RICHARD BERKOWITZ

Mount Sinai School of Medicine, New York, New York

Current methods for intrauterine fetal therapy encompass noninvasive measures, principally bed rest and transplacental drug delivery, and invasive procedures, such as preterm delivery, blood sampling and transfusion, percutaneous shunts, and open surgery.

Bed rest, the most common form of noninvasive therapy, is generally thought of as cheap and without significant side effects. Bed rest in the hospital, however, is not cheap, and being confined to bed for weeks can have major side effects. More important, it rarely works. Transplacental therapy, in which drugs given to the mother pass through the placenta to the fetus, effectively treats a variety of conditions. Drugs or vitamins that cross the placenta have been used to accelerate fetal lung maturation, reduce the risk of neural tube defects, and manage cardiac arrhythmias.

Among invasive therapies, percutaneous umbilical blood sampling, which provides direct entry into the fetal blood circulation, enables diagnosis, intravenous transfusions, and drug delivery. PUBS has been used recently to diagnose and track the effectiveness of therapy for alloimmune thrombocytopenia.

Like Rh disease, alloimmune thrombocytopenia is caused by maternal-fetal incompatibility. In this case, maternal antibodies attack the platelets in fetal blood, which causes a marked reduction in their number (i.e., thrombocytopenia) and may lead to devastating intracranial hemorrhaging. The treatment that has been used is gamma globulin administered intravenously to the mother, sometimes with steroid hormones.

To evaluate and refine this therapy, a trial was conducted with women who had previously delivered babies with the disease and had been shown, by PUBS testing, to be carrying severely thrombocytopenic fetuses. Half of the group was given gamma globulin alone, and half, gamma globulin with low doses of a steroid (dexamethasone). Fetal platelet counts were reassessed with PUBS three weeks after the beginning of the regimen and again six weeks later. If at three weeks the fetal platelet count was less than 20,000/ml³, the mothers were additionally given high doses of a steroid, prednisone, for the remainder of the pregnancy. Among the women who did not require the additional therapy and have since delivered, there was no essential difference in outcome with or without hormones.

A therapeutic success was defined as a birth platelet count greater than 30,000/ml³ since there have been no reports of intracranial hemorrhage with higher platelet concentrations. This was achieved in 82 percent of cases. Fifty percent of those fetuses whose initial platelet count was less that 20,000/ml³ showed a therapeutic response at the time of the second PUBS. Of greatest importance, however, is the fact that regardless of the platelet count at birth, no infant in this study had an intracranial hemorrhage. These data strongly suggest that medical therapy for this disorder will be effective in the vast majority of cases.

An additional finding from this multicenter study was the critical role of fetal platelet concentration as a risk factor for PUBS-induced fetal loss. Eight untreated fetuses, all with a platelet concentration of less than 20,000/ml³ (six actually had counts of less than 10,000/ml³), died following the initial diagnostic PUBS procedure. As a result, the investigators recommended obtaining measurement of the platelet concentration before removing the needle from the umbilical blood vessel and, if the concentration was less than 50,000/ml³, transfusing previously prepared antigen-negative packed platelets into the fetus prior to removal of the needle. No fetal losses have occurred after adoption of this regimen.

Percutaneous shunting is a form of intervention designed to drain abnormal accumulations of fluid within the fetus that can severely compromise the growth and development of adjacent organs. The shunts are put into the obstructed area by a needle guided by ultrasound. Shunts have been used to alleviate obstructions of the bladder outlet, pleural space, and ventricles of the brain. A registry of bladder shunt procedures showed an overall survival of about 40 percent, but with a high risk of renal disease later in life. Long-term results have been more encouraging for hydrothorax, which hampers development of the heart and lungs. Shunting in utero has been much less successful for hydrocephalus, however, where fluid builds up within the ventricular system of the brain. Although 83 percent of the shunted hydrocephalic fetuses survived, more than half had severe brain impairment, and as a result, there is now a moratorium on the procedure for this indication.

The most radical form of invasive intervention is now being attempted outside the uterus. In a small number of selected cases where closed procedures cannot be performed, the uterus has been opened and surgery performed directly on the fetus. The results of this approach, have thus far been mixed, and its ultimate role remains to be determined.