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Chronic Endometritis in Women with and without Infertility who Underwent Hysteroscopic Polypectomy
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Chronic Endometritis in Women with and without Infertility who Underwent Hysteroscopic Polypectomy Alexander Volodarsky-Perel MD , Ahmad Badeghiesh MD , Guy Shrem MD , Naama Steiner MD , Togas Tulandi MD, MHCM PII: DOI: Reference:
S1553-4650(19)30380-2 https://doi.org/10.1016/j.jmig.2019.08.017 JMIG 3914
To appear in:
The Journal of Minimally Invasive Gynecology
Received date: Revised date: Accepted date:
28 June 2019 7 August 2019 17 August 2019
Please cite this article as: Alexander Volodarsky-Perel MD , Ahmad Badeghiesh MD , Guy Shrem MD , Naama Steiner MD , Togas Tulandi MD, MHCM , Chronic Endometritis in Women with and without Infertility who Underwent Hysteroscopic Polypectomy, The Journal of Minimally Invasive Gynecology (2019), doi: https://doi.org/10.1016/j.jmig.2019.08.017
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of AAGL.
Chronic Endometritis in Women with and without Infertility who Underwent Hysteroscopic Polypectomy
Alexander Volodarsky-Perel, MD*, Ahmad Badeghiesh, MD, Guy Shrem, MD, Naama Steiner, MD, Togas Tulandi, MD, MHCM.
Department of Obstetrics and Gynecology, McGill University Health Centre, Montreal, QC, Canada. *
Corresponding address: 888 Boul de Maisonneuve E #200, Montréal, QC H2L 4S8. Tel:
+1(514)843-1650. E-mail: [email protected]
The authors declare that they have no conflict of interest.
The authors have not received any funding to support this study.
The study was not previously published or presented at national or international conferences. The Institutional Review Board of the McGill University Health Centre approved the study (MUHC 2019-5411; Feb 8nd, 2019).
Précis: In women with endometrial polyps the prevalence of chronic endometritis is higher in those with infertility compared to women without infertility.
Abstract Study Objective: To evaluate the prevalence of chronic endometritis (CE) among women with and without infertility who underwent hysteroscopic polypectomy. Design: A retrospective cohort study. Setting: University affiliated tertiary hospital. Study Participants: A total of 277 women who underwent hysteroscopic polypectomy in the period of 2015 to 2018. Interventions:
Endometrial
polyp
samples
were
obtained
after
hysteroscopy
for
histopathological analysis using hematoxylin and eosin and immunohistochemistry staining with CD138 antibodies for plasma cells detection. All infertile women diagnosed with CE were treated with oral Doxycycline 100 mg twice daily for 14 days before infertility treatment. Measurements and Main Results: The prevalence of CE in women with infertility (n=137) was significantly higher compared to those with no history of infertility (n=140) [22.6% vs. 8.6%; p = .001]. The prevalence of CE between women with primary and secondary infertility was similar (25.0% vs. 19.3%; p = .43). Clinical pregnancy (32.3% vs. 41.5%; p = .35), live birth (29.0% vs. 38.7%; p = .33) and miscarriage (10.0% vs. 6.8%; p = .73) rates were similar between infertile women with treated CE and those without CE. Multivariate model showed that infertility diagnosis was significantly associated with the diagnosis of CE (OR 3.16; 95% CI 1.53 – 6.49). Conclusion: In women with endometrial polyps the prevalence of CE is higher in those with infertility compared to women without infertility. Pregnancy outcome of infertile women with treated CE was similar to those with infertility and without CE.
Key words: Chronic endometritis; endometrial polyp; hysteroscopy; immunohistochemistry; infertility.
Introduction Adequately functioning endometrium is a necessary factor for successful implantation and pregnancy development. Chronic endometritis (CE) is usually an asymptomatic inflammatory condition, which affects normal differentiation, proliferation and decidualization of endometrium [1, 2]. CE is characterized by plasma cell infiltration in the endometrial stromal areas [3]. It leads to abnormal expression of estrogen and progesterone receptors [2], numerous growth factors and cytokines that regulate cell proliferation and apoptosis [4, 5]. Factors associated with CE include multiparity, abnormal uterine bleeding [6], bacterial vaginosis [7] and endometriosis [8, 9]. Significantly higher incidence of CE was recently demonstrated in premenopausal women with hysteroscopically and histologically diagnosed endometrial polyps (EP) (61.7%) compared to those without polyps (24.2%) [10]. Recent review of relevant studies demonstrated that the prevalence of CE ranges from 8% to 72% in women of reproductive age [11]. Chronic endometritis is found in up to 55.7% of women with infertility [4, 11, 12]. However, the diagnostic criteria of CE used in different studies vary making it difficult to compare its prevalence [13]. Studies comparing the CE prevalence between infertile and fertile women have not been previously published. An association between EP and CE was reported in 27.4% of infertile women [14]. Endometrium from infertile women exhibited a broad spectrum of vascular changes, which can cause an endometrial polyp development. Whether those endometrial abnormalities are associated with CE remains unclear. The purpose of our study was to evaluate the prevalence of CE among women with and without infertility who underwent hysteroscopic polypectomy. Additionally we evaluated the CE
prevalence in women with primary and secondary infertility. Pregnancy outcome of infertile women after hysteroscopic polypectomy and CE treatment was compared with that of infertile women without CE.
Materials and Methods Population We conducted a retrospective cohort study evaluating all women who underwent a hysteroscopic polypectomy at McGill University Health Centre in the period of 2015 to 2018. The inclusion criteria were age 25-42 years and histologically confirmed endometrial polyp. We excluded women with early follicular phase serum FSH of >10 mIU/mL, with intrauterine device, autoimmune diseases, endometrial cancer or hyperplasia, history of previous infertility treatment and recurrent pregnancy loss defined as a loss of two or more pregnancies [15]. Women who were previously diagnosed with CE or received any antibiotic treatment in the period of 3 months before hysteroscopy were also excluded. If one patient underwent more than one hysteroscopic polypectomy, only the first procedure was included in the study. The Institutional Review Board of the McGill University Health Centre approved the study (MUHC 2019-5411).
