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Chapter: Medical Immunology: Immunohematology

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Hemolytic Disease of the Newborn (Erythroblastosis Fetalis)

What is the most probable cause of the neonatal jaundice, and what treatment, if any, is usually indicated in such cases?


Case 22.1

A 25-year-old gravida 1, para 0 woman who had not received prenatal care appeared at the emergency room just prior to delivering a 3.5 kg baby girl. The mother was found to be group O, Rh-negative, and her antibody screen was negative. Twenty hours later the nurse observed that the neonate was jaundiced. A hemogram with differential showed WBC of 6200/ µL, RBC of 4.1×106 µL, and hemoglobin of 15 g/dL. The differential showed 5% reticulocytes.

This case raises several questions:

1.           What is the most probable cause of the neonatal jaundice, and what treatment, if any, is usually indicated in such cases?


2.           What laboratory tests should be ordered to investigate the cause of this new-born’s jaundice?


3.           Can this situation be prevented? How?


A.   Pathogenesis

Immunological destruction of fetal and/or newborn erythrocytes is likely to occur when IgG antibodies are present in the maternal circulation directed against the corresponding antigen(s) present on the fetal red blood cells (only IgG antibodies can cross the placenta and reach the fetal circulation).

The two types of incompatibility most usually involved in hemolytic disease of the newborn are anti-D and anti-A or -B antibodies. Anti-A or anti-B antibodies are usually IgM, but in some circumstances, IgG antibodies may develop (usually in group O moth-ers). This can be secondary to immune stimulation (some vaccines contain blood group substances or cross-reactive polysaccharides) or may occur without apparent cause for un-known reasons.

B. Mechanisms of Sensitization

Although the exchange of red cells between mother and fetus is prevented by the placental barrier during pregnancy, about two thirds of all women after delivery (or miscarriage) have fetal red cells in their circulation.

If the mother is Rh-negative and the infant Rh-positive, the mother may produce antibodies to the D antigen. The immune response is usually initiated at term, when large amounts of fetal red cells reach maternal circulation. In subsequent pregnancies, even the small number of red cells crossing the placenta during pregnancy are significant enough to elicit a strong secondary response, with production of IgG antibodies. As IgG anti-bodies are produced in larger amounts, they will cross the placenta, bind to the Rh-posi-tive cells, and cause their destruction in the spleen through Fc-mediated phagocytosis. Usually, the first child is not affected, since the red cells that cross the placenta after the 28th week of gestation do so in small numbers and are unlikely to elicit a primary im-mune response.

IgG anti-D antibodies do not appear to activate the complement system, perhaps be-cause the D antigenic sites on the red cell surface are too separated to allow the formation of IgG doublets with sufficient density of IgG molecules to induce complement activation. Complement, however, is not required for phagocytosis that can be mediated by the Fc re-ceptors in monocytes and macrophages.

C. Epidemiology

Prior to the introduction of immunoprophylaxis, the frequency of clinically evident hemolytic disease of the newborn was estimated to be about 0.5% of total births, mostly due to anti-D, with a mortality rate close to 6% among affected newborns. Recent figures are considerably lower: 0.15–0.3% incidence of clinically evident disease, and the perina-tal mortality rate appears to be declining to about 4% of affected newborns. Due to the in-troduction of immunoprophylaxis, the proportion of cases due to anti-D antibodies de-creased, while the proportion of cases due to other Rh antibodies, and to antibodies to antigens of other systems, increased.

D.  Clinical Presentation

The usual clinical features of this disease are anemia and jaundice present at birth or, more frequently, in the first 24 hours of life. In severe cases, the infant may die in utero. Unless treated appropriately, other severely affected children who survive until the third day de-velop signs of central nervous system damage, attributed to the high concentrations of un-conjugated bilirubin (kernicterus). The peripheral blood shows reticulocytes and circulat-ing erythroblasts (hence the term “erythroblastosis fetalis”).

E. Immunological Diagnosis

A strongly positive direct Coombs’ (antiglobulin) test with cord red blood cells is invari-ably found in cases of Rh incompatibility, although 40% of the cases with a positive reac-tion do not require treatment. In ABO incompatibility, the direct antiglobulin test is usually weakly positive and may be confirmed by eluting antibodies from the infant’s red cells and testing the eluate with A and B cells.

F. Prevention

Rh hemolytic disease of the newborn is rarely seen when mother and infant are incompat-ible in both Rh and ABO systems. In such cases, the ABO isoagglutinins in the maternal circulation appear to eliminate any fetal red cells before maternal sensitization occurs. This observation led to a very effective form of prevention of Rh hemolytic disease of the new-born, achieved by the administration of anti-D IgG antibodies (Rh immune globulin) to Rh-negative mothers.

