Hemolytic Disease of the Fetus and Newborn: Fetal RHD Genotyping, Targeted Prophylaxis, and Prenatal Therapies

Hemolytic disease of the fetus and newborn (HDFN) remains a significant concern in prenatal care primarily caused by maternal alloimmunization against fetal red blood cell antigens, most commonly the D antigen. Noninvasive fetal RHD genotyping, used as a screening tool, enables targeted antenatal prophylaxis and has been implemented in several European countries. Despite the success of anti-D prophylaxis programs, D alloimmunization still occurs and addressing these gaps is essential to ensure optimal maternal care. In pregnancies affected by HDFN, Doppler ultrasound assessment of middle cerebral artery peak systolic velocity (MCA-PSV) is the gold standard for detecting fetal anemia, though its reliability following intrauterine blood transfusion (IUT) remains debated. IUT is the primary treatment for severe fetal anemia; however, it remains an invasive procedure with inherent risks, particularly when performed early in pregnancy. Intravenous immunoglobulin (IVIG) has been proposed as a treatment, though its efficacy remains inconclusive. A promising alternative involves monoclonal antibodies blocking the neonatal Fc receptor (FcRn), reducing IgG recycling and placental transfer-with the potential to delay or obviate the need for IUT. This review provides an overview of fetal RHD genotyping in modern obstetric care and discusses prenatal monitoring and treatment strategies for HDFN within high-quality healthcare settings.