All new drug applications filed with the Food and Drug Administration include data from developmental and reproductive toxicology (DART) studies. These studies, most of which are conducted in mice, rats, and rabbits, examine the effects of the particular agent on all aspects of reproduction, including oogenesis, sper-matogenesis, fertility, and fecundity, as well as effects on litter size, spontaneous resorption, fetal malformation, fetal size, and newborn pup function. All studies are designed with dose escalations and with maternal death as the endpoint. Information from these tera-tologic experiments with the drug is included in the drug labeling. Most human teratogenic reactions to new drugs have been predicted from animal studies. However, animal data are not always applicable to humans, since most animals have a shorter gestational clock than humans have. Species vary in their susceptibility to teratogens, with some animal models being either more or less susceptible to teratogenesis than humans are. If an agent does not produce an anomaly in animal studies, it does not prove that the agent is innocuous in humans.
Safety of a drug for use in human pregnancy is demonstrated by observational studies after the drug is marketed. Proof of teratogenicity in humans is supported by the following events: a recognizable pattern of anomalies; a higher prevalence of the particular anomaly or anomalies in patients exposed to an agent than in a control population; presence of the agent during the stage of organogenesis of the organ system affected; increased incidence of the anomaly after introduction of the agent; and production of the anomaly in experimental animals by administration of the agent during the appropriate stage of organogenesis. Epidemiologic clues to teratogenesis are often found in case reports of abnormal infants, but these are biased in that an abnormal infant is more likely reported than is a normal infant, and the background rate of malformations is high. Better studies are conducted prospectively with an exposed and unexposed control population found before pregnancy outcome is known. Although population-based large-cohort studies begun prior to pregnancy are considered the best type, they are expensive to conduct and limited to those agents used at the time of the study.
A general approach to reduce the risk of human teratogenesis includes planning for pregnancy. Prior to conception, women with medical problems should be counseled about medications they chronically use, which ones can safely be continued throughout pregnancy, and which ones should be discontinued. Medications should be evaluated and changed if necessary to decrease teratogenic risk. Plasma level monitoring of unbound concentrations of antiepileptic drugs may be helpful in optimizing seizure control, decreasing the need for multiple-drug therapy, and minimizing dosage and fetal risk. Since more than 50% of pregnancies in the United States are unplanned, all women should be treated as potential antenatal patients and counseled regarding use of any new drug in a potential pregnancy. Therefore, when a woman of childbearing potential develops a new medical problem, counseling for pregnancy should be included in management. In general, the use of agents widely used during pregnancy is preferred to use of newer agents. Just stopping pharmacologic therapy or leaving the issue up to the woman does not help her and may place both the mother and the fetus at risk for adverse pregnancy outcome.
When using a known human teratogen, particular attention should be given to prevention of pregnancy. This includes counseling the patient on the fetal effects of the drug being used and on the use of one or more effective forms of contraception. Therapy should be begun with a normal menstrual period or no more than 2 weeks from a negative pregnancy test. When renewing prescriptions for these drugs, it is necessary to verify again that the patient is not pregnant.
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