JBRA Assisted Reproduction 2022;26(3):538-546

doi: 10.5935/1518-0557.20220015 Review

Endometritis - Diagnosis,Treatment and its impact on fertility - A

Scoping Review
Neeta Singh1, Ankita Sethi1

1
Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, New Delhi, India

ABSTRACT DISCUSSION
Endometritis is defined as an infection or inflammation Endometritis can be divided into two subcategories
of the endometrium. Endometritis is of two types: acute based on histopathology, as acute or chronic endometritis.
and chronic. Acute endometritis is the symptomatic acute
inflammation of the endometrium, which upon examination 1 Acute Endometritis
with a microscope shows micro-abscess and neutrophil
invasion in the superficial endometrium. One of its most 1.1 Definition and Clinical presentation
common manifestations is postpartum endometritis. Acute Endometritis is characterized in histopathology
Chronic endometritis is a silent disease usually diagnosed by micro-abscesses in the endometrium and presence of
on the workup of secondary amenorrhoea and infertility. neutrophils in the superficial epithelium and in the lumen
An important cause of chronic endometritis is tuberculosis, of the glands of the endometrium. Acute endometritis
especially in developing nations. Chronic and acute presents with symptoms such as fever, pelvic pain, in-
endometritis have been associated with poor reproductive creased vaginal discharge, bad odour, unusual consistency
outcomes. Worse outcomes have been reported for and colour, abdominal pain and distension, abnormal vagi-
individuals with chronic endometritis. This is a scoping nal bleeding, abnormal bowel movements, and generalised
review of endometritis and its impact on fertility. malaise.
Group A streptococcus endometritis presents with pain,
Keywords: acute endometritis, chronic endometritis, diarrhoea and vaginal discharge, and may progress to sep-
infertility, Asherman’s syndrome, thin endometrium sis, toxic shock and necrotising fasciitis. Therefore, these
patients should be treated with utmost care. On clinical
examination, patients may present with vaginal discharge,
uterine or cervical tenderness, and decreased bowel
INTRODUCTION sounds in case of pelvic abscess. According to the CDC
(Centers for Disease Control and Prevention) guidelines,
Endometritis is defined as an infection or inflammation
a diagnosis of acute PID (Pelvic inflammatory disease) re-
of the endometrium. The normal endometrium does not
quires the identification of at least one of the following
harbour any microorganisms, but microbes from the cervix
clinical findings: adnexal or cervical or uterine tenderness.
and vagina can ascend upwards and lead to inflammation
and infection of the endometrium. A very common cause
1.2 Etiopathogenesis
of postpartum endometritis is preterm prelabour rupture
Endometritis results from the ascension of bacteria
of membranes (PPROM) (Sherman et al., 1999). Puerper-
from the cervix and vagina into the uterus. The uterus
al/Postpartum endometritis is more frequently seen in pa-
does not harbour microorganisms until the amniotic sac
tients with caesarean sections than normal vaginal delivery
ruptures, which thus provides passage for bacteria to as-
and is polymicrobial in nature (Chaim et al., 2000). Chronic
cend into the uterus. Microorganisms tend to harbour in an
endometritis is a silent disease usually diagnosed on the
endometrium that is then devitalized and injured (such as
workup of secondary amenorrhoea and infertility.
in case of a caesarean section or uterine surgery). In any
pelvic procedure, if proper asepsis is not maintained or if
METHODS the woman has an untreated vaginal infection prior to a
A literature search was performed on the following pelvic intervention such as dilatation, curettage, or endo-
databases: MEDLINE, Google Scholar, Scopus, EMBASE, metrial aspiration, then the risk of endometritis is higher.
Global health, the COCHRANE library, and Web of Science. Patients without risk factors may still have endometritis
We searched these databases for studies published until following normal spontaneous vaginal delivery, with an in-
July 2020 in the English language. The literature search cidence of 1-2% (Boggess et al., 2017). Patients with risk
was conducted using the combination of the following factors incidence increase to 5-6%. Risk factors include
Medical Subject headings (MeSH) and relevant keywords being a young female from a lower socioeconomic status,
in different orders: “endometritis”, “acute”, “chronic”, having a high BMI (body mass index), prolonged rupture
“management”, “diagnosis”, “immunohistochemical”, “hys- of membranes, repeated per-vaginal examinations, fe-
teroscopy”, “medical management”, “tubercular”, “Asher- tal scalp sampling/monitoring, chorioamnionitis, meco-
man’s”, “infertility”, “pathophysiology” and “reproductive nium-stained amniotic fluid, and undiagnosed untreated
outcome”. The reference lists of the included studies were vaginal infection (Boggess et al., 2017). The route of deliv-
also checked to look for studies that were not found in the ery is the most important risk factor. Caesarean deliveries
electronic literature search. A total of 328 articles were have higher risk of endometritis than normal vaginal deliv-
found pertaining to endometritis. Original articles and ery (Karsnitz, 2013).
some review articles published within the last five years Acute Endometritis: Acute infections can be caused
were given priority. All articles were accessed in full text. by both aerobes and anaerobes. Post-caesarean section
In this review, individual data sources were not sought for, endometritis is generally due to Streptococcus pyogenes
and a descriptive analysis was done. The data were sum- and Staphylococcus aureus infection. Chlamydia endo-
marized in the form of a descriptive review. metritis has a late presentation and generally manifests

