**2. Chronic endometritis**

CE is the continuous inflammation of the uterine endometrium. The prevalence of CE ranges from 0.8 to 19% in the general population and 0.2 to 46% in patients with infertility, based on the population type and the diagnostic criteria of the studies [18]. The pregnancy rate following one cycle of IVF/ET can be as high as 60%. However, even in the very successful units, some couples fail repeatedly. Failure could be due to many different factors, such as inappropriate ovarian stimulation, suboptimal embryo culture conditions and faults in ET techniques. CE is one of the pathologies, which can not be evaluated and diagnosed by HSG and ultrasound, since it is a subtle abnormality, which is usually asymptomatic or with only mild symptoms.

Kasius et al. demonstrated the histological detection of plasma cells (Figure 1) in the endome‐ trial stroma as the gold standard for the diagnosis of CE. It is good to note that even histology can miss the diagnosis due to the normal presence of leukocytes in the endometrium, mostly prior to menstruation.

Matteo et al. [18] showed that CE may reduce endometrial receptivity and may cause infertility because the endometrium is characterized by an abnormal pattern of lymphocyte subsets and, consequently, an aberrant endometrial microenvironment.

In a recent study by Cicinelli et al in 2014 [29], it was demonstrated that in women with repeated abortions, CE is a frequent finding and that women who received adequate antibiotic treatment had a significantly higher rate of successful pregnancies compared with women who were not treated or with persistent disease.

Moreover, in a research study by Quaas and Dokras [109], CE was identified in 30.3% of patients with repeated implantation failure at IVF, and women diagnosed with CE had lower implantation rates (11.5%) after an IVF cycle.

#### **2.1. Chronic endometritis and IVF**

Although CE has been related to infertility and recurrent abortion, it is usually asymptomatic, and the diagnosis is rarely clinically suspected [13]. It has also been demonstrated that a present or a recent inflammation of the upper genital tract can affect uterine receptivity and be implicated in worse results in IVF and ET (IVF-ET) [19].

The uterine cavity and its receptivity, despite the constant progress in the assisted reproductive technologies, seem somewhat left behind [20]. ET and implantation are the stages of IVF procedures that have the highest failure rate, and it seems that endometrial abnormality is an important causative factor in this failure. Consequently, any endometrial abnormality should be detected and treated before an IVF-ET cycle to improve pregnancy rates [21].

Approximately, 8% of all couples seek for infertility treatment during their reproductive life. Although the frequency of infertility etiologically depends on the population studied, pelvic infections and their sequelae have been considered important causative factors. CE has been related to infertility and recurrent abortion, particularly because it could affect uterine receptivity and embryo implantation [22].

**2. Chronic endometritis**

102 Genital Infections and Infertility

prior to menstruation.

treated or with persistent disease.

**2.1. Chronic endometritis and IVF**

implantation rates (11.5%) after an IVF cycle.

receptivity and embryo implantation [22].

implicated in worse results in IVF and ET (IVF-ET) [19].

CE is the continuous inflammation of the uterine endometrium. The prevalence of CE ranges from 0.8 to 19% in the general population and 0.2 to 46% in patients with infertility, based on the population type and the diagnostic criteria of the studies [18]. The pregnancy rate following one cycle of IVF/ET can be as high as 60%. However, even in the very successful units, some couples fail repeatedly. Failure could be due to many different factors, such as inappropriate ovarian stimulation, suboptimal embryo culture conditions and faults in ET techniques. CE is one of the pathologies, which can not be evaluated and diagnosed by HSG and ultrasound, since it is a subtle abnormality, which is usually asymptomatic or with only mild symptoms. Kasius et al. demonstrated the histological detection of plasma cells (Figure 1) in the endome‐ trial stroma as the gold standard for the diagnosis of CE. It is good to note that even histology can miss the diagnosis due to the normal presence of leukocytes in the endometrium, mostly

Matteo et al. [18] showed that CE may reduce endometrial receptivity and may cause infertility because the endometrium is characterized by an abnormal pattern of lymphocyte subsets and,

In a recent study by Cicinelli et al in 2014 [29], it was demonstrated that in women with repeated abortions, CE is a frequent finding and that women who received adequate antibiotic treatment had a significantly higher rate of successful pregnancies compared with women who were not

Moreover, in a research study by Quaas and Dokras [109], CE was identified in 30.3% of patients with repeated implantation failure at IVF, and women diagnosed with CE had lower

