Which antibody is most likely to mediate Hemolytic Disease of the Fetus/Newborn (HDFN) in a susceptible pregnancy?

Anti-D (Rh) Antibody Most Likely Mediates Hemolytic Disease of the Fetus/Newborn

Anti-D antibody is the most likely antibody to mediate Hemolytic Disease of the Fetus/Newborn (HDFN) in a susceptible pregnancy. This is supported by extensive clinical evidence and guidelines that highlight the historical significance and continued prevalence of anti-D in causing clinically significant HDFN 1, 2.

Evidence Supporting Anti-D as Primary Cause of HDFN

Pathophysiology and Prevalence

• Anti-D antibodies develop when an RhD-negative pregnant person is exposed to the RhD antigen from an RhD-positive fetus 1
• The RhD antigen is well-developed by 6 weeks' gestation and can trigger maternal immune response 1
• Before the discovery of RhD immune globulin (RhIG), HDFN from anti-D was a significant cause of perinatal mortality and long-term disability 3
• Even with modern prophylaxis, RhD alloimmunization remains a primary cause of moderate to severe HDFN 4

Clinical Significance

• The Society for Maternal-Fetal Medicine guidelines indicate that antibodies in the Rh system (D, C, c, E, e) and Kell system have historically been the most common causes of clinically significant HDFN 2
• When maternal anti-D antibodies cross the placenta, they can cause:
  • Hemolysis of fetal red blood cells
  • Fetal anemia
  • Hydrops fetalis (in severe cases)
  • Hyperbilirubinemia in the newborn 3

Prevention of Anti-D Alloimmunization

• RhIG administration to RhD-negative mothers has been the cornerstone of HDFN prevention 5
• Without RhIG prophylaxis, approximately 12-13% of RhD-negative mothers delivering RhD-positive infants would develop alloimmunization 5
• With proper RhIG administration, this rate is reduced to 1-2% 5
• Further reduction to less than 0.1% can be achieved with two-dose protocol (antenatal at 28 weeks and postpartum) 5

Comparative Risk with Other Antibodies

While other antibodies can cause HDFN, anti-D historically has been the most significant:

• Anti-Jsa can cause moderate to severe HDFN but is less common 2
• Kell system antibodies can cause severe HDFN but are less prevalent 4
• ABO incompatibility typically causes milder disease than Rh incompatibility 4
• Recent data shows that RhD-induced HDFN accounts for 4.3% of cases, but these cases are more likely to require medical interventions including transfusions 4

Clinical Implications

• RhD-negative pregnant women should receive RhIG prophylaxis during pregnancy and after delivery of an RhD-positive infant 1, 5
• RhIG should be administered within 72 hours after potential sensitizing events including:
  • Delivery of an RhD-positive infant
  • Spontaneous or induced abortion
  • Ruptured tubal pregnancy
  • Amniocentesis
  • Abdominal trauma 5
• Obesity may be a risk factor for failure of RhIG prophylaxis 6

Monitoring and Management

For pregnancies with known anti-D alloimmunization:

• Serial maternal antibody titers
• Middle cerebral artery Doppler studies to detect fetal anemia
• Potential intrauterine transfusions for severe cases
• Preparation for neonatal management including phototherapy and exchange transfusion 2

Despite advances in prevention and management, anti-D antibody remains the most clinically significant antibody mediating HDFN in susceptible pregnancies, with the potential to cause severe fetal and neonatal morbidity and mortality if not properly managed.