Description

• Hemolytic disease of a fetus or newborn (HDFN) occurs due to the destruction of fetal and newborn red blood cells (RBCs) by maternal antibodies passively transferred across the placenta.
• Primarily related to rhesus (Rh) and less often ABO blood group isoimmunization

Epidemiology

• Rh incompatibility
  • Incidence of Rh hemolytic disease: 6 to 7/1,000 live births
  • Prevalence of RhD-positive (RhD+) fetus in RhD-negative (RhD−) mother: 15%
  • RhD− status in 15% of white, 7–8% of black and Hispanic, and 2% of Asian persons
  • 48–55% are heterozygous (Dd)
  • 35–45% are homozygous (DD)
  • Of all Rh-sensitized pregnancies:
    • 9% require intrauterine transfusion
    • 10% are delivered early and require newborn exchange transfusion
    • 31% require treatment after a full-term delivery
    • 50% require no treatment
• ABO incompatibility
  • Occurs in 12% of first pregnancies
  • Only 10–20% become significantly jaundiced, requiring phototherapy.

Risk Factors

• RhD− mother becomes pregnant with an RhD+ fetus; D-antigen is inherited from the father.
• Omitted or failed RhIG (anti-D) prophylaxis
• Type O mother pregnant with a type A, type B, or type AB fetus
• Only a fraction of women at risk develop antibodies.

General Prevention

• Rh incompatibility: RhIG is given to an RhD− woman after any exposure to RhD+ blood.
  • Given at 28 weeks, 34 weeks (prophylaxis), and within 72 hours of birth, or following maternal event, for example, amniocentesis, abortion, antepartum bleeds
• No prophylaxis for HDFN caused by other blood group incompatibilities

Pathophysiology

• Isoimmunization—general principles:
  • Passage of fetal RBCs into maternal circulation occurs as a result of asymptomatic transplacental hemorrhage.
  • Initial sensitization of mother from fetomaternal hemorrhage can occur with placental abruption, abortion, ectopic pregnancy, or procedures (chorionic villus sampling, amniocentesis, or cordocentesis).
  • Exposure triggers maternal immune response (anti-D antibodies).
  • Maternal IgG antibodies cross the placenta and bind to fetal RBCs. Coated RBCs are then destroyed in the reticuloendothelial system, primarily the spleen.
  • Isoimmunization may lead to hyperbilirubinemia, severe anemia, and potentially hydrops.
  • Extramedullary hematopoiesis in the fetal liver and spleen is a response to severe fetal anemia, leading to hepatosplenomegaly.
• Rh isoimmunization
  • Passage of RhD+ fetal RBCs which cross the placenta into the circulation of an Rh− mother
  • RhD− state is the absence of D antigens on RBCs.
  • Decreased risk of RhD sensitization of mother if fetus is also ABO incompatible (<2%) versus ABO compatible (~16% risk).
  • Rh isoimmunization rarely occurs in first pregnancy.
• ABO isoimmunization
  • Occurs in type O mothers with a type A or B fetus; clinically a milder hemolysis compared to Rh incompatibility and rarely requires intervention
  • 1% of type O mothers have high titers of IgG antibodies against both A and B that cross the placenta and cause HDFN.
  • Hemolysis due to anti-A is more common.
  • Hemolysis due to anti-B can be more severe and may require exchange transfusion in the newborn.

Etiology

• Fetomaternal hemorrhage, usually asymptomatic, with maternal immune response to foreign fetal RBC antigens
• Most common systems involved: RhD antigens, with more severe HDFN, and ABO blood group antigens, with milder anemia, jaundice
• 1% of cases involve other RBC antigens, such as Kell, Kidd, Duffy, or MNS blood groups.

History

• Maternal exposure to incompatible blood products
• Previous stillbirths and/or abortions
• Neonatal hyperbilirubinemia requiring exchange transfusion in previous pregnancy
• RhIG not given after previous pregnancy or abortion

Physical Exam

• Milder cases—hyperbilirubinemia only
• Minimal jaundice at birth but rapidly develops within 24 hours
• Pallor, tachycardia, tachypnea due to congestive heart failure (CHF) secondary to severe anemia
• Generalized edema and massive hepatosplenomegaly in cases with severe anemia and hydrops