Although CE has been related to infertility and recurrent abortion, it is usually asymptomatic, and the diagnosis is rarely clinically suspected [13]. It has also been demonstrated that a present or a recent inflammation of the upper genital tract can affect uterine receptivity and be

The uterine cavity and its receptivity, despite the constant progress in the assisted reproductive technologies, seem somewhat left behind [20]. ET and implantation are the stages of IVF procedures that have the highest failure rate, and it seems that endometrial abnormality is an important causative factor in this failure. Consequently, any endometrial abnormality should

Approximately, 8% of all couples seek for infertility treatment during their reproductive life. Although the frequency of infertility etiologically depends on the population studied, pelvic infections and their sequelae have been considered important causative factors. CE has been related to infertility and recurrent abortion, particularly because it could affect uterine

be detected and treated before an IVF-ET cycle to improve pregnancy rates [21].

consequently, an aberrant endometrial microenvironment.

Reproduced with the permission from Polisseni et al. [5]. Copyright © 2003. *Detection of Chronic Endometritis by Diag‐ nostic Hysteroscopy in Asymptomatic Infertile Patients Fernanda Polissenia Eduardo A. Bambirrab Aroldo F. Camargosa. De‐ partments of Obstetrics and Gynecology, and Pathology and Legal Medicine, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil.*

**Figure 1.** A. Photomicrograph of an endometrial biopsy specimen showing a proliferative endometrium. B. Photomi‐ crograph of an endometrial biopsy specimen showing plasma cell endometritis (arrow).

A specific therapy is required in these cases; so it is important to have a reliable diagnostic test to detect the pathology. Endometritis causes specific stromal, vascular, and glandular modi‐ fications that can be detected by hysteroscopy.

Very few studies have investigated the value of diagnostic hysteroscopy in the detection of CE in infertile patients, and they failed in analyzing the real value of this method in these cases.

In evaluating the role of diagnostic hysteroscopy (Figure 2) in the detection of asymptomatic endometritis in infertile patients, a high negative predictive value (89.1%) is identified. This means that when the hysteroscopy shows a negative result for endometritis, it is highly probable that the result is correct and that the patient does not really have an endometrial inflammation.

**Figure 2.** Chronic endometritis at fluid hysteroscopy. Endometrial mucosa appears thick, edematous, hyperemic and covered by micropolyps (less than 1 mm size), which float into the uterine cavity.

If a diagnostic hysteroscopy shows the absence of endometritis, it is possible to assert, with a good margin of safety, that the patient does not exhibit an endometrial inflammation, which could hinder embryo implantation.

Hysteroscopy is also found to have a low positive predictive value in the detection of endo‐ metritis. This means that when the hysteroscopy shows a positive result for endometritis, it is better to consider that this could be an incorrect result and that the patient could have a normal endometrium.

Gump et al. [23] studied 204 infertile patients attending an infertility clinic, and all but 1 had negative cultures for *Chlamydia trachomatis* in cervical and endometrial specimens. These authors have found a significant correlation between prevalence of chlamydial antibodies and prior pelvic inflammatory disease (PID), as documented by HSG and/or laparoscopy. From these data, Gump et al. [23] concluded that antecedent infection caused by *C. trachomatis*, as measured by antibody prevalence, is an important factor in infertility of tubal origin, but they could not find infections in the cervical or in the endometrial specimens.

In conclusion, data suggest that hysteroscopy is not useful in the screening for CE in asymp‐ tomatic infertile women.

#### **2.2. Chronic endometritis and recurrent miscarriage**

Very few studies have investigated the value of diagnostic hysteroscopy in the detection of CE in infertile patients, and they failed in analyzing the real value of this method in these cases.

In evaluating the role of diagnostic hysteroscopy (Figure 2) in the detection of asymptomatic endometritis in infertile patients, a high negative predictive value (89.1%) is identified. This means that when the hysteroscopy shows a negative result for endometritis, it is highly probable that the result is correct and that the patient does not really have an endometrial

Reproduced with the permission from Cicinelli. Microorganisms and chronic endometritis. Fertil Steril 2008;89 (3).

covered by micropolyps (less than 1 mm size), which float into the uterine cavity.

could hinder embryo implantation.

endometrium.

