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Study question We sought to explore the levels of myeloid-derived suppressor cells (MDSCs) in women experiencing recurrent miscarriage (RM) or recurrent implantation failure (RIF) Summary answer MDSCs were significantly expanded in RM patients with respect to fertile healthy women (p = 0.03, 8.25 vs 7.00). What is known already RM and RIF are two distinct disorders that can be associated with a baseline pro-inflammatory state. Different surrogate inflammatory biomarkers have been associated with these disorders in a subgroup of patients, including expanded cytotoxic NK cells, increased pro-inflammatory cytokines or reduced regulatory T cells (TReg). MDSCs are a heterogeneous population of leukocytes, known for their capacity to modulate immune responses. The immunosuppressive function of MDSC in cancer has been well established, while a controversial role in autoimmune diseases has been reported. Typically, there are two major groups of MDSCs in humans: granulocytic/polymorphonuclear MDSCs (PMN-MDSCs) and monocytic MDSCs (M-MDSCs). Study design, size, duration A cross-sectional study to evaluate the levels of MDSCs in women with RM and RIF consecutively referred to our Reproductive Immunology Unit. 55 patients and 23 healthy women were evaluated from 2021 to 2022. RM was defined as the loss of two or more pregnancies and not necessarily consecutive. RIF was defined as the failure to achieve a clinical pregnancy after transferring at least four good-quality embryos. Participants/materials, setting, methods A full fertility screening was performed for all women and their partners as part of routine care. A group of healthy non-pregnant women up to 45 years old with two or more children (proven fertility) and no spontaneous miscarriage was used as control group. Freshly collected blood samples were analyzed by multiparametric flow cytometry using a BD FACS CANTO II. Peripheral blood M-MDSCs were characterized based on HLA-DR, CD14, CD33 and CD45 expression. Main results and the role of chance In this study, we evaluated 55 women, 35 that fulfilled RM criteria and 20 with RIF. In addition, a group of 23 non-pregnant fertile women was included as a control group. We characterized MDSCs as CD14+CD33+CD45+HLA-DR-/LOW, according to previous reports. We observed a significant expansion of peripheral blood MDSCs in RM group compared to the control group (8.25% [6.62-11.9] vs 7.05% [6-7.8], p = 0.03) and RIF group showed a similar increasing trend compared to controls (8.6% [5.65-12.35] vs 7.05% [6-7.8], p = 0.09). We performed ROC curves analysis to evaluate the predictive power. We established an optimal cut-off level of 8.3% in RM group, with a sensitivity of 50% and a specificity of 86.96%. Moreover, women with more than 8.3% had a higher probability of presenting RM compared to the control group (OR: 6.66; CI: 1.68-26.46). MDSCs are characterized by their ability to exert a potent immunosuppressive function. However, recent investigations have shown that MDSCs could act as pro-inflammatory cells under certain inflammatory conditions, such as autoimmune diseases. In this context, MDSCs could worsen the pro-inflammatory state in women, leading to miscarriage or implantation failure. Limitations, reasons for caution In order to validate these results, we should extend our cohort and control group. Moreover, we need to perform a functional evaluation of this subset so we could elucidate their role in these conditions. Wider implications of the findings MDSCs might be a good predictor for RM and RIF patients and with others (as expanded NK cells) may classify a subgroup of patients with a pro-inflammatory profile that can benefit from personalized therapies. Trial registration number Not aplicable

Study question Should the centromeric and telomeric motifs been studied separately and taked them in to account in women with recurrent reproductive failure? Summary answer The results show that when the classic KIR study is performed, there is a 12,5% of AA centromeric KIR patients with reproductive failure unidentified. What is known already During human pregnancy, the decidua is mainly populated by NK lymphocytes that express immunoglobulin-type receptors (KIR) recognizing their HLA-C ligands from trophoblast. The objective of this study was to analyze the association of KIR-HLAC phenotypes in couples with sterility, recurrent pregnancy loss (RPL), recurrent implantation failure (RIF), and fetal death (FD) in comparison with reference population and fertile control. Study design, size, duration It is a retrospective real-life observational study from 2015 to 2019 Participants/materials, setting, methods The frequency of the KIR and HLA-C genes were analyzed in 397 women and their partners with reproductive failure. We compare them with 33 fertile controls and reference Spanish population. KIR and HLA-C genotypes of the patients and controls were determined by Lifecodes Sequence-Specific Oligonucleotides (SSO) Typing KIT (Diagnostica Longwood®) performed at Centro de Transfusiones de la Comunidad de Madrid and those of controls at the Hospital Universitario Clínico San Carlos. Main results and the role of chance Centromeric (Cen) AA was the most frequent KIR genotype in women with unexplained RPL and RIG with respect to reference Spanish population (p = 0.001 and 0.02, respectively). Moreover, cenAA was associated with 1.51-fold risk of RPL and 1.2-fold risk of RIF. On the other hand, BB KIR showed lower risk of any reproductive failure tan non-BB KIR (0.12; p Limitations, reasons for caution The fact of having stratified a lot by groups means that a small number of patients is obtained in each subgroup, which makes it more difficult to conclude the results. Wider implications of the findings Our study demonstrates the importance of the complete KIR genotype study, which would give us more comprehensive information on the behavior of NK cells, moreover we propose that centromeric KIR classification is superior to the KIR classical haplotypes, better identifying those patients with potential KIR-HLA-C mismatch. Trial registration number Not applicable