Endometritis: new time,

new concepts
Kotaro Kitaya, M.D.,a,b Takumi Takeuchi, M.D.,c Shimpei Mizuta, M.Sc.,a,c Hidehiko Matsubayashi, M.D.,a,c
and Tomomoto Ishikawa, M.D.a,c
a
Reproduction Clinic Osaka; and b Department of Anatomy and Cell Science, Kansai Medical University, Osaka; and
c
Reproduction Clinic Tokyo, Tokyo, Japan

Endometritis is subdivided into two categories. Acute endometritis is symptomatic and characterized by microabscess formation and
neutrophil invasion in the endometrial superficial epithelium, gland lumina, and uterine cavity. Chronic endometritis is rather silent
and recognized as unusual plasmacyte infiltration in the endometrial stromal areas. Over the last decade, studies have disclosed the
potential association between poor reproductive outcomes and endometritis, particularly chronic endometritis. The aim of this review
is to address the current literature surrounding chronic endometritis and highlight recent advances in the research of this long-neglected
gynecologic disease. (Fertil SterilÒ 2018;110:344–50. Ó2018 by American Society for Reproductive Medicine.)
Key Words: Chronic endometritis, infertility, obstetric and neonatal complications, recurrent pregnancy loss, repeated implantation
failure

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and-sterility/posts/32020-26049

U
nder physiological conditions, pregnancy or elevated infertility (3). not favored in gynecologic practice.
human cycling endometrium The other is chronic endometritis (CE), Accurate histopathologic diagnosis of
is infiltrated by a wide variety the histopathologic features of which CE has been demanding and time-
of immunocompetent cells, including are endometrial superficial edematous consuming until recently (5). Increasing
macrophages, natural killer cells, and change, high stromal cell density, disso- attention, however, has been focused
T lymphocyte subsets. The composition ciated maturation between epithelium on the potential association between
and density of endometrial immuno- and stroma, and infiltration of endome- poor reproductive outcomes and CE.
competent cells vary periodically trial stromal plasmacytes (ESPCs) (2, 4). Here we aim to address the current
across the menstrual cycle. Such timed There are currently no universally literature surrounding CE and highlight
fluctuation in local leukocyte subpopu- accepted standardized definitions or recent advances in research of this
lations is thought to play a role in the established diagnostic guidelines for long-neglected gynecologic disease.
tissue remodeling required to obtain CE, although experts agree that the The following databases were searched
endometrial receptivity (1). presence of multiple ESPCs is the most for articles regarding CE until February
Endometritis is an infectious and specific and sensitive finding in this 2018: PubMed, Embase, ScienceDirect,
inflammatory disorder of the endome- pathology (5–7). Wiley-Blackwell, Lippincott Williams
trium. Endometritis is histopathologi- In sharp contrast to acute endome- & Wilkins, Highwire, and Google
cally subdivided into two categories tritis being manifested with fever, pel- Scholar. Each database was searched
(2). One is acute endometritis, which is vic pain, and vaginal discharge, the using the following terms: ‘‘endome-
characterized by microabscess forma- subtle and nondescript symptoms (pel- tritis’’, ‘‘deciduitis’’, ‘‘subclinical pelvic
tion and neutrophil invasion in the vic discomfort, spotting, and leucor- inflammatory diseases’’, and ‘‘upper fe-
endometrial superficial epithelium, rhea) of CE are often unnoticed by male tract infection’’.
gland lumina, and uterine cavity. The patients and ignored by gynecologists
results of randomized controlled trials (5). As a benign disease, interventional MICROORGANISMS IN
have demonstrated that acute endome- endometrial biopsy and arduous histo- CHRONIC ENDOMETRITIS
tritis is not associated with reduced pathologic examinations for CE are
The major cause of CE is microbial
Received March 29, 2018; revised April 4, 2018; accepted April 9, 2018; published online June 28, 2018.
infection in the uterine cavity. This is
K.K. has nothing to disclose. T.T. has nothing to disclose. S.M. has nothing to disclose. H.M. has supported by the fact that some anti-
nothing to disclose. T.I. has nothing to disclose. biotic therapies are effective to elimi-
Reprint requests: Kotaro Kitaya, M.D., 4-20 Oofuka-cho, Kita-ku, Osaka 530-0011, Japan (E-mail:
[email protected]). nate ESPCs in the affected patients
(8–12). The microorganisms detected
Fertility and Sterility® Vol. 110, No. 3, August 2018 0015-0282/$36.00
Copyright ©2018 American Society for Reproductive Medicine, Published by Elsevier Inc.
frequently in endometrium with CE
https://doi.org/10.1016/j.fertnstert.2018.04.012 are common bacteria (streptococcus

