Hemolytic disease of the fetus and newborn

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) and other conditions not caused by red cell alloimmunization (e.g., congenital heart defects) can also cause HDFN. In Rh incompatibility, maternal IgG antibodies form after maternal exposure to fetal Rh-positive blood during birth or potentially sensitizing antepartum events. The initial pregnancy is usually 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 (RhIG) is administered to Rh-negative pregnant women. ABO incompatibility, on the other hand, rarely presents with complications and does not require immunoglobulin prophylaxis.

HDFN is a condition characterized by blood group incompatibility between the mother and fetus that leads to the destruction of fetal erythrocytes by maternal antibodies.

• 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 ^[1]
  • Antenatal procedures (e.g., amniocentesis, cesarean delivery, termination of pregnancy)
  • Pregnancy-related complications (e.g., ectopic pregnancy, placental abruption)
  • Trauma

References:^[2][3]

ABO incompatibility ^[2][4]

• 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.

Rh incompatibility ^[2][4]

• Rh-negative mother and Rh-positive fetus ; ^[5]
  • Production of maternal IgM antibodies against the Rh antigen ; occurs after exposure of fetal blood cells to the maternal circulation (fetomaternal hemorrhage) during delivery or an antepartum Rh sensitizing event, e.g.:
    • Threatened or confirmed pregnancy loss
    • Termination of pregnancy
    • Ectopic pregnancy
    • Invasive obstetric procedures
    • External cephalic version
    • Antepartum hemorrhage
    • Abdominal trauma
  • Over time, maternal IgM antibodies seroconvert to Rh-IgG (antibodies are able to cross the placenta).
  • In a subsequent pregnancy with an Rh-positive fetus: rapid production of maternal IgG anti-D antibodies to fetal RhD antigens → Rh-IgG agglutination of fetal RBCs with hemolytic anemia → risk of HDFN with possible hydrops fetalis
• Rh-incompatibility in combination with ABO incompatibility: reduction of Rh(D)-isoimmunization in Rh-negative mothers

Kell blood group system incompatibility ^[6][7]

• The Kell blood group system includes K (K1), k (K2), Kp^a, Kp^b, Js^a, and Js^bantigens (for more information, see “Kell antigen system”), which can trigger substantial immune responses.
• Responsible for up to 10% of severe cases of HDFN ^[8]
• Maternal exposure to Kell antigen in previous pregnancy through the placenta or through blood transfusions → sensitization and production of maternal anti-Kell antibodies → antibodies enter circulation of Kell-positive fetus through placenta → destruction of fetal RBC precursors and mature RBCs → ↓ production of RBCs and ↑ hemolysis → severe fetal anemia

Nonimmune hydrops fetalis ^[9]

• Definition: a subgroup of hemolytic diseases of the fetus and newborn not caused by red cell alloimmunization
• Epidemiology
  • Incidence: ∼ 1 in 4,000 pregnancies
  • Accounts for over 90% of all hydrops fetalis cases
• Etiology
  • Congenital heart defects and arrhythmias
  • Chromosomal aberrations (e.g., Turner syndrome, Down syndrome, trisomy 18)
  • Severe fetal anemia (e.g., thalassemia, twin-to-twin transfusion syndrome, fetomaternal hemorrhage)
  • Congenital TORCH infections (especially parvovirus B19 infection)
• Pathophysiology: severe fetal anemia → hypoxia →; ↓ hepatic and renal blood flow → activation of RAAS → ↑ central venous pressure and ↓ lymphatic flow → fetal edema ^[10]

Prenatal

• Hydrops fetalis (expected in cases of Rh incompatibility and in nonimmune hydrops fetalis)

Postnatal

• Neonatal anemia
• Hepatosplenomegaly
• Neonatal jaundice
  • Usually present at birth or manifests within the first 24 hours of life
  • In Rh incompatibility, unconjugated bilirubin levels may be dangerously high, causing kernicterus.
• Hypoxia
• Prematurity
• Scattered petechiae (rare but associated with poor prognosis) ^[11]

ABO incompatibility usually has a significantly milder course of disease than Rh incompatibility.

Anemia may conceal cyanosis.

The diagnosis of HDFN requires evidence of hemolysis in the presence of fetomaternal blood incompatibility.

Prenatal diagnosis

• Imaging
  • Ultrasound: to determine hydrops fetalis
    • Fetal pleural or pericardial effusions
    • Fetal ascites
    • Fetal subcutaneous or nuchal edema
    • Placental edema
  • Doppler sonography of fetal blood vessels: Increased flow rate indicates fetal anemia.

