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Hysteroscopic Centre, Fu Xing Hospital, Capital Medical University, Beijing, ChinaAssisted Reproductive Technology Unit, Department of Obstetrics and Gynaecology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
In this retrospective cohort study, a consecutive series of 1551 premenopausal women underwent hysteroscopy and endometrial biopsy. Chronic endometritis was diagnosed when plasma cell in endometrial tissue was detected by immunohistochemistry using CD138 epitope. The overall prevalence of chronic endometritis in the population studied was 24.4% The prevalence was significantly increased in the following conditions: recurrent implantation failure (40.8%; P < 0.001), abnormal uterine bleeding (40.7 %; P < 0.001), endometrial hyperplasia (50.0%, P < 0.05) and submucosal fibroid (59.1%; P < 0.001) than those without the respective conditions. The prevalence in specimens obtained from the proliferative phase (26.0%) was significantly higher (P < 0.05) than those from the luteal phase (17.5%). Logistic regression analysis showed three significant factors affecting the prevalence, in descending order of importance: clinical presentation, endometrial hyperplasia and stage of the cycle from which the specimen was obtained. The confounding variables identified in this study may account for the wide range of published prevalence of the condition, and should be considered in the analysis of prevalence data relating to chronic endometritis.
Chronic endometritis is a persistent inflammation of uterine endometrium. Histologically, the diagnosis of chronic endometritis is based on the presence of plasma cells in the endometrial stroma. The identification of plasma cell by the use of haematoxylin-eosin staining in wax-embedded endometrial specimen has been used for some time as the gold standard for the diagnosis of chronic endometritis (
). One challenge of haematoxylin-eosin staining is the identification of rare plasma cells, as these cells can appear morphologically similar to other stromal cells and leukocytes (
). Recent studies have shown that the use of immunohistochemistry for CD138, a cell surface proteoglycan that is expressed on plasma cells, improves the diagnostic accuracy (
The prevalence of chronic endometritis in different populations, including women with abnormal uterine bleeding (AUB), recurrent implantation failure (RIF), recurrent pregnancy loss (RPL), infertility and intrauterine adhesion (IUA), has been examined by various investigators (Table 1). Few investigators, however, have simultaneously examined the prevalence in the different populations. It is difficult to compare the prevalence data from these various studies because the criteria used for the diagnosis of chronic endometritis is often different (Table 1). In addition, it is also possible that the prevalence may be affected by a number of confounding clinical and pathological conditions. For example, it has been reported that the prevalence of chronic endometritis may be affected by the stage of the cycle from which the specimen was obtained (
). It is also unclear if certain uterine pathologies such as endometrial polyp, fibroid, endometrial hyperplasia or congenital uterine anomaly affect the prevalence of chronic endometritis.
Table 1Reported prevalence of chronic endometritis in various populations studied and the criteria used for diagnosis.
Chronic endometritis due to common bacteria is prevalent in women with recurrent miscarriage as confirmed by improved pregnancy outcome after antibiotic treatment.
Chronic endometritis in women with recurrent pregnancy loss and recurrent implantation failure: prevalence and role of office hysteroscopy and immunohistochemistry in diagnosis.
Chronic endometritis in women with recurrent pregnancy loss and recurrent implantation failure: prevalence and role of office hysteroscopy and immunohistochemistry in diagnosis.
Analysis of the diagnostic value of CD138 for chronic endometritis, the risk factors for the pathogenesis of chronic endometritis and the effect of chronic endometritis on pregnancy: a cohort study.
Analysis of the diagnostic value of CD138 for chronic endometritis, the risk factors for the pathogenesis of chronic endometritis and the effect of chronic endometritis on pregnancy: a cohort study.
The aim of the present study was to examine the prevalence of chronic endometritis in a consecutive series of endometrial biopsies obtained from premenopausal women who presented with abnormal uterine bleeding or reproductive failure, and to identify confounding variables that may affect the prevalence of chronic endometritis.
Materials and methods
Participants
A total of 1551 premenopausal women referred to the Hysteroscopy Centre of Fu Xing Hospital, Capital Medical University, Beijing, for investigation of abnormal uterine bleeding or reproductive failure were included. All women underwent hysteroscopy and endometrial biopsy for histological analysis. The study was carried out between September 2014 and November 2016. The Hysteroscopic Centre of Fu Xing Hospital is a national training centre for hysteroscopy, in which about 10,000 cases of hysteroscopy are carried out annually among six consultant teams. The present study was recruited from patients attending one of the consultant teams.
The exclusion criteria included the following: menstruating at the time of examination; suspected reproductive tract infection; presence of intrauterine contraceptive device; history of endometrial carcinoma; pregnancy or pregnancy-related complications, i.e. retained product of conception; and hysteroscopic surgery within the last 3 months. The study was approved by the hospital Institutional Review Board on 1 August 2014 (reference number 2014 FXHEC-KY056).
