Rhesus Isoimmunization

Published on 10/03/2015 by admin

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Chapter 15 Rhesus Isoimmunization

Lony C. Castro

Rhesus (Rh) isoimmunization is an immunologic disorder that occurs in a pregnant, Rh-negative patient carrying an Rh-positive fetus. The immunologic system in the mother is stimulated to produce antibodies to the Rh antigen, which then cross the placenta and destroy fetal red blood cells.

image Pathophysiology

The Rh complex is made up of a number of antigens, including C, D, E, c, e, and other variants, such as Du antigen. More than 90% of cases of Rh isoimmunization are due to antibodies to D antigens. Therefore, this chapter is mainly limited to a discussion of the D antigen, although the same principles apply to any other antigen-antibody combination. A person who lacks the D antigen on the surface of the red blood cells is called “Rh negative,” and an individual with the D antigen is considered “Rh positive.”

Among African Americans, about 8% are Rh negative, whereas among white Americans, about 15% are Rh negative. Only 1% to 2% of Asians and Native Americans are Rh negative. When Rh-negative patients are exposed to the Rh antigen, they may become sensitized. Two mechanisms are proposed for this sensitization. The most likely mechanism is the occurrence of an undetected placental leak of fetal red blood cells into the maternal circulation during pregnancy. The other proposal is the “grandmother” theory. This theory suggests that an Rh-negative woman may have been sensitized from birth by receiving enough Rh-positive cells from her mother during her own delivery to produce an antibody response.

In general, two exposures to the Rh antigen are required to produce any significant sensitization, unless the first exposure is massive. The first exposure leads to primary sensitization, whereas the second causes an anamnestic response leading to the rapid production of immunoglobulins, which can cause a “transfusion reaction” or hemolytic disease of the fetus during pregnancy.

The initial response to exposure to Rh antigen is the production of immunoglobulin M (IgM) antibodies for a short period of time, followed by the production of IgG antibodies that are capable of crossing the placenta. If the fetus has the Rh antigen, these antibodies will coat the fetal red blood cells and cause hemolysis. If the hemolysis is mild, the fetus can compensate by increasing the rate of erythropoiesis. If the hemolysis is severe, it can lead to profound anemia, resulting in hydrops fetalis from congestive cardiac failure and intrauterine fetal death. High bilirubin levels can damage the central nervous system and lead to neonatal kernicterus. Before the widespread use of Rh immune globulin for prevention of Rhesus isoimmunization, neonatal kernicterus was one of the leading causes of cerebral palsy.

The fetal and maternal circulations are normally separated by the placental “barrier.” Small hemorrhages occur in either direction across the intact placenta throughout pregnancy. With advancing gestational age, the incidence and size of these transplacental hemorrhages increase, with the largest hemorrhages usually occurring at delivery. Most immunizations occur at the time of delivery, and antibodies appear either during the postpartum period or following exposure to the antigen in the next pregnancy.

If a pattern of mild, moderate, or severe disease has been established with two or more previous pregnancies, the disease tends either to be of the same severity or to become progressively more severe with subsequent pregnancies. If a woman has a history of fetal hydrops with a previous pregnancy, the risk for hydrops with a subsequent pregnancy is about 90%. Hydrops usually develops at the same time as, or earlier than, in the previous pregnancy.

image Incidence

Although transplacental hemorrhage is very common, the incidence of Rh immunization within 6 months of the delivery of the first Rh-positive, ABO-compatible infant is only about 8%. In addition, the incidence of sensitization with the development of a secondary immune response before the next Rh-positive pregnancy is 8%. Therefore, the overall risk of immunization for the second full-term, Rh-positive, ABO-compatible pregnancy is about 1 in 6 pregnancies. The risk for Rh sensitization following an ABO-incompatible, Rh-positive pregnancy is only about 2%. The protection against immunization in ABO-incompatible pregnancies is due to the destruction of the ABO-incompatible cells in the maternal circulation and the removal of the red blood cell debris by the liver.

