Hemolytic disease of the newborn
also see Anemia, General Approach, Anemia, Acute hemolytic, Anemia in the newborn, Normal values, CBC
 

Explain in detail to every parent the risk of adverse outcome of an alloimmunized gestation irrespective of its severity, including fetal loss, prematurity, brain injury, risk of bilirubin encephalopathy, and subsequent CP.

Rh Incompatibility

• Rh antibody is the most common cause of severe hemolytic disease of the newborn (HDN)
• Severe hemolytic disease of newborn presenting with fetal hydrops (anasarca), jaundice, anemia, and erythroblasts (RBC precursors due to increased hemotopoeisis stimulated by anemia) in the circulation is known as erythroblastosis fetalis
• Other alloimmune antibodies belonging to Kell (K and k), Duffy (Fya), Kidd (Jka and Jkb), and MNSs (M, N, S, and s) systems do cause severe HDN

Rh epidemiology: Frequency of Rh negativity is higher in whites (15%) than in blacks (5%), and it is rare in Asians. The paternal heterozygosity determines the likelihood of an Rh-positive child being born to an Rh-negative mother.

Pathophysiology

• Kleihauer-Betke acid elution technique: determines the proportion of fetal RBCs in maternal circulation
  • incidence of fetomaternal hemorrhage is 75% of all pregnancies
• Risk of fetomaternal hemorrhage and subsequent alloimmunization increases with:
  • increased gestational age
  • placental abruption
  • spontaneous or therapeutic abortion
  • toxemia
  • after cesarean delivery or  ectopic pregnancy.
  • procedures such as amniocentesis, chorionic villus sampling, and cordocentesis
• Because in most pregnancies the transplacental hemorrhage is less than 0.1 mL, most women are sensitized as a result of small undetectable fetomaternal hemorrhage.

After fetomaternal hemorrhage...

1. Primary response: maternal immune system produces IgM antibodies that do not cross the placenta. The primary response is dose dependent - the higher the volume of foreign (Rh-positive) cells, the higher the percentage of response (3% with <0.1 mL versus 22% with >0.1 mL, 70%; 250 mL)
2. Secondary response: A repeat exposure to the same antigen rapidly induces the production of IgG. This secondary immune response can be induced with as little as 0.03 mL of Rh-positive RBCs.
3. In a first time (more strictly: nulliparous) Rh-negative mother who has delivered an Rh+ baby, risk of Rh allo-immunization is:
   • 16% if the Rh-positive fetus is ABO compatible with its mother
   • 2% if ABO incompatible (ABO-incompatible fetal RBCs are rapidly destroyed in the maternal circulation, reducing the likelihood of exposure to the immune system)
   • 2-5% after an abortion.
4. After sensitization
   • maternal IgG anti-D (anti-Rh) antibodies cross the placenta into fetal circulation and attach to Rh antigen on fetal RBCs
   • antibody-coated fetal RBC's form rosettes on macrophages in the reticuloendothelial system, especially in the spleen.
   • macrophages and natural killer lymphocytes release lysosomal enzymes that lyse these antibody-coated RBCs (independent of the activation of the complement system)
5. Prolonged hemolysis -> severe anemia -> stimulates fetal erythropoiesis in liver, spleen, bone marrow, and extramedullary sites, such as placenta and  skin (blueberry muffin rash, seen in rubella, CMV, etc).
6. In severe hemolysis, this can lead to displacement and destruction of hepatic parenchyma by erythroid cells, resulting in dysfunction and hypoproteinemia.
7. Destruction of RBCs releases heme that is converted to unconjugated bilirubin.
8. Hyperbilirubinemia becomes apparent only in the delivered newborn because the placenta effectively metabolizes bilirubin
9. Rarely presents in 1st pregnancy (5%) (but IgG antibodies are produced)
10. Increased severity in future pregnancies
11. RhoGAM (anti-Rh immunoglobin) is given >28 wks and w/i 72 hrs of birth (after birth) prevents erythroblastosis

Clinical manifestations:

• Broad spectrum of disease, from mild hemolysis to hydrops fetalis
• Massive HSM
• Profound anemia
• CHF, circulatory collapse
• Respiratory distress (pulmonary edema, effusions)
• Jaundice
• Death in-utero, or shortly after birth

Treatment: Rh-, group matched PRBC, up to 70% require exchange transfusion; In-utero transfusion; Exchange transfusion

ABO Incompatibility

Usually result in milder disease than Rh

Presentation: Jaundice, HSM, pallor extremely rare

• Most common cause of iso-immune hemolysis
• Group O mom produces IgG against infant RBCs (A or B)
• 50% occur in first pregnancy
• Subsequent pregnancies are no more severe

Discussion of pathophysiology

• Hemolysis associated with ABO incompatibility is limited to type O mothers with fetuses who have type A or B blood.
• In mothers with type A or B blood, naturally occurring antibodies are of IgM class, which do not cross the placenta, whereas in type O mothers, the antibodies are predominantly IgG in nature.
  • Mother is type A. She has IgM anti-B antibodies. IgM Ab's do not cross the placenta and cannot attack fetal RBC's.
  • Mother is type B. She has IgM anti-A antibodies. IgM Ab's do not cross the placenta and cannot attack fetal RBC's.
  • Mother is type O. She has IgG anti-A and IgG anti-B antibodies, which can cross the placenta.
• Why is there a low incidence of significant hemolysis in affected neonates?
  • Once antibodies cross the placenta most attack a wide variety of tissues that have A and B antigens (unlike Rh which is only expressed on RBCs). Therefore, only small portion of antibodies crossing the placenta is available to bind to fetal RBCs. In addition, fetal RBCs appear to have less surface expression of A or B antigen, resulting in few reactive sites—hence the low incidence of significant hemolysis in affected neonates.

Treatment: Depends on degree of anemia and hyperbilirubinemia; only 1% require exchange transfusion due to significant hemolysis; may transfuse group O, Rh matched blood. *All neonates need CMV neg, irradiated blood

Hemolytic disease: non-immune
 

• (Coombs negative)
• Congenital infections
• Thalassemia
• Hereditary spherocytosis
• Pyruvate kinase deficiency
• G6PD deficiency

CHLA Board review 2005
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