Multi‐institutional Study on the Teratogenicity and Fetal Toxicity of Antiepileptic Drugs: A Report of a Collaborative Study Group in Japan

Abstract

A multi-institutional collaborative study was conducted concerning the course of pregnancy and delivery and the incidence of abnormal infants delivered of epileptic women. Of 657 women receiving antiepileptic drugs, 73% delivered live infants, 14% had miscarriage or stillbirth, and 13% underwent induced abortion. In contrast to the above findings, 80% of 162 patients not receiving antiepileptic drugs delivered live infants and 4% had miscarriage or stillbirth. The latter outcome was significantly increased in the medicated patients. In this series, 63 (9.9%) of 638 live births were malformed, 55 (11.5%) being from medicated mothers and 3 (2.3%) from nonmedicated mothers. The incidence of fetal malformation in medicated mothers was thus five times as high as that in nonmedicated mothers. Cleft lip and/or palate and malformations involving the cardiovascular system were found frequently in the infants from medicated mothers. General background factors that might exert teratogenic effects on pregnant patients with epilepsy were studied, and the potential toxicity of antiepileptic drugs to the fetus was also analyzed. In this regard, consideration should be given to whether the patient has partial epileptic seizures, whether the patient herself exhibits any malformation, or whether her previous pregnancy resulted in an abnormal outcome. The incidence of fetal malformation was the highest (12.7%) in the medicated patients who had epileptic seizures during the pregnancy. It is presumed on the basis of the results of analysis of the data that a combination of more than three drugs and a daily dose greater than a certain minimal level is likely to produce malformed infants.

The Importance of Drug Interactions in Epilepsy Therapy

“…Certain AED combinations are associated with enhanced risk (e.g., VPA), and an enzyme-inducing AED (e.g., PB, PHT, and CBZ) enhances the risk of malformations and hepatotoxicity and therefore alternative AEDs should perhaps be considered (47)(48)(49). Furthermore, there is evidence to suggest, from a study of a relatively small number of patients receiving polytherapy, that the incidence of malformations increases with increasing number of AEDs; exposure to two, three, or four AEDs is associated with an incidence rate of malformations of 5.5, 11, and 23%, respectively (50). A recent prospective study reported that whereas the odds ratio of malformations for an infant exposed to a single AED was 2.8, the odds ratio for two or more AEDs was 4.2 (51).…”

Managing Bipolar Disorder during Pregnancy: Weighing the Risks and Benefits

“…Fetal exposure to anticonvulsants has been associated not only with relatively high rates of neural tube defects (NTDs), such as spina bifida, but also with multiple anomalies, including craniofacial abnormalities (also known as the "anticonvulsant face"), congenital heart disease, cleft lip or palate, growth retardation, and microcephaly (76)(77)(78)(79). Factors that may increase the risk for teratogenisis include high maternal serum anticonvulsant levels and exposure to more than a single anticonvulsant (77,(82)(83)(84). The lowest effective dosage should be used, and given in frequent divided doses over the course of the day (85).…”

Teratogenic effects of lamotrigine on rat fetal brain: a morphometric study

“…However other authors -Lindhout and Omtizigt 5 in 1992 -found an absolute risk factor of 7 to 10%, i.e., 3 to 5% higher than that in the general population. The number and doses of AEDs utilized can also interfere with the final result , high doses and polytherapy increasing this risk 6,7 . Anomalies and malformations commonly found in association with the use of AED are: a) neural tube defects -"spina bifida", mostly related to the use of sodium valproate 8 and carbamazepine 9 ; b) facial cleft -labial or palatal 10 and, c) congenital cardiac defects (atrial septal defect, Fallot's tetralogy, ventricular septal defect, aortic coarctation, pulmonary stenosis and persistence of the arterial channel) 11 .…”

“…Anomalies and malformations commonly found in association with the use of AED are: a) neural tube defects -"spina bifida", mostly related to the use of sodium valproate 8 and carbamazepine 9 ; b) facial cleft -labial or palatal 10 and, c) congenital cardiac defects (atrial septal defect, Fallot's tetralogy, ventricular septal defect, aortic coarctation, pulmonary stenosis and persistence of the arterial channel) 11 . The majority of studies on fetal malformations and AEDs, have been made in patients treated with the five leading AEDs -phenytoin (DPH), carbamazepine (CBZ), phenobarbital (PB), primidone (PR), and sodium valproate (VPA) [4][5][6][7][8][9][10][11] . In general, investigators agree that the risk of fetal malformations due to AEDs is about twofold above normal, and is enhanced by polytherapy and high AED serum levels.…”