Transplacental hemorrhage may also occur before delivery. Establishment of the fetal circulation occurs at about 4 weeks’ gestation, and the presence of the Rh D antigen has been demonstrated as early as 38 days after conception. Consequently, Rh isoimmunization can occur at any time during pregnancy, from the early first trimester on. In the first trimester, the most common causes of transplacental hemorrhage are spontaneous or induced abortions. The incidence of immunization following spontaneous abortion is 3.5%, whereas that following induced abortion is 5.5%. The risk is low in the first 8 weeks, but it rises to significant levels by 12 weeks’ gestation. The risk for immunization following ectopic pregnancy is about 1%. Transplacental hemorrhage can also occur in the setting of second- or third-trimester vaginal bleeding, after invasive procedures such as amniocentesis or chorionic villus sampling, after abdominal trauma, or after external cephalic version. If necessary the amount of fetal blood entering the maternal circulation after an episode associated with transplacental hemorrhage can be estimated using the Kleihauer-Betke test (described later). All pregnant Rh-negative women who are not sensitized to the D antigen should routinely receive prophylactic Rh immune globulin (RhOGAM) at 28 weeks of gestation, within 72 hours of delivery of an Rh-positive fetus, and at the time of recognition of any of the problems cited previously that are associated with transplacental hemorrhage.

image Detecting Fetomaternal or Transplacental Hemorrhage

The Kleihauer-Betke test is dependent on the fact that adult hemoglobin is more readily eluted through the cell membrane in the presence of acid than is fetal hemoglobin (HbF). The maternal blood is fixed on a slide with ethanol (80%) and treated with a citrate phosphate buffer to remove the adult hemoglobin. After staining with hematoxylin and eosin, the fetal cells can readily be distinguished from the empty maternal cells. All cells are then counted, and an estimate of the extent of the fetal to maternal hemorrhage (measured in milliliters) is made on the basis of the following equation:

image

image Recognition of the Pregnancy at Risk

A blood sample from every pregnant woman should be sent at the first prenatal visit for determination of the blood group and Rh type and for antibody screening. In Rh-negative patients, whose anti-D antibody titers are positive (i.e., those who are Rh sensitized), the blood group and Rh status of the father of the baby should be determined. If the father is Rh negative, the fetus will be Rh negative, and hemolytic disease will not occur. If the father is Rh positive, his Rh genotype and ABO status should be determined. This may be done by testing the father’s red blood cells with the reagents available for the antigens D, E, C, e, and c. Newer molecular techniques are now available to assess fetal Rh genotype. If he is homozygous for the D antigen, every fetus he fathers will be Rh positive and could potentially be affected. If he is heterozygous, only half of his children will be affected. Information regarding the zygosity of the father is of value in absolutely predicting the presence or absence of the Rh antigen in the fetus if the father is homozygous and in signaling the potential need for fetal antigen testing if the father is heterozygous. About 56% of Rh-positive whites are heterozygous for the Rh D antigen. If it is not possible to test the antigen status and zygosity of the father, it must be assumed that he is antigen positive.

MATERNAL RH-ANTIBODY TITER

Anti-D antibody titers generally provide limited information regarding the severity of fetal hemolysis in Rh disease. However, many centers continue to use anti-D antibody titers to help guide their decision making regarding the initiation of testing procedures (e.g., amniocentesis, middle cerebral artery Doppler studies, and percutaneous umbilical blood sampling). The American College of Obstetricians and Gynecologists (ACOG) and other independent researchers have recommended that, in an initially immunized pregnancy, the fetus is not in serious jeopardy if the titer remains below 1:16. In patients with a positive titer less than 1:16, repeat titers should be obtained every 2 to 4 weeks. If the titer rises to 1:16 or greater, a more detailed assessment and determination of fetal Rh status is indicated. The timing and methods of invasive testing will depend on the current clinical status of the fetus, the gestational age, and the patient’s obstetric history. Titers are not generally useful for following a patient with a history of a previous fetus or neonate with hemolytic disease. In this setting, even if the titers are below the critical threshold, the patient should be followed and evaluated as if her titers were high.

TECHNIQUES FOR EVALUATING FETAL RH STATUS

In the United States, amniocentesis is the most commonly employed method to test fetal blood type in cases of a heterozygous paternal genotype.

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