Received July 3, 2021

538
Accepted January 29, 2022
 Endometritis and impact on fertility - Singh, N. 539

seven days after delivery (Morgan & Roberts, 2013). Table ultrasound. CT scans can show infection and inflammation
1 enumerates the aerobic and anaerobic bacteria that may of the surrounding uterine tissue or parametrium (Nalaboff
cause acute endometritis. et al., 2001; Vandermeermd & Wong-You-Cheong, 2010;
Plunk et al., 2013; Laifer-Narin et al., 2014).
1.3 Laboratory Evaluation
Diagnostic investigations for acute endometritis include 1.5 Treatment
total leucocyte count, swab culture from cervix, and micro- Apart from symptomatic management, rest, adequate
scopic examination of vaginal discharge samples. Patients hydration and antibiotics need to be started immediate-
unresponsive to treatment may have a pelvic abscess; ly through the intravenous route for the first 48 hours,
these cases require a laparoscopic procedure to drain the followed by oral antibiotics in cases of severe infection;
abscess, followed by intravenous antibiotics in the post- otherwise, oral antibiotics should be given to patients with
operative period. Proper clinical evaluation and diagnosis mild to moderate disease. Simultaneously, sexual part-
are required, since wrong diagnosis and treatment of PID ner/s need to be treated and advised on use of barrier
(Pelvic inflammatory disease) unnecessarily hampers pa- contraceptives (Workowski & Bolan, 2015).
tient quality of life. For instance, signs of cervicitis or vag- Treatment of acute endometritis should provide broad
initis along with one of the minimum criteria, increases spectrum coverage against the pathogens most likely
the probability of an accurate diagnosis. Table 2 enumer- causing the infection. Treatment should begin as early as
ates the findings and the clinical criteria that increase the possible, as this helps to prevent of long-term complica-
specificity of a diagnosis of PID as per the CDC guidelines tions. Appropriate treatment regimen selection depend on
(2015) (Workowski & Bolan, 2015). Table 3 enumerates availability, acceptability, and cost. In mild and moderate
the most specific findings for the diagnosis of PID. PID, parenteral and oral treatment regimens are equally
In women undergoing a diagnostic laparoscopy for PID, efficacious. The need of hospitalisation should be decided
endometrial aspirate should be taken if there is no sign of based on clinical assessment (Workowski & Bolan, 2015).
salpingitis, since in some women endometritis alone may Table 4 enumerates the factors that, when associated with
be present without signs of PID. acute endometritis, decide in favour of patient hospital-
isation.
1.4 Imaging Parenteral Treatment (Workowski & Bolan, 2015)
Ultrasound helps in the diagnosis of postpartum pa- Oral Medications can be started usually within 24 to
tients with abdominal pain and fever. Ultrasound findings 48 hours of observable clinical improvement. Presence of
of endometritis are a thickened, heterogeneous endome- tubo-ovarian abscesses mandates hospital admission and
trium, fluid collection in the uterus, and foci of air in the observation for at least 24 hours.
uterus (Karsnitz, 2013). Recommended Parenteral Regimens according to CDC
Differential diagnosis includes retained products of 2015 guidelines are:
conception, infected blood collection (as blood is a good
culture media for any bacteria), and pus collection. • Inj Cefotetan 2g iv BD (twice a day) or Inj Cefoxi-
Clots and debris may be present in up to 24% of post- tin 2 g iv QID (four times a day) plus Tab Doxycy-
partum patients (Plunk et al., 2013). In normal and healthy cline 100 mg BD
postpartum patients, ultrasound examination may find gas • Tab doxycycline 100 mg BD is given orally after
in the endometrium up to three weeks after delivery. The 24–48 hours of clinical improvement to complete
ultrasound findings used to diagnose endometritis may also the two weeks therapy or
be seen in normal postpartum patients; therefore, good • Inj Clindamycin 900mg intravenous (iv) every 8
clinical acumen is required to arrive at the final diagno- hours along with inj Gentamycin loading dose iv
sis. A patient with endometritis may have a normal pelvic (2 mg/kg), (followed by a maintenance dose of

