Parental KIR/HLA-C Profiles and Reproductive Failure: A Phenotype-Stratified Retrospective Analysis of Couples With Fertility Disorders.

Interactions between maternal killer-cell immunoglobulin-like receptors (KIR) and fetal human leukocyte antigen-C (HLA-C) play a key role in implantation and placentation, yet their clinical relevance remains controversial, partly due to heterogeneous phenotyping of reproductive failure. We conducted a retrospective observational study of 73 biologically comparable clinically referred couples undergoing reproductive immunology assessment. Couples involving donor gametes, surrogacy, or multiple male partners were excluded. Clinical phenotypes were classified as isolated recurrent implantation failure (RIF-only), isolated recurrent pregnancy loss/adverse pregnancy outcome (RPL/APO-only), combined RIF + RPL/APO, or no reproductive failure. Maternal KIR phenotype (AA vs. Bx) was determined by flow cytometry and genetically confirmed. Maternal and paternal HLA-C genotypes were classified as C1C1, C1C2, or C2C2. Associations were assessed using univariable, age-adjusted, and multivariable logistic regression models. Maternal KIR-AA was present in 53.4% of women and was more frequent in the RIF-only group than in the RPL/APO-only group (56.8% vs. 35.3%). In age-adjusted analysis, KIR-AA was associated with increased odds of RIF (OR 2.35; p = 0.054), but not with RPL/APO. Maternal HLA-C genotype showed an exploratory signal consistent with implantation outcomes: C1C2 (OR 0.28; p = 0.031) and C2C2 (OR 0.10; p = 0.002) were protective against RIF compared to C1C1. In multivariable models, maternal C2C2 remained independently protective (aOR 0.08; p = 0.0048). Paternal HLA-C genotype showed no independent associations. In conclusion, immunogenetic effects in reproductive failure are phenotype-specific and predominantly influence implantation rather than postimplantation pregnancy loss.