize the analysis of risk for a specific patient with regards to specific AEDs. R. Sankar David Geffen School of Medicine and Mattel Children's Hospital at UCLA, Los Angeles, CA, USA Key words: antiepileptic drug; pregnancy; teratogenicity; fetal malformation; drug metabolism; pharmacogenomics Raman Sankar, Room 22-474 MDCC, UCLA Medical Center Los Angeles, CA 90095-1752, USA Tel.: +1-310-794-1024 Fax: +1-310-825-5834 e-mail: rsankar@ucla.edu Accepted for publication January 23, 2007 65