The results of animal investigations cannot be directly extrapolated to pregnant women. Clinical and analytical epidemiological studies for human teratogenic risks have many inherent methodological problems and their predictions must be regarded with caution. Evaluation of the potential teratogenicity of extremely large doses of drugs in self-poisoned pregnant women who attempted suicide offers a unique model for finding associations between congenital abnormalities and different drugs. All self-poisoned patients were cared for at a toxicological inpatient clinic in Budapest, between 1960 and 1993. Out of 1044 pregnant women identified from three different periods of the project, 19 died. Women who survived were visited at home to reveal birth outcomes, and their children were evaluated medically to identify congenital abnormalities and to estimate cognitive-behavioral status. The previous or subsequent children of these pregnant women were used as controls. In general, self-poisoned pregnant women were young (peak age was 18 to 20 years) and primiparous; 55% were unmarried and of lower socioeconomic status. Suicide attempts with drugs were most frequent in the fourth postconceptional week and second pregnancy month. Of 1044 self-poisoned pregnant women, 411 delivered live-born babies, of which 367 children (89.3%) were evaluated. The self-poisoning model appears to have several benefits (e.g., dose-response estimation) in comparison with other methods. It is suggested that an international monitoring system of self-poisoned pregnant women should be established to provide a larger database.

The very large doses of nitrazepam used for suicide attempt during pregnancy resulted in a high rate of CAs which may be connected with the disruption of protein metabolism in fetal mesenchyma. The self-poisoning pregnant women model is feasible for the evaluation of teratogenic effect of drugs.

The purpose of this article is to report an evaluation of the teratogenic and fetotoxic potential of medezepam in humans based on pregnant women who used very large doses of medazepam for a suicide attempt. All self-poisoned patients were cared for at the Department of Toxicology Internal Medicine, Koranyi Hospital, a toxicological inpatients clinic in Budapest, Hungary, between 1960 and 1993. Pregnant women were identified from self-poisoned subjects admitted from a population base of three million people of Budapest and the surrounding region. The rates of congenital abnormalities (CAs), intrauterine fetal development, cognitive and behavioral status in children born to mothers who attempted suicide with medazepam alone or in combination with other drugs during pregnancy was compared in their sib controls. Between 1980 and 1993, 835 pregnant women in our study attempted suicide during pregnancy with drugs. Of these, 314 delivered live-born infants and 283 were examined and/or evaluated. Thirty-two (3.8%) of these 835 pregnant women used medazepam with or without other drugs for self-poisoning; 10 of these women delivered live-born babies. The dose of medazepam used for the suicide attempt ranged between 60 and 500 mg, with a mean of 276 mg. Eight of the 32 suicide attempts involving medazepam occurred between the 4th and 12th postconceptional weeks. Of the 10 live-born exposed children, one was affected with congenital inguinal hernia; one of the 13 sib controls had a lethal hydronephrosis. No adverse effects were observed on intrauterine growth, cognitive status, or behavioral deviations in the 10 children born to mothers who attempted suicide with medazepam during pregnancy. Very large doses of medazepam were used for self-poisoning during pregnancy. These doses did not increase the rate of CAs even though eight mothers attempted suicide during the most critical period for production of CAs. No fetotoxic, including neurotoxic, effects of exposure of live-born children to a very large dose of medazepam were observed. Our experiences show the feasibility and benefits of use of the self-poisoning model in estimating human teratogenic and fetotoxic risks of drugs.

The teratogenic potential of diazepam is debated. The objective of this study was to examine the effects of extremely high doses of diazepam used for attempted suicide during pregnancy on embryo-fetal development. Pregnant women were identified from the female patients of the Department of Toxicology Internal Medicine, Korányi Hospital, Budapest, who had been admitted as self-poisoned subjects from the three million people of Budapest and the surrounding region. This evaluation compares the incidences and types of congenital abnormalities observed in exposed children born to mothers who attempted suicide with diazepam alone or in combination with other drugs during pregnancy with their sib controls. The database consists of a total of 1044 women with self-poisoning during pregnancy between 1960 and 1993. Of these 1044 self-poisoned pregnant women, 229 (21.9%) used diazepam with or without other drugs for a suicide attempt; 112 of these women delivered live-born infants. Doses of diazepam taken ranged between 25 and 800 mg. Of 112 exposed children, 15 (13.4%) had congenital abnormalities, whereas of their 112 matched sibs, eight (7.1%) had congenital abnormalities (odds ratios with 95% confidence intervals: 2.0, 0.8-5.0). Of 37 pregnant women who attempted suicide between the 4th and 12th postconceptional weeks, five (13.5%) delivered live-born babies with a congenital abnormality (undescended testis in two exposed children; congenital dysplasia of the hip, talipes equinovarus deformation type, congenital inguinal hernia-each in one exposed child). The suicide attempts of the mothers of these children did not occur during the critical periods for induction of these defects, indicating that the observations were unrelated to diazepam. The very large doses of diazepam used for self-poisoning during pregnancy did not increase the rate of congenital abnormalities in the offspring.