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 Fertility and Sterility®

species, Escherichia coli, Enterococcus faecalis, and basal layer. These overpopulated B cells amass in the endome-
staphylococcus species), mycoplasma/ureaplasma species trial stromal compartment, trespass on the glandular epithe-
(Mycoplasma genitalium, Mycoplasma hominis, lial areas, and invade further into the gland lumina (30, 31).
and Ureaplasma urealyticum), proteus species, Klebsiella Additionally, the secretory phase endometrium with CE was
pneumoniae, Pseudomonas aeruginosa, Gardnerella vaginalis, reported to contain a lower percentage of CD16negative
Corynebacterium, and yeasts (Saccharomyces cerevisiae and CD56positive/bright natural killer cells compared with those
candida species) (13–15). In some developing countries, without CE, along with an increase in T cells, indicating the
Mycobacterium tuberculosis is a microorganism causing aberrant mucosal leukocyte composition in this pathologic
chronic granulomatous endometritis, a subtype of CE condition (32).
characterized by poorly developed caseating granuloma and Several adhesion molecules and chemokines involved in
surrounding lymphocyte infiltrates including ESPCs (16). B cell extravasation and migration (CD62E, CXCL1, and
By contrast, accumulating studies found that the detec- CXCL13) are aberrantly expressed in endometrial endothelial
tion rate of Chlamydia trachomatis and Neisseria gonor- and epithelial cells with CE (31). The concentration of inter-
rhoeae, the principal pathogens causing acute endometritis, leukin (IL)-6, a differentiation factor of mature B cells, is
are very low in patients with CE (2%–7% and 0%–8%, respec- also markedly higher in the menstrual effluents of women
tively) (13, 17, 18). Moreover, administration of azithromycin with CE compared with those without CE (33). In vitro studies
or cefixime, the antibiotics targeting C. trachomatis and N. demonstrated that these proinflammatory molecules are
gonorrhoeae, failed to preserve future fertility in women induced in endometrial cells by microbial antigens such as
with CE (19). C. trachomatis and N. gonorrhoeae are thereby lipopolysaccharide (31). These findings suggest that microbial
unlikely to be the major pathogens in CE. Although their infection in the uterine cavity triggers the immune responses
cause-effect relationship remains undetermined, such differ- unusual to human cycling endometrium. Such immune re-
ences in the microbial profiles suggest that acute endometritis sponses provide an abnormal microenvironment for the
and CE are distinct pathologic entities (20). recruitment of circulating B cells into the endometrial stromal
Altered proportion in anaerobic lactobacilli species, the pre- compartment and gravitation of these lymphocytes to the
dominant bacteria in the female reproductive tracts (21–24), glandular areas. Furthermore, a fraction of accrued endome-
may be another characteristic of CE, although the results are trial B cells may differentiate in situ into ESPCs.
conflicting between the studies. While the report employing Similar to other chronic inflammatory diseases, like rheu-
conventional tissue culture showed a lower detection rate of matoid arthritis and inflammatory bowel disease, the levels of
lactobacilli in the endometrium of infertile women with CE IL-1b and tumor necrosis factor (TNF)-a are also elevated in
than in those without CE, the others using barcoded the uterine cavity of CE (33). Exposure to TNF-a is known
sequencing demonstrated an increase of local lactobacilli in to raise estrogen biosynthesis in endometrial glandular cells
CE (15, 25). Further studies are required to confirm the (34), which may be associated with the occurrence of endome-
change of lactobacilli species in the uterine cavity in CE. trial micropolyposis, a hysteroscopic finding that is often seen
A few reports implicate human immunodeficiency virus in CE (see below) (9, 35).
(26, 27) and cytomegalovirus (28) in CE. The association The ESPCs in CE legions express a high level of multiple
between these viral infections and CE remains uncertain. immunoglobulin (Ig) subclasses (IgM, IgA1, IgA2, IgG1, and
Importantly, the microorganisms detected in the endome- IgG2) with a predominance of IgG2 (36). The excessive
trial tissue are often inconsistent with those detected in the mucosal antibodies in CE potentially have a negative impact
endocervical tissue or vaginal discharge (14), suggesting on the embryo implantation process. These local immune re-
that the microbial examinations using lower genital tract sponses in CE rarely develop into systemic inflammation, as
samples cannot predict the pathogens of CE. In addition, the values of the peripheral blood leukocyte counts, serum
endometrial tissue culture and conventional polymerase C-reactive protein, and fever index of the affected patients
chain reaction were unable to identify microorganisms in stay within the normal ranges (37, 38).
more than half of infertile women with CE (15). These findings One of the histomorphological characteristics of CE is
indicate the limitation of the traditional microbial examina- delayed differentiation of endometrium in the midsecretory
tions in the diagnosis of CE. phase. Approximately one-third of the endometrial samples
with CE obtained from infertile women exhibit such
‘‘out-of-phase’’ morphology (37). The endometrium with CE
INFLAMMATION IN CHRONIC ENDOMETRITIS obtained in the secretory phase often displays pseudostratifi-
B lymphocytes account for only less than 1% of entire leuko- cation and mitotic nuclei in both glandular and surface
cyte population in the nonpathological human endometrium. epithelial cells. The expression of the antiapoptotic genes
Endometrial B cells are mainly seen in the basal layer (the (BCL2 and BAX), proliferation-associated nuclear marker
portion that persists across the menstrual cycle) as central (Ki-67), and ovarian steroid receptors (estrogen receptor-a,
cells in the unique lymphocyte aggregates surrounded by and -b, progesterone receptor-A, and -B) are also upregulated
numerous CD8(þ) T cells and macrophages (29). The role of during the secretory phase in the endometrium with CE
B cells and lymphocyte aggregates in the human endome- (39–42). By contrast, the expression of the genes potentially
trium remains open to debate. In contrast, in CE, a large num- associated with embryo receptivity (IL11, CCL4, IGF1,
ber of B cells infiltrate both the endometrial functional layer and CASP8) and decidualization (PRL and IGFBP1) are
(the portion shed with the onset of menstruation) and the downregulated in the endometrium with CE during this

