Association of cured chronic endometritis after antibiotic treatment with outcomes of the subsequent frozen-thawed embryo transfer cycle among women with first implantation failure: a retrospective cohort study.

The study flowchart is illustrated in Fig.  1 . A total of 6,371 women who experienced their first implantation failure after IVF/ICSI treatment at Henan Provincial People’s Hospital between May 2019 and December 2023 were initially identified. Following the application of stringent exclusion criteria, 2,555 subsequent FET cycles were ultimately included in this retrospective cohort study. Only the first FET cycle performed within 6 months after hysteroscopy was included in the analysis. The exclusion criteria were as follows: (1) female age > 40 years; (2) transfer of fewer than one high-quality cleavage-stage embryo or one high-quality blastocyst in the first cycle; (3) endometrial thickness (EMT) on the day of transfer  14 mm; and (4) failure to undergo FET within 6 months after hysteroscopy. (5) Patients with intrauterine adhesions (IUA), submucosal myoma, uterine malformation, or intrauterine mass; (6) Patients with hydrosalpinx; (7) Patients with chromosomal abnormalities in either or both partners; (8) Patients with primary ovarian insufficiency; (9) Patients diagnosed with immune-related diseases, such as systemic lupus erythematosus or ankylosing spondylitis; (10) Patients with endometriosis identified via ultrasound examination or adenomyosis. High-quality cleavage-stage embryos: (I) Seven to nine blastomeres on day 3; (II) Fragmentation proportion ≤ 5%; (III) No multinucleation in the pronuclear stage. High-quality blastocysts were defined according to the Istanbul consensus [ 19 ]. Fig. 1 Study flow chart. The flow diagram shows patient selection from women with first implantation failure to the final analytic cohort of subsequent FET cycles. CE, chronic endometritis; NCE, women with no CE; PCE, persistent chronic endometritis after one course of antibiotic therapy, defined by persistence of ≥ 5 CD138-positive plasma cells per high-power field on repeat endometrial biopsy; CCE, women with cured CE after one course of antibiotic treatment; EMT, endometrial thickness; POI, primary ovarian insufficiency Study flow chart. The flow diagram shows patient selection from women with first implantation failure to the final analytic cohort of subsequent FET cycles. CE, chronic endometritis; NCE, women with no CE; PCE, persistent chronic endometritis after one course of antibiotic therapy, defined by persistence of ≥ 5 CD138-positive plasma cells per high-power field on repeat endometrial biopsy; CCE, women with cured CE after one course of antibiotic treatment; EMT, endometrial thickness; POI, primary ovarian insufficiency This study was conducted as a retrospective chart-review study, and ethical approval was obtained from the Ethics Committee of Henan Provincial People’s Hospital (Approval No. SYSZ-LL-2021091501). The approved protocol explicitly authorized the retrospective use of anonymized clinical records from the reproductive center for research and scholarly publication. Because of the retrospective nature of the study and the use of de-identified data, the requirement for individual written informed consent was waived by the Institutional Review Board. All data were analyzed anonymously to protect patient confidentiality. All patients underwent thorough preoperative evaluations to exclude significant surgical contraindications prior to hysteroscopy. Hysteroscopy was conducted during the proliferative phase of the menstrual cycle (days 9–11) by experienced physicians. The intrauterine environment was systematically evaluated under direct visualization, and intrauterine abnormalities were managed as clinically indicated. Endometrial tissue samples were obtained at the time of hysteroscopy for routine histopathological examination and immunohistochemical analysis. In the present study, hysteroscopy was used as an adjunctive tool for morphological assessment, whereas the definitive diagnosis of CE was based on histopathological identification of endometrial stromal plasma cells by CD138 immunohistochemical staining. Tissue samples underwent hematoxylin and eosin staining for routine histological evaluation, and CD138-positive plasma cells were detected by immunohistochemistry using a mouse monoclonal antibody against human CD138. Histopathological evaluation was conducted by pathologists from an independent pathology department separate from the reproductive center. As patient outcome information was not available to the pathology department, the pathologists were blinded to subsequent reproductive outcomes at the time of diagnostic assessment. In the present study, CE was defined as the presence of ≥ 5 CD138-positive plasma cells per HPF, in accordance with previously used criteria [ 4 , 5 ]. Women diagnosed with CE received a 14-day course of oral doxycycline (100 mg twice daily) and metronidazole (200 mg twice