Isoimmunization

Medvediev M.V., MD, PhD

Department of Obstetrics and Gynecology

Definition

• Incompatibility between circulating maternal antibodies and fetal red blood cell antigens may result in fetal hemolysis with a potential for severe fetal or newborn illness
• Any of the many blood group antigen systems can lead to isoimmunization, but the number of antigens involved in fetal and neonatal hemolytic disease is limited. The most common antigen involved is part of the Rh (CDE) system, specifically the D antigen.

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Isoimmunization can occur when an Rh D-negative woman is pregnant with a fetus who has inherited the Rh D antigen from its father and is thus Rh D-positive. Any event associated with fetomaternal bleeding can potentially lead to maternal exposure to fetal red blood cells, which can trigger a maternal immune response. These events include:

• • Childbirth
• • Delivery of the placenta
• • Threatened, spontaneous, elective, or therapeutic
• abortion
• • Ectopic pregnancy
• • Bleeding associated with placenta previa or abruption
• • Amniocentesis
• • Abdominal trauma
• • External cephalic version

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Pathology

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Diagnosis

• All pregnant women should be tested at the time of the first prenatal visit for ABO blood group and Rh-D type and screened for the presence of erythrocyte antibodies. These laboratory assessments should be repeated in each subsequent pregnancy
• Repeated antibody screening is also recommended before administration of anti-D immunoglobulin at 28 weeks of gestation, postpartum, and the time of any event in pregnancy
• Any antibodies potentially associated with fetal hemolysis found during this routine screening are further evaluated based on the strength of the antibody response, which is reported in titer format (1:4, 1:8, 1:16, etc.)

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Assessment

• Although antibody titers reflect the strength and the amount of the maternal antibody response, their utility in pregnancy management is limited. Titers provide no information about fetal status
• In an initial sensitized pregnancy, serial antibody titer values can assist in determining when the maternal antibody response is strong enough to represent a risk of fetal anemia
• If the initial antibody titer is 1:8 or less, the Rh D-negative patient can be monitored with titer assessment every 4 weeks.
• A critical titer is that titer associated with a significant risk for severe fetal hemolytic disease and hydrops fetalis. In most centers, this is between 1:8 and 1:32.

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Assessment

• Evaluation for possible fetal anemia is usually undertaken in the second trimester, although management may be individualized depending on history and available expertise
• Traditionally, amniotic fluid assessment of the level of bilirubin has been used as a measure of fetal status and an indirect means of estimating the potential for severe fetal anemia
• Until recently, serial amniocenteses were performed to determine the level of bilirubin in the amniotic fluid, which in turn reflected the severity of fetal anemia

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Assessment

• The current trend in management is the measurement of peak velocity of middle cerebral artery (MCA) flow using Doppler ultrasound

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Assessment

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Evaluation of a Pregnancy With a Positive�Maternal Antibody Screen

• Maternal antibody identification and titer
• Careful obstetric history for prior affected fetus
• Paternal antigen testing, possible fetal DNA testing
• Assessment of risk for fetal anemia if a critical titer is found or if there has been a prior affected child
• Amniotic fluid bilirubin assessment
• Serial antibody titers, if first sensitized pregnancy
• Middle cerebral artery Doppler Ultrasound
• Cordocentesis/percutaneous umbilical blood sampling if monitoring test is abnormal

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Ultrasound assessment of the fetus is also helpful in detecting severe signs of hemolysis that have resulted in profound fetal anemia:

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• Regardless of the methods used to monitor pregnancies at risk for fetal anemia, all techniques are designed to determine the fetal hematocrit using indirect measures
• If the monitoring test indicates a risk for fetal anemia, or if hydrops is diagnosed, cordocentesis or percutaneous umbilical blood sampling (PUBS) is performed to directly measure the fetal hematocrit
• In general, the average fetal hematocrit is 36% to 44% and, with severe anemia, it is less than 30%
• In addition to procedures to monitor the fetus for anemia, general tests for fetal well-being are indicated in all isoimmunized women with titers above the critical threshold, because the ability of an affected fetus, even if only mildly anemic, to withstand the stresses of pregnancy and labor may be compromised

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Management

• Previously, blood was transfused into the fetal abdominal cavity, where absorption of the red cells could take place over several days through the lymphatic channels
• Currently, transfusion of antigen-negative red blood cells (depending on the blood group involved) to the fetus is indicated when PUBS determines that the fetus has moderate or severe anemia with a hematocrit less than 30%.

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Transumbilical blood transfusion

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Prevention

Indications for Anti-D Immune Globulin Administration in an Unsensitized Rh-Patient:

• At approximately 28 weeks of gestation
• At time of procedures associated with possible fetal-to-maternal bleeding, such as amniocentesis or chorionic villus sampling
• After ectopic pregnancy
• After a threatened, spontaneous, or induced abortion
• Within 72 hours of delivery of an Rh D-positive infant
• Conditions associated with fetal-maternal hemorrhage (e.g., abdominal trauma, abruptio placentae)
• Unexplained vaginal bleeding during pregnancy

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Prevention

• Because even a minute amount of fetal red cells can result in sensitization to the Rh D antigen, in any circumstance when a fetomaternal hemorrhage can occur, a prophylactic dose of 300 μg of anti-D immune globulin should be administered. Each dose of anti-D immune globulin provides protection against sensitization for up to 30 mL of fetal blood
• In cases of trauma or bleeding during pregnancy in which there is a potential for more than a 30-mL fetomaternal transfusion, the extent of the fetomaternal hemorrhage can be assessed using the Kleihauer-Betke test

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ISOIMMUNIZATION TO OTHER RED CELL ANTIGENS

• The most important cause of hemolytic disease of the fetus not associated with the D antigen is isoimmunization to the Kell antigen
• This sensitization commonly results from a prior blood transfusion
• If a maternal antibody screen reveals the presence of an anti-Kell antibody, paternal blood typing for the Kell antigen should be performed
• Anemia resulting from Kell isoimmunization is unique in that the predominant effect of the antibody is destruction and suppression of hematopoietic precursor cells; hemolysis is only a minimal component of the fetal problem

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ISOIMMUNIZATION TO OTHER RED CELL ANTIGENS

• ABO hemolytic disease, due to maternal-fetal incompatibility for the major blood group antigens, can occur
• It is usually associated with mild fetal and newborn hyperbilirubinemia
• It is not associated with severe fetal disease

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Thank you!

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