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VIEWS AND REVIEWS

period (39, 42). These findings support the idea that the potentially affected by laboratory test setting and quality
endometrium with CE is unable to respond to ovarian control including antibody selection and dilution, incubation
steroids and modulate its component cells into a receptive time, thickness of endometrial sections, and number and area
phenotype, implicating the potential relationship between of sections examined (52). This problem is illustrated by a
progesterone resistance and CE, as seen in endometriosis (43). comparison of several published studies that scored inconsis-
tent detection rates of ESPCs in cohorts of infertile women.
For example, one study using a 1:1,000 dilution of clone
DIAGNOSIS OF CHRONIC ENDOMETRITIS B-B4, one of representative anti-CD138 monoclonal anti-
Symptomatology does not seem to help gynecologists diag- bodies, showed that the prevalence of CE was 2.8% in asymp-
nose CE, as a quarter of the affected patients lack symptoms tomatic infertile women undergoing their first IVF-ET cycle
(37). The above mentioned microbial examinations and blood (52). Meanwhile, other studies using a higher concentration
tests are not instrumental. Thus, histopathologic detection of of anti-CD138 antibodies (1:100 dilution of B-B4 or stock so-
multiple ESPCs in endometrial biopsy is of primary impor- lution of another frequently used clone B-A38) identified CE
tance in the diagnosis of CE in current clinical practice. in 12%–30% of infertile patients (8, 31, 53, 54). Accordingly,
Be that as it may, identification of ESPCs by conventional the standardized test setting and quality control for CD138
tissue staining alone is not easy even for experienced pathol- immunostaining are indispensable to minimize the
ogists. Plasmacytes typically have a large cell body, high discrepancies in the diagnosis of CE.
nuclei/cytoplasm ratio, basophilic cytoplasm, and nuclei The timing and method of endometrial sampling are also
with heterochromatin rearrangement referred as the ‘‘spoke- a major issue for accurate assessment of CE. ESPCs may be
wheel’’ or ‘‘clock-face’’ pattern (44). These morphological fea- missed in small biopsy specimens, as these lymphoid cells
tures of plasmacytes are not always evident in ESPCs under often gather focally within the endometrial stroma (4, 45).
microscopic examination, as ESPCs often exhibit an appear- In some cases of CE, ESPCs are identifiable only in the
ance similar to stromal fibroblasts and mononuclear leuko- endometrial basal layer. A study using full-thickness endo-
cytes that reside in the human endometrium. Some metrium of patients undergoing hysterectomy for benign pel-
histological findings common in the secretory phase endome- vic diseases demonstrated that overlooking of ESPCs can
trium such as superficial edematous change and elevated stro- occur more frequently in the endometrial samples obtained
mal cell density may also interfere with the identification of from surface layers during the secretory phase compared
ESPCs (45). Identification of glandular-stromal dyssynchrony with the proliferative phase (37). Indeed, several studies
and endometrial eosinophil infiltrates (cytoplasmic eosino- showed a higher prevalence of CE in the proliferative phase
philic granules) on routine hematoxylin and eosin staining than in the secretory phase (46, 55–57). Examiners should
sections was proposed as a convenient screening tool to be aware of the date in the menstrual cycle and the volume
discover ESPCs but are not the absolute findings in CE (46). of the endometrial biopsy specimens for the exact diagnosis
Histopathologic evaluation using immunohistochemistry of CE.
for plasmacyte marker CD138 (also known as syndecan-1, a Finally, stringent criteria have not yet been established
transmembrane-type heparan sulfate proteoglycan) is for the evaluation of the ESPC density in the endometrial bi-
currently the most reliable and time-saving diagnostic opsy specimen. Although the presence of multiple (two or
method for CE (47). It was shown that CD138 immunostaining more) ESPCs is a sine qua non for the confirmation of CE,
is greatly superior in the detection of ESPCs to conventional there are some biases and variances in definitions of CE
tissue staining using methyl green pyronin, hematoxylin, among the studies. While one study diagnosed CE with
and eosin (odds ratio, 2.8; sensitivity, 100% vs. 75%; speci- more than five CD138(þ) ESPCs in at least one out of three
ficity, 100% vs. 65%) with less interobserver (96% vs. 68%) sections levels in the endometrial biopsy specimens (47),
and intraobserver variability (93% vs. 47%) (48–50). others set the values for CE as one or more CD138(þ) ESPCs
Despite the usefulness of CD138 immunostaining in the in one microscopic high-power field (8). Another issue is
diagnosis of CE, some caution should be exercised in its prac- that the endometrium of the healthy women may potentially
tical use and interpretation of results. Endometrial epithelial contain some (even if only a few) ESPCs. It is crucial to rede-
cells are known to constitutively express CD138 on the baso- fine the minimum volumes of the endometrial samples eval-
lateral sides of their plasma membrane. Many of monoclonal uated and the cutoff density of ESPCs that is required for
antibodies targeting CD138 on plasmacytes are also reactive histopathologic diagnosis of CE.
to the epitope of this antigen expressed on endometrial epithe- Hysteroscopy has the potential to be a screening tool for
lial cells, despite that staining intensity is generally weaker CE. The representative hysteroscopic findings seen in CE are
than that in ESPCs (51). The conditions of the sections and endometrial micropolyposis and strawberry aspects. Endome-
immunoreactivity may occasionally cause misidentification trial micropolyposis is recognized as multiple small-sized
of endometrial epithelial cells for ESPCs, resulting in potential (typically 1–2 mm in diameter) protrusions arising from the
overdiagnosis of CE. Combined use of immunohistochemistry endometrial surface. Endometrial micropolyposis was found
and conventional nucleic staining is a recommended option to in 11% of women undergoing hysteroscopy and associated
avoid this kind of misinterpretation. with endometrial stromal edema and thickening (35). Endo-
There are currently no technical standards or conditions metrial micropolyposis is identifiable in 50%–67% of infertile
setting regarding CD138 immunostaining for endometrial women undergoing repeated implantation failure (RIF) and/or
specimens, suggesting that the diagnostic rates of CE are recurrent pregnancy loss (RPL) with immunohistochemically/

