I. Prevalence and Harm of CE

(I) Unexplained Infertility, Repeated Implantation Failure (RIF), and Recurrent Pregnancy Loss (RPL)

• Unexplained infertility population: 2.8% to 56.8%, with a pooled prevalence of 26.38% (95%CI 20.97% to 32.16%) in Meta-analysis (45 studies included, 32,644 cases);
• RIF population: 7.7% to 66.3%, with a pooled prevalence of 36.32% (95%CI 30.71% to 42.12%) in Meta-analysis (36 studies included, 6,504 cases);
• RPL population: 9% to 67.6%, with a pooled prevalence of 29.19% (95%CI 20.8% to 39.29%) in Meta-analysis (17 studies included, 3,653 cases).

(II) Endometrial Polyps and Endometriosis

1. Endometrial polyps: Meta-analysis shows that the prevalence of CE in patients with endometrial polyps is 28.71% to 92.59%, with a pooled prevalence of 51.35% (95%CI 27.24% to 75.13%), which is significantly higher than that in patients without polyps (OR=3.07); the prevalence of CE in patients with ≥3 polyps is higher than that in patients with single polyps (OR=3.43), and CE increases the recurrence risk after polypectomy.
2. Endometriosis: 3% to 53% of patients with endometriosis are complicated with CE. The prevalence of CE (52.94%) is higher than that of non-endometriosis patients (27.02%), and CE increases the risk of endometriosis (OR=3.037).

(III) Other Related Factors

II. Pathogenic Microorganisms and Intrauterine Flora of CE

(I) Normal Intrauterine Flora

(II) Pathogenic Microorganisms of CE

1. Culture method: The most common are bacteria such as Escherichia coli, Enterococcus faecalis, Streptococcus, and Staphylococcus (accounting for 59.7%), followed by Mycoplasma (11.0%), and there are also Corynebacterium, Klebsiella pneumoniae, Candida, etc.; the detection rates of Chlamydia trachomatis and Neisseria gonorrhoeae are low (2.8% and 0.2% respectively).
2. NGS detection: In CE patients, the proportion of Lactobacillus in the uterine cavity decreases, the proportion of non-Lactobacillus increases, and microbial metabolism is abnormal (such as significant up-regulation of arginine, proline, and vitamin A metabolic pathways). However, the microecological environment and core pathogenic flora of CE have not been clarified.

III. Mechanism of CE-Induced Changes in Intrauterine Immune Microenvironment

(I) Immune Microenvironment of Normal Endometrium

• Innate immunity: Responses mediated by mechanical barriers, macrophages (M1 pro-inflammatory, M2 anti-inflammatory), and uterine natural killer (uNK) cells (involved in immune tolerance and angiogenesis);
• Adaptive immunity: Responses mediated by B cells (differentiated into plasma cells to produce antibodies) and T cells (Th1 pro-inflammatory, Th2 regulating immune tolerance, Treg maintaining maternal-fetal tolerance).

(II) Impact and Mechanism of CE on Immunity and Fertility

1. Macrophages polarize to M1 type, and pro-inflammatory factors (IL-6, IL-12, IL-23, etc.) increase, inducing Th1 response, which is toxic to embryos;
2. The number of uNK cells decreases in the secretory phase and early pregnancy, which is not conducive to the establishment of maternal-fetal immune tolerance and affects implantation;
3. Lipopolysaccharide (LPS) induces B cell migration and differentiation into plasma cells, producing IgM, IgA1, IgA2, IgG1, IgG2 (especially increased IgG2), which may be unfavorable for embryo implantation;
4. The proportion of CD8+ T cells increases, Th1 response is hyperactive (increased pro-inflammatory factors IL-1β, IL-6, TNF-α), Th2 and Treg are suppressed (decreased anti-inflammatory factors IL-10, TGF-β), and immune imbalance leads to the destruction of maternal-fetal tolerance;
5. The differentiation of the endometrium is delayed in the mid-secretory phase, changing the implantation window, affecting receptivity, and leading to RIF, RPL, etc.

IV. Diagnosis of CE

(I) Clinical Manifestations and Medical History

(II) Auxiliary Examinations

1. Blood routine and gynecological ultrasound: No specificity, used to exclude acute infections and other intrauterine abnormalities.
2. Hysteroscopy: It can intuitively understand the intrauterine situation and is an important diagnostic method with a negative predictive value of 98.8%. Using the 2019 criteria of the International Standardization Working Group for CE, the hysteroscopic features include:

• Strawberry sign: White punctate glandular openings on a background of diffuse congestion;
• Focal congestion: Small area of congestion;
• Bleeding points: Focal red areas with clear and irregular edges, possibly connected to capillaries;
• Micro-polyps (diameter <1mm): With obvious vascular axis, composed of a mixture of inflammatory cells, small blood vessels, and glands;
• Stromal edema: Irregular thickening and paleness of the endometrium in the follicular phase.

