Hemolytic disease of the fetus and newborn (HDFN) is a condition characterized by the destruction of fetal red blood cells (RBC) and subsequent anemia. It is commonly caused by a Rhesus (Rh) or ABO incompatibility between the mother and fetus, although other blood incompatibilities (e.g., Kell blood group incompatibility) can also cause HDFN. In Rh incompatibility, maternal IgG antibodies form after maternal exposure to fetal Rh-positive blood during birth or pregnancy-related complications (e.g., fetomaternal hemorrhage). The initial pregnancy is not affected; however, subsequent pregnancies are at risk of fetal hemolysis and, in severe cases, intrauterine hydrops fetalis. ABO incompatibility, on the other hand, may lead to fetal hemolysis in the first pregnancy because of preexisting antibodies in the mother, and it usually has a milder course of disease. Newborns may present with pallor, jaundice, and hepatosplenomegaly. Diagnosis of HDFN involves clinical and laboratory assessment for evidence of antibody-mediated hemolysis (e.g., Coombs test). Prenatal imaging may be used to exclude hydrops fetalis. Treatment includes iron supplementation and, in the case of severe jaundice, phototherapy. In rare cases, extremely low hemoglobin (Hb) levels require transfusion of red cell concentrates. Since Rh incompatibility may be fatal, anti-D immunoglobulin prophylaxis is administered to Rh-negative pregnant women. ABO incompatibility, on the other hand, rarely presents with complications and does not require immunoglobulin prophylaxis.
- ABO incompatibility: present in ∼ 20% of all pregnancies; however, only 5–10% of newborns from these pregnancies are symptomatic.
- Rh incompatibility: rare following routine anti-D prophylaxis
- Kell blood group system incompatibility: second most common cause of severe HDFN after Rh disease
- Risk factors: maternal exposure to fetal blood during pregnancy 
- Highest risk: mother with blood group O; newborn with blood group A or B
- Maternal antibodies (anti-A and/or anti-B) against nonself antigens of the ABO system are present even if sensitization has not occurred ; , so fetal hemolysis may occur during the first pregnancy.
- In an Rh-negative mother and Rh-positive newborn: maternal exposure to fetal blood (fetomaternal hemorrhage) → production of maternal IgM antibodies against the Rh antigen → over time, seroconversion to Rh-IgG (able to cross the placenta)
- In a subsequent pregnancy with an Rh-positive newborn: rapid production of maternal IgG anti-D antibodies to fetal RhD antigens → Rh-IgG agglutination of fetal RBCs with → risk of HDFN with possible
- Neonatal anemia
The diagnosis of HDFN requires evidence of hemolysis in the presence of fetomaternal blood incompatibility.
- If the newborn has signs of , conduct a Coombs test (either direct or indirect).
|ABO vs. Rh incompatibility|
|Incidence|| || |
|Disease during the first pregnancy|| || |
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Coombs test (direct or indirect)
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|Spherocytosis|| || |
The differential diagnoses listed here are not exhaustive.
- Intrauterine blood transfusion
ABO and Rh typing of the mother
- Rh-positive mothers do not need further screening.
Rh-negative mothers: screening for anti-D antibodies
- No anti-D antibodies (unsensitized mothers): antibody screening repeated at 28 weeks' gestation and at delivery. See “Anti-D immunoglobulin (RhoGAM)” below.
- Anti-D antibodies manifest with an anti-D antibody titer > 1:8, which indicates maternal sensitization to fetal Rh antigens (sensitized mothers). Further monitoring with amniocentesis and imaging is required for evidence of hemolysis.
Fetomaternal hemorrhage in Rh-negative mother
- Conduct a rosette test (initial test of choice). This is a qualitative test that assesses whether fetomaternal hemorrhage has occurred.
- If the rosette test is positive, conduct a Kleihauer-Betke test.
- Fetal Rh genotyping
Anti-D immunoglobulin (RhoGAM)
- Indication and implementation
- Further indications in Rh negativity
- Standard dose: 300 μg (1500 IU) IV/IM
- If whole fetal blood is > 30 mL (i.e., fetal RBCs > 15 mL): 300 μg (1500 IU) IM should be given for every 30 mL of fetal blood volume.