Assessing the safety of drugs in pregnancy: the role of prospective cohort studies.

Since, for obvious reasons, systematic testing of the teratogenic properties of drugs in humans is not possible in the premarketing phase, the epidemiological approaches to postmarketing risk evaluation are of major importance. Cohort studies, with their prospective exposure assessment, their ability to study even exposure to drugs not commonly used in pregnancy, and their ability to monitor both adverse and beneficial fetal outcomes, seem to be the most promising study type from a methodological viewpoint. Although there are numerous cohort studies on the harmful effects of drug use in pregnant women, only a few have been able to demonstrate a risk in terms of an increase in the prevalence of malformations. Most studies with significant findings were those investigating the risk potential of one group of drugs, the anticonvulsants. The lack of cohort studies showing a risk for drug use in pregnancy, however, is not necessarily indicative of some methodological deficiency. Rather, it may suggest that, for the majority of drugs, their use in pregnancy is not associated with an increased risk of congenital malformations.

[Cardiovascular abnormalities in Bavaria 1984-1991]. / Kardiovaskuläre Fehlbildungen in Bayern 1984-1991.

The study presents data on cardiovascular malformations in Bavarian livebirths, born between 1984 and 1991. Cases have been ascertained retrospectively by reviewing hospital records of all children being referred to a children's hospital up to 2 years of age. The classification scheme was based on abnormalities in developmental mechanisms. Among 984,570 livebirths, 7020 cases with structural congenital heart disease were identified. The birth prevalence was 7.1 per 1000 livebirths. Between 1984 and 1991, total prevalence increased from 5.9/10(3) to 8.0/10(3). Prevalence in males was 7.3/10(3) and in females 6.9/10(3). 78.1% of all heart defects were isolated, the remaining 21.9% were associated either with chromosomal abnormalities (9.6%), non-chromosomal syndromes (1.0%), or noncardiac malformations of other organ systems (11.3%). Total fatality rate was 12.0%, with two thirds of deaths occurring within a month of birth or the following month of life. Data were compared with those of the Baltimore-Washington Infant Study. This study presents for the first time regional data on birth prevalences of congenital heart defects in Germany. The classification scheme reduces the wide spectrum of phenotype cardiovascular defects to several pathogenetic groups. The defects in each group may be related to similar causal factors.

Perinatal mortality in Bavaria, Germany, after the Chernobyl reactor accident.

As has been shown by the authors of a paper recently published in this journal, a deviation from a long-term trend in perinatal mortality within the former Federal Republic of Germany occurred in 1987, i.e. 1 year following the Chernobyl disaster. It is the aim of this study to make a comparison between the areas of the state Bavaria. Germany, with different fallout levels as well as between the observed and expected numbers of perinatal deaths relating to these areas. The expected numbers of perinatal deaths, defined as external standard, were derived from the remainder of the former FRG. Testing an a priori formulated hypothesis revealed no differences in the temporal development of perinatal mortality between the areas with different fallout levels and subsequent exposure. Including May 1986 into the analysis revealed a significant increase during the first 3 months after the accident, which is due to an excess in May alone. Since no elevated radiation risks for the last days in utero are known, the additional Chernobyl radiation exposure is not plausible as a causative agent. Further analyses on stillbirths showed an increase in Southern Bavaria during the first 2 years following the accident. Later on, the rates were comparable to the expected values again.

The PEGASUS project--a prospective cohort study for the investigation of drug use in pregnancy. PEGASUS Study Group.

Since the thalidomide disaster, it is well accepted that drugs can have adverse effects on the developing human being. Although numerous studies show that medication during pregnancy is wide-spread, there still is a serious lack of comprehensive and valid data concerning the risks of drug use during pregnancy. One objective of the PEGASUS project, a population-based cohort study focusing on Munich, is to prospectively record information on drug exposure during pregnancy, to evaluate these data with regard to teratogenic properties, and to contribute to the quality assurance of medical treatment in pregnancy. The results of PEGASUS confirm that drug utilization during pregnancy is rather common--84% of the women use at least one preparation. The most frequent groups are minerals (mainly magnesium), iodide, and iron preparations. Although randomized studies have shown that periconceptional folic acid supplementation considerably reduces the risk of neural tube defects, only very few women in the PEGASUS project recorded folic acid intake during the critical period and in sufficient dosage. Moreover, only 42% of the pregnant women apply iodide prophylaxis in the recommended dosage.

Drug use assessment and risk evaluation in pregnancy--the PEGASUS-project.

Since the thalidomide tragedy it is well accepted that drugs can have adverse effects on the unborn child. Although numerous studies show that drug use during pregnancy is widespread, there still is a serious lack of comprehensive and valid data on the risks of drug use during pregnancy. One objective of the PEGASUS-project, which focuses on Munich, is to enlarge the knowledge on embryo- and fetotoxic properties of drugs by prospectively recording information on drug exposure during pregnancy and analysing these data with regard to untoward fetal outcome. First results of PEGASUS confirm that drug utilization during pregnancy is rather common-85% of women use at least one preparation. The most frequent groups are haematologicals, minerals, iodide, and vitamins. Randomized studies have shown that periconceptional folic acid supplementation considerably reduces the risk of neural tube defects. However, only very few women in the PEGASUS-project recorded folic acid intake during the critical period or in sufficient dosage.

Birth prevalence of congenital malformations in Bavaria, Germany, after the Chernobyl accident.

This study considers whether or not exposure to radioactive fallout from the Chernobyl accident led to an increased prevalence of congenital malformations in infants born in Bavaria, the German state with the highest levels of contamination after the accident. The odds ratios for major malformations after the accident relative to before were used as indicators for adverse health effects. Since measurements of caesium in soil showed that contamination was considerably higher in Southern Bavaria than in Northern Bavaria, the odds ratios were calculated for both regions separately. Analysis did not show a significant increase in any of the odds ratios of the selected malformations in Southern Bavaria as compared to Northern Bavaria. Consequently, this study provides no evidence that radiation from Chernobyl caused an increase in the birth prevalence of major congenital malformations.

[Social ecological analysis of birth prevalence and mortality of children with malformations]. / Sozialökologische Analyse der Geburtsprävalenz und Sterblichkeit fehlgebildeter Kinder.

Based on retrospective data collected from all over Bavaria, the influence of socioeconomic status defined for geographic areas rather than individuals and urbanisation on birth prevalence, fatality rate, and survival time of malformed infants was investigated. Urbanisation shows a negative effect on all of the outcome variables: the higher the degree of urbanisation, the higher the birth prevalence and fatality rate of malformed infants, whereas survival time decreases with increasing degree of urbanisation. Social status has a positive, but not statistically significant, effect on the outcome variables "fatality rate" and "survival time", both of which can be influenced by postnatal care and medical intervention. Increasing social status increases birth prevalence. This effect is not statistically significant.