Drug disposition and effects in the fetus

Surveys of drug use in pregnancy demonstrate that a significant proportion of human fetuses are exposed to prescription and non-prescription drugs antenatally or during labor, although recently a decrease in licit drug consumption during pregnancy may have occurred. However, legitimate medical reasons for drug therapy of the mother or fetus remain and there is an increasing problem with illicit drugs. Several approaches are used to examine placental transfer of and fetal exposure to drugs, including studies on pregnant women, the use of chronically catheterized pregnant animals (particularly sheep), acute studies on small animals (e.g. guinea pig and rabbit) and the use of the perfused placenta. Fetal drug exposure is affected by large number of maternal, placental and fetal factors. For long term maternal drug administration, drug binding in maternal and fetal plasma, and fetal drug elimination seem particularly important. Thus, the rate of non-placental clearance of morphine, methadone, acetamionophen, metoclopramide, ritodrine and diphenhydramine in the fetal lamb is comparable to that in the ewe, although the routes of fetal elimination are not fully elucidated. The fetal liver may be of lesser importance in overall drug elimination than in the adult, but conjugated drug metabolites in the fetus may persist because of limited placental transfer. Hence, we have observed that the glucuronide conjugate of ritodrine accumulates in amniotic fluid after intravenous ritodrine administration. Accumulation of intact drugs in amniotic fluid also occurs via fetal renal excretion and perhaps via the fetal membranes. Also, a number of basic amine drugs are also concentrated in fetal tracheal fluid, probably as a consequence of pulmonary uptake, which also takes place in the adult. However, this could result in high fetal lung levels of agents, such as beta 2-adrenergic agonists, that have potent effects on pulmonary function and maturation. When digoxin, metoclopramide and diphenhydramine are injected into amniotic fluid, they are preferentially distributed to the fetus and, for the latter 2 drugs, uptake by the chorioallantoic membranes appears to be important. Thus, there is the possibility of recycling of drugs from amniotic fluid to the fetal circulation and their persistence in the fetus. Many of the therapeutic agents given to pregnant women in late pregnancy have effects on fetal CNS, cardiovascular or metabolic functions. Alterations in fetal behaviour are elicited by prescription sedatives and anesthetics and illicit drugs, and also by the antihistamine, diphenhydramine, present in various nonprescription medications.