Diagnostics of Chronic Endometritis in Infertility

Study Overview
=================
Brief Summary
-----------------
Chronic endometritis (CE) is characterized by the presence of atypical plasma cell infiltrates (CD138 positive) in the endometrial stroma. Recent analyzes suggest that CE adversely affects fertility by reducing endometrial receptivity, impairing decidualization and uterine contractility, thus increasing the risk of recurrent pregnancy loss and implantation failure. It is likely that a significant proportion of idiopathic infertility cases are due to CE. The diagnosis of CE is a challenge because the clinical examination and transvaginal ultrasonography are considered non-specific. The recent scientific research has been aimed at identifying hysteroscopic CE diagnostic criteria and establishing the compatibility of ultrasonographic, hysteroscopic, histopathological (including the use of immunohistochemical testing with antibodies against human CD138) and microbiological diagnoses. Preliminary literature results suggested that successful treatment of CE with antibiotics could improve live birth rates.

Detailed Description
-----------------
The main objective of the study is to estimate the incidence of chronic endometritis (CE) in the population of women of childbearing age who underwent hysteroscopy for infertility. The specific objectives are as follows: Estimation of the diagnostic congruity of hysteroscopic, histopathological and microbiological diagnoses of CE Estimation of the effectiveness of empirical antibiotic therapy in the treatment of CE, confirmed by normalization of the hysteroscopic appearance of the uterine cavity, normalization of histopathological results of endometrial biopsies and decrease in plasma cell count/1 mm2 Estimation of the percentage of clinical pregnancies achieved in women subjected to empiric antibiotic therapy for CE vs. in women without treatment. The study group will consist of women of childbearing age subjected hysteroscopy due to idiopathic infertility. The prerequisite for hysteroscopy is a normal cervical cytology result, a negative blood pregnancy test, a normal vaginal biocenosis and the first phase of the cycle. During hysteroscopy, the following will be performed: visual inspection of the uterine cavity in search of focal lesions and features of the endometrium suggestive of CE, such as: focal or diffuse hyperemia, micropolyps, stromal edema, then collection of washings from the uterine cavity for microbiological examination (aerobic and anaerobic culture, PCR for Chlamydia, culture for Mycoplasma, Ureaplsma) and excision of the focal lesion or endometrial biopsy. The extracted tissue material will be subjected to standard histopathological examination with hematoxylin and eosin staining. Additional immunohistochemical staining with Monoclonal Mouse Anti-Human CD138 antibodies will be used to detect plasmocytes. The cut-off point for the number of CE-defining plasmocytes will be determined by the Receiver Operating Characteristic (ROC) curve. Women with infertility diagnosed with CE will be randomized to 2 arms: 1) ofloxacin 2x200 mg orally for 10 days + metronidazole 1x500 mg vaginally for 10 days, 2) control arm (no treatment). After 3 cycles from surgery or completion of treatment, women will undergo a repeat hysteroscopy for a visual assessment of the uterine cavity and a follow-up endometrial biopsy. The percentage of women with improvement in the clinical appearance of the uterine cavity, normalization of histopathology and persistent CE in both arms will be determined. Data will be obtained on the results of infertility treatment (obtaining a clinical pregnancy) within 12 months of the procedure or completion of antibiotic therapy.

Official Title
-----------------
Evaluation of the Congruity of Methods Used in the Diagnostics of Chronic Endometritis in the Course of Infertility and the Effectiveness of Antibiotic Therapy in the Context of Remission of Symptoms and Obstetric Results

Conditions
-----------------
Infertility Unexplained

Intervention / Treatment
-----------------
* Drug: Ofloxacin + Metronidazole


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: age 18-45 years lack of previous diagnosis and treatment due to suspected pathology of the uterine cavity lack of active infection of the reproductive tract Exclusion Criteria: pelvic surgery performed within 6 months preceding the hysteroscopy confirmed pelvic endometriosis antibiotic or probiotic treatment within 3 months preceding the hysteroscopy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective randomized open-label comparative parallel-group study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Antibiotic therapy<br>Women with infertility diagnosed with CE undergoing empirical antibiotic therapy | Drug: Ofloxacin + Metronidazole<br>* Ofloxacin 2x200mg orally for 10 days + Metronidazole 1x500 mg vaginally for 10 days<br>|
| No Intervention: Control<br>Women with infertility diagnosed with CE not subjected to empirical antibiotic therapy | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of CE in women with idiopathic infertility | Estimation of the percentage of women diagnosed with CE in the population of women with idiopathic infertility | 3 months | 
| Determination of the cut-off point of the number of plasma cells/1 mm2 defining CE | Diagnostic compatibility assessment of immunohistochemistry and histopathology will be performed to estimate the cut-off point for the number of plasma cells defining CE using the ROC (Receiver Operating Characteristic) curve | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of the reliability of polyp visualization in diagnosing CE | The percentage of women with CE and a hysteroscopy-visible endometrial polyp and without a polyp will be calculated and compared | 3 months | 
| Assessment of the reliability of the visualization of focal endometrial hyperemia in the diagnosis of CE | The percentage of women with CE and hysteroscopy-visible focal hyperemia and without hyperaemia will be calculated and compared | 3 months | 
| Assesment of the reliability of the visualization of diffuse endometrial hyperemia in the diagnosis of CE | The percentage of women with CE and hysteroscopy-visible diffuse hyperaemia and without hyperaemia will be calculated and compared | 3 months | 
| Assessment of the reliability of the visualization of endometrial micropolyps in the diagnosis of CE | The percentage of women with CE and hysteroscopy-visible micropolyps and without micropolyps will be calculated and compared | 3 months | 
| Assessment of the reliability of the visualization of endometrial edema in the diagnosis of CE | The proportion of women with CE and hysteroscopy-visible endometrial edema and without endometrial edema will be calculated and compared | 3 months | 
| Evaluation of the effectiveness of antibiotic therapy in the context of reducing the number of plasma cells/1 mm2 | The number of plasma cells/1 mm2 will be calculated and compared among women who received antibiotic therapy in the course of CE and untreated women | 3 months | 
| Evaluation of the effectiveness of antibiotic therapy in the context of visual normalization of the uterine cavity in follow-up hysteroscopy | The percentage of women with persistent hysteroscopic CE symptoms: visualization of focal hyperemia or diffuse hyperemia or endometrial micropolyps or endometrial edema in follow-up hysteroscopy will be assessed and compared among women who received antibiotic therapy in the course of CE and untreated women | 3 months | 
| Evaluation of the effectiveness of antibiotic therapy in the context of normalization of histopathological results of a control endometrial biopsy | The percentage of women with persistent histopathological CE symptoms: presence of plasma cells and/or other inflammatory cells (lymphocytes or neutrophilic granulocytes or histiocytes/macrophages or eosinophilic granulocytes) destructing the endometrial tubuli among women who received antibiotic therapy in the course of CE and untreated women will be evaluated and compared in follow-up hysteroscopic endometrial biopsy | 3 months | 
| Evaluation of the effectiveness of antibiotic therapy in the treatment of CE - dependent infertility | Pregnancy rates will be assessed and compared among women who received antibiotics for CE and untreated women | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Infertility Unexplained, Chronic endometritis, Office hysteroscopy