daily) after hysteroscopy with endometrial biopsy. Histological reassessment was subsequently performed by repeat endometrial biopsy with CD138 immunohistochemical evaluation before the next FET cycle to determine whether CE had cured or persisted. In this study, PCE was operationally defined as the persistence of ≥ 5 CD138-positive plasma cells per HPF on repeat endometrial biopsy after one standardized course of oral antibiotic therapy. This approach was adopted with reference to previous studies in which repeat endometrial biopsy was performed after antibiotic treatment to evaluate the histological persistence or cure of CE [ 5 , 20 ]. For women with PCE after one antibiotic course, subsequent management was individualized rather than protocol-mandated. There was no uniform post-diagnosis treatment pathway for these patients in routine clinical practice. After counseling regarding the uncertain prognostic significance of persistent histological findings, the lack of a standardized management algorithm, the potential risks of repeated antibiotic exposure, and the possible delay in subsequent FET, further treatment decisions were made jointly by the patient and physician. Endometrial preparation protocols were implemented according to individual characteristics, including hormone replacement therapy (HRT), the natural cycle (NC), and the combination of gonadotropin-releasing hormone (GnRH) agonist (GnRH-a) downregulation with HRT (GnRH-a-HRT) protocol. In women undergoing the NC protocol (including modified cycles), follicular development and endometrial maturation were monitored by transvaginal ultrasound starting on days 10–12 of the menstrual cycle and continuing until ovulation or luteinization was confirmed. FET was performed 3 days after ovulation for embryos at the cleavage stage. By contrast, blastocyst transfer was performed 5 days after ovulation. In HRT cycles, oral administration of estradiol valerate was initiated at 4–8 mg daily beginning on the 3rd day of the menstrual cycle. Transvaginal ultrasound was performed on days 10–12 of medication administration to evaluate EMT. Progesterone was initiated when the EMT approached the maximum thickness observed in previous transfer cycles or reached 7 mm. Subsequently, cleavage-stage FET was performed following 4 days of progesterone therapy, whereas blastocyst transfer was performed after 6 days. In the GnRH-a-HRT protocol, triptorelin (3.75 mg) was administered on days 2–4; pituitary downregulation was confirmed by endometrial thickness < 5 mm, LH < 5 IU/L, estradiol < 50 pg/mL, and absence of dominant follicles or ovarian cysts. Subsequently, estrogen stimulation was initiated approximately 28–30 days later, according to the HRT protocol. A sustained-release vaginal gel at 90 mg/day and oral progesterone tablets at 40 mg/day were administered to the NC, HRT, and GnRH-a–HRT groups to support the luteal phase. In the HRT and GnRH-a–HRT groups, estradiol valerate therapy was continued as previously described. Luteal phase support was continued in all women until serum β-hCG testing on day 14 after FET. If the test result was positive, hormone supplementation was continued until 12 weeks of gestation. The primary outcomes were clinical pregnancy rate (CPR) and live birth rate (LBR) per FET cycle. The secondary outcome was early miscarriage rate (EMR), which was calculated among women who achieved a clinical pregnancy. Clinical pregnancy was defined as the presence of an intrauterine gestational sac on ultrasound, and live birth was defined as the delivery of a viable infant after 28 weeks of gestation. This threshold was chosen in accordance with local obstetric and perinatal reporting practice in China [ 21 , 22 ]. Early miscarriage was defined as spontaneous pregnancy loss before 12 completed weeks of gestation. All statistical analyses and data visualizations were conducted using SPSS 20.0 software (SPSS Inc., Chicago, IL). Continuous variables were first assessed for normality. Normally distributed variables are presented as mean ± standard deviation (SD) and were compared using one-way analysis of variance (ANOVA). Non-normally distributed variables are presented as median and interquartile range (IQR) and were compared using the Kruskal-Wallis test. Categorical variables are presented as frequencies and percentages and were compared using the chi-square test or Fisher’s exact test, as appropriate. When the overall comparison was statistically significant, pairwise comparisons were further performed with Bonferroni correction. Statistical significance was defined as a two-sided P  < 0.05 for overall analyses and P  < 0.0167 for pairwise comparisons after correction. To account for potential confounding, multivariable logistic regression was performed, adjusting for female age, body mass index (BMI), duration of infertility, aetiology of infertility, endometrial preparation protocols, EMT on the day of embryo transfer, number of embryos transferred, and type of embryo transfer.