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 Fertility and Sterility®

histopathologically confirmed CE (9, 57, 58). The etiological deciduitis may represent chronic semiallograft rejection by
relationship between endometrial micropolyposis and CE the maternal immune system of the conceptus (75–77). The
remains yet to be elucidated. Meanwhile, strawberry aspects expression level of several proinflammatory genes (IGJ,
are characterized by the presence of the hyperemic IGLL1, CXCL13, CD27, CXCL9, CXCL10, ICOS, and KLRC1)
endometrial areas flushed with a white central point (59). is increased in the placenta with chronic deciduitis
Strawberry aspects were found in 65% of women with compared with in the placenta without inflammation
immunohistochemically/histopathologically confirmed CE (72, 78, 79). Overexpression of IgJ chain in chronic
(60). There is a good positive correlation (16%–54% in deciduitis seems to be attributable to placental infiltration
sensitivity and 60%–94% in specificity) between these of IgM and/or IgG-bearing PCs and immature B cells. An
unique hysteroscopy findings and CE, although the studies epidemiologic study supports the idea that chronic deciduitis
so far suggest that hysteroscopy cannot replace the originates in preconceptional CE rather than in ascending
histopathologic examinations using CD138 immunostaining infection during the gestational period (74).
in the diagnosis of CE (9, 19, 60–62).

TREATMENT FOR CHRONIC ENDOMETRITIS

REPRODUCTIVE FAILURE AND CHRONIC Accumulating evidence indicates the effectiveness of the oral
ENDOMETRITIS antibiotic treatment to eliminate ESPCs in CE. A few studies
The reported prevalence of CE in premenopausal women reported that some progestogens (such as megestrol acetate)
ranges from 8% to 72% (5, 61). This interstudy variance is, are another treatment option for CE, but the data are insuffi-
at least in part, due to the facts that CE was investigated in cient to demonstrate its effectiveness and safety (48).
a relatively small cohort (less than 100) of patients and that Based upon its broad antibacterial spectrum covering
the conventional tissue staining was used for detection of from common bacteria to mycoplasma, doxycycline has
ESPCs. Recent published data using CD138 immunostaining been used as a treatment of CE (3). Johnston-MacAnanny
estimated that the overall prevalence of CE in 1,551 et al. prescribed oral doxycycline (200 mg per day for
premenopausal women undergoing hysteroscopy and 14 days) in CE patients with a history of RIF, which resulted
endometrial biopsy was 24.4% (57). in the clearance of CD138(þ) ESPC in 70% (7/10) of the sec-
Several risk factors have been proposed in regard to the ond endometrial biopsy specimens in these women. An addi-
onset of CE. Among them is continuous use of intrauterine tional treatment with a combination of ciprofloxacin and
contraceptive devices, which is characterized by prolonged metronidazole (500 mg of each per day for 14 days) was effec-
ESPC accumulation even after their removal from the uterine tive to eliminate ESPCs in the remaining three patients resis-
cavity (37, 62). Multiparity, abortion, prolonged menstruation, tant to doxycycline (8). Using the same antibiotic regimen, we
