Erythroblastosis fetalis classically results from Rho(D) incompatibility, which may develop when a woman with Rh-negative blood is impregnated by a man with Rh-positive blood and conceives a fetus with Rh-positive blood, sometimes resulting in hemolysis Hemolysis Anemia is a reduction in red cell mass or hemoglobin and is usually defined as hemoglobin or hematocrit > 2 standard deviations below the mean for age. Some authorities also consider a relative... read more .
Other fetomaternal incompatibilities that can cause erythroblastosis fetalis involve the Kell, Duffy, Kidd, MNSs, Lutheran, Diego, Xg, P, Ee, and Cc antigen systems, as well as other antigens. Incompatibilities of ABO blood types do not cause erythroblastosis fetalis.
Pathophysiology of Hemolytic Disease of the Fetus and Neonate
Fetal red blood cells (RBCs) normally move across the placenta to the maternal circulation throughout pregnancy. Movement is greatest at delivery or termination of pregnancy. Movement of large volumes (eg, 10 to 150 mL) is considered significant fetomaternal hemorrhage; it can occur after trauma and sometimes after delivery or termination of pregnancy. In women who have Rh-negative blood and who are carrying a fetus with Rh-positive blood, fetal RBCs stimulate maternal antibody production against the Rh antigens. The larger the fetomaternal hemorrhage, the more antibodies produced. The mechanism is the same when other antigen systems are involved; however, Kell antibody incompatibility also directly suppresses RBC production in bone marrow.
Other causes of maternal anti-Rh antibody production include injection with needles contaminated with Rh-positive blood and inadvertent transfusion of Rh-positive blood.
No complications develop during the initial sensitizing pregnancy; however, in subsequent pregnancies, maternal antibodies cross the placenta and lyse fetal RBCs, causing anemia, hypoalbuminemia, and possibly high-output heart failure or fetal death. Anemia stimulates fetal bone marrow to produce and release immature RBCs (erythroblasts) into fetal peripheral circulation (erythroblastosis fetalis). Hemolysis results in elevated indirect bilirubin levels in neonates, causing kernicterus Kernicterus Kernicterus is brain damage caused by unconjugated bilirubin deposition in basal ganglia and brain stem nuclei. Normally, bilirubin bound to serum albumin stays in the intravascular space. However... read more . Usually, isoimmunization does not cause symptoms in pregnant women.
Diagnosis of Hemolytic Disease of the Fetus and Neonate
Maternal blood and Rh typing and reflex antibody screening
Serial antibody level measurements and middle cerebral artery blood flow measurements for pregnancies considered at risk
Cell-free fetal DNA screening
At the first prenatal visit, all women are screened for blood type, Rh type, and anti-Rho(D) and other antibodies that are formed in response to antigens and that can cause erythroblastosis fetalis (reflex antibody screening).
If women have Rh-negative blood and test positive for anti-Rho(D) or they test positive for another antibody that can cause erythroblastosis fetalis, the father’s blood type and zygosity (if paternity is certain) are determined. If he has Rh-negative blood and is negative for the antigen corresponding to the antibody identified in the mother, no further testing is necessary. If he has Rh-positive blood or has the antigen, maternal anti-Rh antibody titers are measured.
If maternal anti-Rh antibody titers are positive but less than a laboratory-specific critical value (usually 1:8 to 1:32), they are measured every 2 to 4 weeks after 20 weeks. If the critical value is exceeded, fetal middle cerebral artery (MCA) blood flow is measured at intervals of 1 to 2 weeks depending on the initial blood flow result and patient history; the purpose is to detect high-output heart failure, indicating high risk of anemia. Elevated blood flow for gestational age should prompt consideration of percutaneous umbilical blood sampling and intrauterine blood transfusion.
If paternity is reasonably certain and the father is likely to be heterozygous for Rho(D), the fetus’s Rh type is determined. If fetal blood is Rh positive or status is unknown and if MCA blood flow is elevated, fetal anemia is likely.