The prevalence of uterine abnormalities among women with first implantation failure was 40.1% (1,725/4307). Among these abnormalities, endometrial polyps (EPs) and endometrial hyperplasia were the most common, accounting for 19.9% (858/4307) of cases. Furthermore, the distribution of other uterine abnormalities was as follows: CE, 15.3% (659/4307); intrauterine adhesions, 10.9% (469/4307); septate uterus, 1.8% (76/4307); unicornuate uterus, 1.6% (69/4307); arcuate uterus, 0.07% (3/4307); submucosal fibroids, 0.5% (20/4307); and intrauterine foreign bodies, 0.7% (29/4307). Notably, 15.7% (675/4307) of the patients exhibited two or more concurrent uterine abnormalities. Of the 2555 women included in the final analysis, 383 (15.0%) were diagnosed with CE on the basis of histological confirmation with CD138 immunohistochemistry at the initial assessment, whereas 2172 had no histological evidence of CE. All 383 women with CE received oral antibiotic treatment. After one standardized course of oral antibiotic therapy, 309 (80.7%) were classified as having cured CE (CCE), whereas 74 (19.3%) showed persistent CE (PCE) on the second evaluation. The study cohort consisted of 2555 patients who experienced implantation failure. Initially, the participants were divided into three groups: women with cured CE after one course of antibiotic treatment (CCE group), women with no CE (NCE group), and women with PCE after one course of antibiotic treatment, as confirmed by the second evaluation (PCE group). As shown in Table  1 , the three groups differed significantly in female age (31.5 ± 3.8 vs. 30.6 ± 4.1 vs. 32.1 ± 3.8; P  = 0.035), infertility duration years (3.3 [1.5, 4.0] vs. 2.7 [2.0, 4.1] vs. 5.2 [3.0, 6.1]; P  = 0.039), as well as aetiology of infertility ( P  = 0.001). In addition, no statistically significant differences were observed in BMI, infertility type, fertilization type, basal FSH, AMH, AFC, endometrium preparation protocols, EMT on the day of transfer, number of embryos transferred, and type of embryo transfer. Table 1 Baseline characteristics and subsequent reproductive outcomes in the CCE, NCE, and PCE groups Characteristic CCE ( N  = 309) NCE ( N  = 2172) PCE ( N  = 74) P value Female age (y) 31.5 ± 3.8 30.6 ± 4.1 32.1 ± 3.8 0.035 BMI (kg/m2) 22.9 ± 3.5 23.8 ± 3.6 24.2 ± 3.5 0.350 Infertility duration years (y) ( M , P25 , P75 ) 3.3 (1.5, 4.0) 2.7 (2.0, 4.1) 5.2 (3.0, 6.1) 0.039 Infertility type ( n , %)  Primary infertility 142 (46.0) 1062 (48.9) 35 (47.3) 0.547  Secondary infertility 167 (54.0) 1110 (51.1) 39 (52.7) Aetiology, n (%)  Tubal factor 170 (55.0) 1101 (50.7) 41 (55.4) 0.001  Male factor 52 (16.8) 432 (19.9) 12 (16.2)  Ovulatory factor 50 (16.2) 376 (17.3) 14 (18.9)  Others 37 (12.0) 263 (12.1) 7 (9.5) Fertilization type ( n , %)  IVF 256 (82.8) 1616 (74.4) 57 (77.6) 0.370  ICSI 53 (17.2) 556 (25.6) 17 (22.4) Basal FSH (mIU/ml) ( M , P25 , P75 ) 6.39 (5.53, 7.61) 6.54 (5.89, 7.95) 6.08 (5.29,7.43) 0.522 AMH (ng/ml) ( M , P25 , P75 ) 1.71 (0.92, 3.21) 1.39 (0.75, 2.95) 2.21 (1.29,3.68) 0.297 AFC ( n ) ( M , P25 , P75 ) 7.50 (4.00, 11.75) 8.00 (5.00, 13.00) 8.50 (6.00,14.00) 0.656 Endometrium preparation protocols  NC 74 (23.9) 556 (25.6) 27 (36.0) 0.425  HRT 197 (63.8) 1414 (65.1) 39 (53.2)  GnRHa-HRT 38 (12.3) 202 (9.3) 8 (10.8) Endometrial thickness on the day of transfer (mm) ( M , P25 , P75 ) 9.8 (9.0, 10.7) 9.8 (8.7, 11.0) 10.02 (9.2, 11.4) 0.761 Number of embryos transferred 1.5 ± 0.5 1.6 ± 0.5 1.5 ± 0.5 0.504 Type of embryo transfer, ( n %)  Cleavage stage embryo 112 (36.4) 656 (30.2) 21 (28.6) 0.907  Blastocyst 197 (63.6) 1516 (69.8) 53 (71.4) Reproductive outcomes  Live birth rate (%) 163/309 (52.8) 982/2172 (45.2) 20/74 (27.0) < 0.001  Clinical pregnancy rate (%) 211/309 (68.3) 1297/2172 (59.7) 27/74 (36.5) < 0.001  Early miscarriage rate (%) 19/211 (9.0) 175/1297 (13.5) 5/27 (18.5) 0.113 Data are presented as mean ± SD, median (P25, P75), or n (%), as appropriate Abbreviations : CCE cured chronic endometritis, NCE no chronic endometritis, PCE persistent chronic endometritis, NC natural cycle, HRT hormone replacement therapy, GnRHa-HRT gonadotropin-releasing hormone agonist plus hormone replacement therapy, BMI body mass index, IVF in vitro fertilization, ICSI intracytoplasmic sperm injection, FSH follicle-stimulating hormone, AMH anti-Müllerian hormone, AFC  antral follicle count P values were