Rh Isoimmunisation (Rh Incompatibility)

Summary

Rh isoimmunisation is a preventable cause of severe fetal and neonatal morbidity. Advances in universal maternal screening, routine anti-D prophylaxis, and modern fetal monitoring (MCA Doppler) have dramatically reduced its incidence and improved outcomes. While other causes of HDFN (ABO, Kell, and nonimmune hydrops) remain clinically relevant, strict adherence to anti-D immunoglobulin protocols remains the most effective intervention in safeguarding against this condition.

Definition

Rh isoimmunisation, also known as erythroblastosis fetalis, refers to maternal alloimmunisation against fetal red blood cell (RBC) antigens, most commonly the Rhesus D (RhD) antigen. It remains a major cause of haemolytic disease of the fetus and newborn (HDFN), which can range from mild neonatal jaundice to severe fetal anaemia, hydrops fetalis, and intrauterine death.

Pathophysiology

Isoimmunisation occurs when fetal erythrocytes enter the maternal circulation, typically during sensitising events such as delivery, miscarriage, abortion, antepartum haemorrhage, trauma, or invasive obstetric procedures (e.g., amniocentesis, chorionic villus sampling). In an unsensitised RhD-negative woman carrying an RhD-positive fetus, maternal exposure to RhD antigens triggers an immune response.

• Primary response: IgM anti-D antibodies are produced, which do not cross the placenta; therefore, the first affected pregnancy is usually spared.

• Secondary response: In subsequent pregnancies, memory B-cells rapidly produce IgG anti-D antibodies, which cross the placenta, bind to fetal erythrocytes, and cause haemolysis.

This process leads to fetal anaemia, extramedullary haematopoiesis, hepatosplenomegaly, hydrops fetalis, hyperbilirubinaemia, and, in severe cases, kernicterus or death.

While RhD is the most clinically significant antigen, other blood group systems (Kell, C, c, E, e, and ABO) can also cause HDFN. Notably, ABO incompatibility is common but usually mild, whereas Kell alloimmunisation is the second leading cause of severe HDFN after RhD.

Clinical Features

Prenatal

• Hydrops fetalis (ascites, pleural/pericardial effusion, skin edema, placental edema)

• Signs of fetal anaemia (tachycardia, hyperdynamic circulation on Doppler, cardiomegaly)

Postnatal

• Early-onset jaundice (within 24 hours)

• Neonatal anaemia, pallor, hepatosplenomegaly

• High unconjugated bilirubin → risk of kernicterus

• Hypoxia, prematurity, rarely petechiae

Diagnosis

Maternal Screening

• Blood group and antibody screen (ABO and RhD typing, indirect Coombs test) at booking and 28 weeks.

• Rising maternal anti-D titers (>15 IU/mL) indicate significant risk.

Fetal Assessment

• Ultrasound: hydrops fetalis, placental thickening, hepatosplenomegaly.

• Middle cerebral artery (MCA) Doppler: increased peak systolic velocity indicates fetal anaemia.

• Invasive methods (amniotic fluid bilirubin analysis) are now largely replaced by Doppler studies.

Neonatal Diagnosis

• Direct Coombs test: confirms antibody-coated erythrocytes.

• Blood count: anaemia, reticulocytosis, spherocytosis (ABO incompatibility).

• Bilirubin levels: high unconjugated fraction.

Management

Prenatal

• Close monitoring with serial antibody titers and MCA Doppler.

• Intrauterine transfusion (umbilical vein, intrahepatic vein, or intraperitoneal route) for severe anaemia.

• IV immunoglobulin (IVIG) in selected severe cases.

• Early delivery if the fetus is mature or deterioration is imminent.

Postnatal

• Phototherapy for hyperbilirubinaemia.

• Exchange transfusion in severe cases.

• RBC transfusion for anaemia.

• IVIG may reduce haemolysis.

• Supportive care: iron supplementation, monitoring for hypoglycaemia, hypocalcaemia, and heart failure.

Prevention

Prevention of RhD alloimmunisation is highly effective and remains the cornerstone of management.

Anti-D Immunoglobulin (RhIG) Prophylaxis

• Routine antenatal prophylaxis: 500 IU at 28 and 34 weeks (or a single 1500 IU dose at 28 weeks, depending on protocol).

• Following sensitising events: administered within 72 hours (dose depends on gestation and FMH test results).

• Postpartum: given within 72 hours of delivery if the newborn is RhD-positive.

Fetomaternal Haemorrhage (FMH) Testing

• Kleihauer-Betke or flow cytometry quantifies fetal RBCs in maternal blood to determine additional RhIG dosing when large bleeds occur.

Variants of Hemolytic Disease

• RhD incompatibility: most severe, now rare with routine prophylaxis.

• ABO incompatibility: more common, often mild, can affect first pregnancies.

• Kell incompatibility: causes both haemolysis and suppression of erythropoiesis; responsible for ~10% of severe HDFN.

• Nonimmune hydrops fetalis: most cases are unrelated to isoimmunisation (e.g., cardiac defects, chromosomal anomalies, infections, thalassaemia).

Key Summary Table – ABO vs. Rh Incompatibility