Study groups The study group included women with infertility with previously demonstrated patent fallopian tubes, regular ovulatory cycles confirmed by midluteal serum progesterone level over 30 nmol/L or positive urine luteinizing hormone kit test, and normal partner’s sperm parameters [16, 17].
Those tests were performed in all women referred for infertility evaluation. The control group included women with no previous history and treatment of infertility, not taking hormone treatment in the past 3 months before hysteroscopy or having spontaneous pregnancy in the previous 3 years before the procedure.
Diagnosis and treatment Transvaginal ultrasonography was performed in all women prior to hysteroscopy. Endometrial polyp size was calculated as a mean diameter after its measurement in three dimensions [18]. Hysteroscopy was performed using a continuous-flow 30o rigid operating hysteroscope with a diameter of 5-mm and an operating channel (Karl Storz, Tutlingen, Germany). Normal saline was used for distention of the uterine cavity up to 100 mm Hg pressure. We specified the location of the endometrial polyp and polypectomy was then performed using semirigid hysteroscopic scissors. The tissue sample was fixed in formalin and sent for histological analysis. Staining of tissue samples was done using hematoxylin and eosin. Additionally the samples were analyzed after immunohistochemistry staining with CD 138 antibodies to detect plasma cells. The sample analysis was performed by two gynecologic pathologists in the Department of Pathology at McGill University Health Centre. They were unaware of the clinical characteristics of included patients. The diagnosis of CE was based on the presence of one or more plasma cells per 10 high-power fields [19]. All Infertile women with histologically confirmed diagnosis of CE were treated with Doxycycline orally 100 mg twice daily for 14 days and reassessed with follow-up endometrial biopsy before infertility treatment [4, 20].
Outcomes and definitions The primary outcome was the prevalence of CE in infertile women with EP compared to those with no infertility. The secondary outcomes included the prevalence of CE in women with primary infertility compared to those with secondary infertility. Clinical pregnancy rate (CPR), live birth rate (LBR) and miscarriage rate (MR) of infertile women in two year interval after hysteroscopic polypectomy were also evaluated.
Statistical analysis Statistical analysis was performed using JMP Pro 13.2.0 software (SAS Institute Inc., USA). Shapiro-Wilk test was used to evaluate the data distribution. Normally distributed data was presented as mean ± standard deviation (SD) and analyzed using Student t-test. Skewed data was presented as median (with inter quartile range) and compared using Wilcoxon test. Chisquare test was used for categorical data. To evaluate factors associated with CE we conducted a univariate analysis. The determinants with p-value < 0.2 were subsequently included in the multivariate analyses in order to define factors independently associated with CE. Pearson or Spearman correlation test of determinants was calculated according to the data distribution. In case of high correlation, only one of them was included in the multivariate model. Stepwise regression was performed and the odds ratios (OR) with 95% confidence intervals (95%CI) were calculated.
Results A total of 801 women underwent hysteroscopic polypectomy in the period of 2015 to 2018. Two hundred seventy seven women fulfilled the inclusion and exclusion criteria and were included in the final analysis (Fig. 1). Since tubal patency, ovulation and sperm analyses were performed to all infertile women, there were no cases excluded due to a lack of primary evaluation tests. Demography characteristics including age, body mass index (BMI) and smoking behavior of the study and the control groups were similar (Table 1). Cycle day of hysteroscopy, polyp diameter and location were also similar. The incidence of CE in group of women with infertility was significantly higher compared to the control group (22.6% vs. 8.6%; p = .001). Women with primary infertility were additionally compared to those with secondary infertility (Table 2). Demography parameters, hysteroscopy day, polyp characteristics (diameter and location) were similar as well as the prevalence of CE between the groups. Table 3 shows the pregnancy outcome of infertile women with treated CE and those without CE. Demography, polyp diameter and location, infertility treatment characteristics (treatment modality distribution, sperm parameters, number of transferred embryos) were similar between the groups. CPR, LBR and MR were also comparable. The results of univariate analysis to define factors potentially associated with CE are shown in Table 4. Infertility, gravidity and history of miscarriages were included in multivariate analysis. Logistic regression model (Table 5) demonstrated that history of infertility was significantly associated with diagnosis of CE (OR 3.16; 95% CI 1.53 – 6.49).
Discussion Our study demonstrates significantly higher prevalence of CE in women with infertility and EP compared to those with EP and no previous history of infertility. Multivariate analysis showed that history of infertility is significantly associated with CE diagnosis in women with EP. Large spectrum of vascular changes including hyaline thickening of the vascular wall, small vessel thrombosis, high vascular density with endothelial proliferation and swelling was reported in the functional layer of the endometrium of 39% of asymptomatic infertile women [14]. Patients with infertility demonstrated significantly reduced uterine artery flow velocity in all menstrual phases and significantly elevated uterine and subendometrial artery impedance in the periovulatory and midluteal phases [21]. It has been proposed that vascular changes in endometrium of infertile women might present an evolving stage of vasculopathy that was related to CE. Although the comparison between infertile and fertile groups was not performed, previous clinical studies [4, 14] demonstrated a high prevalence of CE in infertile women. The association of EP and CE is not clearly understood. Factors such as hormonal dysfunction, imbalance between proliferation and apoptosis, abnormal expression of ovarian steroid hormone receptors, and chromosomal abnormalities are thought to play important roles in the pathogenesis of EP [22–25].