**Figure 2.** Chronic endometritis at fluid hysteroscopy. Endometrial mucosa appears thick, edematous, hyperemic and

If a diagnostic hysteroscopy shows the absence of endometritis, it is possible to assert, with a good margin of safety, that the patient does not exhibit an endometrial inflammation, which

Hysteroscopy is also found to have a low positive predictive value in the detection of endo‐ metritis. This means that when the hysteroscopy shows a positive result for endometritis, it is better to consider that this could be an incorrect result and that the patient could have a normal

Gump et al. [23] studied 204 infertile patients attending an infertility clinic, and all but 1 had negative cultures for *Chlamydia trachomatis* in cervical and endometrial specimens. These authors have found a significant correlation between prevalence of chlamydial antibodies and

inflammation.

104 Genital Infections and Infertility

Recurrent miscarriage (RM) is defined as three or more miscarriages before 20 weeks of gestation and it affects 3% of couples.

Genetic abnormalities, anti-phospholipid syndrome, endocrine disorders, and uterine abnormalities have been diagnosed in 50% of these couples. The other 50% are diagnosed as with unexplained RM. The competence of the uterine environment is an issue of big interest these days. The regular infertility investigations, such as HSG and ultrasounds, are unable to detect small intrauterine pathologies, and the prevalence of unsuspected intrauterine abnor‐ malities in hysteroscopy has been shown to range between 11% and 45%.

In recent years, the focus on CE, a slight and mostly asymptomatic inflammation of the endometrial lining, is growing [24, 25].

A retrospective pilot study [26] showed a relationship between RM and chronic endometrial inflammation, which could have several clinical implications.

First, they showed that CE is a common finding in women with RM. Second, this study showed that mycoplasmas and the bacteria are the most frequently involved micro organisms in CE.

Third, the study demonstrated hysteroscopy as a reliable diagnostic technique for CE and that the previously noted endometrial pathologies [26, 27] such as micropolyps, stromal edema, and diffuse or focal hyperemia are clearly related to the inflammatory state of the endometri‐ um. Moreover, results indicated an improved reproductive outcome and a normal hystero‐ scopic exam after an appropriate antibiotic treatment in patients with CE.

Fourth, the results showed a restored fertility status in women with CE after appropriate antibiotic treatment, suggesting the appropriateness of performing a hysteroscopy in women with RM.

Fifth, the sustained signs of CE in hysteroscopy after treatment, even with negative endome‐ trial cultures, were related to a worse reproductive outcome.

Their results are in concordance with those from the PID Evaluation and Clinical Health (PEACH) study, which showed non-gonococcal, and non-chlamydial infection in approxi‐ mately 60% of women with PID [28].

Considering the high prevalence of bacterial vaginosis and the fact that ascending bacteria can colonize the uterine cavity, those data are not surprising [29]. In fact, bacterial vaginosis has been associated with PID and, in ART, may decrease implantation rates, increase early miscarriages, and may also increase the risk of preterm labor [30]. This study suggested Mycoplasma and *Ureaplasma urealyticum* to be responsible for CE in about 24% of the cases.

This data do not disagree with the recent opinion that the uterine cavity is normally not sterile and that the presence of microorganisms does not mean inflammation [31–33]. Therefore, the main issue that causes the pathology is rather the interactions between the infectious agents and the endometrial environment than just the presence of infectious agents within the uterine cavity [30].

Fluid mini-hysteroscopy is a minimally invasive procedure that can be performed in an office without anesthesia [34], so the benefit in terms of evaluation, diagnosis and treatment sufficiently overcome the cost of hysteroscopy. The improvement of the reproductive outcome after both antibiogram-guided antibiotic therapy and the CDC guideline-based treatment supported the value of the hysteroscopic evaluation in women with RM.

Another important finding in the mentioned study data was that in the subjects with a negative endometrial culture, the ones with persistent CE diagnosed by hysteroscopy had a worse reproductive outcome compared to patients without CE in hysteroscopic evaluations after treatment. This shows that the hysteroscopic evaluation in patients with endometrial inflam‐ mation has a higher sensitivity than cultures and that a normal hysteroscopic evaluation could be more accurate in predicting of a successful pregnancy after treatment.

In conclusion, although some limitations are related to retrospective studies, in this study, Cicinelli et al, evaluating a large number of patients, demonstrated that CE is a condition commonly associated with RM. Mycoplasma and common bacteria were most prevalent microorganism for CE.

In women with RM, hysteroscopy reliably detects the existence of CE. The normalization of the hysteroscopic endometrial pattern seems to be associated with a significant improvement in the reproductive outcome [25].

