{"paper_id":"c32ff308-37f3-44e2-bbc8-83b02d6a69b6","body_text":"Chronic endometritis (CE) is characterized by persistent inflammation of the\nendometrial mucosa, and is often associated with polymicrobial infections,\nendometrial dysbiosis, or immunological alterations ( Ticconi  et al. , 2024 ). While many patients remain\nasymptomatic, CE has been increasingly associated with recurrent implantation\nfailure (RIF) and recurrent pregnancy loss (RPL) ( Cicinelli  et al. , 2019 ;  Ticconi  et al. , 2024 ).\nThe reported prevalence varies widely (3%-68%) depending on the population studied\nand the diagnostic criteria applied ( Cicinelli\n et al. , 2019 ;  Li\n et al ., 2021 ;  Liu\n et al. , 2022 ;  Ticconi  et al. , 2024 ), highlighting the heterogeneity\nof diagnostic criteria and study populations.\nDiagnosis is typically based on a combination of hysteroscopy, endometrial biopsy,\nand immunohistochemistry for CD138-positive plasma cells, with MUM1 recently\nproposed as an additional marker to improve diagnostic sensitivity ( Santoro  et al. , 2023 ). Several\nstudies have suggested improved reproductive outcomes after antibiotic therapy,\nparticularly when histological resolution is achieved ( Cheng  et al. , 2022 ;  Liu  et al. , 2022 ;  Veiga  et al. , 2023 ;  Vitagliano  et al. , 2022 ). However, variability\nin diagnostic approaches and treatment protocols still hinders the development of\nclear clinical guidance.\nThis study aimed to evaluate whether the diagnosis and treatment of CE improve\nreproductive outcomes in women with reproductive failure.\n\nA retrospective study was conducted at a tertiary care hospital from January 2019 to\nDecember 2024, including 67 patients with a history of reproductive failure, as\nshown in  Figure 1 . Reproductive failure was\ndefined as either RPL - two or more miscarriages according to the 2017 ESHRE\nGuideline (ESHRE Guideline Group on RPL  et al .,  2018 ) - or RIF - three or more unsuccessful\nembryo transfers with morphologically good-quality embryos, as established by the\nBritish Fertility Society ( Mascarenhas  et\nal. , 2022 ). Embryo quality was assessed according to the\nmorphological classification described in the updated Istanbul Consensus Workshop on\nOocyte and Embryo Morphological Assessment (Working Group on the update of the\nESHRE/ALPHA Istanbul Consensus,  2025 ).\nFigure 1 Treatment, post-treatment follow-up, and reproductive outcomes.\nTreatment, post-treatment follow-up, and reproductive outcomes.\nThe inclusion criteria were women diagnosed with RPL or RIF who underwent\nhysteroscopic, histological, or microbiological evaluation for suspected CE.\nExclusion criteria included loss to follow-up after diagnostic evaluation or refusal\nto receive antibiotic therapy.\nAll patients underwent diagnostic hysteroscopy with directed endometrial biopsy. In\nselected cases, microbiological cultures were obtained under hysteroscopic guidance.\nCE was diagnosed when at least one of the following criteria was met: (1)\nhysteroscopic features suggestive of CE, according to the criteria described by\n Cicinelli  et al . (2019) ;\n(2) histological identification of at least one CD138-positive plasma cell per\nhigh-power field; or (3) positive endometrial culture.\nAll patients diagnosed with CE received first-line antibiotic therapy following  Cicinelli  et al . (2018) \nprotocol, most commonly doxycycline 200 mg/day for 14 days. Post-treatment\nevaluation was performed by repeat biopsy or culture using a Cornier cannula. CE was\nconsidered resolved when no plasma cells or pathogens were detected. Otherwise, the\ncondition was classified as persistent. Most patients with persistent CE received\nsecond-line antibiotic therapy, most commonly ceftriaxone 500 mg single dose with\ndoxycycline 200 mg/day and metronidazole 500 mg/12 hours.