Recent study [10] showed a higher CE prevalence in
premenopausal women with EP compared to control group without EP (61.7% vs 24.2%; p < .0001). The presence of micropolyps on hysteroscopy has been shown to be associated with histological diagnosis of CE [26]. Chronic inflammation resulting from CE may have implications on
the
function
of
pro-inflammatory
cytokines
(Interleukin-6,
interleukin-1β,
and tumor necrosis factor α) which may affect migration, proliferation and apoptosis of endometrial cells [27]. It might also cause micro- and macropolyps formation [10].
In order to evaluate the effect of gravidity on the prevalence of CE in infertile patients, we compared women with primary and secondary infertility. No statistical difference was found. In a previous retrospective analysis of 234 endometrial specimens obtained by hysterectomy, the authors reported that multiparity is an independent risk factor for CE; whereas multigravidity and past history of miscarriage are not risk factors for CE [6]. This is in agreement with our results in a group of women with infertility. Treatment of CE especially in infertile women including antibiotic type, administration route, treatment duration, and efficacy assessment are still unclear [28]. Yet, a few authors reported an improvement CPR and LBR after antibiotic administration [4, 20, 29]. In our study, we found that the cumulative CPR and LBR in infertile women with CE treated with one course of oral Doxycycline were similar to infertile women without CE. Miscarriage rate was also similar between two groups. To the best of our knowledge, our report was the first clinical study evaluating the prevalence of CE in women with EP and infertility compared to those without infertility. In addition, we evaluated the infertility type (primary or secondary) effect on the prevalence of CE. Further, we reported the pregnancy outcome of infertile women with CE treated with antibiotics and without CE. The limitation of our study is its retrospective design and the relatively low number of patients included in the analysis of secondary outcomes. However, strict inclusion and exclusion criteria as well as similar diagnostic and treatment protocols used for all included women mitigate those limitations. We excluded women with a history of infertility treatment, as previous hormonal treatment may apply significant changes in physiology of endometrium [14] and may affect the comparison of fertile and infertile women. Since all women with highly suspected endometriosis previously underwent infertility treatment, they were also excluded from final analysis. Women with tubal, ovulatory and male infertility factors were excluded from infertility group, in order to
compare infertile women with only uterine infertility factor (EP) to those without infertility avoiding confounding effect of other infertility factors [8, 9, 14, 21]. Since the criteria used for CE diagnosis is often different, it is difficult to compare the CE prevalence among different studies [13]. Additionally, results may be affected by different clinical and pathological confounding factors. In our study, CE was diagnosed using immunohistochemistry staining with CD 138 antibodies in addition to hematoxylin and eosin staining for plasma cells detection. For immunohistochemistry staining, we used previously published protocol, which has demonstrated the correlation between histological results of CE and clinical signs such as abnormal uterine bleeding [19]. All tissue samples were analyzed according to the same strict protocol by two gynecologic pathologists. All hysteroscopic procedures and histological analyses were performed in one tertiary care center. In conclusion, the main results of our study demonstrate a higher prevalence of chronic endometritis in endometrial polyps from women with infertility compared to those without infertility. This finding supports the hypothesis of multifactorial etiology of endometrial polyps and the pathophysiological role of CE in the development of infertility. This hypothesis should be elucidated in future randomized studies.
Acknowledgments The authors would like to make special thanks to all the gynecologists, nurses and other team member of MUHC Department of Obstetrics and Gynecology and Reproductive Centre.
Disclosures The authors declare that they have no conflict of interest. The authors have not received any funding to support this study.
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Cicinelli E, Matteo M, Trojano G, et al. Chronic endometritis in patients with unexplained infertility: Prevalence and effects of antibiotic treatment on spontaneous conception. Am J Reprod Immunol. 2018;79:e12782.
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Di Pietro C, Cicinelli E, Guglielmino MR, et al. Altered transcriptional regulation of cytokines, growth factors, and apoptotic proteins in the endometrium of infertile women with chronic endometritis. Am J Reprod Immunol. 2013;69:509-517.
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Beruchashvili M, Gogiashvili L, Datunashvili E, Topuria Z, Tsagareli Z. Morphological peculiarities of endometrium in chronic endometritis associated with bacterial vaginosis. Georgian Med News. 2010;181:59-63.
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Cicinelli E, Trojano G, Mastromauro M, et al. Higher prevalence of chronic endometritis in women with endometriosis: a possible etiopathogenetic link. Fertil Steril. 2017;108:289-295.
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Takebayashi A, Kimura F, Kishi Y, et al. The association between endometriosis and chronic endometritis. PloS One. 2014;9:e88354.
10. Cicinelli E, Bettocchi S, de Ziegler D, et al. Chronic Endometritis, a Common Disease Hidden Behind Endometrial Polyps in Premenopausal Women: First Evidence From a Case-Control Study. J Minim Invasive Gynecol. In press. 11. Kimura F, Takebayashi A, Ishida M, et al. Review: Chronic endometritis and its effect on reproduction. J Obstet Gynaecol Res. 2019;45:951-960. 12. Kasius JC, Fatemi HM, Bourgain C, et al. The impact of chronic endometritis on reproductive outcome. Fertil Steril. 2011;96:1451-1456. 13. Song D, Feng X, Zhang Q, et al. Prevalence and confounders of chronic endometritis in premenopausal women with abnormal bleeding or reproductive failure. Reprod Biomed Online. 2018;36:78-83. 14. Carvalho FM, Aguiar FN, Tomioka R, et al. Functional endometrial polyps in infertile asymptomatic patients: a possible evolution of vascular changes secondary to endometritis. Eur J Obstet Gynecol Reprod Biol. 2013;170:152-156. 15. Atik RB, Christiansen OB, Elson J, et al. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open. 2018;2:1-12. 16. Cooper TG, Noonan E, von Eckardstein S, et al. World Health Organization reference values for human semen characteristics. Hum Reprod Update. 2010;16:231-245. 17. Bjorndahl L, Barratt CL, Mortimer D, Jouannet P. 'How to count sperm properly': checklist for acceptability of studies based on human semen analysis. Hum Reprod. 2016;31:227232. 18. Hassa H, Tekin B, Senses T, Kaya M, Karatas A. Are the site, diameter, and number of endometrial polyps related with symptomatology? Am J Obstet Gynecol. 2006;194:718-721. 19. Kannar V, Lingaiah HK, Sunita V. Evaluation of endometrium for chronic endometritis by using syndecan-1 in abnormal uterine bleeding. J Lab Physicians. 2012;4:69-73. 20. McQueen DB, Perfetto CO, Hazard FK, Lathi RB. Pregnancy outcomes in women with chronic endometritis and recurrent pregnancy loss. Fertil Steril. 2015;104:927-931.