In one study by Kitaya et al [36] using immuno-histochemical analysis of the stromal plasma‐ cyte marker syndecan-1, CE was identified in approximate 10% of the women with RMs. In patients with RMs of unknown etiology, its prevalence was approximately 12-13%. It was lower compared with the reported prevalence (approximately 30%) in repeated embryo implantation failure after IVF-ET [35] and unexplained infertility [36]. All patients with CE had a history of RMs in the first trimester of pregnancy. Amassment of stromal B cells was observed in all the endometrium exhibiting CE. A flow cytometric study demonstrated that the proportion of B cells in endometrial mononuclear cells was threefold higher in the patients with RMs than in fertile women during the mid-secretory phase [37].

In addition, another morphometric study found that 2 of 22 patients with unexplained RMs had more endometrial B cells than any other patient or fertile woman in the mid-secretory phase [38].

#### **2.3. Diagnosis**

Most of the patients with CE are asymptomatic, which causes some diagnostic challenge.

The gold standard for diagnosis of CE remains the histopathologic evaluation of the endome‐ trial biopsy specimen, which is through the identification of plasma cells in the stroma of the endometrium by immunohistochemistry [4].

This method of diagnosis is limited by

miscarriages, and may also increase the risk of preterm labor [30]. This study suggested Mycoplasma and *Ureaplasma urealyticum* to be responsible for CE in about 24% of the cases. This data do not disagree with the recent opinion that the uterine cavity is normally not sterile and that the presence of microorganisms does not mean inflammation [31–33]. Therefore, the main issue that causes the pathology is rather the interactions between the infectious agents and the endometrial environment than just the presence of infectious agents within the uterine

Fluid mini-hysteroscopy is a minimally invasive procedure that can be performed in an office without anesthesia [34], so the benefit in terms of evaluation, diagnosis and treatment sufficiently overcome the cost of hysteroscopy. The improvement of the reproductive outcome after both antibiogram-guided antibiotic therapy and the CDC guideline-based treatment

Another important finding in the mentioned study data was that in the subjects with a negative endometrial culture, the ones with persistent CE diagnosed by hysteroscopy had a worse reproductive outcome compared to patients without CE in hysteroscopic evaluations after treatment. This shows that the hysteroscopic evaluation in patients with endometrial inflam‐ mation has a higher sensitivity than cultures and that a normal hysteroscopic evaluation could

In conclusion, although some limitations are related to retrospective studies, in this study, Cicinelli et al, evaluating a large number of patients, demonstrated that CE is a condition commonly associated with RM. Mycoplasma and common bacteria were most prevalent

In women with RM, hysteroscopy reliably detects the existence of CE. The normalization of the hysteroscopic endometrial pattern seems to be associated with a significant improvement

In one study by Kitaya et al [36] using immuno-histochemical analysis of the stromal plasma‐ cyte marker syndecan-1, CE was identified in approximate 10% of the women with RMs. In patients with RMs of unknown etiology, its prevalence was approximately 12-13%. It was lower compared with the reported prevalence (approximately 30%) in repeated embryo implantation failure after IVF-ET [35] and unexplained infertility [36]. All patients with CE had a history of RMs in the first trimester of pregnancy. Amassment of stromal B cells was observed in all the endometrium exhibiting CE. A flow cytometric study demonstrated that the proportion of B cells in endometrial mononuclear cells was threefold higher in the patients

In addition, another morphometric study found that 2 of 22 patients with unexplained RMs had more endometrial B cells than any other patient or fertile woman in the mid-secretory

Most of the patients with CE are asymptomatic, which causes some diagnostic challenge.

supported the value of the hysteroscopic evaluation in women with RM.

be more accurate in predicting of a successful pregnancy after treatment.

with RMs than in fertile women during the mid-secretory phase [37].

cavity [30].

106 Genital Infections and Infertility

microorganism for CE.

phase [38].

**2.3. Diagnosis**

in the reproductive outcome [25].


Considering these limitations, physicians have studied the role of hysteroscopic evaluation of the endometrium to diagnose CE with mixed results. The suggested hysteroscopic findings for the diagnosis for CE have been mucosal edema, areas of hyperemia, and micropolyps [39].

A study by Yang et al in patients with RIF showed a sensitivity and specificity of 35% and 68%, respectively, for diagnosis of CE by hysteroscopy. In addition, hysteroscopic and histological evaluations resulted in identification of 66% and 44% of CE cases, respectively [39].

Proponents of hysteroscopy as a diagnostic tool for CE argue that hysteroscopy allows a complete evaluation of the uterine cavity, whereas the endometrial biopsy is a random biopsy of the uterine cavity and therefore may miss focal points of inflammation.