calculated using one-way ANOVA, the Kruskal-Wallis test, or the chi-square test, as appropriate Baseline characteristics and subsequent reproductive outcomes in the CCE, NCE, and PCE groups Data are presented as mean ± SD, median (P25, P75), or n (%), as appropriate Abbreviations : CCE cured chronic endometritis, NCE no chronic endometritis, PCE persistent chronic endometritis, NC natural cycle, HRT hormone replacement therapy, GnRHa-HRT gonadotropin-releasing hormone agonist plus hormone replacement therapy, BMI body mass index, IVF in vitro fertilization, ICSI intracytoplasmic sperm injection, FSH follicle-stimulating hormone, AMH anti-Müllerian hormone, AFC  antral follicle count P values were calculated using one-way ANOVA, the Kruskal-Wallis test, or the chi-square test, as appropriate The LBR differed significantly among the CCE, NCE, and PCE groups (52.8% vs. 45.2% vs. 27.0%, respectively; P  < 0.001). Post hoc analysis showed that the PCE group had a significantly lower LBR than both the NCE and CCE groups, whereas the CCE group had a significantly higher LBR than the NCE group. These associations remained significant after multivariable adjustment (Table  2 ). Additionally, the LBR in the CCE group was significantly higher compared to that in the NCE group ( P  = 0.013) (adjusted OR, 1.55 [1.06, 2.12]) (Table  2 ). Similarly, the CPR differed significantly among the three groups (68.3% vs. 59.7% vs. 36.5%, respectively; P  < 0.001). Post hoc analysis demonstrated that the CPR was significantly lower in the PCE group than in both the NCE and CCE groups, while the CCE group had a significantly higher CPR than the NCE group. These findings remained significant after adjustment for potential confounders (Table  2 ). No significant differences in early miscarriage rates were observed across the three groups; however, a trend toward higher rates was observed in the PCE group (9.0% vs. 13.5% vs. 18.5%) (Table  1 ). These reproductive outcomes are visually summarized in Fig.  2 . Table 2 Adjusted odds ratios of clinical outcomes according to CE status Variable CCE vs. NCE CCE vs. PCE PCE vs. NCE Adjusted OR (95% CI) P value Adjusted OR (95% CI) P value Adjusted OR (95% CI) P value Live Birth Rate 1.55 (1.06, 2.12) 0.013 2.82 (1.58, 4.47) < 0.001 0.67 (0.44, 0.90) < 0.001 Clinical Pregnancy Rate 1.58 (1.43, 2.36) 0.004 1.91 (1.47, 2.47) < 0.001 0.64 (0.42, 0.89) < 0.001 Early miscarriage rate 0.83 (0.62, 1.04) 0.084 0.75 (0.51,1.01) 0.122 1.34 (0.69, 1.99) 0.486 Adjusted odds ratios and 95% CIs are based on the multiple logistic regression model. Adjusted for female age, BMI, infertility duration years, aetiology of infertility, endometrium preparation protocols, endometrial thickness on the day of transfer, number of embryos transferred, and type of embryo transfer Abbreviations : CCE cured chronic endometritis, NCE no chronic endometritis, PCE  persistent chronic endometritis Adjusted odds ratios of clinical outcomes according to CE status Adjusted odds ratios and 95% CIs are based on the multiple logistic regression model. Adjusted for female age, BMI, infertility duration years, aetiology of infertility, endometrium preparation protocols, endometrial thickness on the day of transfer, number of embryos transferred, and type of embryo transfer Abbreviations : CCE cured chronic endometritis, NCE no chronic endometritis, PCE  persistent chronic endometritis Fig. 2 Comparison of reproductive outcomes among the CCE, NCE, and PCE groups. Live birth rate (LBR) and clinical pregnancy rate (CPR) were calculated per embryo transfer cycle, whereas early miscarriage rate (EMR) was calculated among clinical pregnancies. Pairwise P values are shown above the bars after Bonferroni correction Comparison of reproductive outcomes among the CCE, NCE, and PCE groups. Live birth rate (LBR) and clinical pregnancy rate (CPR) were calculated per embryo transfer cycle, whereas early miscarriage rate (EMR) was calculated among clinical pregnancies. Pairwise P values are shown above the bars after Bonferroni correction