Definitions
Recurrent pregnancy loss was defined as two or more clinical pregnancy losses (miscarriages) before 20 weeks' gestation (
). Recurrent implantation failure was defined as the failure to achieve a clinical pregnancy after transfer of at least four good-quality embryos in three or more transfer cycles in women younger than 40 years (
Hysteroscopy and endometrial biopsy were carried out as an outpatient procedure without anaesthesia. Hysteroscopy was carried out using a 3-mm 30° rigid hysteroscope (Olympus, Germany). Normal saline solution was used to distend the uterine cavity at 100 mmHg pressure. On completion of hysteroscopy, an endometrial biopsy was obtained with the use of a curette.
Histological analysis and immunohistochemistry
Endometrial samples were fixed in neutral formalin and later embedded in paraffin for histological analysis and immunohistochemistry. Five-micrometer sections were cut and incubated with mouse anti-human monoclonal CD138 antibody (Biocare Medical, Concord, CA) at 1:100 dilution for 1 h after dewaxing and antigen retrieval. The secondary antibody used was a labelled polymer horseradish peroxidase anti-mouse antibody (Maixin, Fuzhou, China) and incubated for 30 min. Slides were then washed and incubated with diaminobenzidine. The biopsies were graded as ‘negative’ if there was less than one plasma cell identified per 10 high power field and ‘positive’ when there was one or more plasma cell identified per 10 high power field (
). All endometrial biopsy specimens were examined by a single consultant histopathologist.
Statistical analysis
Comparison of the results between groups in the case of continuous variables was made by using student's t-test for data with normal distribution and non-parametric Mann–Whitney U-test for data with skewed distribution. Comparison of the results between groups in the case of categorical variables was made with the use of contingency table analysis. Binary logistic regression analysis (stepwise forward entry) was used to determine independent factors that affect the prevalence of chronic endometritis. SPSS version 21 (IBM Corp., USA) was used for statistical analysis. P < 0.05 was considered to be significant.
Results
In total, 1551 women were included in the study. The mean ± SD of age, parity and number of miscarriages were 32.6 ± 5.3 years, 1.1 ± 0.4 and 1.9 ± 1.1, respectively.
The result of plasma cells in the stroma of an endometrial biopsy specimen identified by CD138 antibody are presented in Figure 1. The overall prevalence of chronic endometritis in the population studied was 24.4%. The relationship between various clinical features and the prevalence of chronic endometritis was analysed in Table 2. The prevalence was not affected by age, parity and the number of previous miscarriages, but a significantly higher prevalence was observed in women with RIF, AUB, submucous fibroid and endometrial hyperplasia compared with those without the respective condition (P < 0.001; P < 0.001; P < 0.001; and P < 0.05, respectively).
Figure 1Immunohistochemical staining of plasma cells in an endometrial biopsy specimen by using CD138 antibody in a woman with abnormal uterine bleeding. The plasma cells are shown with brown staining.
The effect of the various confounding variables on the prevalence of chronic endometritis was examined with the use of logistic multiple regression analysis. The results are shown in Table 3. The factors identified were, in descending order of importance, clinical presentation, whether biopsy was obtained in proliferative or luteal phase and histological diagnosis of hyperplasia.
Table 3Binary logistic regression analysis of factors affecting the prevalence of chronic endometritis showing the variable selected for inclusion in each step.
In the present study, we reported on the prevalence of chronic endometritis in a consecutive series of 1551 endometrial biopsies obtained in a reproductive and general gynaecology setting. We found that the overall prevalence of chronic endometritis was 24.4%, and examined the possible effect of various parameters on the prevalence.
Among factors affecting prevalence, the most important was the presenting clinical feature, selected as the first step of the logistic regression analysis. Both RIF and AUB were associated with a significantly high prevalence of chronic endometritis (40.8% and 40.7%, respectively) compared with those without the conditions. The observations are consistent with several earlier reports (Table 1). On the contrary, we found that the prevalence of chronic endometritis in women with RPL did not increase compared with those without RPL. Published data on the prevalence of chronic endometritis in women with RPL varies greatly, from as low as 9% to as high as 56% (Table 1). Several possible explanations for the conflicting reports can be offered, namely, a lack of consensus in the diagnosis of recurrent pregnancy loss (two or three consecutive miscarriages) as well as the criteria used to define chronic endometritis. A prospective cohort study with a control fertile population is required to resolve the controversy.
The second most important factor affecting the prevalence of chronic endometritis was the stage of the cycle from which the endometrial sample was obtained for diagnosis. We found that the prevalence of chronic endometritis was higher in samples obtained in the proliferative phase (26%) compared with the secretory phase (17.5%). The possible relationship between prevalence of chronic endometritis and the stage of the cycle in which the specimen was obtained was examined in four previous studies, with one of them unable to detect any difference in the prevalence between the proliferative and luteal phases (
) Our study, which is based on a sufficiently large sample size of 1551 specimens, showed that the prevalence of chronic endometritis in proliferative phase was about 50 % higher than that in the secretory phase. A possible explanation for the difference is that plasma cells (CD138+) tend to reside in the deeper layer of the endometrium (
) as the endometrium in the secretory phase has a thicker superficial layer; biopsy specimen at this stage is likely to contain a reduced proportion of the deeper, more compact layer. Another possible explanation of the apparently higher prevalence of chronic endometritis in the proliferative phase may be secondary to an association between chronic endometritis and AUB (as observed in our study), the latter being more likely to have anovulatory cycles and consequently more likely to have proliferative changes and occasionally hyperplastic changes in the endometrium. Our finding highlights the importance of obtaining biopsy at the same stage of the cycle in any cohort or prospectively planned randomized controlled trial on chronic endometritis. This particular confounding variable may contribute to the discrepancies between reports in the literature regarding prevalence studies (Table 1).
