Congenital malformations due to antiepileptic drugs

doi:10.1016/S0920-1211(98)00084-9

Epilepsy Research

Volume 33, Issues 2–3, February 1999, Pages 145-158

https://doi.org/10.1016/S0920-1211(98)00084-9 Get rights and content

Abstract

To identify the major risk factors for the increased incidence of congenital malformations in offspring of mothers being treated for epilepsy with antiepileptic drugs (AEDs) during pregnancy and, to determine the relative teratogenic risk of AEDs, we prospectively analyzed 983 offspring born in Japan, Italy, and Canada. The incidence of congenital malformations in offspring without drug exposure was 3.1%, versus an incidence with drug exposure of 9.0%. The highest incidence in offspring exposed to a single AED occurred with primidone (PRM; 14.3%), which was followed by valproate (VPA; 11.1%), phenytoin (PHT; 9.1%), carbamazepine (CBZ; 5.7%), and phenobarbital (PB; 5.1%). The VPA dose and level positively correlated with the incidence of malformations. This study first determined a cut-off value of VPA dose and level at 1000 mg/day and 70 μg/ml, respectively, to avoid the occurrence of malformations. The incidence of malformations increases as the number of drugs increases, and as the total daily dose increases. Specific combinations of AEDs such as VPA+CBZ and PHT+PRM+PB produced a higher incidence of congenital malformations. The incidence of malformations was not associated with any background factors studied except for the presence of malformations in siblings. These results indicate that the increased incidence of congenital malformations was caused primarily by AEDs, suggesting that malformations can be prevented by improvements in drug regimen, and by avoiding polypharmacy and high levels of VPA (more than 70 μg/ml) in the treatment of epileptic women of childbearimg age.

Introduction

Improved diagnosis and therapy of epilepsy has allowed most women with epilepsy to marry and bear children. However, the incidence of congenital malformations in offspring of mothers with epilepsy who were treated with antiepileptic drugs (AEDs) during pregnancy is higher than the normal population (Dansky et al., 1982, Nakane, 1982) and higher than in offspring whose mothers were not treated with AEDs during pregnancy (Koch et al., 1982, Lindhout et al., 1982, Kaneko et al., 1986).

In recent prospective studies, teratogenicity appeared to be attributable to AEDs rather than to epilepsy (Kaneko et al., 1986, Kaneko et al., 1992). Folate deficiency in response to AED therapy (Ogawa et al., 1991, Dansky et al., 1992) and genetically determined drug detoxifying enzyme activity have been related to the occurrence of malformations (Buehler et al., 1990). The involvement of other risk factors, however, such as maternal hypoxia, and genetic influences, must also be considered in the etiology of congenital malformations. The aim of the present study was to identify the major risk factors for the occurrence of congenital malformations, the relative teratogenic risk of each AED, and the advisable ranges of AED doses to reduce the risk of congenital malformations in offspring.

Section snippets

Subjects and methods

For this prospective study, the same study design was used to collect and analyze the same data from three countries (Japan (Hirosaki, Fukushima, Nagoya, and Nagasaki), Italy (Milan), and Canada (Montreal)). This study was approved by the Ethics Committee in each center.

Recruitment of subjects began in April 1978, and was completed in December 1991. At each center, where the study was introduced, the nature and purpose of the study was explained to every female patient of childbearing age with

Statistics

For statistical analysis, first we estimated the incidence of malformations in the total group and in each subgroup. Next, we examined the correlation between the occurrence of malformations and the following factors: (a) background factors of the mothers, (b) AED combination profiles, (c) the number of AEDs administered, and (d) AED doses and levels.

We used the following tests for each data group: exact probability method, chi-square test, Wilcoxon rank sum test and Welch's test in evaluating

Results

Among 983 pregnancies, 83 malformed infants were observed (8.4%). The overall incidence of malformations in AED exposed offspring was 9.0% (80/885). Three anomalies such as a flexion of the thumb, distorted fingers, and a small nevus were observed in AED unexposed offspring. None of the mothers had any associated chronic illness.

Discussion

Reported risk factors for congenital malformations in offspring vary from report to report (Dansky et al., 1982Koch et al., 1982Lindhout et al., 1982Nakane, 1982Kaneko et al., 1986Kaneko et al., 1992). This is due mainly to the small number of subjects in each study which inevitably results in insufficient statistical power. Thus, this study was designed to collect many cases from epilepsy centers where collaborative study and precise follow-ups were possible.

A significantly higher incidence of

Acknowledgements

This study was supported by a Grant in Aid for Scientific Research from the Japanese Ministry of Education, Science and Culture (05454309) and a grant from the Japan Epilepsy Research Foundation. Part of the present study was reported at the 19th CINP congress held in Washington DC, USA, in June 1994, and the 21st International Epilepsy Congress held in Sydney, Australia in September 1995. A preliminary report (in Japanese) of this study was reported in the Annual Report of the Japanese

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Congenital malformations due to antiepileptic drugs

Abstract

Introduction

Section snippets

Subjects and methods

Statistics

Results

Discussion

Acknowledgements

Lancet

J. Pediatr.

J. Pediatr.

Reprod. Toxicol.

Lancet

Epilepsy Res.

Lancet

Malformations in offspring of 305 epileptic women: a prospective study

Acta Neurol. Scand.

Prenatal prediction of risk of the fetal hydantoin syndrome

N. Engl. J. Med.

Mechanisms of teratogenesis: folic acid and antiepileptic therapy

Neurology

Protection from phenytoin-induced congenital malformations by coadministration of the antiepileptic drug stripentol in a mouse model

Epilepsia

Monitoring system of congenital malformation

J. Perinat. Med.

Maternal drug histories and congenital abnormalities

Br. Med. J.

Clinical application of therapeutic drug monitoring of antiepileptic drugs (in Japanese)

Clin. Pathol.

Teratogenicity of antiepileptic drugs—a prospective study

Jpn. J. Psychiatry Neurol.

Teratogenicity of antiepileptic drugs: analysis of possible risk factors

Epilepsia