Postnatal diagnosis

• If the newborn has signs of hemolysis, conduct a Coombs test (either direct or indirect).
  • Rh incompatibility: positive
  • ABO incompatibility: weak positive or negative

ABO vs. Rh incompatibility

Differential diagnoses of petechiae in newborns

Neonatal alloimmune thrombocytopenia

• Description: a rare condition in newborns characterized by maternal-fetal platelet incompatibility resulting in fetal thrombocytopenia
• Epidemiology: the leading cause of severe thrombocytopenia in the newborn
• Pathophysiology: formation of maternal antibodies against fetal platelets (most commonly targeting platelet antigen 1a) → maternal IgG cross the placenta and result in the destruction of fetal platelets → fetal and neonatal thrombocytopenia
• Clinical features
  • Mild: asymptomatic thrombocytopenia
  • Moderate: petechia and/or ecchymoses within a few hours after birth
  • Severe: spontaneous intracranial hemorrhage

Other

• Immune thrombocytopenic purpura
• Kasabach-Meritt syndrome
• Perinatal infections
• For an overview of thrombocytopenias and disorders of platelet function, see “Differential diagnosis of platelet disorders.”

The differential diagnoses listed here are not exhaustive.

• All patients
  • Refer to specialists, e.g., maternal-fetal medicine, for management.
  • Consider repeat titers in patients with a positive RhD screen, as prior RhIG administration can lead to false positives. ^[13]
• Prenatal
  • Intrauterine blood transfusion via the umbilical vein, umbilical artery, peritoneal cavity, or heart (should only be performed in centers with experience in fetal transfusions.)
  • Possible IV immunoglobulin (IVIG) in severe cases
  • Early delivery in severely affected pregnancies
• Postnatal
  • Anemia: iron supplementation and, if necessary, RBC transfusion. ^[14]
  • Hyperbilirubinemia: phototherapy; if necessary, exchange transfusion with red blood cells
  • See “Treatment” in neonatal jaundice.
  • In severe cases, IV immunoglobulin (IVIG) may be administered.

Previous administration of RhIG may cause false-positive anti-D antibodies. ^[13]

Of the causes of HDFN, only RhD incompatibility has a proven prophylactic treatment (i.e., RhIG). ^[15]

Screening for RhD alloimmunization in pregnancy ^[15][16]

• All pregnancies: Perform routine maternal ABO typing and Rh typing at the initial prenatal visit.
• RhD-positive pregnant individuals: Further screening is not indicated; provide routine prenatal care.
• RhD-negative pregnant individuals: Screen for anti-D antibodies with an indirect antiglobulin test. ; ^[12]
  • Anti-D titers positive (sensitized): Refer to maternal-fetal medicine for treatment of alloimmunization in pregnancy. ^[12][15]
  • Anti-D negative (not sensitized): See “Management of unsensitized RhD-negative individuals during pregnancy.” ^[17]

Discuss patients with RhD variants (partial D and weak D) with a specialist; treatment with anti-D immunoglobulin may be required. ^[15]

If paternity is certain (e.g., IVF) and paternal Rh type is negative, pregnant RhD-negative individuals do not require additional screening, testing, or RhIG. Paternal Rh typing is not routine; the cost is similar to RhIG, and there is a potential for discrepancy between the reported father and biological father. ^[12][15]

Management of unsensitized RhD-negative individuals during pregnancy ^[12][15]

• Educate patients to seek care immediately after potentially Rh-sensitizing events.
• Give RhIG as indicated.
  • Routine prophylaxis at 28 weeks' gestation
  • Within 72 hours of Rh-sensitizing events (including invasive prenatal diagnostic testing)
  • At delivery if newborn blood tests show the infant is RhD-positive
• Reassess for sensitization at 24–28 weeks' gestation and before each dose of RhIG (if feasible). ^[12][15]

If repeat screening shows the patient is now sensitized, do not give RhIG; start treatment of alloimmunization in pregnancy. ^[12]

If fetal noninvasive cell-free DNA testing shows the fetus is RhD-negative, RhIG is not required; however, the test is not routinely performed because of cost and the high rate of inconclusive results. ^[15]

Anti-D immunoglobulin (RhIG)

• Given to unsensitized RhD-negative pregnant individuals to prevent Rh-sensitization
• Rapidly clears Rh-positive erythrocytes, preventing the development of anti-D antibodies ^[18]
• Dosages of RhIG are usually fixed, but fetomaternal hemorrhage tests may be needed to determine if larger doses are required.

RhIG protects fetuses in subsequent pregnancies. ^[15]

Fetomaternal hemorrhage tests

• Indications
  • Rh-sensitizing events > 20 weeks' gestation
  • After delivery of a RhD-positive fetus
• Initial testing: rosette test to qualitatively detect fetal-maternal hemorrhage
• Subsequent testing (if positive rosette test): Kleihauer-Betke test ; (most common) or flow cytometry
  • Quantitative tests that calculate fetal blood in the maternal circulation
  • Used to determine RhIG dosing

Dosages of RhIG