UTERINE AND PERIPHERAL NK CELLS IN RECURRENT SPONTANEOUS ABORTION: A QUALITATIVE SYSTEMATIC REVIEW OF BIOMARKER MECHANISMS (KIR/HLA-C) AND IMMUNOMODULATIVE THERAPIES (2010-2025)
Keywords:
Recurrent Miscarriage, NK Cells, KIR, HLA-C, ImmunotherapyAbstract
Objective: To critically synthesize evidence (2010–2025) on the role of uterine (uNK) and peripheral (pNK) Natural Killer cells in recurrent pregnancy loss (RPL), covering uNK biology, KIR/HLA-C genetics, clinical utility of NK testing, and the effects of immunomodulatory therapies (intravenous immunoglobulin, corticosteroids, lipid emulsion). Methods: Systematic review (PRISMA-2020) conducted across PubMed/MEDLINE, Embase, Web of Science, and Scopus (Jan-2010–Oct-2025). Human observational studies, clinical trials, and systematic reviews assessing uNK/pNK, KIR/HLA-C, reproductive outcomes (live birth, miscarriage recurrence, preeclampsia), or NK- targeted therapies were included. Risk of bias: RoB-2 (RCTs) and Newcastle–Ottawa (observational). Narrative qualitative synthesis. Results: Evidence supports a pivotal role of uNK in spiral artery remodeling and maternal–fetal tolerance. KIR/HLA-C combinations, notably maternal KIR AA with fetal HLA-C2, were associated with increased RPL risk, though findings were heterogeneous. Clinical NK testing remains unstandardized and not recommended for therapeutic selection per ESHRE 2022/2023 guidelines. Immunotherapies such as IVIG showed potential benefits in selected subgroups by reducing NK cytotoxicity and improving live birth rates, yet evidence remains moderate; prednisolone trials are ongoing. Conclusions: uNK and pNK are key regulators of reproductive immunology. The KIR/HLA-C pathway may influence RPL risk, but standardized phenotyping and large randomized multicenter trials are required. Routine NK testing is not endorsed by current guidelines, and immunotherapies remain investigational outside research protocols.
