Rhesus Disease and Isoimmunization

Introduction


Isoimmunization is an immune-mediated process that is caused by maternal antibodies directed toward fetal red cell antigens, and results in extravascular hemolysis in the fetus. 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 with reticulocytosis. In cases of severe isoimmunization, the fetus develops profound anemia, hydrops fetalis, and eventual demise. Prevention and treatment strategies for this condition have significantly improved fetal and neonatal outcomes. This chapter will review the pathogenesis, management, and prevention of red blood cell isoimmunization.


Pathogenesis


Red blood cell (RBC) isoimmunization develops after an initial exposure of foreign erythrocyte surface antigens to the maternal immune system, referred to as the sensitization event. The most common sensitization event is a prior pregnancy in which the fetal erythrocytes contained paternally inherited antigens that were not present on the maternal erythrocytes. The highest risk of sensitization is at time of delivery, whether at term or at time of miscarriage or abortion, although fetal-maternal transfusion may occur at any time during pregnancy. Nonpregnancy-related causes of sensitization include blood transfusions and shared needles. Once erythrocytes containing nonnative surface antigens enter into the maternal circulation, maternal B-lymphocyte clones recognize the erythrocyte antigens as foreign and antibodies directed to those antigens are produced. The initial maternal antibody response results in IgM production, which does not cross the placenta. A gradual rise in maternal IgG production, which can cross the placenta and enter the fetal circulation, occurs 6–16 weeks after the initial sensitization event.


Subsequent antigenic exposure during a succeeding pregnancy in an isoimmunized mother can result in significant increase in maternal antibody titer. Maternal memory B-lymphocytes differentiate into plasma cells and IgG antibodies are produced. The maternal IgG antibodies cross the placenta and target the fetal erythrocytes. The “sensitized” fetal RBC are destroyed by hemolysis via macrophages in the fetal spleen, resulting in fetal anemia. The most common cause of RBC isoimmunization used to be the Rhesus (D) (Rh(D)) antigen but 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). A second mechanism of fetal anemia, unique to the Kell antigen system, results from erythropoietic suppression due to direct destruction of Kell antigen containing fetal erthroid progenitor cells.


The hypoxemia that ensues due to severe fetal anemia stimulates increased fetal erythropoiesis. Whereas the bone marrow is the primary site of blood cell formation in the normal fetus by mid-pregnancy, additional erythropoietic sites, primarily the fetal liver, are stimulated under this hypoxemic stress to produce red cells. The name of this condition, erythroblastosis, arises from the appearance of red cell precursors, erythroblasts, in the peripheral circulation of the fetus. As hematopoietic tissue supplants liver parenchyma, liver functions, including protein synthesis, are impaired. High cardiac output, a compensatory response to anemia and hypoxemia, leads to cardiac failure. Hypoproteinemia and impaired cardiac function combine to produce fetal body cavity effusions and generalized edema, the clinical picture referred to as hydrops fetalis. Untreated, hydrops fetalis results in perinatal death.


Rhesus blood group system


Several dozen red cell antigens have been associated with isoimmunization. However, the Rh blood group system has historically had the greatest clinical impact with regard to the number of affected cases and severity of disease. Typically, when healthcare providers are discussing a patient’s Rh status, they are referring exclusively to the Rh(D) status. In fact, the Rh blood group system can produce five potential antigens: D, C, c, E, and e. The Rh(D) antigen is the most immunogenic of the five main Rh antigens. Two genes on chromosome 1, the RhD gene and the RhCE gene, encode the various antigens. The single RhCE gene produces two different gene products due to alternative mRNA splicing. Slight variation in amino acid composition results in the antigenically distinct C versus c and E versus e.


Understanding the genetics of the RhD gene locus is important for appropriate interpretation of tests that ascertain serologic versus genotypic status. Patients who are referred to as serologically negative for Rh(D) antigen either are missing the RhD gene from both alleles or have an RhD pseudogene. The RhD pseudogene, which occurs in about one-quarter of African Americans, contains a stop codon within the gene that does not allow translation of the mRNA product. Because there is no gene product, patients who have the RhD pseudogene exclusively are serologically Rh(D) negative but genotypically RhD positive. Thus, these patients are at risk for isoimmunization. Patients who are serologically Rh(D) antigen positive have either one or two RhD alleles. A subgroup of patients, particularly African Americans and Asians, may have a modified version of the gene, called RhDu, which produces an abridged gene product. Laboratories often will report that these patients are serologically weakly positive or are Rh(Du) positive. These patients are not at risk of Rh(D) isoimmunization.


In summary, it is the patient’s serologic status that confers risk for isoimmunization. This has important implications with regard to prenatal diagnosis.


Irregular antibodies


Antibodies to erythrocyte antigens other than the Rh blood group system are referred to as irregular antibodies. The most common irregular antibodies are to the Kell, Duffy, MNS, and Kidd blood group systems. These antibodies are more often produced in response to maternal blood transfusion, and have a higher likelihood of being absent in specimens from the father and fetus. It is important to note that the assessment and management of isoimmunization are dependent on the type of antibody. Unless otherwise specified, this chapter will focus on the management of Rh(D) isoimmunization.


Identifying the at-risk fetus

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Jun 6, 2016 | Posted by in GYNECOLOGY | Comments Off on Rhesus Disease and Isoimmunization

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