Killer Immunoglobulin-Like Receptor Haplotypes, Fetal Hla-C2 Exposure, and Immune Dysregulation in Recurrent Pregnancy Loss Patients Undergoing Comprehensive Reproductive and Immunologic Evaluation

Objective: To evaluate reproductive outcomes and immune-genetic factors associated with implantation failure and pregnancy loss in recurrent pregnancy loss (RPL) patients undergoing reproductive immunologic assessment using the Immunologic Reproductive Assessment from Pregmune (IRMA). Design: Retrospective cohort study. Materials and Methods: Seventy-five RPL patients undergoing in vitro fertilization (IVF) were evaluated across 116 embryo transfers. IRMA included killer immunoglobulin-like receptor (KIR) genotyping, maternal/paternal HLA-C typing, HY immunity assessment, HLA antibody profiling, Th1/Th2 ratio, natural killer activity (NKa), and regulatory T-cell (Treg) analysis. Outcomes were categorized as successful pregnancy, failed implantation, or miscarriage. Results: Overall implantation rate was 54.3%, with a 42.2% success rate per transfer and 65.3% success rate per patient. Cumulative success increased from 43.2% after one transfer to 86.0% among patients continuing treatment through ≥4 transfers. The strongest association with reproductive outcome was KIR haplotype distribution (p=0.0008). KIR A/A haplotypes were enriched among failure/loss groups (57.7%) compared with successes (16.3%), whereas activating KIR A/B +2DS1 haplotypes were enriched among successful outcomes (49.0%). HY allele burden was higher in failure/loss patients versus successful pregnancies (1.38 vs 0.84; p=0.040), particularly among patients with prior live birth. Failure/loss patients also demonstrated higher Treg levels (4.55 vs 2.70; p=0.0025). Stratified maternal-fetal HLA-C analysis demonstrated reduced success among inhibitory KIR genotypes exposed to excess fetal HLA-C2 burden, whereas activating KIR A/B +2DS1 genotypes appeared relatively protected. Conclusions: Reproductive outcomes in RPL patients appear strongly influenced by uterine natural killer receptor signaling and maternal-fetal HLA-C interactions. Inhibitory KIR profiles, KIR A/A genotypes, and absence of activating receptor 2DS1 were associated with implantation failure and pregnancy loss, supporting the clinical relevance of immune-genetic profiling in complex RPL populations.