Disease Overview

Hemolytic Disease of the Fetus and Newborn (HDFN) is also known as erythroblastosis fetalis, a rare immune-mediated disorder where maternal antibodies target fetal or newborn red blood cells (RBC’s), leading to their destruction. This condition results from blood group antigen incompatibility between the mother and fetus, most commonly involving the Rh factor, but also AVO, Kell and other blood group systems. 

Epidemiology

HDFN primarily affects fetuses and newborns whose mothers have developed antibodies against fetal RBC antigens due to previous pregnancies or transfusions. The incidence of HDFN has significantly decreased globally due to advancements in anti-Rh(D) immunoprophylaxis, from 1% to 0.5% of newborns, and further to 0.1% with antepartum administration of immunoprophylaxis.

Diagnostic Criteria

As per the American College of Obstetricians and Gynecologists (ACOG), American Academy of Pediatrics (AAP), and American Association of Blood Banks (AABB) guidelines, diagnosis involves maternal blood typing and indirect antiglobulin testing to detect IgG antibodies against fetal RBC antigens. Fetal ultrasound may be used to assess for signs of HDFN, such as fetal anemia and hydrops fetalis.

Clinical Presentation

Signs and Symptoms

Clinical manifestations in fetuses include anemia, hydrops fetalis (fluid accumulation), and decreased fetal movements. In neonates, symptoms include jaundice, anemia, and complications such as neurologic dysfunction from hyperbilirubinemia.

Evaluation / Diagnosis

Diagnosis is based on clinical presentation, maternal antibody screening, and ultrasound findings indicating fetal distress or anemia. Early detection is crucial for timely intervention.

Management

Intrauterine Transfusions

For pregnancies at risk, intrauterine transfusions are performed to replace fetal RBCs and maintain stable hemoglobin levels. This intervention helps prevent severe fetal anemia and associated complications.

Phototherapy

Neonates with HDFN exhibiting hyperbilirubinemia undergo phototherapy. Specialized light converts bilirubin into a form that can be excreted by the body, thereby reducing the risk of bilirubin-induced neurologic dysfunction.

Exchange Transfusions

If neonates do not respond adequately to phototherapy or present with signs of bilirubin encephalopathy, exchange transfusions are recommended. This procedure involves replacing the infant’s blood with compatible donor blood to lower bilirubin levels and treat severe anemia.

Experimental Therapies

Several experimental treatments have been explored but remain controversial:

• Intravenous Immunoglobulin (IVIG): Administered to infants to reduce hemolysis, but current guidelines do not universally recommend its use.
• Pharmacological Agents: Including albumin, phenobarbital, metalloporphyrins, zinc, clofibrate, or prebiotics for hyperbilirubinemia management, though these are not currently endorsed due to limited evidence supporting their efficacy.

Nipocalimab (M281)

Nipocalimab is a novel therapy currently in clinical development. It functions by binding to the neonatal Fc receptor (FcRn), thereby preventing the transfer of maternal IgG antibodies, including anti-RBC alloantibodies, across the placenta. This approach aims to reduce fetal and neonatal exposure to harmful antibodies, potentially mitigating the severity of HDFN in high-risk pregnancies.

Clinical Trials

• Phase 2 trials (UNITY, NCT03842189) and ongoing Phase 3 trials (AZALEA, NCT05912517) are evaluating nipocalimab’s efficacy in preventing severe HDFN and improving outcomes for affected pregnancies.