21. Edi-Osagie EC, Seif MW, Aplin JD, Jones CJ, Wilson G, Lieberman BA. Characterizing the endometrium in unexplained and tubal factor infertility: a multiparametric investigation. Fertil Steril. 2004;82:1379-1389. 22. Fang RL, Chen LX, Shu WS, Yao SZ, Wang SW, Chen YQ. Barcoded sequencing reveals diverse intrauterine microbiomes in patients suffering with endometrial polyps. Am J Transl Res. 2016;8:1581-1592. 23. Lopes RG, Baracat EC, de Albuquerque Neto LC, et al. Analysis of estrogen- and progesterone-receptor expression in endometrial polyps. J Minim Invasive Gynecol. 2007;14:300-303. 24. McGurgan P, Taylor LJ, Duffy SR, O'Donovan PJ. Are endometrial polyps from premenopausal women similar to post-menopausal women? An immunohistochemical comparison of endometrial polyps from pre- and post-menopausal women. Maturitas. 2006;54:277-284. 25. Vanni R, Dal Cin P, Marras S, et al. Endometrial polyp: another benign tumor characterized by 12q13-q15 changes. Cancer Genet Cytogenet. 1993;68:32-33. 26. Cicinelli E, Resta L, Nicoletti R, Zappimbulso V, Tartagni M, Saliani N. Endometrial micropolyps at fluid hysteroscopy suggest the existence of chronic endometritis. Hum Reprod. 2005;20:1386-1389. 27. Tortorella C, Piazzolla G, Matteo M, et al. Interleukin-6, interleukin-1beta, and tumor necrosis factor alpha in menstrual effluents as biomarkers of chronic endometritis. Fertil Steril. 2014;101:242-247. 28. Sfakianoudis K, Simopoulou M, Nikas Y, et al. Efficient treatment of chronic endometritis through a novel approach of intrauterine antibiotic infusion: a case series. BMC Womens Health. 2018;18:197.
29. Cicinelli E, Matteo M, Tinelli R, et al. Prevalence of chronic endometritis in repeated unexplained implantation failure and the IVF success rate after antibiotic therapy. Hum Reprod. 2015;30:323-330.
Figure 1. Flowchart of patients’ selection process. CE – chronic endometritis IUD – intrauterine device RPL – recurrent pregnancy loss ABX – antibiotic treatment
Table 1. Characteristics and chronic endometritis prevalence in women with endometrial polyp with and without infertility.
Parameter Age (years) BMI (kg/m2) Smoking (%) Gravidity Previous miscarriages Hysteroscopy cycle day Polyp diameter (mm) Polyp location: Anterior wall (%) Posterior wall (%) Fundus (%) Lateral wall (%) CE prevalence (%)
Infertility (n = 137) 38 (35 – 41) 25 (24 – 29) 6 (4.4) 0 (0 – 1) 0 (0 – 1) 9 (7 – 11) 10 (9 – 10)
No infertility (n = 140) 40 (36 – 42) 25 (23 – 28) 11 (7.9) 0 (0 – 2) 0 (0 – 1) 8 (7 – 10) 10 (8 – 10)
33 (24.1) 38 (27.7) 38 (27.7) 28 (20.5) 31 (22.6)
44 (31.4) 35 (25.0) 41 (29.3) 20 (14.3) 12 (8.6)
Data are median (quartiles) unless stated otherwise. BMI – body mass index CE - chronic endometritis
P-value .13 .33 .23 .27 .73 .81 .33
.38
.001
Table 2. Characteristics and chronic endometritis prevalence in women with primary and secondary infertility.
Parameter Age (years) BMI (kg/m2) Smoking (%) Hysteroscopy cycle day Polyp diameter (mm) Polyp location: Anterior wall (%) Posterior wall (%) Fundus (%) Lateral wall (%) CE prevalence (%)
Primary infertility (n = 80) 38 (34 – 41) 24 (24 – 27) 3 (3.8) 8 (7 – 9) 10 (8 -10)
Secondary infertility (n = 57) 39 (37 – 42) 24 (26 – 28) 3 (5.3) 9 (7 – 11) 10 (8 – 10)
18 (22.5) 26 (32.5) 25 (31.3) 11 (13.7) 20 (25.0)
15 (26.3) 12 (21.1) 13 (22.8) 17 (29.8) 11 (19.3)
Data are median (quartiles) unless stated otherwise. BMI – body mass index CE - chronic endometritis
P-value
.08 .08 .67 .09 .64
.08
.43
Table 3. Characteristics and pregnancy outcome of infertile women with treated CE and without CE.