When Rho(D) status is uncertain, noninvasive cell-free fetal DNA screening Cell-free fetal nucleic acid testing Noninvasive maternal screening, unlike invasive testing, has no risk of test-related complications. By more precisely assessing the risk of fetal abnormalities, noninvasive maternal screening... read more 
of maternal blood for the RHD gene can be done. Noninvasive testing of other genes (eg, RHCE, KEL) is available in Europe.
Treatment of Hemolytic Disease of the Fetus and Neonate
Fetal blood transfusions
Sometimes delivery at 32 to 35 weeks
If fetal blood is Rh negative or if MCA blood flow remains normal, pregnancy can continue to term untreated.
If fetal anemia is likely, the fetus can be given intravascular intrauterine blood transfusions by a specialist at an institution equipped to care for high-risk pregnancies. Transfusions occur every 1 to 2 weeks, usually until 32 to 35 weeks. During that time period, delivery may be recommended if there is continuing evidence of severe fetal anemia (based on MCA blood flow). The woman may continue to term delivery if there is no evidence of severe fetal anemia based on MCA blood flow. Corticosteroids should be given before the first transfusion if the pregnancy is > 24 weeks, possibly > 23 weeks.
Neonates with erythroblastosis are immediately evaluated by a pediatrician to determine need for exchange transfusion Exchange transfusion Anemia is a reduction in red cell mass or hemoglobin and is usually defined as hemoglobin or hematocrit > 2 standard deviations below the mean for age. Some authorities also consider a relative... read more .
Prevention of Hemolytic Disease of the Fetus and Neonate
Prevention involves giving Rh-negative mothers Rho(D) immune globulin at the following times:
At 28 weeks gestation
Within 72 hours of pregnancy termination
After any episode of vaginal bleeding
After amniocentesis or chorionic villus sampling
Manual removal of the placenta should be avoided because it may force fetal cells into maternal circulation.
Maternal sensitization and antibody production due to Rh incompatibility can be prevented by giving the woman Rho(D) immune globulin. This preparation contains high titers of anti-Rh antibodies, which neutralize Rh-positive fetal RBCs. Because fetomaternal transfer and likelihood of sensitization is greatest at termination of pregnancy, the preparation is given within 72 hours after termination of each pregnancy, whether by delivery, abortion, or treatment of ectopic pregnancy. The standard dose is 300 mcg IM. A rosette test can be used to rule out significant fetomaternal hemorrhage, and if results are positive, a Kleihauer-Betke (acid elution) test can measure the amount of fetal blood in the maternal circulation. If test results indicate fetomaternal hemorrhage is massive (> 30 mL whole blood), additional injections (300 mcg for every 30 mL of fetal whole blood, up to 5 doses within 24 hours) are necessary.
If given only after delivery or termination of pregnancy, treatment is occasionally ineffective because sensitization can occur earlier during pregnancy. Therefore, at about 28 weeks, all pregnant women with Rh-negative blood and no known prior sensitization are given a dose of Rho(D) immune globulin. Some experts recommend a 2nd dose if delivery has not occurred by 40 weeks.
Rho(D) immune globulin should also be given after any episode of vaginal bleeding and after amniocentesis or chorionic villus sampling.
Anti-Rh antibodies persist for > 3 months after one dose.
Key Points
Erythroblastosis fetalis is hemolytic anemia in the fetus caused by transplacental transmission of maternal antibodies to fetal red blood cells, usually due to incompatibility between maternal and fetal blood groups, often Rho(D) antigens.
Screen all pregnant women for blood type, Rh type, anti-Rho(D), and other antibodies that can cause erythroblastosis fetalis.
Give women at risk of sensitization Rho(D) immune globulin at 28 weeks gestation, within 72 hours of pregnancy termination, after any episode of vaginal bleeding during pregnancy, and after amniocentesis or chorionic villus sampling.
If women are at risk, periodically measure antibody levels and, if needed, middle cerebral artery blood flow.
Treat erythroblastosis fetalis with intrauterine fetal blood transfusions as needed and, if severe fetal anemia is detected, delivery at 32 to 35 weeks, depending on the clinical situation.