The isolation of infectious agents (common bacteria, *Neisseria gonorrhea*, *Chlamydia trachoma‐ tis*, *Mycoplasma* species, *Ureaplasma urealyticum* and yeast) from the endometrial cavity is the last method of diagnosis for CE. A study completed by Cicinelli et al showed that among 483 women with hysteroscopic-diagnosed CE, 73% had at least a single microorganism isolated from endometrial cultures vs. 5% in the control group [18].

Syndecan-1 (Figure 3) is a plasma cell, cell membrane marker. It has been broadly used to detect plasma cells in flow cytometry and is a useful marker to detect both malignant and benign plasma cells in paraffin-embedded bone marrow biopsies [40]. Syndecan-1 is a cell surface proteoglycan that facilitates cell to cell adhesion, cell to extracellular matrix adhesion, cell proliferation and migration [41].

Syndecan-1 expression was evaluated in CE and dysfunctional uterine bleeding. In all subjects with CE, plasma cells were noted by light microscopic study of both hematoxylin and eosin (H&E) and syndecan-1 dyed slides. Immunohistochemical staining with syndecan-1 increased the plasma cell detection. Plasma cells have characteristic "clock-face chromatin in an eccen‐ trically placed nucleus with a perinuclear halo" appearance. This characteristic can be easily visible by syndecan-1 staining. This staining also showed that some plasma cells lacking some of the classic features, were actually plasma cells.

Identifying plasma cells in the endometrial stroma of CE can be very challenging.

Some conditions can present with the histologic findings of CE or affect the search for plasma cells. These conditions are early proliferative endometrium or late menstrual, monocytic

Reproduced with the permission from Ilene et al. [44]. University of Arkansas for Medical Sciences, Little Rock, Arkan‐ sas. Copyright © 2001 by The United States and Canadian Academy of Pathology, Inc.

**Figure 3.** A. Plasma cells membrane staining with syndecan-1 in endometrial tissue showing a prominent spindle cell stromal component in chronic endometritis. B. H&E staining of the same field showing plasma cells.

inflammatory infiltrates, ample stromal mitoses, the plasmacytoid appearance of stromal cells, stromal cell proliferation or a marked pre-decidual reaction in a late secretory endometrium [4, 42].

This is notable that plasmacytoid stromal cells and macrophages do not stain with syndecan-1 and plasma cells can be recognized by immunohistochemical staining with syndecan-1 even in conditions that may interfere with their identification on H&E.

The search to localize plasma cells, in order to establish CE, does not always involve a quick examination of the specimen. It is usually a time-consuming task. Many times there are suspicious for CE, when plasma cells cannot be detected in H&E slides, and syndecan-1 immunohistochemistry staining helps in identifying the plasma cells and then the diagnosis of CE can be documented. Immunohistochemical syndecan-1 staining decreases the time consumption looking for plasma cells in patients suspicious for having CE, and will help the diagnosis in cases with other histological findings that can interfere with the detection of plasma cells.

It is of importance to mention that CE should not be the diagnosis when only mere number of plasma cells are detected, since endometrial stroma can contain limited number of plasma cells without an inflammatory process [43]. Only in the presence of a characteristic setting of CE, the diagnosis can be considered and the detection of plasma cells will be confirmatory.

In conclusion, syndecan-1 staining can be a great assistance and tool identifying the plasma cells and aid in the diagnosis of CE in patient with suspected CE when plasma cells can not be localized in H&E stained also when there are other histologic findings interfering the detection of plasma cells [44].

### **2.4. Pathophysiology**

inflammatory infiltrates, ample stromal mitoses, the plasmacytoid appearance of stromal cells, stromal cell proliferation or a marked pre-decidual reaction in a late secretory endometrium

Reproduced with the permission from Ilene et al. [44]. University of Arkansas for Medical Sciences, Little Rock, Arkan‐

**Figure 3.** A. Plasma cells membrane staining with syndecan-1 in endometrial tissue showing a prominent spindle cell

This is notable that plasmacytoid stromal cells and macrophages do not stain with syndecan-1 and plasma cells can be recognized by immunohistochemical staining with syndecan-1 even

The search to localize plasma cells, in order to establish CE, does not always involve a quick examination of the specimen. It is usually a time-consuming task. Many times there are suspicious for CE, when plasma cells cannot be detected in H&E slides, and syndecan-1

in conditions that may interfere with their identification on H&E.

sas. Copyright © 2001 by The United States and Canadian Academy of Pathology, Inc.

stromal component in chronic endometritis. B. H&E staining of the same field showing plasma cells.