Table 1. Aerobic and anaerobic bacteria causing acute endometritis

Aerobic Bacteria Anaerobic Bacteria
• group A Streptococci • Peptostreptococcus
• group B Streptococci • Peptococcus
• Staphylococcus • Bacteroides
• E.coli • Prevotella
• Klebsiella pneumoniae • Clostridium
• Enterococcus
• Proteus

Table 2. As per the CDC (Centers for Disease Control and Prevention) guidelines (2015) (Workowski & Bolan, 2015), one
of the findings listed below along with clinical criteria increase the specificity of diagnosing Pelvic Inflammatory Disease
Pelvic Inflammatory Disease: findings
• Neisseria Gonorrhoeae or Chlamydia Trachomatis cervical infection

• Elevated ESR (Erythrocyte Sedimentation rate)

• Elevated CRP (C-Reactive Protein)
• Abnormal cervical discharge
• Abundant WBCs (White blood cells) in vaginal fluid on saline microscopy

• Fever (temperature >101°F />38.3°C)

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Table 3. The most specific findings for the diagnosis of PID (Pelvic Inflammatory Disease)
The following findings are the most specific for arriving at a diagnosis of PID:
• Histopathology diagnosis of endometritis on endometrial aspirate tissue sample.
• Hydrosalpinx with or without free pelvic fluid on transvaginal sonogram or
• MRI showing TO (tubo-ovarian) mass, or
• Doppler studies suggestive of pelvic infection (e.g. tubal hyperaemia)
• Hysterosalpingography (HSG) is not recommended in acute infection, but if HSG is done then irregularity of the contour
of the endometrial cavity and intravasation of contrast into the vascular and lymphatic system is sign of acute endometritis.
• Acute Salpingitis is identified by a ragged contour of the lumen of the tubes and diverticular outpouchings on HSG. Pelvic
tuberculosis leads to oedematous thickening of the walls of the tubes and dilatation. The tubes are dilated, convoluted
and form a C or S shape. On HSG, tubercular salpingitis presents as hydrosalpinx, beaded tubes (lead pipe appearance).
• Hysteroscopy is not recommended in acute infection (endometritis/salpingitis)
• In chronic endometritis, hysteroscopic features: endometrial micropolyposis, they are multiple 1–2 mm sized protrusions
or polyps arising from the endometrium with associated endometrial stromal thickening and oedema
• Laparoscopically proven signs of PID