Differential Diagnosis

Hydrops fetalis

• Hematologic: α-thalassemia, severe G6PD deficiency, twin-to-twin transfusion
• Cardiac: hypoplastic left heart syndrome, myocarditis, endocardial fibroelastosis, heart block
• Congenital infections: parvovirus, syphilis, cytomegalovirus (CMV), rubella
• Renal: renal vein thrombosis, urinary tract obstruction, nephrosis
• Placental: umbilical vein thrombosis, true knot of umbilical cord
• Genetic: trisomy 13, 18, 21; triploidy; aneuploidy
• Other: diaphragmatic hernia

Diagnostic Tests and Interpretation

General Measures

• Antenatal
  • Serial fetal monitoring
  • Intrauterine RBC transfusion: for severely affected fetuses (fetal Hct <25–30%) where early delivery is not possible; usually performed after 20 weeks’ gestation
  • Early delivery and neonatal resuscitation may be required if with severe HDFN.
    • For high-risk fetus after amniocentesis or history of a prior stillbirth or hydrops
• Neonatal
  • Phototherapy, IV hydration, and serial bilirubin monitoring begins immediately.
  • Exchange transfusion: removes sensitized fetal RBCs and circulating bilirubin, and also
    • Corrects anemia in severely anemic infants
    • Removes circulating antibodies
• Indications for early exchange transfusion:
  • Cord blood bilirubin >3 mg/dL and Hgb <13 g/dL
  • Bilirubin rising at rate >1 mg/dL/h despite optimal phototherapy
  • Indirect bilirubin ≥20 to 25 mg/dL or rising to reach that level
  • Hgb 11 to 13 g/dL and bilirubin rising at rate >0.5 mg/dL/h despite optimal phototherapy
  • Lower indirect bilirubin triggers are used in preterm or high-risk infants.
• In hydropic infants, immediate partial exchange may be needed to correct anemia and CHF.
• Double-volume exchanges may be needed for hyperbilirubinemia.
• Selection of blood for exchange transfusion:
  • Fresh, washed, CMV-safe, and irradiated, Hgb S negative
  • For Rh disease: type O, Rh− cross-matched against mother’s blood
  • For ABO disease: type O, Rh− or Rh compatible cross-matched against mother or infant’s serum
  • For other antibodies: antigen-negative RBCs selected to avoid the clinically significant antibody. ABO type–specific blood can be used if baby’s type confirmed.
• Risks of exchange transfusion include prolonged neutropenia, thrombocytopenia, hypocalcemia, arrhythmias, thrombosis, late anemia, and death.
• Some infants with milder Rh isoimmunization may have only exaggerated late physiologic anemia at 8 to 12 weeks.
• Most infants with ABO incompatibility require either no treatment or phototherapy only.
• Avoid drugs that interfere with bilirubin metabolism or its binding to albumin (e.g., sulfonamides, caffeine, and sodium benzoate).

Issue for Referral

Late anemia: Infants who had significant HDFN are at risk due to reticulocytopenia related to persistent high titers of circulating maternal antibody. Small-volume RBC transfusion may be required.

Additional Therapies

• Intravenous immunoglobulin (IVIG): in some studies shown to diminish hemolysis and may prevent the need for exchange transfusion
• Oral iron supplementation
• Erythropoietin, with iron, may be used to support infants at high risk for late anemia.
• Recombinant Rh immune globulin is in development.

Follow-Up Recommendations

Prognosis

• ~50% of affected infants have minimal anemia and hyperbilirubinemia and require either no treatment or phototherapy only.
• ~25% with severe HDFN will require exchange transfusions.
• Data suggest normal neurologic outcome in 94% of cases following intrauterine transfusion
• Hydropic infants have a ~30% mortality rate.

Complications

• Hydrops fetalis
• Stillbirths
• Kernicterus—bilirubin encephalopathy

ICD-9

• 773.1 Hemolytic disease of fetus or newborn due to ABO isoimmunization
• 773.0 Hemolytic disease of fetus or newborn due to Rh isoimmunization
• 773.2 Hemolytic disease of fetus or newborn due to other and unspecified isoimmunization
• 773.5 Late anemia of fetus or newborn due to isoimmunization

ICD-10

• P55.1 ABO isoimmunization of newborn
• P55.0 Rh isoimmunization of newborn
• P55.8 Other hemolytic diseases of newborn
• P55.9 Hemolytic disease of newborn, unspecified

SNOMED

• 32858009 Hemolytic disease of fetus OR newborn due to ABO immunization
• 86986002 Hemolytic disease of fetus OR newborn due to RhD isoimmunization
• 387705004 Hemolytic disease of fetus OR newborn due to isoimmunization (disorder)
• 206434001 Late anemia of newborn due to isoimmunization (disorder)