The third most important factor was the histological diagnosis of endometrial hyperplasia. In women who had endometrial hyperplasia, the prevalence of chronic endometritis was as high as 50%. The observation that hyperplasia is associated with chronic endometritis is new and has not been previouly reported. In this study, we excluded cases of endometrial adenocarcinoma, so it not possible to say if the same association also applies to cases of endometrial adenocarcinoma. The association of chronic endometritis with endometrial hyperplasia and possibly with adenocarcinoma is currently the subject of an ongoing audit in our department. If the association is confirmed in the extended study, it would raise the question of whether chronic endometritis or chronic infection in the endometrium is a predisposing factor for endometrial neoplasm.
The presence of a submucous fibroid confirmed by hysteroscopy also seemed to be associated with an increased prevalence of chronic endometritis (59.1%) compared with those without submucous fibriod. This particular factor was not selected for inclusion in the regression model presumably because of the relatively small number of participants in this category (n = 22) and because of its positive association (P < 0.05) with AUB, which was preferentially selected for inclusion in the regression analysis.
The prevalence of chronic endometritis in IUA has not been previously examined. In this study, we found that the prevalence of chronic endometritis in women with IUA was not significantly different to the overall prevalence of the entire population. In a recent study, however,
reported that the finding of chronic endometritis in women with IUA is of prognostic relevance in determining recurrence; the recurrence rate of IUA in women with chronic endometritis (13/29 [44.8%]) was significantly higher than those without chronic endometritis (11/53 [20.8%]).
The findings in this study have a number of clinical implications. First, given that the prevalence of chronic endometritis is affected by a number of clinical and pathological conditions, these confounding variables should be considered in future clinical studies. For example, the stage of the cycle in which the specimens are to be obtained should be standardized. Second, in examining the relationship between chronic endometritis and reproductive failure, appropriate investigations, such as ultrasonography (or saline infusion sonography), should be conducted to rule out any concurrent, underlying uterine pathology, which may affect the diagnosis of chronic endometritis. Third, the observation that the prevalence of chronic endometritis is affected by several clinical and pathological conditions, which do not appear to be directly related to infection raises the question of how often is chronic endometritis a direct consequence of chronic low-grade infection of the endometrium. It would be of interest to investigate the correlation between the diagnosis of chronic endometritis and the uterine microbiome in well-planned sequenced-based studies to better understand the contribution of altered bacteriological flora on endometrial function and reproductive failure.
A particular strength of our study is the large number of samples collected over a 2-year period of time in a single centre, which was made possible because of its high referral volume with an average of 300 outpatient hysteroscopy per week during the period of study. The various clinical and histopathological data obtained permitted the use of logistic regression analysis to determine factors which affected the prevalence. We believe that our study has identified important confounding variables, which have contributed to the controversy in the literature regarding chronic endometritis and which must be controlled for in future studies.
Acknowledgement
The authors would like to thank Drs Liu Yingyu, Zhao Dan, Zhou Fengqiong, Liu Linlin, Zhou Qiaoyun and Guo Yan for their help.
References
Adegboyega P.A.
Pei Y.
McLarty J.
Relationship between eosinophils and chronic endometritis.
Chronic endometritis in women with recurrent pregnancy loss and recurrent implantation failure: prevalence and role of office hysteroscopy and immunohistochemistry in diagnosis.
Analysis of the diagnostic value of CD138 for chronic endometritis, the risk factors for the pathogenesis of chronic endometritis and the effect of chronic endometritis on pregnancy: a cohort study.
Chronic endometritis due to common bacteria is prevalent in women with recurrent miscarriage as confirmed by improved pregnancy outcome after antibiotic treatment.
Dr Song is Consultant Gynaecologist at Hysteroscopic Centre of Fu Xing Hospital, Capital Medical University, Beijing, China, which is a national training centre for gynaecological endoscopy. She has a special interest in gynaecological endoscopy and reproductive surgery. She is currently conducting clinical and basic research into chronic endometritis.
Key message
The prevalence of chronic endometritis was increased in women with recurrent implantation failure, abnormal uterine bleeding and endometrial hyperplasia compared with those without the respective conditions, and also significantly higher in the proliferative stage of menstrual cycle compared with the luteal phase.
Article info
Publication history
Published online: October 06, 2017
Accepted:
September 12,
2017
Received in revised form:
September 11,
2017
Received:
March 8,
2017
Declaration: This work was supported by a grant from the Capital Medical University Foundation – Clinical Research Cooperation Fund (15JL63). Professor TC Li is supported by ‘Sea Poly Project of Beijing Overseas Talents’. The authors report no financial or commercial conflicts of interest.
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