such as pigtail insertion may be required if the infection

Table 4. Factors that decide for need of hospitalization
has produced a drainable fluid collection (Karsnitz, 2013).
Hospitalization In the long run, if not treated properly or incompletely,
Acute abdomen (Surgical emergency)
patients may develop pelvic adhesions, distortion of the
pelvic anatomy, disturbed tubo-ovarian relationship, and
TO or pelvic abscess intrauterine adhesions, which may eventually lead to in-
PID in Pregnancy fertility. Acute endometritis may lead to Asherman’s syn-
drome and eventually uterine factor infertility or secondary
High grade fever amenorrhoea.
Excessive nausea and vomiting
1.7 Prevention
Non-compliance with oral regimen Endometritis can be prevented by early detection and
No improvement to oral antibiotics management of STIs (Sexually transmitted infections),
safer sex practices, sterile techniques during pelvic proce-
dures such as vaginal delivery, C-section, abortions, etc.
1.5 mg/kg) every 8 hours. Single daily dosing (3-5
1.8 Differential Diagnosis
mg/kg) can also be substituted alternatively.
Whenever a postpartum patient presents with post-
• Oral therapy with Tab Clindamycin 450 mg QID PO
partum fever and abdominal pain, the following conditions
(per orally) or Tab Doxycycline 100 mg BD can be
should be considered in differential diagnosis: lower uri-
used to complete the two weeks therapy
nary tract infections, pneumonia, and septic pelvic throm-
Intramuscular (IM) and Oral Treatment (Workowski &
bophlebitis. If the patient does not improve clinically even
Bolan, 2015)
after antibiotic and/or surgical management for endome-
Oral or Intramuscular treatment are recommended
tritis, then the conditions mentioned above should be con-
and can be administered to patients with mild or moder-
sidered and the patient re-evaluated (Karsnitz, 2013).
ate acute PID. Intramuscular or oral therapy produces the
same clinical outcomes in patients with mild or moderate
PID. Patients not responding to oral/IM treatment with- 1.9 Prognosis
in 72 hours should be reassessed and given intravenous Delayed initiation of treatment has been associated
therapy. with a mortality rate of approximately 17%. Death rate
Recommended Regimens is reduced to 2% with early recognition and appropriate
• Inj Ceftriaxone 250mg i.m. single dose and Tab treatment. Caesarean deliveries have a 25-fold increase
Doxycycline 100 mg BD with or without Tab Metro- in endometritis-related mortality (Meaney-Delman et al.,
nidazole 500 mg BD for 2 weeks 2015).
• Single dose of Inj Cefoxitin 2 g i.m. and Probenecid
1 g orally and Tab Doxycycline 100 mg BD for 2 2. Chronic Endometritis
weeks with or without Tab Metronidazole 500 mg
BD for 2 weeks 2.1 Definition and histopathology
• Injectable third generation cephalosporin and Tab Chronic endometritis (CE) is a disorder of prolonged,
Doxycycline 100 mg BD for 2 weeks with or with- continuous, mild endometrial inflammation, which is char-
out Tab Metronidazole 500 mg BD for 2 weeks acterized by plasma cell infiltration into the endometrial
stromal area. The prevalence of chronic endometritis is
1.6 Complications often underestimated because it is a condition difficult to
One to four per cent of patients with acute PID may diagnose. According to the literature, the prevalence of
have complications such as pelvic peritonitis, pelvic ab- chronic endometritis ranges from 0.2% to 46%, depending
scess, septicaemia, septic shock, septic pelvic throm- on patient profile and biopsy method. Kushnir et al. (2016)
bophlebitis and necrotizing fasciitis, which may lead to found that 45% of infertile patients had chronic endome-
uterine necrosis and eventually hysterectomy for the in- tritis, especially those with recurrent implantation failure.
fection to resolve. Pus drainage or a surgical intervention Histopathology is characterised by superficial endo-
metrial lining oedema, abnormally increased stromal cell

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 Endometritis and impact on fertility - Singh, N. 541

