ABSTRACT
In recent years there have been several experimental approaches relating to drug-induced congenital defects in children. Among these have been attempts to understand the underlying mechanisms, to develop methods for predicting risk of exposure to drugs and chemicals, and to develop strategies to prevent or attenuate potentially detrimental effects of exposure. Heavy metals or their organic salts, ethanol, and opiates seem to have attracted the brightest spotlights, probably because of the numerous clinical reports of adverse sequelae associated with exposure. Animal studies too have reported behavioral, biochemical, and morphological consequences following perinatal exposure to these agents.
However, in many cases, not enough attention has been paid to the relevance of the dose necessary to produce these effects or to differences in disposition between man and animal or to the potential confounding influences of other, early experience factors, such as maternal-offspring interactions, nutrition, or stress. It should not be necessary to study survivors of excessive or clinically nonrelevant treatment schedules, as has often been the case, to search for evidence of so-called subtle functional alterations in mature animals. In fact, such an approach may be counterproductive because sensitive subjects may not survive or because it raises questions about the veracity of the data. Our experience with opiates as the insulting agent has allowed us to develop strategies that are sensitive to behavioral and/or biochemical sequelae and has allowed us, in many instances, to separate direct effects of drugs from indirect effects. For example, we have examined the role of maternal involvement by conducting parallel studies with chickens and rats, the influence of nutritional status by separating 226neonates from their lactating mothers, as well as other factors (opiate toxicity or withdrawal in mother and/or fetus), all of which may contribute to the outcome of a developmental drug study. With this strategy we have found that many of the detrimental effects previously attributed to in utero opiate exposure, mainly from animal studies, may only be indirectly related to drug exposure. Furthermore, they may be controllable or even preventable, with more prudent attention paid to experimental details that would better justify extrapolation of animal data to clinical experiences. Therefore, evidence of functional teratogenicity of an agent emerging from questionable animal studies should not automatically result in a call for its banishment, particularly if the agent conveys therapeutic benefit as well. Conclusions of this kind should be left until a better understanding of the reason for the observation of altered function or so-called underlying mechanisms have been worked out satisfactorily.
