Antiepileptic Medication During Pregnancy: Does Fetal Genotype Affect Outcome?

0031-3998/07/6202-0120 PEDIATRIC RESEARCH Copyright © 2007 International Pediatric Research Foundation, Inc. Vol. 62, No. 2, 2007 Printed in U.S.A. Antiepileptic Medication During Pregnancy: Does Fetal Genotype Affect Outcome? DIANE E. ATKINSON, SOPHIE BRICE-BENNETT, AND STEPHEN W. D’SOUZA Division of Human Development, The Medical School, University of Manchester, Manchester, M13 OJH, United Kingdom The common MCMs associated with AEDs include cardiac defects, orofacial clefts, urological defects, defects of the gastrointestinal tract, skeletal abnormalities, and neural tube defects. The MCM rate among children of women with epilepsy was 4%. The reasons why these infants had MCMs with exposure to AEDs while the remaining 96% were unaffected are not clearly understood. However, there is increasing evidence that the placenta has the capability to protect the fetus from drugs and xenobiotics in the maternal circulation (6). Therefore, there may be a relationship between the protective function of the placenta and the susceptibility to birth defects in some fetuses. Within the placenta, there are mechanisms that can influence the transfer of drugs and xenobiotics from the maternal to the fetal circulation and that may have a role in influencing drug effects on the fetus. The rate at which a drug crosses the placenta from maternal to fetal circulation depends on its physicochemical properties and the activity of transporters and drug-metabolizing enzymes expressed on the microvillous (MVM maternal facing) and basal (BM fetal facing) plasma membranes of the transporting epithelium of the placenta, the syncytiotrophoblast (7–9). The placenta expresses a range of transporters capable of drug transport, including MDR1, P-gp (7,8), MRP1 and MRP2 (7,8), and BCRP (10). These proteins are capable of transporting a wide range of structurally unrelated compounds out of cells in which they are expressed. A hypothesis that links a reduced level of expression of these placental transporters and AEDs prescribed during pregnancy with birth defects and neurodevelopmental impairments in later childhood opens potential avenues for research. In this review, we consider, in sequence, the studies on pregnancy outcome in epileptic women, including those from pregnancy registries relating prenatal AED exposure to the risks of MCMs and follow-up studies that suggest impaired development in later childhood. Furthermore we discuss the role of the placenta in drug transfer and its potential to protect the fetus. Understanding the mechanisms of drug transfer by the placenta could provide clues as to why some infants of epileptic mothers are vulnerable to AED exposure in utero, whereas most are protected from congenital malformations, cognitive impairment, and additional educational needs (1,11,12). ABSTRACT: Congenital abnormalities and impaired development in childhood are attributable to fetal exposure to antiepileptic drugs (AEDs). Pregnancy registries set up to obtain information about the potential risks of fetal exposure to AEDs, in particular major congenital malformations (MCMs), suggest that valproate exposure increases the frequency of congenital malformations more than other AEDs. Furthermore, follow-up studies have drawn attention to cognitive impairments in later childhood after prenatal exposure to valproate. Fetal exposure to AEDs may be influenced by drug transporting proteins in the placenta, including P-glycoprotein (P-gp), multidrug resistance protein (MRP) 1, and breast cancer resistance protein (BCRP). Their location in the syncytiotrophoblast plasma membrane, at the interface of the maternal and fetal circulations, allows these transport proteins to efflux xenobiotics back to the mother and offers the fetus protection from medications taken during pregnancy. Genetic variations in the expression and activity of these transport proteins may influence fetal exposure to AEDs and thus the risk of teratogenicity. Identification of a hierarchy of haplotypes ranging from susceptible to protective of congenital abnormalities could assist genetic counseling, in assessing fetal risks from exposure to AEDs. (Pediatr Res 62: 120–127, 2007) M ost women with epilepsy have healthy children. However, hospital- or community-based studies and data collected in pregnancy registries suggest an association between an increase in birth defects and developmental disorders affecting cognitive functioning and behavior in later childhood and AEDs used during pregnancy (1– 4). There are obvious safety concerns when birth defects seem more likely with exposure to certain types of AEDs and are increased with higher drug dose and polytherapy. Furthermore, poorly controlled epilepsy during pregnancy may carry risks for complications and adverse obstetric outcome (5). Therefore, the potential risk of AED teratogenesis must be balanced against those of seizures to the mother and baby for the duration of gestation. AEDs commonly considered for monotherapy are carbamazepine, valproate, phenobarbitone, and phenytoin. New AEDs introduced in the United Kingdom include vigabatrin, lamotrigine, gabapentin, topiramate, tiagabine, oxcarbazepine, levetiracetam, and pregabalin (1). The UK Epilepsy and Pregnancy Register, established in 1996, defined an MCM as an abnormality of an essential embryonic nature present at birth or in the first 6 wk of life (1). Abbreviations: AEDs, antiepileptic drugs; BCRP, breast cancer resistance protein; FACS, fetal anticonvulsant syndrome; MCMs, major congenital malformations; MDR1, multidrug resistance protein; MRP, multidrug resistance– associated protein; P-gp, P-glycoprotein; SNP, single nucleotide polymorphism Received December 1, 2006; accepted February 15, 2007. Correspondence: Diane E. Atkinson, Ph.D., Academic Unit of Child Health, Division of Human Development, St. Mary’s Hospital, Hathersage Road, Manchester. M13 OJH, UK; e-mail: . 120 FACS: DOES FETAL GENOTYPE AFFECT OUTCOME PREGNANCY OUTCOME IN EPILEPTIC WOMEN Fetal Losses Fetal losses tend to vary between studies; in the UK Epilepsy and Pregnancy Register they occurred in 5.7% of 3607 women with epilepsy (1), whereas the EURAP Study Group (13) reported one stillbirth (0.05%) in 1950 pregnancies. In normal populations, fetal death and stillbirth rates are 0.5% and 0.42%, respectively. These rates were not significantly increased with maternal epilepsy in prospective studies in the United States (14) or Finland (5). However, a multicenter study in the United Kingdom and the United States reported that fetal death rates among women prescribed carbamazepine, lamotrigine, phenytoin, and valproate were 3.6%, 0%, 3.6%, and 2.9%, respectively (4). Congenital Malformations Fetal anticonvulsant syndrome (FACS) has been described with all the AEDs, including MCMs, minor congenital anomalies, microcephaly, cognitive impairment, intrauterine growth restriction, and infant mortality (15). In the UK Pregnancy and Birth Register (...truncated)