Early screening and post-treatment chronic endometritis in subsequent frozen embryo transfer cycles among women with first implantation failure: a retrospective cohort study

Background: fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET), and a considerable proportion of affected women subsequently progress to recurrent implantation failure (RIF). Chronic endometritis (CE), an inflammatory disorder of the endometrium, is associated with implantation failure and poor reproductive outcomes. However, the clinical significance of varying CD138-positive plasma cell thresholds and the role of antibiotic therapy in women with FIF remain inadequately defined. Methods: A total of 4,528 women who experienced FIF following IVF/ICSI at Henan Provincial People's Hospital were initially screened; of these, 2,885 women who underwent a subsequent frozen-thawed embryo transfer (FET) cycle were included in the final analysis. All participants underwent hysteroscopy-guided endometrial biopsy with CD138 immunohistochemical evaluation at the initial post-FIF assessment. Women diagnosed with CE received standardized empirical antibiotic treatment followed by post-treatment CD138 reassessment before the subsequent FET cycle. Multivariable logistic regression was performed to adjust for prespecified clinically relevant confounders. In addition, inverse probability of treatment weighting (IPTW) based on propensity scores was applied as a sensitivity analysis for the comparison between the PCE group and the CD138-positive/HPF ≤4 group. The primary outcome was live birth rate (LBR), and secondary outcomes included clinical pregnancy rate (CPR) and early miscarriage rate (EMR). Results: CE, defined as ≥5 CD138-positive plasma cells per high-power field (HPF), was identified in 16.8% of participants. The cure rate was 89.1% in women with CD138-positive plasma cells ≥5/HPF after two courses of standardized antibiotic treatment. No significant difference in pregnancy outcomes was observed between women with CD138-positive cell counts of 0/HPF and those with counts of 1-4/HPF. Women with CE who achieved histological remission (≤4/HPF on post-treatment biopsy) after treatment had pregnancy outcomes comparable to those of women with CD138-positive/HPF ≤4. Persistent chronic endometritis (PCE), defined as persistent ≥5 CD138-positive plasma cells per HPF after two standard antibiotic courses, was associated with lower LBR (28.3% vs. 41.8%, P = 0.034) and CPR (39.6% vs. 56.6%, P = 0.016) than in women with CD138-positive/HPF ≤4. In the IPTW-weighted analysis, baseline imbalance was substantially reduced, and PCE remained significantly associated with lower CPR (weighted OR 0.65, 95% CI 0.47-0.89, P = 0.008), while the association with lower LBR remained directionally consistent but attenuated to borderline significance (weighted OR 0.73, 95% CI 0.53-1.02, P = 0.056). Conclusion: Among women who have experienced FIF, an endometrial CD138-positive plasma cell count of ≤4/HPF is not associated with impaired pregnancy outcomes. Furthermore, following standard antibiotic therapy, women with ≥5 CD138-positive plasma cells/HPF had pregnancy outcomes comparable to those of women with ≤4 CD138-positive plasma cells/HPF. However, PCE was consistently associated with poorer reproductive outcomes, including in the IPTW-weighted analysis, although causal inference remains limited by the observational design.