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 (hemolytic disease of the fetus and neonate). 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-Rho(D) and other antibodies that are formed in response to antigens and that can cause hemolytic disease of the fetus and neonate (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 hemolytic disease of the fetus and neonate, 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 of maternal blood for the RHD gene can be done. Noninvasive testing of other genes (eg, RHCE, KEL) is available in Europe.

• 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.

Prevention involves giving Rh-negative pregnant women Rho(D) immune globulin at the following times:

• At 28 weeks of gestation (or at both 28 and 34 weeks)

• Within 72 hours after pregnancy loss or termination at < 20 weeks of gestation

• After any episode of vaginal bleeding

• After amniocentesis or chorionic villus sampling

Maternal sensitization and antibody production due to hemolytic disease of the fetus and newborn 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.

Rho(D) immune globulin is usually given as an intramuscular injection but can be given intravenously. Anti-Rh antibodies persist for > 3 months after one dose.

Rho(D) immune globulin is given routinely to all Rh-negative pregnant women with no known prior sensitization and a fetus that might be Rh-positive. It is given routinely rather than solely as treatment for episodes with a risk of fetomaternal bleeding (eg, after delivery or termination of pregnancy), because sensitization can occur earlier during pregnancy without a recognized high-risk episode.

In some countries (including the United States), a single 300-mcg dose is given at 28 weeks and, in other countries, 2 doses (ranging from 100 to 300 mcg, depending on local practice and guidelines) are given at 28 and 34 weeks (1). An additional dose is given within 72 hours after delivery (if a newborn is confirmed to have Rh-positive blood or if neonatal blood typing is not done).

Rho(D) immune globulin should also be given to these patients within 72 hours after any episode that may cause significant fetomaternal bleeding, including

• Spontaneous or induced abortion (including uterine evacuation for hydatidiform mole) at ≥ 12 and < 20 weeks

• Ectopic pregnancy

• Chorionic villous sampling or amniocentesis

• Fetal death in the second or third trimester

• Vaginal bleeding in the second or third trimester (prior to labor)

• Blunt abdominal trauma

• External cephalic version

Recommendations vary regarding whether Rho(D) immune globulin is required for spontaneous or induced abortion at < 12 weeks (2, 3, 4). For these early pregnancies, some medical societies advise no prophylaxis and others advise prophylaxis only if there was a surgical procedure.

If the presence of fetomaternal hemorrhage is uncertain, a rosette test (addition of an anti-D reagent to maternal blood) is used as an initial qualitative screening test. If results are positive, a Kleihauer-Betke assay (acid elution) or flow cytometry can measure the volume 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.