Alloimmunization is an immune-mediated process that is caused by maternal antibodies that cross the placenta and target fetal red blood cell antigens. This causes hemolysis (destruction of red blood cells) and fetal anemia (low blood count). This condition, also referred to as hemolytic disease of the fetus and newborn, ranges from mild to severe disease. In mild cases the fetus has slight anemia. In cases of severe alloimmunization, the fetus develops profound anemia, hydrops fetalis (heart failure), and eventual death. Prevention and treatment strategies of this condition have significantly improved fetal and neonatal outcomes.
Background
Red blood cell alloimmunization develops after an initial exposure of “foreign” red blood cells to the mother’s immune system. This is referred to as the sensitization event. The most common sensitization event is a prior pregnancy in which the fetal red blood cells contained antigens (unique characteristics on the cell surface) that are not present on the mother’s cells. The highest risk of sensitization is at time of delivery, whether at term or at time of miscarriage or abortion. Nonpregnancy related causes of sensitization include blood transfusions and shared needles.
Subsequent antigenic exposure during a succeeding pregnancy in an alloimmunized mother can result in significant increase in maternal antibody titer. The maternal antibodies cross the placenta and target the fetal red blood cells. The “sensitized” fetal RBC’s are destroyed by hemolysis. In cases of severe anemia, oxygen delivery to the baby becomes impaired. High cardiac output, a compensatory response to anemia and poor oxygen supply, leads to heart failure. Eventually the baby develops fluid collections in various body cavities; this is called hydrops fetalis. Untreated, hydrops fetalis results in death.
The most common cause of RBC alloimmunization was the Rh(D) antigen, however the practice of Rh(D) immune prophylaxis has reduced the frequency of alloimmunization from Rh disease, resulting in relatively increased rate of sensitization to non-Rh(D) antigens (irregular antigens).
Identifying the At-Risk Fetus
All pregnant women undergo screening for alloimmunization at the time of routine prenatal laboratory testing. A positive antibody screen means that the fetus is at risk for hemolytic disease. If the antibody screen is positive, the laboratory performs antibody identification and titer on the maternal specimen. Not all types of maternal antibodies to erythrocyte antigens cause hemolytic disease of the fetus and newborn. A reference table should be used to ascertain fetal risk if an irregular antibody is identified. The antibody titers can then be followed during the pregnancy. Monitoring of maternal antibody titers is useful in the evaluation of the index pregnancy, but has limited utility in monitoring patients with a prior affected pregnancy.
Once a maternal antibody has been identified, it is important to determine if the fetal red blood cells express the target antigen. The first step is to obtain blood from the father to determine his antigen status. If the father of the baby is serologically negative, then the fetus is theoretically not at risk. The second step is to directly determine fetal blood type by DNA testing. This may be done by doing cell free fetal DNA (cffDNA) testing on the mother, or direct testing via chorionic villus sampling (CVS), amniocentesis, or fetal blood sampling.
Prenatal Diagnosis of Fetal Anemia
The next clinical step in the evaluation of the alloimmunized patient is determination of the severity of disease. There are three methods that are currently used to ascertain if the at-risk fetus is actually anemic. The first method utilizes spectrophotometry to quantify the bilirubin level in the amniotic fluid acquired via amniocentesis. The bilirubin level in the amniotic fluid correlates with the degree of hemolysis. The result is plotted on a normative curve based on gestational age. This semi-logarithmic graph, called the Liley Curve, is separated into three zones according to risk of anemia.
The second method utilizes ultrasound to assess for fetal anemia. Overt evidence of fetal hydrops on ultrasound is an end-stage sign of severe fetal anemia. Obviously the goal of fetal surveillance is to identify the anemic fetus prior to the onset of hydrops. The ultrasound acquired Doppler measurement of a vessel in the fetal brain called the middle cerebral artery (MCA) has been shown to accurately identify moderate to severe fetal anemia even in non-hydropic fetuses. Because this technique is noninvasive and has been shown to be more accurate than the Liley Curve, the MCA Doppler has largely replaced serial amniocenteses in current clinical practice.
The third method for fetal anemia assessment, and the gold standard to which all are compared, is fetal blood sampling. This procedure is the most invasive and thus carries the highest risk. A needle is placed through the maternal abdomen into a fetal vessel via direct ultrasound guidance, and one or two milliliters of fetal blood is obtained. Preparations for intrauterine transfusion are in place at the time of fetal blood sampling to proceed with fetal transfusion if necessary.
Fetal Treatment
Severe fetal anemia is treated in the prenatal period via intrauterine transfusion (IUT). IUT is performed under direct ultrasound guidance using a 22-gauge needle. Umbilical cord IUT is the most common method used in the United States today. The fetal blood transfusions are usually repeated several times over the course of pregnancy to keep the baby’s blood level within target range. Risks of IUT include fetal bradycardia (low heart rate), hemorrhage (bleeding), infection, and rupture of membranes (bag of waters breaks). The overall fetal survival rates in pregnancies complicated by severe fetal anemia and treated by IUT are approximately 92% for nonhydropic fetuses and 70% in hydropic fetuses. Normal neurologic outcome can be expected in over 90% of surviving infants even if hydrops was noted at the time of the first IUT.
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