Rh Incompatibility (Erythroblastosis Fetalis / Hemolytic Disease of the Newborn)

Definition

The Rh Blood Group System

• Two genes - RhD and RhCE - encode Rh membrane proteins on chromosome 1p, located about 30 kb apart.
• Approximately 15% of Caucasians, 5% of Africans, and less than 1% of Asians are RhD-negative.
• The most common RhD-negative allele is a deletion of the RhD gene.
• Rh antigens include D, C, c, E, and e. The D antigen is by far the most immunogenic and the primary cause of clinically significant HDN.

Pathophysiology

Step 1 - Sensitization (usually at first delivery)

• During pregnancy or at delivery, small amounts of Rh-positive fetal blood cross the placenta into the Rh-negative mother's circulation (fetomaternal hemorrhage).
• This exposure causes the mother to mount an IgG anti-Rh(D) antibody response.
• Most women have less than 1 mL of fetal blood in their circulation after delivery; however, fetomaternal hemorrhage exceeding 30 mL occurs in about 1% of pregnancies.
• Sensitization can also occur from a prior incompatible blood transfusion.

Step 2 - Antibody Transfer in Subsequent Pregnancies

• In a subsequent Rh-positive pregnancy, maternal IgG anti-D antibodies are actively transported across the placenta into the fetal circulation.
• These antibodies coat fetal RBCs (detected by the direct antiglobulin test / Coombs test).
• The coated RBCs are destroyed by the fetal spleen via extravascular hemolysis.

Why the First Child is Usually Unaffected

• The first Rh-positive baby is generally normal because the initial sensitization occurs at the time of delivery, and the primary IgM antibody response is too slow and too weak to cause harm.
• About 3% of second Rh-positive babies show signs, rising to ~10% of third babies, and progressively more with subsequent pregnancies.
• About 17% of Rh-positive fetuses born to previously sensitized Rh-negative mothers will have hemolytic disease.

Consequences to the Fetus and Newborn

• Macrocytic anemia (severity varies)
• Elevated nucleated RBCs (>2.0 x 10⁹/L in term; >5.0 x 10⁹/L in premature infants; normal is ~0.5 x 10⁹/L in term neonates)
• Elevated reticulocytes
• Leukocytosis with immature forms
• Positive direct antiglobulin (Coombs) test on fetal erythrocytes
• Thrombocytopenia and coagulopathy in severe cases

Kernicterus

• Permanent mental impairment
• Motor area damage (cerebral palsy-like picture)
• Hypoxia at birth worsens the risk

ABO vs. Rh Incompatibility

Monitoring the Sensitized Mother

1. Antibody screen at the first prenatal visit - if anti-D is found, the titer is measured.
2. Critical titer for risk of hydrops: usually 1:8 to 1:32.
3. Paternal Rh typing - if father is homozygous RhD-negative, no further workup needed.
4. Fetal RhD genotyping from amniocytes or (now preferred) cell-free fetal DNA (cfDNA) from maternal blood.
5. Serial maternal anti-D titers every month until 24 weeks, then every 2 weeks.
6. Middle cerebral artery (MCA) peak systolic velocity by Doppler ultrasound - elevated velocity is a strong indicator of fetal anemia (has replaced amniotic fluid ΔA₄₅₀ bilirubin as the standard).
7. If critical titer is exceeded: ultrasound-guided percutaneous umbilical blood sampling (PUBS) and intrauterine transfusion.

Treatment

In utero

• Intrauterine RBC transfusion via the umbilical cord - the primary intervention for fetal anemia/hydrops.

Postnatal

• Exchange transfusion - Rh-negative blood is infused while the infant's Rh-positive blood is removed over 1.5+ hours. Repeated as needed to:
  • Correct anemia
  • Remove bilirubin and prevent kernicterus
  • Remove circulating maternal anti-D antibodies
  • After 6 weeks, the transfused Rh-negative cells are replaced by the infant's own cells, by which time maternal antibodies have cleared.
• Phototherapy - for hyperbilirubinemia.
• Supportive NICU care.

Prevention - Rh Immunoglobulin (RhIG / RhoGAM)

• 28 weeks gestation (antepartum) - 300 mcg IM dose to all unsensitized Rh-negative mothers (covers undetected antepartum fetomaternal bleeding).
• Within 72 hours of delivery of an Rh-positive baby.
• Also given after: abortion, amniocentesis, chorionic villus sampling (CVS), fetomaternal hemorrhage, or any event risking fetal blood exposure.
• A 300 mcg dose covers exposure to ≤15 mL of Rh-positive fetal RBCs.

Summary Flowchart

Rh-negative mother × Rh-positive father
           ↓
   Rh-positive fetus (first pregnancy)
           ↓
  Fetomaternal hemorrhage at delivery
           ↓
  Mother produces anti-D IgG (sensitized)
           ↓
   Second Rh-positive pregnancy
           ↓
  Anti-D IgG crosses placenta → coats fetal RBCs
           ↓
  Extravascular hemolysis in fetal spleen
           ↓
  Anemia → Extramedullary erythropoiesis → Hepatosplenomegaly
           ↓
  Bilirubin accumulation → Jaundice → Kernicterus
           ↓ (if severe)
  Hydrops fetalis → Fetal death (without treatment)