density, asynchronous maturation between stroma and heterochromatin rearrangement in the nucleus classical-
epithelium, endometrial infiltration with plasma cells (En- ly referred to as the spoke wheel pattern, and basophilic
dometrial stromal plasma cells/ESPCs). Presently, there is cytoplasm
no standardized or accepted definition for chronic endo- On routine Hematoxylin and Eosin (H & E) staining,
metritis, but the presence of numerous endometrial stro- identification of asynchronous stromal and glandular ap-
mal plasma cells (ESPCs) is the most sensitive and specific pearance and endometrial eosinophil infiltrates is an easy
finding for diagnosing and defining this disease (Kitaya & screening method to look for endometrial stromal plasma
Yasuo, 2011; Kitaya et al., 2018). cells/ESPCs, but they are not the only histological changes
in chronic endometritis (Kitaya & Yasuo 2011; Kitaya et
2.2 Clinical Presentation al., 2018).
Chronic Endometritis has ill-defined symptoms such as The most reliable diagnostic method for chronic endo-
pelvic discomfort, spotting and leucorrhoea. Patient may metritis is immunohistochemistry (IHC) for CD138, which
also complain of hypomenorrhoea, secondary amenor- is not just specific but also time saving. CD138 is also
rhoea, and infertility. called syndecan-1, a transmembrane heparin sulphate
proteoglycan and a plasma cell marker.
2.3 Etiopathogenesis
The uterus consists of three layers: the perimetrium or Problems in diagnosing chronic endometritis
outer serosal layer of the uterus, the middle smooth mus- Even experienced pathologists have trouble identi-
cle called the myometrium, and the innermost layer known fying ESPCs on conventional tissue staining. ESPCs are
as the endometrium. The endometrium has two layers: an difficult to identify because they closely resemble mono-
inner glandular layer, which is functional with a stroma that nuclear cells (leucocytes) and stromal fibroblasts in the
is formed by supporting connective tissue and an outer endometrium. Increased stromal cell infiltration into the
basal layer that provides raw material for regenerating the endometrium interferes with ESPC identification. Technical
overlying functional layer after each menstrual cycle. standards and specifications on CD138 immunostaining for
Under normal conditions, the monthly cycling endome- endometrial specimens are currently lacking and there is
trium is infiltrated by a wide variety of leucocytes (immu- little international agreement on the subject. Further stan-
nocompetent cells), which include NK cells, macrophages, dardization and improved quality control for CD138 im-
and T cells. The density and composition of these immuno- munostaining is required to make the diagnosis of chron-
competent cells vary cyclically across the menstrual cycle. ic endometritis more specific. The timing and technique
This fluctuation in local leukocyte subtypes is thought to of endometrial aspiration are important for the correct
contribute to pathogenesis by affecting tissue remodelling analysis of chronic endometritis. ESPCs may be missed if
that makes the endometrium receptive in nature. biopsy samples are inadequate. Literature shows that a
Correct tissue diagnosis of chronic endometritis has diagnosis of chronic endometritis is often possible when
been considered demanding and time-consuming. Recent- tissue samples are taken in the proliferative phase of the
ly, focus has shifted to the potential association between endometrium rather than the secretory phase. Therefore,
chronic endometritis and poor reproductive outcome. it is necessary to know the phase of the menstrual cycle