\nThe primary outcome of this study was the live birth rate following CE treatment,\ndefined as the proportion of patients who achieved at least one live birth after one\nor more embryo transfers (ESHRE Working Group on Recurrent Implantation Failure,\n 2023 ). The secondary outcome was the\nclinical pregnancy rate, defined as the proportion of embryo transfers resulting in\npregnancy confirmed by an ultrasound-detected gestational sac (ESHRE Working Group\non Recurrent Implantation Failure,  2023 ).\nSubgroup analyses compared outcomes between (1) women with RIF versus RPL and (2)\npatients with resolved versus persistent CE after treatment.\nContinuous variables were tested for normality using the Shapiro-Wilk test.\nQualitative variables are presented as absolute frequencies (n) and percentages (%),\nand quantitative variables as mean±standard deviation or median and\ninterquartile range, as appropriate. The chi-square test, linear-by-linear\nassociation test, or Fisher’s exact test was used to assess associations between\nqualitative variables. Statistical analyses were performed using IBM SPSS Statistics\n25.0, with  p <0.05 considered statistically significant. The\nstudy protocol was reviewed and approved by the institutional ethics committee,\nwhich granted a waiver of informed consent because of the retrospective design and\nuse of anonymized data. An anonymized dataset is available at Vázquez Ramos\n( 2025 ).\n\nAmong the 67 women with reproductive failure, CE was diagnosed in 30 (44.8%) based on\none or more diagnostic criteria. Of these, 20 (66.7%) had RIF and 10 (33.3%) had\nRPL. The median age of the cohort was 35 years [32-36], with a mean\nanti-Müllerian hormone (AMH) level of 3.7±2.7 ng/mL and a median total\nmotile sperm count (TMSC) of 7×10 6  [1.5-25.6] ( Table 1 ). Male factor infertility and ovarian\nfactor infertility were each observed in 10 cases (33.3%) ( Table 1 ).\nClinical characteristics and infertility factors of patients with chronic\nendometritis\nHistological detection by CD138 immunostaining was the most common diagnostic\napproach (86.7%), followed by hysteroscopic findings (all showing endometrial\nmicropolyps) (26.7%) and positive cultures (20%). The isolated microorganisms are\nshown in  Table 2 .\nMicroorganisms isolated in cultures\nMost patients received doxycycline 200 mg/day for 14 days as first-line therapy\n(n=20; 66.7%). The remaining 10 patients received ciprofloxacin 500 mg every 12\nhours, amoxicillin-clavulanic acid 875/125 mg every 8 hours, or combined antibiotic\nregimens, as detailed in  Table 3 .\nPost-treatment evaluation was performed in 24 patients (80%), confirming CE\nresolution in 13 (54.2%) and persistence in 11 (45.8%). Among those with persistent\nCE, 8 (72.7%) received second-line antibiotic therapy, most commonly ceftriaxone 500\nmg as a single dose followed by doxycycline 200 mg/day and metronidazole 500 mg\nevery 12 hours. In the remaining cases, treatment included cefixime 400 mg/day,\namoxicillin-clavulanic acid 875/125 mg every 8 hours, or a combination of\nmetronidazole 500 mg every 12 hours and ciprofloxacin 500 mg every 12 hours ( Table 4 ).\nFirst-line antibiotic therapy\nSecond-line antibiotic therapy\nFollowing antibiotic therapy, 17 patients (56.7%) achieved a clinical pregnancy and\n12 (40%) achieved a live birth. On average, each patient underwent 1.37±0.85\nembryo transfers after treatment. Among women with RIF, 55% achieved a clinical\npregnancy and 40% achieved a live birth, whereas among those with RPL the rates were\n60% and 40%, respectively ( Table 5 ). Clinical\npregnancy and live birth rates did not differ significantly between patients with\nresolved CE (46.2% and 38.5%) and those with persistent disease after second-line\nantibiotic therapy (62.5% and 50%) ( p >0.05). However, the small\nsample size of this study limited its power to detect statistically significant\ndifferences. Nevertheless, the observed clinical pregnancy and live birth rates\nsuggest a potentially favorable reproductive trend following antibiotic therapy.