Fetal Conditions Treated

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Red Blood Cell Alloimmunization and Fetal Anemia

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 hemo-
lytic disease of the fetus and newborn, ranges from mild to severe disease. In mild cases the
fetus has slight anemia. In cases of severe isoimmunization, the fetus develops profound ane-
mia, 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 com-
mon sensitization event is a prior pregnancy in which the fetal red blood cells contained anti-
gens (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. Non-pregnancy 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 he-
molysis. In cases of severe anemia, oxygen delivery to the baby becomes impaired. High cardi-
ac 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 isoimmunization 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 isoimmunization at the time of routine prenatal labo-
ratory 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 hemo-
lytic disease of the fetus and newborn. A reference table should be used to ascertain fetal risk

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 Red Blood Cell Alloimmunization and Fetal Anemia

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 lim-
ited 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. In the United States, this is
done by amniocentesis.

Prenatal Diagnosis of Fetal Anemia

The next clinical step in the evaluation of the isoimmunized patient is determination of the severity
of disease. There are three methods that are currently used to ascertain if the at-risk fetus is actu-
ally 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-logarith-
mic 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 measure-
ment of a vessel in the fetal brain called the middle cerebral artery (MCA) has been shown to accu-
rately 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 an intrauterine transfusion if necessary.