atypical uterine bleeding, and fallopian tube obstruction prospectively investigated the effectiveness in a larger cohort
are also suggested to be the independent risk factors for of CE patients with a history of RIF (15). Oral doxycycline
CE, whereas age, obesity, oral contraceptive use, and (200 mg per day for 14 days) alone eradicated CD138(þ)
multigravidity are unlikely (37, 62–64). Bacterial vaginosis, ESPC in 92.3% (108/117) of CE patients and lowered the
endometriosis, endometrial hyperplasia, submucosal fibroids, detection rate of some pathogenic microorganisms including
tuberculosis, and endometrial osseous metaplasia were also corynebacterium, enterococcus, E. coli, Streptococcus agalac-
reported to be associated with CE (37, 65–70). tiae, U. urealyticum, and Ureaplasma parvum in the endome-
A growing body of evidence suggests a link between CE trium of these women, while increasing the detection rate of
and infertility. CE is diagnosed in 28% of infertile patients lactobacillus species. Moreover, the overall cure rate of CE
with unknown etiology, 14%–41% of patients with RIF, and was 99.1% (116/117 patients) following second-line treat-
8%–28% of patients with RPL (9–11, 37, 54, 57, 71). The ment with metronidazole (500 mg per day for 14 days)/cipro-
infertile CE women with a history of RIF have a significantly floxacin (400 mg per day for 14 days) for patients resistant to
lower implantation rate in the IVF-ET cycle after endometrial doxycycline.
biopsy than those with RIF but without CE (15% vs. 46%) (8). According to the results of the endometrial microbial ex-
Likewise, the per-pregnancy live birth rate in women with a aminations, Cicinelli et al. classified the antibiotic regimens
history of RPL and untreated CE is very poor (7%) (10). for the treatment of CE women with a history of RIF (11). Cip-
Furthermore, women of reproductive age who contracted CE rofloxacin (1,000 mg per day for 10 days) was used for most
were at 60% higher risk of future infertility compared with patients who were positive for Gram-negative bacteria,
the non-CE cohort (19). whereas a combination of amoxicillin/clavulanate (2 g per
Diffuse and extensive plasmacyte infiltration is occasion- day for 8 days) was given to those with Gram-positive bacte-
ally found in the basal plate of the placenta of women under- ria. The patients with mycoplasm and/or ureaplasm species
going obstetric complications, which is denoted as chronic were treated with josamycin (2 g per day for 12 days) along
deciduitis (72). Chronic deciduitis was reported to be linked with minocycline (200 mg per day for 12 days) as the
to preterm labor (41%) (72, 73) and neonatal periventricular second-line regimen. The patients with negative endometrial
leukomalacia/cerebral palsy (20%) (74). Intriguingly, chronic microbial examinations were administered a combination of
deciduitis is seen more frequently in IVF-ET pregnancies re- ceftriaxone (250 mg, single dose, IM injection), doxycycline
sulting from donor eggs (2.8%–42%) compared with those (200 mg per day for 14 days), and metronidazole (1,000 mg
from autologous eggs (1.6%–1.8%), suggesting that chronic per day for 14 days). In this retrospective study, 28% (17/

