FETAL DIAGNOSES & TREATMENT
Alloimmunization

During the birthing process, blood cells from the unborn child can escape into the mother's bloodstream. These cells are recognized as foreign if they are a different blood type from the mother and a natural rejection process will ensue with the formation of antibodies. The process is known as red cell alloimmunization.

This event typically occurs after the delivery of a baby at the end of pregnancy, but other pregnancy-related events such as elective abortion or spontaneous miscarriage can result in antibody formation. Although the pregnancy in which the alloimmunization first occurs results in an unaffected child, future children are at substantial risk. In these subsequent pregnancies, newly formed antibodies in the pregnant patient can cross to the unborn child and attach to its red blood cells producing a low blood count (anemia) and in the worst case scenario, fetal death. These antibodies can be measured in a woman's bloodstream by a test called an indirect Coombs or antibody titer. In general, the fetus of each subsequent pregnancy exhibits more severe effects than in the previous pregnancy. The fetal and newborn effects of red cell alloimmunization are known as hemolytic disease of the newborn.

Modes of inheritance
In more than 98 percent of cases, the red blood cell incompatibility involves the Rhesus or Rh D antigen so the disease is known as Rhesus disease or Rh disease. Although the exact percentage varies with race, 15 percent of the United States population is Rh-negative and 85 percent is Rh-positive. If a Rh-negative woman conceives a child with a Rh-positive partner, the potential exists for the child to inherit its father's Rh-positive blood type. There are two types of Rh-positive men. In 55 percent of people, the man is heterozygous. In this situation, his genetics allow him to produce Rh-negative offspring 50 percent of the time and Rh-positive offspring the remaining 50 percent of the time. In the second type of a Rh-positive individual, only Rh-positive offspring can result, a condition known as the homozygous state.

Incidence
Data from the Centers for Disease Control (CDC) indicate that the incidence of hemolytic disease of the newborn secondary to Rhesus disease is approximately one case per 1000 live born infants.

Prevention
Medication is available to prevent Rhesus disease. Rhesus immune globulin (also known as RhoGAM) should be administered to the Rh-negative woman with a Rh-positive partner any time there is a chance fetal cells may enter the pregnant woman's circulation. Such events include threatened miscarriage, spontaneous miscarriage, ectopic pregnancy, chorionic villus sampling or amniocentesis performed for genetic indications, and motor vehicle accidents. Rhesus immune globulin should be administered routinely at 28 weeks of pregnancy and after the delivery of an Rh-positive infant. If given correctly, this medication is more than 99 percent effective in the prevention of Rhesus disease. Rhesus immune globulin is only effective in preventing Rhesus disease; it is not effective in preventing worsening disease once alloimmunization has occurred. Unfortunately, similar medications are not available to prevent alloimmunization to other more rare red cell antigens such as Kell.

Treatment
In 75 percent of first affected pregnancies, the pregnancy can be followed with serial antibody measurements taken from the pregnant patient's blood. These
are called antibody titers. As long as the titer remains below a critical value (usually 1:32), no additional testing is required. In the remaining 25 percent of first affected pregnancies, a high maternal titer will mandate such invasive fetal testing as amniocentesis to measure the amount of bilirubin, an indirect assessment of the rate of breakdown of fetal red blood cells, in the amniotic fluid. Amniocentesis is performed by directing a needle with ultrasound into the fluid-filled space that surrounds the fetus. In a few select cases, it may be necessary to obtain blood directly from the fetal umbilical cord to assess the degree of anemia in the baby while it still remains in the womb. This procedure is known as cordocentesis or percutaneous umbilical blood sampling.

In 12 percent of first affected pregnancies, the infant may require intrauterine transfusions. In this procedure, a needle is directed under ultrasound guidance into the umbilical cord and blood is infused directly into the fetus to correct its anemia. The procedure is usually repeated at 2 to 3 week intervals for the remainder of the pregnancy until approximately 35 weeks of the pregnancy. The survival rate after intrauterine transfusion is approximately 85 percent.

Red Cell Antibodies Other than Anti-D
Red cell alloimmunization secondary to non-RhD antibodies continues to be a problem since prophylactic immune globulin is not available to prevent these cases. Although the RhD antigen causes more than 98% of all cases of hemolytic disease of the newborn, more than 43 other red cell antigens have been implicated. Especially problematic are the Kell (K1), c, Duffy (Fya), and Kidd (Jka and Jk b) antigens. A recent study from a tertiary referral center in New York found 550 cases of antibodies associated with hemolytic disease of the newborn in 37,506 blood samples taken from women of reproductive age (1.1 percent incidence). Anti-D occurred in 25 percent of the samples, anti-Kell in 28 percent, anti-c in 7 percent, anti-Duffy in 7 percent, anti-Kidd in 2 percent, anti-E in 18 percent, anti-C in 6 percent, anti-MNS in 6 percent, and anti-Lutheran in 2%.

The majority of cases of Kell sensitization in the United States are secondary to incompatible red cell transfusions since blood is not routinely cross matched for the Kell antigen. In the case of the Kell antigen, 92 percent of males will be Kell negative; only Kell negative, unaffected offspring can therefore be expected if these individuals father a child. For this reason, Kell typing of the father is the primary step in the management of Kell disease in pregnancy. The remaining 8 percent of males will be Kell positive; 98 percent of these will be heterozygous while 2 percent will be homozygous. In the case of the little c antigen, 80 percent of males will be positive for the antigen and 50% will be heterozygous.

Kell disease in pregnancy is managed more aggressively than Rh disease due to several reported cases of severe fetal anemia with low maternal antibody titers. A titer of 1:8 instead of 1:32 is used to decide when to begin invasive testing. Amniocentesis for bilirubin determination is NOT reliable in cases of Kell disease therefore most authors would use cordocentesis to directly test for fetal anemia. Due to the infrequency of the other non-RhD red cell antibodies, most centers use diagnostic and treatment protocols similar to Rh disease. A critical titer of 1:32 is used to indicate when such invasive testing as amniocentesis or cordocentesis is warranted.

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