- Clinical science
Hemolytic disease of the fetus and newborn (HDFN) is a condition characterized by the destruction of fetal red blood cells (RBC) and anemia. It is commonly caused by a Rhesus (Rh) and ABO incompatibility between the mother and fetus, although other blood incompatibilities also exist. In Rhesus 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, consecutive 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 from infancy and usually has a milder disease course. Newborn infants 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 considered 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 the newborns from these pregnancies are symptomatic
- Rhesus incompatibility: rare following implementation of routine anti-D prophylaxis
- Extremely rare: There are more than 60 additional RBC antigens, that can cause incompatibility
- Risk factors: Maternal exposure to fetal blood during pregnancy
- Highest risk: mother, blood group O; child, blood group A or B
- Maternal antibodies (anti-A and/or anti-B) against non-self antigens of the ABO system are present even if sensitization has not occurred; , therefore fetal hemolysis may occur during the first pregnancy
- In a Rh-negative mother and Rh-positive child: maternal exposure to fetal blood → 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 child: rapid production of maternal IgG anti-D antibodies to fetal RhD antigens → Rh-IgG agglutination of fetal RBCs with → risk of HDFN with possible
- ; (only expected in cases of Rh incompatibility, risk is highest with fetal Hb < 7 g/dL or high maternal anti-Rh titres)
- Neonatal anemia
ABO incompatibility usually has a significantly milder course of disease than Rhesus incompability!
Anemia may conceal cyanosis!
The diagnosis of HDFN requires evidence of hemolysis in the presence of a fetomaternal blood incompatibility. These parameters can be determined during the prenatal period after suggestive screening tests or postnatal period.
- Ultrasound: to determine
- Doppler sonography of fetal blood vessels → increased flow rate indicates fetal anemia
- If newborn has signs of , conduct Coombs test (either direct or indirect)
|ABO vs. Rhesus 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.
- Anemia: iron supplementation and, if necessary, RBC transfusion: According to the premature infants in need of transfusion (PINT) study, the Hb limit is 10 g/dL in the first week of life.
- phototherapy; if necessary, exchange transfusion with red blood cells (→ see :
- In severe cases, (IVIG) may be administered
ABO and Rh(D) 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 of gestation and at delivery → see indications for
- Anti-D antibodies present; with an Anti-D antibody titer > 1:8 → indicates maternal sensitization to fetal Rh antigens (sensitized mothers) → further monitoring for evidence of hemolysis required: amniocentesis and imaging
In cases of postpartum hemorrhage: in Rh-negative mother
- Conduct Rosette test (initial test of choice): a qualitative test that assesses if fetal-maternal hemorrhage occurred
If Rosette test positive → conduct Kleihauer-Betke test
- Quantitative testing for evaluating fetal-maternal hemorrhage
- The amount of fetal hemoglobin determines amount of RhoGam necessary
- Alternative: flow cytometry (use is limited by equipment and costs)
- Fetal Rh-genotyping
- Indication and implementation
- Further indications (in Rh negativity)