Phenotype- and phase-directed immune interpretation in recurrent implantation failure and pregnancy loss: an integrative framework

Recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL) remain major challenges in reproductive medicine. Although immune mechanisms are integral to implantation, clinical translation has been limited by indiscriminate use of immune-directed therapies in unselected populations, mistimed immune assessment outside the implantation window, and insufficient distinction between immune-mediated failure and non-immune causes, contributing to inconsistent or null outcomes in randomised trials of empiric immunotherapy. To address these limitations, this review introduces the Elgheriany Reproductive Immunology Framework (ERIF) as a conceptual interpretive model integrating prerequisite exclusion, synchronised immune profiling within the implantation window, and cytokine-informed consideration of immunomodulation initiation and withdrawal. The framework emphasises interpretation of immune findings rather than presumption of immune causality and conditions intervention on demonstrable dysfunction. Within this context, a subset of patients may exhibit failure of the normal transition from early inflammatory activation to immune tolerance, reflected by persistent Th1-skewed cytokine activity and, in selected phenotypes, altered natural killer (NK) cell cytotoxicity. Peripheral and uterine immune compartments are interpreted jointly, recognising their functional divergence and temporal specificity during implantation. ERIF is intended to support immune interpretation and the design of phenotype-stratified clinical trials rather than to function as a prescriptive therapeutic algorithm, providing a basis for future validation in recurrent reproductive failure.