This large-scale retrospective study observed that women with cured CE after antibiotic treatment had higher CPR and LBR in subsequent FET cycles than women with PCE, whereas the comparison between the CCE and NCE groups should be interpreted with particular caution. Although the early miscarriage rate was numerically lower in the CCE group than in the NCE group, this difference was not statistically significant. A favorable intrauterine environment is a critical prerequisite for successful ART outcomes. Previous studies have shown that outpatient hysteroscopy identifies uterine abnormalities in a substantial proportion of women with implantation failure undergoing ART [ 23 , 24 ]. In the present study, the prevalence of uterine abnormalities among patients with first implantation failure was 40.1% (1725/4307), which is comparable to that reported in RIF populations. Notably, the prevalence of CE in our cohort was 15.3%, which is higher than the prevalence reported in infertile asymptomatic women without this specific first-failure setting [ 25 ]. These findings suggest that hysteroscopic and histopathological evaluation after first implantation failure may help identify clinically relevant intrauterine abnormalities at an earlier stage. CE is a persistent, low-grade inflammatory condition localized to the endometrium [ 26 ]. In our center, women diagnosed with CE received standardized oral antibiotic therapy consisting of doxycycline combined with metronidazole. Consistent with previous reports, CE generally shows a relatively high histological resolution rate after standardized oral antibiotic treatment; in our cohort, the resolution rate after one treatment course was 80.8%, which was broadly comparable to that reported in previous studies [ 5 , 11 – 13 , 20 ]. Several cohort studies have suggested improved reproductive outcomes after successful treatment of CE, particularly in women with RIF or related infertility conditions [ 5 , 11 – 13 , 27 – 30 ]. At the same time, the existing literature is not entirely concordant. Some meta-analyses have reported no clear improvement in pregnancy outcomes after oral antibiotic treatment when treated women were compared with untreated controls, whereas others have suggested that women with resolved CE may achieve better outcomes than those with persistent disease [ 15 , 16 ]. In addition, a recent systematic review and meta-analysis suggested that IVF outcomes in women with cured CE may become broadly comparable to those in women without CE, rather than clearly superior [ 17 ]. Therefore, our findings should be interpreted within this broader and still evolving evidence base, rather than as definitive proof of treatment effect. The finding that reproductive outcomes in the CCE group were superior to those in the NCE group deserves particular caution. This result differs from some pooled analyses suggesting that IVF outcomes after CE resolution may be broadly comparable, rather than clearly superior, to those in women without CE [ 17 ]. One possible explanation is the combined effect of endometrial biopsy and antibiotic treatment. Endometrial injury has been investigated as a potential adjunctive intervention that may enhance reproductive outcomes by inducing local inflammatory and receptivity-related changes in the endometrium [ 31 , 32 ]. Endometrial injury may stimulate the release of growth factors and pro-inflammatory cytokines, such as leukemia inhibitory factor (LIF), interleukin-6 (IL-6), and tumor necrosis factor (TNF), thereby promoting decidualization. Endometrial injury may alter endometrial gene expression, including genes related to implantation and tissue remodeling [ 33 ]. In addition, endometrial injury may promote the recruitment of macrophages and dendritic cells, which are involved in decidualization and embryo implantation [ 34 ]. Monocytes recruited to the site of injury may persist within endometrial tissue for an extended period, allowing the biological effects of injury in one menstrual cycle to carry over into the subsequent cycle. Nevertheless, the apparent superiority of the CCE group over the NCE group should not be interpreted as definitive evidence of a beneficial treatment effect, but rather as a hypothesis-generating observation that warrants confirmation in prospective studies with more standardized designs. It should be noted that there is currently no universally accepted gold standard for the diagnosis and post-treatment evaluation of CE. Across studies, substantial variability exists in the diagnostic framework, including the relative use of hysteroscopic findings, histopathology, and CD138 immunohistochemistry, as well as the plasma-cell threshold used to define