1. Pathological examination: The pathological features of CE are plasma cell infiltration, congestion and edema, increased density in the endometrial stroma, which may be accompanied by glandular epithelial damage and asynchronous development of epithelium and stroma. CD138 immunohistochemistry is commonly used for plasma cell identification (attention should be paid to false positives of glandular epithelium and cervical squamous cells), and MUM1 double staining can be combined for auxiliary identification.

• Both hysteroscopy and pathology suggest CE: Confirmed diagnosis;
• Neither supports: No diagnosis;
• Pathology suggests but hysteroscopy does not: Diagnosable (hysteroscopy may miss the diagnosis);
• Pathology does not suggest but hysteroscopy has manifestations: Consider diagnosis in combination with high-risk factors and reproductive history (sampling methods, cycles, etc. may affect pathological results).

1. Microbial detection:

• Culture method: Can guide medication, but has a high false negative rate and takes a long time, with limited clinical value;
• Molecular biology methods: PCR can only detect known microorganisms with limited sensitivity; NGS can detect all microorganisms, but the core pathogenic flora is unclear, and clinical application is limited.

(III) Diagnostic Conclusion

V. Treatment of CE

(I) Empirical Antibiotic Treatment

• First-line: Doxycycline 100mg, twice a day, for 14 days;
• Second-line: Ciprofloxacin 200 to 500mg + Metronidazole 250 to 500mg, both twice a day, for 14 days; or Levofloxacin 200mg twice a day + Metronidazole 500mg three times a day, for 14 days.

(II) Pathogen-Targeted Antibiotic Treatment

• G+ bacteria positive: Amoxicillin-clavulanate 1g, twice a day, for 8 days;
• G- bacteria positive: Ciprofloxacin 500mg, twice a day, for 10 days;
• Mycoplasma/Ureaplasma positive: Josamycin 1g, twice a day, for 12 days; Minocycline 100mg, twice a day, for 12 days for relapsed cases;
• Culture negative: Ceftriaxone 250mg single intramuscular injection + Doxycycline 100mg twice a day + Metronidazole 500mg twice a day, all for 14 days.

(III) Other Treatment Methods

1. Integrated traditional Chinese and Western medicine: On the basis of antibiotics, syndrome differentiation supplemented with traditional Chinese medicine for clearing heat and promoting blood circulation, regulating qi and tonifying deficiency can reduce drug resistance and improve the inflammatory state, but it lacks the support of large-sample studies.
2. Immune regulation: Progesterone regulating maternal-fetal immune balance, immune modulators such as Prednisone, and intrauterine perfusion of platelet-rich plasma may improve outcomes, but their safety and effectiveness need further verification.

(IV) Re-Examination After Treatment

VI. Recommendations

1. CE can lead to adverse reproductive outcomes. For patients with unexplained infertility, repeated implantation failure, and recurrent pregnancy loss, it is recommended to complete CE-related examinations (Recommendation level: Class 2A).
2. The common pathogenic microorganisms of CE are bacterial infections (Recommendation level: Class 2A).
3. The mechanism by which CE leads to adverse reproductive outcomes may be that the induced inflammatory response and local immune microenvironment disorder reduce endometrial receptivity and cause embryo implantation and development disorders, affecting conception and pregnancy maintenance (Recommendation level: Class 3).
4. The diagnosis of CE should be made by combining medical history, clinical manifestations, hysteroscopy, and auxiliary examinations such as endometrial tissue pathology (Recommendation level: Class 2A).
5. The hysteroscopic features of CE include strawberry sign, endometrial congestion, micro-polyps, and endometrial stromal edema. The simultaneous occurrence of multiple hysteroscopic manifestations can improve diagnostic accuracy. Hysteroscopy combined with pathological examination is the best diagnostic method for CE (Recommendation level: Class 2B).
6. Although the positive rate of endometrial microbial culture is low, it can guide the selection of antibiotics according to drug sensitivity results; although molecular biology detection methods can improve the sensitivity of microbial detection, the core pathogenic flora of CE is not clear, and clinical application needs further discussion (Recommendation level: Class 3).
7. Oral antibiotic treatment is recommended for CE patients, with a high cure rate and can improve reproductive outcomes (Recommendation level: Class 2A).
8. The treatment plan can choose doxycycline or combined with nitroimidazoles, or quinolones combined with nitroimidazoles. The specific course of treatment can be determined according to the severity of CE (Recommendation level: Class 2B).

VII. Conclusion