Chronic endometritis is most commonly caused by and the endometrial biopsy volume to accurately diagnose
chronic bacterial infection of the innermost lining of the individuals with chronic endometritis. The endometrium of
uterus. In the South-Asian subcontinent, Mycobacterium a healthy fertile woman may also show few endometrial
tuberculosis causes chronic granulomatous endometritis, stromal plasma cells (ESPCs). It is important to define the
a subtype of chronic endometritis. This is characterized by minimum amount of the endometrial aspiration sample re-
multiple caseating granulomas and lymphocyte infiltrates quired and determine the cut-off density of endometrial
including endometrial stromal plasma cells. In developing stromal plasma cells required for histologically identifying
nations, it is very common to have infertile individuals test- chronic endometritis.
ed for endometrial aspirate histopathology, AFB (acid fast
bacilli) stain, and PCR of M. tuberculosis testing to detect Microbial Culture
genital tuberculosis, a very common cause of infertility, is Bacterial culture is one of the most important tools in
also performed. Patients are treated with anti-tubercular the diagnosis of chronic endometritis. This technique al-
therapy prior to infertility treatment. Patients with chron- lows the identification of pathogens and the prescription of
ic granulomatous endometritis caused by M. tuberculosis targeted therapy.
generally develop Asherman’s syndrome intrauterine ad- Limitations of endometrial culture include contamina-
hesions because of endometrial injury, which leads to sec- tion with vaginal bacteria, limited culturability of fastidi-
ondary amenorrhoea and endometrial cause of infertility. ous organisms, and delays in culturing bacteria. The use of
Microorganisms often detected in endometrium with RT-PCR might alleviate several limitations of conventional
chronic endometritis include E. coli, Streptococcus, En- culture techniques by providing fast and more accurate
terococcus, Staphylococcus, Mycoplasma spp, Ureaplas- profiling of the microorganisms responsible for chronic en-
ma urealyticum, Gardnerella vaginalis, Proteus, Klebsiella dometritis (by facilitating the identification of culturable
pneumoniae, Pseudomonas aeruginosa, Corynebacterium, and non-culturable bacterial DNA).
Yeasts (Saccharomyces and candida spp), and Mycobacte- Moreno et al. (2018) conducted a prospective cohort
rium tuberculosis (Kitaya & Yasuo, 2011). study in which endometrial samples were taken from pa-
C. trachomatis and N. gonorrhoeae, the principle tients suspected for chronic endometritis. A multiplex RT
pathogens associated with acute endometritis, are seldom method was used for non-culturable strains and endo-
found in chronic endometritis (2% to 8% and 0% to 7%, metrial samples were inoculated onto media containing
respectively). These differences in microbiological profiles columbia-colistin-nalidix acid agar with 5% sheep blood,
suggest that acute and chronic endometritis are two dis- for gram-positive organisms, and MacConkey agar and
tinct entities pathologically. mannitol salt agar for gram-negative bacteria and Staph
aureus. RT-PCR testing was done using specific primers
2.4 Evaluation for the nine most common bacteria responsible for causing
On histopathology, chronic endometritis is character- chronic endometritis. 16S ribosomal RNA sequencing was
ised by endometrial stromal plasma cells, plasma cells with done and endometrial microbiome profiles were obtained
a characteristically high nuclear-cytoplasmic (N/C) ratio, with Next Generation Sequencing. The authors found that

