A population-based case–control teratologic study of nitrazepam, medazepam, tofisopam, alprazolum and clonazepam treatment during pregnancy

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A population-based case–control teratologic study of nitrazepam, medazepam, tofisopam, alprazolum and clonazepam treatment during pregnancy
Erika Eros, Andrew E. Czeizel, Magda Rockenbauer, Henrik T. Sorensen and Jorn Olsen.
a Foundation for the Community of Hereditary Diseases, National Center for Epidemiology, Budapest, Hungary
b Department of Human Genetics and Teratology, NationalCenter for Epidemiology, Budapest, Hungary
c Department of Epidemiology and Social Medicine, Danish Epidemiology Science Centre, Research Unit of Clinical Epidemiology of Aarhus University, Aarhus, Denmark
Received 24 April 2001; accepted 21 September 2001 Available online 9 February 2002.

Abstract
Objective: To study the association between nitrazepam, medazepam, tofisopam, alprazolum andclonazepam treatments during pregnancy and prevalence of different congenital abnormalities (CAs). Materials and methods: A matched case–control study using cases with CAs and population controls from the dataset of the nationwide Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA), 1980–1996. Results: Of 38,151 pregnant women who had babies without any defects (populationcontrol group), 75 (0.20%) were treated with these five benzodiazepines during pregnancy. Of 22,865 pregnant women who delivered offspring with CAs, 57 (0.25%) had benzodiazepine treatment. The occurrence of five benzodiazepine treatments during the second and third months of gestation, i.e. in the critical period for most major CAs did not show significant differences in matched case–control pairs.Conclusion: Treatment with five benzodiazepines studied during pregnancy did not present detectable teratogenic risk to the fetus in humans but the amount of information was limited for different CAs.
Author Keywords: Benzodiazepines; Nitrazepam; Medazepam; Tofisopam; Alprazolum and clonazepam; Human teratogenic potential; Congenital abnormalities; Case–control analysis

1. IntroductionBenzodiazepines with tranquilizer, sedative, anticonvulsant, and muscle relaxant properties are among the frequently used drugs during pregnancy in Hungary [1]. Benzodiazepines cross the placenta and pharmacologically the fetus acts as a ‘deep compartment’ for benzodiazepines in which these chemicals are slow to accumulate but are also, with their active metabolites, eliminated slowly [2].Benzodiazepines can accumulate therefore in fetal tissues after regular maternal ingestion and the teratogenic risk for children exposed to benzodiazepines particularly diazepam in utero has been reported [3, 4, 5 and 6]. Previously, we evaluated the teratogenic potential of diazepam [7 and 8] and chlordiazepoxide [9]. However, no epidemiologic studies of congenital abnormalities (CAs) in infants born towomen who took nitrazepam, medazepam, tofisopam during pregnancy have been published [10]. We therefore examined the teratogenic effect of the above three benzodiazepines in the large population-based Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA) [11] between 1980 and 1996. In addition, the data of teratogenic analysis of two other benzodiazepines as alprazolam andclonazepam are also presented here.
2. Materials and methods
The Hungarian Congenital Abnormality Registry (HCAR) is a national-based registry of cases with CA [12]. Notification of CAs is compulsory for physicians, mainly obstetricians (practically all deliveries take place in inpatient obstetric clinics) and pediatricians (who are working in the neonatal units of inpatient obstetric clinicsand various inpatient and outpatient pediatric clinics). Autopsy was obligatory for all infant deaths and usual in stillborn fetuses during the study period and pathologists sent a copy of the detailed autopsy report to the HCAR in lethal cases due to CA. The recorded total (birth+fetal) prevalences of cases with CA was 35 per 1000 informative offspring (liveborn infants, stillborn and selectively...