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VIEWS AND REVIEWS

61) of the patients overcame CE with a single course of anti- tive three ET cycles), suggesting that the effectiveness of the
biotic regimen, whereas 23% (14/61) and 25% (15/61) antibiotic treatment for CE is independent of endometrial
required the second course and the third course of antibiotic scratching effect (80).
treatment, respectively. The remaining 25% (15/61) were In infertile women with tuberculosis-associated CE, anti-
resistant to three-time repetition of the same regimen. tubercular chemotherapy based on a positive endometrial
McQueen et al. (10) treated infertile CE women with a his- biopsy–polymerase chain reaction test improved their repro-
tory of early RPL and/or fetal demise. The first-line combina- ductive outcomes (69). After 6-month administration of the
tion of ofloxacin (800 mg per day for 14 days) and antitubercular agents, the clinical pregnancy rate within
metronidazole (1,000 mg per day for 14 days) was effective 12 months was about 90%.
for 73% (19/26) of patients. All of the remaining nine patients These findings support the idea that antibiotic treatment
resistant to this combination were cured with the second-line is a promising therapeutic option to improve the pregnancy
regimens using doxycycline alone, doxycycline and metroni- outcome in infertile women with CE. Prospective randomized
dazole, or metronidazole and ciprofloxacin. controlled trials are required to verify these results.
For infertile women with chronic granulomatous endo-
metritis, antitubercular chemotherapy including isoniazid
(300 mg per day), rifampicin (450–600 mg per day), etham-
CONCLUSION
butol (800–1,200 mg per day), and pyrazinamide (1,200– The impact of endometritis, particularly of CE, on human
1,500 mg per day) was shown to be effective (69). pregnancy has been extensively researched over the last
decade, and the potential association is becoming more
apparent. However, clinical evidence is still scarce about the
PREGNANCY OUTCOME AFTER ANTIBIOTIC causality between endometritis and reproductive failure
TREATMENT FOR CHRONIC ENDOMETRITIS including RIF, RPL, and obstetric complications. The intro-
Some studies suggest that oral antibiotic treatment poten- duction of molecular microbial technology (i.e., microbiome)
tially improves the pregnancy outcome in infertile women into clinical practice is being actively carried out. Recent
with CE. comprehensive microbial analysis based on next-generation
In their retrospective analysis, Cicinelli et al. investigated sequencing of the 16S ribosomal subunit and/or focused
pregnancy outcomes after antibiotic treatment in CE patients real time polymerase chain reaction was shown to be a fast
with a history of RIF (11). In the subsequent fresh day 3 ET cy- and inexpensive tool that can allow for the identification of
cle, the live birth rate (60.9%, 28/46 vs. 13.3%, 2/15) was both culturable and nonculturable pathogenic microorgan-
higher in the cured CE group than in the persistent CE group. isms associated with CE (22, 81, 82). These new approaches
No difference was found in the live birth rate between the pa- have the potential to shed light on the relationship between
tients undergoing single course antibiotic treatment and those endometritis and unknown infectious conditions in the
undergoing multiple course antibiotic treatment. Cicinelli uterine cavity.
et al. recently reported similar results in 95 infertile CE women
with unexplained etiology (71). The cumulative live birth rate REFERENCES
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