Molecular and endocrine differences in early miscarriage associated with KIR polymorphisms in European ancestry women

Do certain killer-cell immunoglobulin-like receptor (KIR) polymorphisms of uterine natural killer (uNK) cells contribute to early pregnancy losses, and if so, how?

This prospective, cohort study included 23 European ancestry women under 43 years old with a normal body mass index (19-25 kg/m²) who experienced idiopathic early pregnancy loss (<12 gestational weeks) after a single euploid embryo transfer following intracytoplasmic sperm injection/preimplantation genetic testing for aneuploidies between June 2022 and December 2024. Participants were categorized based on KIR haplotypes and the presence or absence of the activating genes KIR2DS1 and KIR3DS1. Endometrial biopsies were collected and used for transcriptomic analysis and to establish co-cultures of patient-derived primary uNK cells with trophoblast-derived JEG-3 spheroids.

Participants lacking the KIR2DS1 and KIR3DS1 genes exhibited higher luteal progesterone concentrations (P = 0.0059, P = 0.0151). Transcriptomic analysis revealed that patients with inhibitory KIR profiles showed a down-regulation of cell signalling and molecular transduction coupled with an upregulation of immune response. Functional assays demonstrated that uNK cells derived from individuals with activator KIR profiles exhibited higher cytokine production (AgRP, IFN-γ, IL-8, IL-17A, IP-10, TNF-β; P ≤ 0.0482), with a lower production of IL-12p40 (P = 0.0492), than in patients carrying the inhibitory KIR haplotype. Additionally, intracellular reactive oxygen species production positively correlated with progesterone concentrations (P < 0.05), especially in KIR3DS1^- participants. Further correlations were observed between cytokine secretion, progesterone concentrations and ROS, with key molecules like FGF-4, TGF-β1 and follistatin.

KIR polymorphisms influence endometrial gene expression, progesterone concentrations, cytokine secretion and oxidative stress in women with unexplained early miscarriage in the current cohort, highlighting FGF-4, TGF-β1 and follistatin as candidate mediators of early maternal-fetal cross-talk. However, as this study is limited to a single patient ethnicity, larger cohorts are necessary to validate the results.