Parameter Age (years) BMI (kg/m2) Smoking (%) Hysteroscopy cycle day Polyp diameter (mm) Polyp location: Anterior wall (%) Posterior wall (%) Fundus (%) Lateral wall (%) Infertility treatment: No treatment (%) OI (%) IVF (%) Sperm concentration (106/ml) Sperm motility (mean %) No of transferred embryos CPR (%) LBR (%) Miscarriage rate (%)
Treated CE (n = 31) 38 (34 – 41) 24 (24 – 26) 1 (3.2) 9 (7 – 12) 10 (8 – 10)
Negative CE (n = 106) 38 (35.8 – 41) 25 (24 – 29) 5 (4.3) 9 (7 – 10) 10 (9 – 10)
9 (29.0) 10 (32.3) 8 (25.8) 4 (12.9)
24 (22.6) 28 (26.4) 30 (28.3) 24 (22.7)
6 (19.4) 8 (25.8) 17 (54.8) 36.4 (20.0 – 79.4) 45 (43 – 70) 1 (1 – 1) 10 (32.3) 9 (29.0) 1 (10.0)
18 (17.0) 44 (41.5) 44 (41.5) 42.6 (20.0 – 92.5) 59 (42 – 86) 1 (1 – 1) 44 (41.5) 41 (38.7) 3 (6.8)
Data are median (quartiles) unless stated otherwise. BMI – body mass index CE – chronic endometritis OI – ovulation induction IVF – in vitro fertilization CPR – clinical pregnancy rate LBR – live birth rate
P-value .79 .45 .72 .34 .45
.60
.27
.47 .19 .67 .35 .33 .73
Table 4. Univariate analysis of factors associated with chronic endometritis.
Parameter Age (years) BMI (kg/m2) Smoking (%) Gravidity Previous miscarriages Polyp diameter (mm) Polyp location: Anterior wall (%) Posterior wall (%) Fundus (%) Lateral wall (%) Infertility diagnosis (%)
CE positive (n = 43) 38 (36 – 42) 25 (23 – 29) 2 (4.7) 0 (0 – 1) 0 (0 – 1) 10 (8 – 10)
CE negative (n = 234) 38 (36 – 42) 25 (23 – 29) 15 (6.4) 0 (0 – 2) 0 (0 – 1) 10 (9 – 10)
11 (25.6) 14 (32.6) 12 (27.9) 6 (13.9) 31 (72.1)
66 (28.2) 59 (25.2) 67 (28.7) 42 (17.9) 106 (45.3)
Data are median (quartiles) unless stated otherwise. BMI – body mass index CE - chronic endometritis
P-value .98 .77 .66 .16 .15 .34
.78
.001
Table 5. Multivariate logistic regression analysis of factors associated with chronic endometritis.
Parameter Infertility diagnosis Gravidity Previous miscarriages
OR 3.16 1.33 2.55
95% CI 1.53 – 6.49 0.02 – 91.4 0.26 – 25.11
Chronic Endometritis in Women with and without Infertility who Underwent Hysteroscopic Polypectomy Alexander Volodarsky-Perel MD , Ahmad Badeghiesh MD , Guy Shrem MD , Naama Steiner MD , Togas Tulandi MD, MHCM PII: DOI: Reference:
S1553-4650(19)30380-2 https://doi.org/10.1016/j.jmig.2019.08.017 JMIG 3914
To appear in:
The Journal of Minimally Invasive Gynecology
Received date: Revised date: Accepted date:
28 June 2019 7 August 2019 17 August 2019
Please cite this article as: Alexander Volodarsky-Perel MD , Ahmad Badeghiesh MD , Guy Shrem MD , Naama Steiner MD , Togas Tulandi MD, MHCM , Chronic Endometritis in Women with and without Infertility who Underwent Hysteroscopic Polypectomy, The Journal of Minimally Invasive Gynecology (2019), doi: https://doi.org/10.1016/j.jmig.2019.08.017
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of AAGL.
Chronic Endometritis in Women with and without Infertility who Underwent Hysteroscopic Polypectomy
Alexander Volodarsky-Perel, MD*, Ahmad Badeghiesh, MD, Guy Shrem, MD, Naama Steiner, MD, Togas Tulandi, MD, MHCM.
Department of Obstetrics and Gynecology, McGill University Health Centre, Montreal, QC, Canada. *
Corresponding address: 888 Boul de Maisonneuve E #200, Montréal, QC H2L 4S8. Tel:
+1(514)843-1650. E-mail: [email protected]
The authors declare that they have no conflict of interest.
The authors have not received any funding to support this study.
The study was not previously published or presented at national or international conferences. The Institutional Review Board of the McGill University Health Centre approved the study (MUHC 2019-5411; Feb 8nd, 2019).
Précis: In women with endometrial polyps the prevalence of chronic endometritis is higher in those with infertility compared to women without infertility.
Abstract Study Objective: To evaluate the prevalence of chronic endometritis (CE) among women with and without infertility who underwent hysteroscopic polypectomy. Design: A retrospective cohort study. Setting: University affiliated tertiary hospital. Study Participants: A total of 277 women who underwent hysteroscopic polypectomy in the period of 2015 to 2018. Interventions:
Endometrial
polyp
samples
were
obtained
after
hysteroscopy
for
histopathological analysis using hematoxylin and eosin and immunohistochemistry staining with CD138 antibodies for plasma cells detection. All infertile women diagnosed with CE were treated with oral Doxycycline 100 mg twice daily for 14 days before infertility treatment. Measurements and Main Results: The prevalence of CE in women with infertility (n=137) was significantly higher compared to those with no history of infertility (n=140) [22.6% vs. 8.6%; p = .001]. The prevalence of CE between women with primary and secondary infertility was similar (25.0% vs. 19.3%; p = .43). Clinical pregnancy (32.3% vs. 41.5%; p = .35), live birth (29.0% vs. 38.7%; p = .33) and miscarriage (10.0% vs. 6.8%; p = .73) rates were similar between infertile women with treated CE and those without CE. Multivariate model showed that infertility diagnosis was significantly associated with the diagnosis of CE (OR 3.16; 95% CI 1.53 – 6.49). Conclusion: In women with endometrial polyps the prevalence of CE is higher in those with infertility compared to women without infertility. Pregnancy outcome of infertile women with treated CE was similar to those with infertility and without CE.
