Alloimmunization
Berendena I. M. Vander Tuig
Karin J. Blakemore
Alloimmunization in pregnancy refers to maternal antibody formation against fetal red blood cell (RBC) or platelet antigens. Antibody-coated erythrocytes or platelets are destroyed by the fetal immune system, leading to fetal anemia or thrombocytopenia. Antibodies are formed after uncrossmatched transfusion or fetomaternal hemorrhage (FMH), when foreign or fetal blood components enter the maternal circulation. Untreated alloimmunization can cause significant fetal and newborn morbidity and mortality from hemolytic anemia (hydrops fetalis) or neonatal alloimmune thrombocytopenia.
RED CELL ALLOIMMUNIZATION
Red cell alloimmunization to clinically significant antigens occurs in approximately 25 of 10,000 births. The most common of these antigens is the Rhesus “D” (or Rh D) antigen. Maternal blood type is usually described as ABO+ or ABO−, signifying the presence (+) or absence (—) of the Rh D antigen. The Rhesus system also includes the antigens C, c, E, and e. Other important red cell antigens are the ABO blood group antigens and more than 50 other minor antigens. Only some of these are associated with red cell alloimmunization (Table 21-1).
TABLE 21-1 Blood Group Antibodies and Incidence of Hemolytic Disease of the Newborn | |||||||||||
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Rh D Alloimmunization
Pathophysiology
Prevalence of Rh D blood type varies by ethnicity. Fifteen percent of Caucasians and 8% of African Americans and Hispanic Americans are Rh−. The populations with the highest and lowest Rh− prevalence respectively are Spanish Basque (30%) and Native Americans (1%).
Exposing an Rh− woman to Rh D antigen initiates an immune response that produces anti-D immunoglobulin (Ig) M and IgG and results in memory B cells that produce IgG upon reexposure to the antigen. This process is termed Rh sensitization.
During pregnancy, the RBCs of an Rh+ fetus are targeted by maternal IgG, which can cross the placenta. Fetal anemia develops as Rh+ fetal RBCs are sequestered and hemolyzed.
The fetal response to anemia includes increased erythropoietin production and hematopoiesis. As hemolysis outpaces production, more immature RBCs appear in the fetal circulation, a condition known as erythroblastosis fetalis. Extramedullary hematopoiesis may occur.
If the anemia is left untreated, hydrops fetalis develops. The pathophysiology is not completely understood but is thought to involve heart failure due to anemia, portal hypertension from extramedullary hematopoiesis in the liver, and reduced hepatic protein synthesis leading to hypoalbuminemia.
FMH with transplacental passage of Rh+ fetal erythrocytes into the maternal circulation is the main cause of Rh sensitization. See Table 21-1 for causes of FMH.
An immune response can be generated with as little as 20 µL of blood or possibly even less.
FMH is most likely to occur at delivery. Cesarean delivery, multifetal delivery, abruption, bleeding previa, or manual placental delivery may increase the quantity of FMH.
Fetal RBC antigens are present by 38 days of gestation, so even first-trimester events such as ectopic pregnancy, spontaneous or elective abortion, or threatened abortion can theoretically cause alloimmunization.
Invasive prenatal diagnostic procedures such as chorionic villus sampling, amniocentesis, or fetal blood sampling and external cephalic version can lead to FMH and alloimmunization.
Maternal trauma can also cause FMH and alloimmunization.
Prevention
Injectable anti-D Ig (RhoGAM) was developed in the 1960s as a means to prevent Rh D alloimmunization. It is made from pooled sterile human IgG antibodies to the Rh D antigen.
Before RhoGAM’s development, 17% of all Rh− women carrying an Rh+ fetus developed antibodies during their first incompatible pregnancy.
Now, with routine screening and use of RhoGAM, only 0.1% to 0.2% of pregnancies in Rh− mothers are complicated by anti-Rh D antibody production.
RhoGAM prevents alloimmunization by binding to any fetal RBCs that enter the maternal circulation. The fetal cells are then cleared by the mother’s immune system. Maternal B-cell immune response is not initiated, so no memory response develops.
In the United States, RhoGAM is routinely administered to Rh− women at 28 weeks’ estimated gestational age (EGA) and again postpartum if neonatal Rh+ status is confirmed.
The standard RhoGAM dose for routine prophylaxis is 300 µg intramuscularly (IM).
“Mini-dose” RhoGAM (50 µg) IM is sufficient in the first trimester as the fetus’ circulating volume is smaller.
Ten micrograms of RhoGAM IgG “neutralizes” 1 mL of fetal blood. Therefore, the standard dose protects against up to 30 mL of fetal blood entering the maternal system. After an event likely to cause FMH, quantification of FMH with a Kleihauer-Betke (KB) test guides additional RhoGAM dosing.
The half-life of RhoGAM is 24 days but it can be detected on maternal antibody screens for up to 12 weeks.
Management of Rh-Unsensitized Patients
Pregnant patients are screened for antibodies by indirect Coombs test, in which maternal serum is exposed to Rh+ red cells.
Lack of agglutination signifies the absence of circulating antibody in maternal serum and suggests unsensitized status (Table 21-2).
If the indirect Coombs test is positive (i.e., agglutination occurs), the laboratory must distinguish between sensitization and RhoGAM administration earlier in pregnancy.
Rh− pregnant patients should be screened at the first prenatal visit. If unsensitized, no intervention is required at that time. If sensitized, see “Management of Rh-Sensitized Patients.”
The antibody screen may be repeated at 28 weeks of EGA. If the screen is negative, the standard dose of 300 µg of RhoGAM is administered. If the patient is sensitized, see “Management of Rh-Sensitized Patients.”
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