Teratogens in the human: current problems.

Drugs administered to the mother can affect the fetus by preventing implantation or by causing resorption of the embryo, abortion or intrauterine death. It is a sobering thought that the first of these mechanisms is dignified by the name 'contraception' and that the remainder have far less medicolegal and economic significance than the survival of a defective fetus after a less drastic chemical or physical insult (Law Commission, 1974). The general principles of teratogenesis in humans have recently been reviewed by Lewis (1974). The majority of drugs are of molecular weight below 1000 and pass the placenta into the fetus. Their rate of transfer is enhanced by small molecular weight, lipophilic properties, and a high concentration of nonionized drug, not bound to plasma protein, in the maternal circulation. Drugs for which detoxication mechanisms, metabolic degradation or urinary excretion are deficient in the fetus are more likely to accumulate. The extent and nature of a teratogenic effect depend on length of gestation. In general, agents administered before implantation either destroy the embryo or damage cells in the blastocyst which can be replaced by undifferentiated cells which retain totipotency. Maximum susceptibility in man is during organogenesis, from the first week after fertilization until the ninth week, that is, from three to 11 weeks after the last menstrual period. The same stimulus may produce a different anomaly at different stages of gestation, depending on which organs are in a critical stage of development. Some agents show a predilection for causing abnormalities in particular organ systems; sometimes this can be related to a high local tissue concentration or specific influence on a particular metabolic pathway but in other instances the mechanism is unknown. The genetic constitution of the embryo has a major influence on its response, and species differences are the primary hindrance to the screening of agents in animals for teratogenic potential and the interpretation of the relevance of the results to humans. Even in man, racial and familial predisposition to particular anomalies may influence the nature of a teratogenic response. 15C Recognition of a Teratogenic Effect