CE [ 17 , 18 ]. In addition, treatment strategies differ with respect to antibiotic regimens, treatment duration, the number of treatment courses, and whether repeat biopsy is routinely performed [ 16 , 18 ]. These differences complicate direct comparison across studies and may partly explain the inconsistent findings reported in the literature. They may also introduce a degree of misclassification bias in CE categorization, particularly in retrospective studies such as ours. Therefore, the PCE definition used in the present study should be regarded as a literature-supported operational definition within our clinical protocol, rather than a universally established standard. Because this was a retrospective real-world study, patients with PCE after the initial antibiotic course were not uniformly managed with a second mandatory course of antibiotics, repeat biopsy, or GnRH-a-HRT. Instead, subsequent management was individualized according to shared decision-making and routine clinical indications. This treatment heterogeneity may have influenced reproductive outcomes in the PCE group and should therefore be taken into account when interpreting the present findings. In the present study, PCE was significantly associated with poorer pregnancy outcomes in subsequent FET cycles, consistent with previous studies [ 5 , 30 ]. Possible mechanisms by which CE contributes to implantation failure include aberrant expression of growth factors, cytokines, and apoptosis-related proteins, leading to impaired endometrial receptivity. In addition, CE may disrupt the local immune and inflammatory microenvironment of the endometrium, thereby impairing decidualization as well as embryo adhesion, penetration, and trophoblast invasion [ 11 , 35 ]. Although early miscarriage rates did not differ significantly among the three groups, a numerical increasing trend was observed in the PCE group. This finding should be interpreted cautiously, as the number of clinical pregnancies and miscarriage events in the PCE group was limited, which may have reduced the statistical power to detect a significant difference. Therefore, the possibility that PCE is associated with an increased risk of early miscarriage cannot be excluded and warrants further investigation in larger cohorts. Personalized treatment strategies targeting either pathogen-specific antibiotic susceptibility or the altered immune microenvironment in women with PCE may represent promising approaches to improving reproductive outcomes in these complex cases. This study has several strengths. First, to our knowledge, this is one of the few studies focusing specifically on women with first implantation failure rather than established RIF or RPL, thereby extending the clinical relevance of CE screening to an earlier stage of treatment failure. Second, all endometrial samples were collected during the proliferative phase of the menstrual cycle, thereby minimizing potential variability related to sampling timing. Third, only subsequent FET cycles were included, which reduced potential confounding effects of ovarian stimulation on endometrial receptivity. Fourth, the relatively large overall sample size and the homogeneous single-center clinical setting enhanced the internal consistency of the study. However, several limitations should also be acknowledged. First, the retrospective nature of the study may have introduced selection bias and residual confounding. Second, the subgroup of women with PCE was relatively small, which may have limited statistical power for some secondary outcomes, particularly early miscarriage. Third, because the post-treatment management of PCE was individualized rather than protocol-mandated, treatment heterogeneity in this subgroup could not be avoided and may have introduced additional confounding in the interpretation of subsequent reproductive outcomes. Fourth, as this was a single-center study conducted in a relatively homogeneous clinical setting, the generalizability of our findings to other populations, institutions, diagnostic pathways, and treatment protocols may be limited. Finally, given the lack of a universally accepted diagnostic standard for CE/PCE, some degree of misclassification bias cannot be excluded, and caution is warranted when comparing our findings directly with those of previous studies using different definitions or re-evaluation strategies.

