Intravenous Immunoglobulin (IVIG) as a Replacement for Anti-D Prophylaxis: A Systematic Review and Translational Analysis on the Future of Fetal Rhesus Alloimmunization Prevention

Rhesus D alloimmunization remains a preventable cause of fetal anemia and perinatal morbidity, yet anti-D immunoglobulin prophylaxis continues to face limitations related to availability, cold-chain logistics, and incomplete protection. This systematic review examined whether intravenous immunoglobulin (IVIG) can functionally replace anti-D prophylaxis and explored its translational mechanisms across maternal–fetal contexts. Comprehensive searches of PubMed, Scopus, and Embase identified 1,277 records. Following PRISMA-guided screening and eligibility assessment, 38 studies were included, encompassing randomized trials, cohort and case-control studies, meta-analyses, and mechanistic reports. Evidence synthesis demonstrated that IVIG administration was associated with reduced maternal antibody titers, delayed need for intrauterine transfusion, lower exchange-transfusion rates, and improved neonatal survival, without increased adverse effects. Mechanistic data indicated that IVIG may exert immune modulation through Fc-receptor blockade, B-cell down-regulation, and FcRn saturation, mirroring the immunologic tolerance induced by anti-D. Emerging evidence integrating cfDNA-based fetal RhD genotyping further refines patient selection, minimizing unnecessary prophylaxis. Despite heterogeneity in study design and dosing, pooled outcomes supported a protective effect of IVIG comparable to or exceeding conventional anti-D in high-risk pregnancies. The evidence map highlights current gaps in large randomized prophylactic trials and underscores the translational potential of IVIG as a globally accessible immune-tolerant strategy. These findings call for next-generation clinical programs to redefine alloimmunization prevention, integrating molecular diagnostics, personalized immune monitoring, and sustainable biologic replacement of anti-D prophylaxis.