Objective: To investigate whether chronic endometritis (CE) affects the immune status of peripheral blood and endometrium in patients with recurrent reproductive failure (RRF). Design: Retrospective study. Setting: Private fertility center. Patients(s): A total of 524 RRF patients, including 324 women with recurrent miscarriage (RM) and 200 women with recurrent implantation failure (RIF). Intervention(s): Peripheral blood and endometrium samples were collected in the midluteal phase before in vitro fertilization treatment or pregnancy. The number of peripheral T, natural killer (NK), and B cells, as well as cytotoxicity of NK cells and expression of T H 1 cytokines were analyzed with the use of flow cytometry, and uterine immune cells were subjected to immunohistochemistry. Main Outcome Measure(s): Peripheral immune cells, cytokines, NK cytotoxicity, and endometrial immune cells were compared in RRF patients with versus without CE. Result(s): The proportion and function of the analyzed immune cell subsets in peripheral blood as well as the percentages of CD56 þ NK cells, CD163 þ M2 macrophages, and CD1a þ immature dendritic cells in the endometrium were not significantly altered between non-CE and CE patients, whereas the proportions of uterine CD68 þ macrophages, CD83 þ mature dendritic cells, CD8 þ T cells, and Foxp3 þ regulatory T cells were significantly elevated in CE patients. After antibiotic treatment, the percentage of CD68 þ macrophages, CD83 þ mature dendritic cells, CD8 þ T cells, and Foxp3 þ regulatory T cells in endometrium were significantly reduced in patients with cured CE. Conclusion(s): CE contributes to elevated endometrial infiltration levels of immune cells. The excessive presence of endometrial immune cells in CE patients may be involved in reduced endometrial receptivity and recurrent pregnancy failures. (Fertil Steril Ò 2020;113: 187-96. Ó2019 by American Society for Reproductive Medicine.) El resumen está disponible en Español al final del artículo.

Problem The definition of chronic endometritis (CE) differs among studies, and currently, there is no accepted consensus. This study aimed to establish the minimum number of immunohistochemical analysis of CD138+ plasma cells to identify a clinically relevant CE. Method of study We performed a retrospective study on 716 infertile patients who never did CE analysis and respective antibiotic treatment before. Samples were obtained by endometrial scratching in the mid‐luteal phase before IVF‐ET treatment. The number and distribution of CD138+ cells were analyzed by immunohistochemistry. Thirty high‐power fields (HPF) were evaluated for each sample. Patients were classified in 2 main groups: (a) CD138low (<5 CD138+ cells in all HPFs), (b) CD138high (≥5 CD138+ cells in at least one HPF). Pregnancy outcome was compared among the groups. Results In the CD138high group, β‐hCG positive rate, clinical pregnancy rate and live birth rate were significantly decreased (P = .04, P = .01, P = .04, respectively). Also after adjusting for patient age, body mass index (BMI), and clinical characteristics, the β‐hCG positive rate (P = .05), clinical pregnancy rate (P = .01) and live birth rate (P = .02) were significantly lower in the CD138high than those in the CD138low group. Within the CD138low group, these parameters were not significantly different between patients without any plasma cells and patients with up to 4 plasma cells/HPF. Conclusion We conclude that immunohistochemical analysis of CD138+ cells is a reliable method to detect CE which can be identified by the presence of ≥5 plasma cells in at least one out of 30 HPF.

Limited information is available on the balance state of pro- and anti-inflammatory cytokines in patients with recurrent implantation failure (RIF). This study assessed the pro- and anti-inflammatory cytokines in plasma of 34 patients with RIF, compared with those of 25 women with a successful pregnancy in the first IVF/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) cycle. The IFN-γ, IL-1β, IL-6 and IL-4 concentrations were higher, whereas the TGF-β1 concentration was lower in the RIF group compared with the control group. Furthermore, the ratios of pro-inflammatory and anti-inflammatory cytokines IFN-γ/IL-4, IFN-γ/IL-10, IFN-γ/TGF-β1, IL-6/IL-10, IL-6/TGF-β1, IL-1β/TGF-β1 and TNF-α/TGF-β1 were higher in the RIF group (all P < 0.01). The results suggested a shift toward a pro-inflammatory state in peripheral blood of the patients with RIF.

The data suggest that the abnormalities of cellular immune response were observed in RM patients with a low vitamin D level, which could be regulated to some extent with 1,25(OH) D supplementation.

The results of this study provide novel evidence supporting a role of hCG in regulating the differentiation of peripheral FOXP3 Tregs. The alterations of circulating Tregs may positively affect the pregnancy outcomes of patients with a history of RIF.