In conclusion, CE may be an important factor associated with first implantation failure in women undergoing IVF/ICSI. Antibiotic treatment was associated with improved reproductive outcomes when CE was cured after treatment, whereas PCE remained associated with poorer subsequent outcomes. The clinical value of CE management may lie not only in the treatment itself but also in post-treatment reassessment to confirm histological cure. However, our results should be regarded as hypothesis-generating and interpreted cautiously given the retrospective design and the possibility of residual confounding.

Chronic endometritis (CE) is a persistent inflammatory disorder of the endometrium that is typically associated with pathogenic microorganisms. It may be asymptomatic or present with nonspecific symptoms such as abnormal uterine bleeding, pelvic pain, dyspareunia, and leukorrhea [ 1 ]. Hysteroscopy can identify characteristic intrauterine findings suggestive of CE, including endometrial micropolyps, focal or diffuse hyperemia, and stromal edema [ 2 ]. Histopathological diagnosis is primarily based on the identification of plasma cell infiltration within the endometrial stroma, and CD138 immunohistochemistry is commonly used to improve plasma-cell detection [ 3 ]. Different centers have used different plasma-cell thresholds, and a cutoff of ≥ 5 CD138-positive plasma cells per HPF is among the commonly adopted criteria [ 4 , 5 ]. However, no universally accepted histopathological threshold for CE has yet been established, and this diagnostic variability may affect the comparability of findings across studies. In this study, hysteroscopy was used for morphological assessment, whereas the definitive diagnosis of CE was based on CD138 immunohistochemical staining. CE was defined as the presence of ≥ 5 CD138-positive plasma cells per high-power field (HPF), while women with < 5 CD138-positive plasma cells per HPF were classified as having no CE and were included in the NCE group [ 2 , 3 , 6 , 7 ]. Accumulating evidence indicates that CE is associated with infertility, implantation failure, and recurrent pregnancy loss (RPL) [ 1 , 8 ]. CE may impair implantation through multiple mechanisms, including chronic inflammation, immune dysregulation, stromal edema, abnormal uterine contractility, and impaired decidualization [ 9 , 10 ]. Standard antibiotic therapy is effective in a substantial proportion of patients with CE [ 11 , 12 ]. Several studies have also suggested that successful treatment may improve subsequent reproductive outcomes, particularly in women with RPL or RIF [ 11 – 13 ]. One study reported that, after standard antibiotic treatment, CPR and LBR were higher in women with cured CE than in those with persistent CE (PCE) [ 13 ]. However, conflicting evidence exists. Although some studies have suggested reproductive benefit after successful treatment of CE, other analyses have reported no clear improvement in pregnancy outcomes after oral antibiotic therapy, and concerns remain regarding potential overtreatment and heterogeneity in study design [ 14 – 17 ]. In addition, interpretation across studies is complicated by substantial variability in diagnostic criteria, histological thresholds, and treatment strategies for CE [ 17 , 18 ]. Furthermore, most previous studies and pooled analyses have focused on women with RPL or RIF, whereas evidence in women with first implantation failure remains limited [ 16 ]. Therefore, this retrospective study aimed to investigate the incidence of CE among women with first implantation failure, as well as the association between antibiotic treatment and outcomes in subsequent embryo transfer cycles, to clarify the potential clinical relevance of early identification and treatment of CE in this population.