Assessing the Safety of Drugs in Pregnancy
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Drug Safety 2000 Mar; 22 (3): 169-177 0114-5916/00/0003-0169/$20.00/0 © Adis International Limited. All rights reserved.
Assessing the Safety of Drugs in Pregnancy The Role of Prospective Cohort Studies Cornelia Irl and Joerg Hasford Institute for Medical Informatics, Biometry and Epidemiology, University of Munich, Munich, Germany
Abstract
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.
Only some decades ago, the general opinion was that the placenta served as a barrier to protect the fetus from harmful agents. The rubella embryopathy in the 1940s, however, demonstrated that external factors such as maternal diseases or even unapparent infections can affect the child’s development.[1] The thalidomide catastrophe in the 1960s, with the birth of several thousands of severely malformed babies, clearly showed that preparations used by the mother can cross the placenta and can have untoward effects on the fetus.[2,3] The consequence of the thalidomide disaster was an increased awareness of the potential for drugs to cause congenital malformations and other developmental disorders and the necessity to investigate this.1 Since thalidomide, 30 drugs have been
proven as being teratogenic, not all of which are currently in clinical use.[4] The drugs and their effects on the embryo, fetus or neonate are summarised below: • ACE inhibitors: prolonged renal failure in neonates, decreased skull ossification, renal tubular dysgenesis • aminopterin (not currently in clinical use), methotrexate: CNS and limb malformations • anticholinergic drugs: neonatal meconium ileus • antihyperglycaemic drugs: neonatal hypoglycaemia • antithyroid drugs [propylthiouracil and thiamazole 1 The terms ‘congenital malformations’ or ‘teratogenicity’ used within the text include all other untoward effects on the newborn or the potential to cause them.
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(methimazole)]: fetal and neonatal goitre and hypothyroidism, aplasia cutis (with thiama
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