Key words: Chronic endometritis; endometrial polyp; hysteroscopy; immunohistochemistry; infertility.
Introduction Adequately functioning endometrium is a necessary factor for successful implantation and pregnancy development. Chronic endometritis (CE) is usually an asymptomatic inflammatory condition, which affects normal differentiation, proliferation and decidualization of endometrium [1, 2]. CE is characterized by plasma cell infiltration in the endometrial stromal areas [3]. It leads to abnormal expression of estrogen and progesterone receptors [2], numerous growth factors and cytokines that regulate cell proliferation and apoptosis [4, 5]. Factors associated with CE include multiparity, abnormal uterine bleeding [6], bacterial vaginosis [7] and endometriosis [8, 9]. Significantly higher incidence of CE was recently demonstrated in premenopausal women with hysteroscopically and histologically diagnosed endometrial polyps (EP) (61.7%) compared to those without polyps (24.2%) [10]. Recent review of relevant studies demonstrated that the prevalence of CE ranges from 8% to 72% in women of reproductive age [11]. Chronic endometritis is found in up to 55.7% of women with infertility [4, 11, 12]. However, the diagnostic criteria of CE used in different studies vary making it difficult to compare its prevalence [13]. Studies comparing the CE prevalence between infertile and fertile women have not been previously published. An association between EP and CE was reported in 27.4% of infertile women [14]. Endometrium from infertile women exhibited a broad spectrum of vascular changes, which can cause an endometrial polyp development. Whether those endometrial abnormalities are associated with CE remains unclear. The purpose of our study was to evaluate the prevalence of CE among women with and without infertility who underwent hysteroscopic polypectomy. Additionally we evaluated the CE
prevalence in women with primary and secondary infertility. Pregnancy outcome of infertile women after hysteroscopic polypectomy and CE treatment was compared with that of infertile women without CE.
Materials and Methods Population We conducted a retrospective cohort study evaluating all women who underwent a hysteroscopic polypectomy at McGill University Health Centre in the period of 2015 to 2018. The inclusion criteria were age 25-42 years and histologically confirmed endometrial polyp. We excluded women with early follicular phase serum FSH of >10 mIU/mL, with intrauterine device, autoimmune diseases, endometrial cancer or hyperplasia, history of previous infertility treatment and recurrent pregnancy loss defined as a loss of two or more pregnancies [15]. Women who were previously diagnosed with CE or received any antibiotic treatment in the period of 3 months before hysteroscopy were also excluded. If one patient underwent more than one hysteroscopic polypectomy, only the first procedure was included in the study. The Institutional Review Board of the McGill University Health Centre approved the study (MUHC 2019-5411).
Study groups The study group included women with infertility with previously demonstrated patent fallopian tubes, regular ovulatory cycles confirmed by midluteal serum progesterone level over 30 nmol/L or positive urine luteinizing hormone kit test, and normal partner’s sperm parameters [16, 17].
Those tests were performed in all women referred for infertility evaluation. The control group included women with no previous history and treatment of infertility, not taking hormone treatment in the past 3 months before hysteroscopy or having spontaneous pregnancy in the previous 3 years before the procedure.
Diagnosis and treatment Transvaginal ultrasonography was performed in all women prior to hysteroscopy. Endometrial polyp size was calculated as a mean diameter after its measurement in three dimensions [18]. Hysteroscopy was performed using a continuous-flow 30o rigid operating hysteroscope with a diameter of 5-mm and an operating channel (Karl Storz, Tutlingen, Germany). Normal saline was used for distention of the uterine cavity up to 100 mm Hg pressure. We specified the location of the endometrial polyp and polypectomy was then performed using semirigid hysteroscopic scissors. The tissue sample was fixed in formalin and sent for histological analysis. Staining of tissue samples was done using hematoxylin and eosin. Additionally the samples were analyzed after immunohistochemistry staining with CD 138 antibodies to detect plasma cells. The sample analysis was performed by two gynecologic pathologists in the Department of Pathology at McGill University Health Centre. They were unaware of the clinical characteristics of included patients. The diagnosis of CE was based on the presence of one or more plasma cells per 10 high-power fields [19]. All Infertile women with histologically confirmed diagnosis of CE were treated with Doxycycline orally 100 mg twice daily for 14 days and reassessed with follow-up endometrial biopsy before infertility treatment [4, 20].
Outcomes and definitions The primary outcome was the prevalence of CE in infertile women with EP compared to those with no infertility. The secondary outcomes included the prevalence of CE in women with primary infertility compared to those with secondary infertility. Clinical pregnancy rate (CPR), live birth rate (LBR) and miscarriage rate (MR) of infertile women in two year interval after hysteroscopic polypectomy were also evaluated.
Statistical analysis Statistical analysis was performed using JMP Pro 13.2.0 software (SAS Institute Inc., USA). Shapiro-Wilk test was used to evaluate the data distribution. Normally distributed data was presented as mean ± standard deviation (SD) and analyzed using Student t-test. Skewed data was presented as median (with inter quartile range) and compared using Wilcoxon test. Chisquare test was used for categorical data. To evaluate factors associated with CE we conducted a univariate analysis. The determinants with p-value < 0.2 were subsequently included in the multivariate analyses in order to define factors independently associated with CE. Pearson or Spearman correlation test of determinants was calculated according to the data distribution. In case of high correlation, only one of them was included in the multivariate model. Stepwise regression was performed and the odds ratios (OR) with 95% confidence intervals (95%CI) were calculated.
