Fetal therapeutics is an emerging area in perinatal pharmacology. This involves drug administration, mostly to the pregnant woman, with the fetus as the target of the drug. At present, corticosteroids are used to stimulate fetal lung maturation when preterm birth is expected. Phenobarbital, when given to pregnant women near term, can induce fetal hepatic enzymes responsible for the glucuronidation of bilirubin, and the incidence of jaundice is lower in newborns when mothers are given phenobarbital than when phenobarbital is not used. Before phototherapy became the preferred mode of therapy for neonatal indirect hyperbilirubinemia, phenobarbital was used for this indication. Administration of phenobarbital to the mother was suggested recently as a means of decreasing the risk of intracranial bleeding in preterm infants. However, large randomized studies failed to confirm this effect. Antiarrhythmic drugs have also been given to mothers for treatment of fetal cardiac arrhythmias. Although their efficacy has not yet been established by controlled studies, digoxin, flecainide, procainamide, verapamil, and other antiarrhythmic agents have been shown to be effective in case series. Similarly, it has been shown that maternal use of zidovudine and other HIV drugs substantially decreases transmission of HIV from the mother to the fetus, and use of combinations of three antiretroviral agents can eliminate fetal infection almost entirely (see Chapter 49).
C. Predictable Toxic Drug Actions in the Fetus
Chronic use of opioids by the mother often produces dependence in the fetus and newborn. This dependence may be manifested after delivery as a neonatal withdrawal syndrome. A less well understood fetal drug toxicity is caused by the use of angiotensinconverting enzyme inhibitors during late pregnancy. These drugs can result in significant and irreversible renal damage in the fetus and are therefore contraindicated in pregnant women. Adverse effects may also be delayed, as in the case of female fetuses exposed to diethylstilbestrol, who may be at increased risk for adenocarcinoma of the vagina after puberty.
D. Teratogenic Drug Actions
A single intrauterine exposure to a drug can affect the fetal structures undergoing rapid development at the time of exposure. Thalidomide is an example of a drug that may profoundly affect the development of the limbs after only brief exposure. This exposure, however, must be at a critical time in the development of the limbs. Thalidomide-induced phocomelia occurs during the fourth through the seventh weeks of gestation because it is during this time that the arms and legs develop (Figure 59–1).
1. Teratogenic mechanisms—The mechanisms by which different drugs produce teratogenic effects are poorly understood and are probably multifactorial. For example, drugs may have a direct effect on maternal tissues with secondary or indirect effects on fetal tissues. Drugs may interfere with the passage of oxygen or nutrients through the placenta and therefore have effects on the most rapidly metabolizing tissues of the fetus. Finally, drugs may have important direct actions on the processes of differentiation in developing tissues. For example, vitamin A (retinol) 20-38 Full term Fetal period (weeks) Embryonic period (weeks) 3816987654321 Heart CNS Eye Eye Heart Arm Leg Teeth Ear External genitalia Central nervous system Arms Eyes Legs Teeth Palate External genitalia Ear Major morphologic abnormalities Prenatal death Usually not susceptible to teratogen Brain Physiologic defects and minor morphologic abnormalities Period of dividing zygote, implantation, and bilaminar embryo Palate Indicates common site of action of teratogen Heart