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Erythroblastosis Fetalis

(Rh Incompatibility)

By Antonette T. Dulay, MD, Attending Physician, Maternal-Fetal Medicine Section, Department of Obstetrics and Gynecology; Senior Physician, Main Line Health System; Axia Women’s Health

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Erythroblastosis fetalis is hemolytic anemia in the fetus (or neonate, as erythroblastosis neonatorum) caused by transplacental transmission of maternal antibodies to fetal RBCs. The disorder usually results from incompatibility between maternal and fetal blood groups, often Rh0(D) antigens. Diagnosis begins with prenatal maternal antigenic and antibody screening and may require paternal screening, serial measurement of maternal antibody titers, and fetal testing. Treatment may involve intrauterine fetal transfusion or neonatal exchange transfusion. Prevention is Rh0(D) immune globulin injection for women who are Rh-negative.

Erythroblastosis fetalis classically results from Rh0(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.

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.


Fetal 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. Usually, isoimmunization does not cause symptoms in pregnant women.


  • 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-Rh0(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-Rh0(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 titers are positive but less than a laboratory-specific critical value (usually 1:8 to 1:32), they are measured every 2 to 4 wk after 20 wk. If the critical value is exceeded, fetal middle cerebral artery (MCA) blood flow is measured at intervals of 1 to 2 wk 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 Rh0(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 Rh0(D) status is uncertain, noninvasive cell-free fetal DNA screening of maternal blood for the RHD gene can be done. This test is available in North America. Noninvasive testing of other genes (eg, RHCE, KEL) is available in Europe.


  • Fetal blood transfusions

  • Sometimes delivery at 32 to 35 wk

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 wk, usually until 32 to 35 wk. 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 wk, possibly > 23 wk.

Neonates with erythroblastosis are immediately evaluated by a pediatrician to determine need for exchange transfusion.


Prevention involves giving the Rh-negative mother Rh0(D) immune globulin at the following times:

  • At 28 wk gestation

  • Within 72 h of pregnancy termination

  • After any episode of vaginal bleeding

  • After amniocentesis or chorionic villus sampling

Delivery should be as atraumatic as possible. 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 Rh0(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 h 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 h) 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 wk, all pregnant women with Rh-negative blood and no known prior sensitization are given a dose of Rh0(D) immune globulin. Some experts recommend a 2nd dose if delivery has not occurred by 40 wk. Rh0(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 mo after one dose.

Key Points

  • The largest number of fetal RBCs move to the maternal circulation (resulting in the greatest risk of maternal sensitization) after delivery or termination of pregnancy.

  • Screen all pregnant women for blood type, Rh type, anti-Rh0(D), and other antibodies that can cause erythroblastosis fetalis.

  • If women are at risk, measure antibody levels and, if needed, middle cerebral artery blood flow periodically.

  • Treat erythroblastosis fetalis with intrauterine fetal blood transfusions as needed and, if severe fetal anemia is detected, delivery at 32 to 35 wk, depending on the clinical situation.

  • Give Rh0(D) immune globulin at 28 wk gestation and within 72 h of pregnancy termination to women at risk of sensitization.