Results A total of 801 women underwent hysteroscopic polypectomy in the period of 2015 to 2018. Two hundred seventy seven women fulfilled the inclusion and exclusion criteria and were included in the final analysis (Fig. 1). Since tubal patency, ovulation and sperm analyses were performed to all infertile women, there were no cases excluded due to a lack of primary evaluation tests. Demography characteristics including age, body mass index (BMI) and smoking behavior of the study and the control groups were similar (Table 1). Cycle day of hysteroscopy, polyp diameter and location were also similar. The incidence of CE in group of women with infertility was significantly higher compared to the control group (22.6% vs. 8.6%; p = .001). Women with primary infertility were additionally compared to those with secondary infertility (Table 2). Demography parameters, hysteroscopy day, polyp characteristics (diameter and location) were similar as well as the prevalence of CE between the groups. Table 3 shows the pregnancy outcome of infertile women with treated CE and those without CE. Demography, polyp diameter and location, infertility treatment characteristics (treatment modality distribution, sperm parameters, number of transferred embryos) were similar between the groups. CPR, LBR and MR were also comparable. The results of univariate analysis to define factors potentially associated with CE are shown in Table 4. Infertility, gravidity and history of miscarriages were included in multivariate analysis. Logistic regression model (Table 5) demonstrated that history of infertility was significantly associated with diagnosis of CE (OR 3.16; 95% CI 1.53 – 6.49).
Discussion Our study demonstrates significantly higher prevalence of CE in women with infertility and EP compared to those with EP and no previous history of infertility. Multivariate analysis showed that history of infertility is significantly associated with CE diagnosis in women with EP. Large spectrum of vascular changes including hyaline thickening of the vascular wall, small vessel thrombosis, high vascular density with endothelial proliferation and swelling was reported in the functional layer of the endometrium of 39% of asymptomatic infertile women [14]. Patients with infertility demonstrated significantly reduced uterine artery flow velocity in all menstrual phases and significantly elevated uterine and subendometrial artery impedance in the periovulatory and midluteal phases [21]. It has been proposed that vascular changes in endometrium of infertile women might present an evolving stage of vasculopathy that was related to CE. Although the comparison between infertile and fertile groups was not performed, previous clinical studies [4, 14] demonstrated a high prevalence of CE in infertile women. The association of EP and CE is not clearly understood. Factors such as hormonal dysfunction, imbalance between proliferation and apoptosis, abnormal expression of ovarian steroid hormone receptors, and chromosomal abnormalities are thought to play important roles in the pathogenesis of EP [22–25].
Recent study [10] showed a higher CE prevalence in
premenopausal women with EP compared to control group without EP (61.7% vs 24.2%; p < .0001). The presence of micropolyps on hysteroscopy has been shown to be associated with histological diagnosis of CE [26]. Chronic inflammation resulting from CE may have implications on
the
function
of
pro-inflammatory
cytokines
(Interleukin-6,
interleukin-1β,
and tumor necrosis factor α) which may affect migration, proliferation and apoptosis of endometrial cells [27]. It might also cause micro- and macropolyps formation [10].
In order to evaluate the effect of gravidity on the prevalence of CE in infertile patients, we compared women with primary and secondary infertility. No statistical difference was found. In a previous retrospective analysis of 234 endometrial specimens obtained by hysterectomy, the authors reported that multiparity is an independent risk factor for CE; whereas multigravidity and past history of miscarriage are not risk factors for CE [6]. This is in agreement with our results in a group of women with infertility. Treatment of CE especially in infertile women including antibiotic type, administration route, treatment duration, and efficacy assessment are still unclear [28]. Yet, a few authors reported an improvement CPR and LBR after antibiotic administration [4, 20, 29]. In our study, we found that the cumulative CPR and LBR in infertile women with CE treated with one course of oral Doxycycline were similar to infertile women without CE. Miscarriage rate was also similar between two groups. To the best of our knowledge, our report was the first clinical study evaluating the prevalence of CE in women with EP and infertility compared to those without infertility. In addition, we evaluated the infertility type (primary or secondary) effect on the prevalence of CE. Further, we reported the pregnancy outcome of infertile women with CE treated with antibiotics and without CE. The limitation of our study is its retrospective design and the relatively low number of patients included in the analysis of secondary outcomes. However, strict inclusion and exclusion criteria as well as similar diagnostic and treatment protocols used for all included women mitigate those limitations. We excluded women with a history of infertility treatment, as previous hormonal treatment may apply significant changes in physiology of endometrium [14] and may affect the comparison of fertile and infertile women. Since all women with highly suspected endometriosis previously underwent infertility treatment, they were also excluded from final analysis. Women with tubal, ovulatory and male infertility factors were excluded from infertility group, in order to
compare infertile women with only uterine infertility factor (EP) to those without infertility avoiding confounding effect of other infertility factors [8, 9, 14, 21]. Since the criteria used for CE diagnosis is often different, it is difficult to compare the CE prevalence among different studies [13]. Additionally, results may be affected by different clinical and pathological confounding factors. In our study, CE was diagnosed using immunohistochemistry staining with CD 138 antibodies in addition to hematoxylin and eosin staining for plasma cells detection. For immunohistochemistry staining, we used previously published protocol, which has demonstrated the correlation between histological results of CE and clinical signs such as abnormal uterine bleeding [19]. All tissue samples were analyzed according to the same strict protocol by two gynecologic pathologists. All hysteroscopic procedures and histological analyses were performed in one tertiary care center. In conclusion, the main results of our study demonstrate a higher prevalence of chronic endometritis in endometrial polyps from women with infertility compared to those without infertility. This finding supports the hypothesis of multifactorial etiology of endometrial polyps and the pathophysiological role of CE in the development of infertility. This hypothesis should be elucidated in future randomized studies.