[4, 42].

108 Genital Infections and Infertility

Studies characterizing the distribution of leukocytes in CE have noted an abnormal pattern of leukocytes. Not only the overall number of leukocytes rise, but also the accumulation of the leukocytes is superficial under the endometrial surface as well as around the superficial blood vessels and glands [4].

Plasma cells have been also identified in unusual locations, such as within the lumen of the glands or the intraepithelial [36]. It is believed that these plasma cells provide an abnormal local micro-environment, that decreases the endometrial receptivity.

Since plasma cells are in a minimal number in a healthy endometrial cavity, their presence in larger numbers in CE is considered pathologic. Immature B cells only normally express IgM immunoglobulins. Yet, when naïve B cell meets a particular antigen, a class-switch DNA recombination occurs, causing its differentiation into a plasma cell [45].

Based on the type of inflammatory response, plasmacells are able to produce a variety of immunoglobulins. The majority of the immunoglobulins in the endometrial cavity are IgM and IgA in the epithelial cells and IgG in the stromal cells.

The density of the Ig-bearing stromal cells, including IgM, IgA and IgG, is higher in patient with CE compared to people with normal healthy endometrium. Specially, IgG2 cells are noted to have an extremely higher density than other immunoglobulin subclasses in the endometrial stroma cells of the patients with CE [46]. This special Ig subclass expression is suggested to be a possible mechanism contributing to CE and implantation failure.

The role of matrix metalloproteinases (MMPs) is another interesting hypothesis contributing to inflammation, CE and implantation failure. Lately, a difference in the expression profile of several inflammatory cytokines has been demonstrated through endometrial gene expression studies in women with CE and infertility [47]. Endometrial stromal and epithelial cells by down-regulating the IL-11,could cause a dysregulation of trophoblast invasion. The noted significant decline in CCL4 in CE, may also increase the employment of NK cells and macro‐ phages into the endometrial environment [48].

#### **2.5. Treatment**

Mostly due to non-standardized treatment protocols and conflicting results about pregnancy outcomes, so far the management of CE to increase in the implantation rate has been contro‐ versial.

Some authors recommend treating CE first with of doxycycline for 2 weeks, then with persistent inflammation in a second biopsy, and ciprofloxacin and metronidazole for another 2 weeks [49]. Some others base the treatment on the identified infectious agent and the antibiotic sensitivity profile, giving ciprofloxacin for gram-negative bacteria, amoxicillin/ clavulanate for gram-positive bacteria, and wide spectrum antibiotics (metronidazole cef‐ triaxone, doxycycline) for even negative cultures [18].

In one study, a treatment of antibiotics plus steroid was used to treat women with increased MMP activity in uterine fluid lavage [48].

The efficacy of treatment of CE to increase endometrial implantation and pregnancy rate is unclear. In a cohort study, clinical pregnancy per embryo transferred and live birth rates showed no change between the treated and non-treated patients with CE undergoing their first IVF/ICSI cycles. Both groups underwent endometrial biopsy and hysteroscopy as part of a larger RCT [18].

Another study on RIF compared treated women with a positive biopsy for CE (10) to women with a negative biopsy (23). Even after antibiotic therapy, the implantation rates stayed lower in women with CE (11.5 vs. 32.7%) [49]. Cicinelli et al, in a recently published retrospective study of women with RIF, showed an improvement in pregnancy rates and live birth rates with antibiotic treatment in patient with CE compared with the patient with persistent CE, 65 versus 33% and 60.8 versus 13.3%, respectively [18]. To date, this is the only study showing a significant higher live birth rates after antibiotic therapy of CE. Although, it is good to note before generalizing these results as subjects in this research had hysteroscopic evaluation as a first diagnostic module for diagnosis of CE, which can be subjective. Also, instead of blastocyststage embryos, cleavage-stage embryos, were transferred, which may not be applicable to all practices.

#### **2.6. Summary**

Physicians mostly look for the diagnosis of CE, in cases of RIF; however, because the lack of a universally accepted definition for RIF indirectly biases the pool of patients who are worked up for CE. The diagnosis of CE becomes even more complex and difficult by limitations in microbiology and immunohistopatholog, and the subjective nature of hysteroscopy. Manage‐ ment of CE is also non-standardized. Taken all together, the absence of definitive evidence to establish improved pregnancy outcomes after the treatment of CE precludes establishing a standard of care [48].