The therapeutic anti-D preparation is manufactured from the plasma of previously immunized mothers with persistently high titers, or from male donors immunized against Rh-positive RBCs. Its mechanism of action is not entirely clear, but a recently proposed mechanism to explain the immunotherapeutic effect of intravenous gamma globulin in id-iopathic thrombocytopenia has some interesting parallels. According to this postulate, it is possible that Rh immune globulin may downregulate anti-D–producing B cells as a consequence of co-ligation of surface immunoglobulin (by anti-idiotypic specificities present in the Rh immune globulin) and Fcll- γR (by the Fc region of red cell–bound anti-D).

The schedule of administration involves two separate doses. Antepartum administra-tion of a full dose of Rh immune globulin at the 28th week of pregnancy is recommended, in addition to postpartum administration. The rationale for this approach is to avoid sensi-tization due to prenatal spontaneous or posttraumatic bleeding. Prenatal anti-D prophylaxis is also indicated at the time that an Rh-negative pregnant woman is submitted to amnio-centesis and must be continued at 12-week intervals until delivery to maintain sufficient protection. The postpartum dose is administered in the first 72 hours after delivery of each Rh-incompatible infant (before sensitization has had time to occur). The risk of immuniza-tion with a postpartum dose alone is 1–2%. Antepartum administration decreases the risk to 0.1%.

The recommended full dose is 300 µg intramuscularly, which can be increased if there is laboratory evidence of severe feto-maternal hemorrhage (by tests able to determine the number of fetal red cells in maternal peripheral blood, from which one can calculate the volume of feto-maternal hemorrhage). Smaller doses (50 µg) should be given after thera-peutic or spontaneous abortion in the first trimester.

G. Treatment

To prevent serious hemolytic disease of the newborn in their infants, pregnant women who have a clinically significant antibody in the maternal circulation directed against a fetal antigen are carefully monitored. Amniocentesis is usually performed if the antibody has an antiglobulin titer greater than 16 or if the woman has a history of a previously affectedchild. The amniotic fluid is examined for bile pigments at appropriate intervals, and the severity of the disease is assessed according to those levels. An alternate approach is to monitor the fetus by percutaneous umbilical blood sampling (PUBS), which allows for di-rect hematological and biochemical measurements by removing blood from the umbilical vessel using ultrasound guidance.

If fetal maturity has been established, labor may be induced, and, if necessary, the baby can be exchange-transfused after delivery. If fetal lung maturity is inadequate (judged by the lecithin/sphyngomyelin ratio in amniotic fluid), intrauterine transfusion may be per-formed by transfusing O, Rh-negative red cells to the fetus.

Case 22.1Revisited

1. Many clinical conditions can cause neonatal jaundice. In a blood group O, Rh-negative mother, hemolytic disease of the newborn secondary to anti-Rh or anti-A/B antibodies needs to be considered. In gravida 1, para 0 females, the disease is unlikely to be due to Rh incompatibility, and ABO hemolytic disease of the newborn is usually mild. Treatment is not usually required. If indicated, pho-totherapy will usually reduce the bilirubin concentration, and exchange transfu-sion is rarely necessary.


2. The following test results were obtained:

Blood group and Rh type:           A, Rh-positive

Characterization of antibodies:

Direct antiglobulin test                 Weakly positive

Antibody eluted from RBC           Anti-A

Bilirubin, total                             7.4 mg/dL

Bilirubin, direct                            0.1 mg/dL

The conclusion from the laboratory tests was that the child had jaundice secondary to a mild hemolytic anemia of immune cause.

3. Prevention of hemolytic disease of the newborn is a multistep process. First, this woman should have had a blood typing and antibody-screening test or-dered in the first trimester. In Rh-negative women the antibody-screening test is repeated at 28 weeks. If a woman has a positive antibody screening test, the antibody must be identified and its clinical significance assessed. This basi-cally means determining whether it is  IgG  and can cross the placenta and re-act with incompatible fetal cells at body temperature. Clinically significant an-tibodies must be monitored closely throughout pregnancy so that treatment such as early delivery or intrauterine transfusions may be given if necessary. In addition, if anti-D antibodies were not detected in this patient, she should have been given a full dose of Rh immune globulin at 28 weeks and again within 72 hours after delivery. The risk of sensitization for an Rh-negative woman delivering her first Rh-positive infant is about 8%. The postpartum dose protects at the time of delivery when the largest number of fetal cells en-ters the maternal circulation and reduces the risk of positive red cells (Rh im-mune globulin should be given as a fail-safe approach). The antepartum dose prevents a small number of women who have larger than normal amounts of fetal cells entering their circulation during pregnancy from becoming sensi-tized and decreases the risk. ABO hemolytic disease of the newborn cannot be prevented, but it is rarely serious.

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