\nReproductive outcomes according to type of reproductive failure\n\nThis study adds to the existing evidence on the role of CE in reproductive failure\nand the potential benefit of antibiotic therapy, showing a CE resolution rate of\n54.2%, with 56.7% of patients achieving a clinical pregnancy and 40% achieving a\nlive birth. Although no statistically significant differences were observed\naccording to CE resolution status, these descriptive outcomes still suggest a\npotentially favorable reproductive trend after treatment.\nOur results align with previous studies reporting variable CE resolution rates and\nreproductive outcomes following antibiotic therapy ( Cicinelli  et al. , 2021 ;  Kitaya  et al. , 2017 ;  Sakai  et al. , 2024 ;  Veiga  et al. , 2023 ;  Vitagliano  et al. , 2022 ;  Xiong  et al. , 2021 ). Despite the moderate\nresolution rate, the reproductive outcomes observed in our study were comparable to\nthose reported in larger cohorts, supporting the clinical value of CE management.\nHowever, the heterogeneity of diagnostic methods, small sample size, and\nretrospective design limit the generalizability of our results.\nThe biological plausibility of CE’s negative impact on fertility is well-established.\nPersistent endometrial inflammation leads to leukocyte infiltration, cytokine and\nchemokine overexpression, and transcriptional dysregulation of immune and angiogenic\npathways, together with impaired stromal decidualization, progesterone resistance,\nand abnormal uterine contractility ( Di Pietro\n et al. , 2013 ;  Kitaya\n& Yasuo, 2010 ;  Pirtea  et\nal. , 2021 ;  Wu  et\nal. , 2017 ). These mechanisms compromise endometrial\nreceptivity and may explain the reproductive improvement observed after antibiotic\ntherapy ( Buzzaccarini  et al. ,\n2020 ).\nPotential confounders such as embryo quality, female age, and underlying infertility\nfactors may also have influenced reproductive outcomes in our cohort. Nonetheless,\nall patients underwent hysteroscopy-guided biopsy, which ensured diagnostic accuracy\nand consistency, and most completed post-treatment follow-up, allowing a reliable\nevaluation of therapeutic response.\nThe main limitations of this study are its small sample size and retrospective\ndesign, both of which reduce statistical power and limit generalizability. Despite\nthese constraints, the observed 40% live birth rate is consistent with previous\nreports and supports CE as a potentially modifiable condition affecting reproductive\nprognosis.\nAdditionally, while our study did not demonstrate significant differences based on\npost-treatment CE status, current evidence suggests that confirming histological\nresolution may improve reproductive outcomes ( Cheng\n et al. , 2022 ;  Liu\n et al. , 2022 ). Therefore, several authors advocate\nfor the systematic post-treatment evaluations to optimize clinical management.\nFuture research should aim to investigate the role of CE as a modifiable risk factor\nfor reproductive failure through large, prospective studies using standardized\ndiagnostic and therapeutic criteria. It should also explore adjuvant strategies to\nenhance treatment efficacy. In this regard,  Zou\n et al . (2023)  reported improved implantation and\npregnancy rates with combined antibiotic and corticosteroid treatment, opening new\navenues for investigation.\n\nIn this cohort, antibiotic treatment of CE was associated with clinical pregnancy and\nlive birth rates of 56.7% and 40%, respectively. No statistically significant\ndifferences in reproductive outcomes were observed between patients with resolved\nand persistent CE after treatment. Given the small sample size and diagnostic\nheterogeneity, these findings should be interpreted cautiously; however, the\nobserved trends are consistent with previous studies and support the clinical\nrelevance of CE management in assisted reproduction. Larger prospective studies\nusing standardized diagnostic and therapeutic criteria are needed to clarify its\ntrue impact on reproductive outcomes.","source_license":"CC-BY-4.0","license_restricted":false}