Acknowledgments The authors would like to make special thanks to all the gynecologists, nurses and other team member of MUHC Department of Obstetrics and Gynecology and Reproductive Centre.
Disclosures The authors declare that they have no conflict of interest. The authors have not received any funding to support this study.
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Figure 1. Flowchart of patients’ selection process. CE – chronic endometritis IUD – intrauterine device RPL – recurrent pregnancy loss ABX – antibiotic treatment
Table 1. Characteristics and chronic endometritis prevalence in women with endometrial polyp with and without infertility.
Parameter Age (years) BMI (kg/m2) Smoking (%) Gravidity Previous miscarriages Hysteroscopy cycle day Polyp diameter (mm) Polyp location: Anterior wall (%) Posterior wall (%) Fundus (%) Lateral wall (%) CE prevalence (%)
Infertility (n = 137) 38 (35 – 41) 25 (24 – 29) 6 (4.4) 0 (0 – 1) 0 (0 – 1) 9 (7 – 11) 10 (9 – 10)
No infertility (n = 140) 40 (36 – 42) 25 (23 – 28) 11 (7.9) 0 (0 – 2) 0 (0 – 1) 8 (7 – 10) 10 (8 – 10)
33 (24.1) 38 (27.7) 38 (27.7) 28 (20.5) 31 (22.6)
44 (31.4) 35 (25.0) 41 (29.3) 20 (14.3) 12 (8.6)
Data are median (quartiles) unless stated otherwise. BMI – body mass index CE - chronic endometritis
P-value .13 .33 .23 .27 .73 .81 .33
.38
.001
Table 2. Characteristics and chronic endometritis prevalence in women with primary and secondary infertility.
Parameter Age (years) BMI (kg/m2) Smoking (%) Hysteroscopy cycle day Polyp diameter (mm) Polyp location: Anterior wall (%) Posterior wall (%) Fundus (%) Lateral wall (%) CE prevalence (%)
Primary infertility (n = 80) 38 (34 – 41) 24 (24 – 27) 3 (3.8) 8 (7 – 9) 10 (8 -10)
Secondary infertility (n = 57) 39 (37 – 42) 24 (26 – 28) 3 (5.3) 9 (7 – 11) 10 (8 – 10)
18 (22.5) 26 (32.5) 25 (31.3) 11 (13.7) 20 (25.0)
15 (26.3) 12 (21.1) 13 (22.8) 17 (29.8) 11 (19.3)
Data are median (quartiles) unless stated otherwise. BMI – body mass index CE - chronic endometritis
P-value
.08 .08 .67 .09 .64
.08
.43
Table 3. Characteristics and pregnancy outcome of infertile women with treated CE and without CE.
Parameter Age (years) BMI (kg/m2) Smoking (%) Hysteroscopy cycle day Polyp diameter (mm) Polyp location: Anterior wall (%) Posterior wall (%) Fundus (%) Lateral wall (%) Infertility treatment: No treatment (%) OI (%) IVF (%) Sperm concentration (106/ml) Sperm motility (mean %) No of transferred embryos CPR (%) LBR (%) Miscarriage rate (%)
Treated CE (n = 31) 38 (34 – 41) 24 (24 – 26) 1 (3.2) 9 (7 – 12) 10 (8 – 10)
Negative CE (n = 106) 38 (35.8 – 41) 25 (24 – 29) 5 (4.3) 9 (7 – 10) 10 (9 – 10)
9 (29.0) 10 (32.3) 8 (25.8) 4 (12.9)
24 (22.6) 28 (26.4) 30 (28.3) 24 (22.7)
6 (19.4) 8 (25.8) 17 (54.8) 36.4 (20.0 – 79.4) 45 (43 – 70) 1 (1 – 1) 10 (32.3) 9 (29.0) 1 (10.0)
18 (17.0) 44 (41.5) 44 (41.5) 42.6 (20.0 – 92.5) 59 (42 – 86) 1 (1 – 1) 44 (41.5) 41 (38.7) 3 (6.8)
Data are median (quartiles) unless stated otherwise. BMI – body mass index CE – chronic endometritis OI – ovulation induction IVF – in vitro fertilization CPR – clinical pregnancy rate LBR – live birth rate
P-value .79 .45 .72 .34 .45
.60
.27
.47 .19 .67 .35 .33 .73
Table 4. Univariate analysis of factors associated with chronic endometritis.
Parameter Age (years) BMI (kg/m2) Smoking (%) Gravidity Previous miscarriages Polyp diameter (mm) Polyp location: Anterior wall (%) Posterior wall (%) Fundus (%) Lateral wall (%) Infertility diagnosis (%)
CE positive (n = 43) 38 (36 – 42) 25 (23 – 29) 2 (4.7) 0 (0 – 1) 0 (0 – 1) 10 (8 – 10)
CE negative (n = 234) 38 (36 – 42) 25 (23 – 29) 15 (6.4) 0 (0 – 2) 0 (0 – 1) 10 (9 – 10)
11 (25.6) 14 (32.6) 12 (27.9) 6 (13.9) 31 (72.1)
66 (28.2) 59 (25.2) 67 (28.7) 42 (17.9) 106 (45.3)
Data are median (quartiles) unless stated otherwise. BMI – body mass index CE - chronic endometritis
P-value .98 .77 .66 .16 .15 .34
.78
.001
Table 5. Multivariate logistic regression analysis of factors associated with chronic endometritis.
Parameter Infertility diagnosis Gravidity Previous miscarriages
OR 3.16 1.33 2.55
95% CI 1.53 – 6.49 0.02 – 91.4 0.26 – 25.11