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Review 542

RT-PCR testing was useful in the molecular diagnosis of of chronic endometritis. The correlation between microp-
chronic endometritis from endometrial samples, since it olyposis of the endometrium and chronic endometritis is
uses a comprehensive panel of primers to detect the most still unclear. Strawberry spots are hyperaemic endometrial
commonly involved microorganisms. RT-PCR can detect in- areas flushed with a white central point on the endometri-
trauterine microbiome when histology is negative; when um visualised during hysteroscopy. They are found in 65%
histology is positive, RT-PCR can also inform the choice of women with a tissue diagnosis of chronic endometritis.
of target therapy. The limitations of chronic endometritis Endometrial micropolyposis and strawberry spots on hys-
diagnosis using individual classic techniques and their mis- teroscopy have 16-54% sensitivity and 60-94% specificity
leading results were evident in this study, in which only for diagnosing chronic endometritis (Cicinelli et al., 2005;
13 of 65 (20%) of the samples/patients analysed present- Johnston-MacAnanny et al., 2010). The literature suggests
ed concordant results using all three diagnostic methods that tissue diagnosis with CD138 immunostaining is better
(Moreno et al., 2018). than hysteroscopy in diagnosing chronic endometritis.
Cicinelli et al. (2019) conducted a study to propose
Imaging diagnostic criteria for chronic endometritis based on hys-
HSG may be performed to evaluate tubal status in in- teroscopy, and validated the proposed criteria in a RCT.
fertile women. HSG is contraindicated if acute infection Hysteroscopy is considered as the standard procedure in
is suspected. If HSG is performed during acute infection, the evaluation of the uterine cavity in patients with intra-
acute endometritis manifests with an irregular endometrial uterine conditions such as infertility, RPL, myomas, abnor-
cavity and intravasation of contrast into the vascular and mal uterine bleeding, etc. (Cicinelli et al., 2019). Cicinelli et
lymphatic system (Shah et al., 2015). Chronic endometri- al. (2005) were the first to find the combination of stromal
tis presents with calcification of the endometrium on plain oedema, micropolyps, and focal hyperaemia in subjects
film and irregularity of the endometrial cavity on contrast with chronic endometritis, as later confirmed by other au-
film due to fibrosis, scarring, and calcification. HSG is a thors.
useful diagnostic tool to detect intrauterine adhesions or The authors found that strawberry spots on the en-
Asherman’s syndrome, which are seen as irregular filling dometrium were frequently seen in patients with chronic
defects (linear, angulated, or stellate shaped) with well-de- endometritis, either as an isolated finding or in association
fined borders. If there are grade IV intrauterine adhesions, with endometrial alterations (e.g. focal hyperaemia). Hae-
then the cavity fails to distend and presents with significant morrhagic spots are caused by chronic inflammation and
reductions of volume and capacity (Shah et al., 2015). lead to vascular damage. Chronic inflammation can lead to
Klein et al. (1976) described the criteria to diagnose fibrinoid degeneration or, in rare occasions, to the forma-
Genital TB based on the following HSG findings: intrauter- tion of thrombi in the vessel wall leading to angiopathy/
ine adhesions in the absence of history of curettage or vasculopathy, in patients with chronic endometritis.
surgical termination of pregnancy, multiple constrictions in On hysteroscopy, chronic granulomatous endometri-
the fallopian tubes, obstruction of the isthmo-ampullary tis or genital tuberculosis present as pale-looking cavity,
level of fallopian tubes, and calcification of lymph nodes or tubercles, caseous nodules, and/or intrauterine adhesions
irregular linear/nodular calcifications in the adnexal area. or Asherman’s syndrome (Sharma et al., 2008; 2009). A
On ultrasound (USG), patients with chronic endometri- study by Kumar & Kumar (2007) documented a shining
tis may present with a thin endometrium with hyperechoic star sign on hysteroscopy in patients with genital tubercu-
areas that represent foci of calcification or fibrosis (Shah losis, which actually were white caseous nodules as stars
et al., 2015), irregular endometrial lining; 4D USG shows shining against the blue background of methylene blue
irreversible sequelae of fibrosis and scarring or intrauter- dye. Hysteroscopy in patients with genital tuberculosis is
ine adhesions (Asherman’s Syndrome). On saline infusion difficult and poses a significant risk of complication. Pa-
sonography, intrauterine adhesions appear as linear echo- tients with the condition have a small shrunken cavity, and
genic bridges in the fluid filled uterine cavity; this is a good should preferably undergo laparoscopic guided operative
technique to diagnose Asherman’s syndrome. Deformed or non-operative hysteroscopy procedure performed by an
uterine cavity can give rise to various abnormal shapes expert gynaecologist (Sharma et al., 2011).
and the HSG appearance may mimic a pseudo-unicornuate
uterus or a T-shaped uterus (Shah et al., 2015). 2.5 Treatment / Management
Patients with suspected genital tuberculosis, secondary Treatment of chronic endometritis revolves primari-
amenorrhoea or infertility or with associated tubo-ovarian ly around oral antibiotics, depending on the culture and
masses, may undergo imaging like USG, MRI, CT scan or gram stain findings of the endometrial aspiration/biopsy;
PET- CT scan. A study by Sharma et al. (2012) found that endometrial aspiration is repeated after treatment. There
the detection rates of tubo-ovarian masses with PET CT is no defined antibiotic regimen for chronic endometritis.
was similar to CT or MRI, but the characterization of ad- Different antibiotics and dosages have been prescribed.
nexal masses was less accurate than in CT or MRI. PET-CT Endometrial receptivity tends to improve after antibiotic
was equally precise in detecting the presence or absence, therapy.
localization, and activity of tubo-ovarian (TO) masses, Various antibiotic regimens have been tried. The first
when compared with laparoscopy or laparotomy. line regimen is Tab Doxycycline 100mg BD for 14 days.
Second-line therapy includes ciprofloxacin and metronida-
Hysteroscopy zole 500 mg OD for two weeks or ofloxacin 400 mg OD for
Hysteroscopy can be a useful screening tool for chronic two weeks and metronidazole 500 mg OD for two weeks.
endometritis (Féghali et al., 2003; Johnston-MacAnanny Cicinelli et al. (2015) described the prescription of spe-
et al., 2010). Hysteroscopic findings seen in chronic en- cific antibiotic regimens to infertile chronic endometritis
dometritis are endometrial micropolyposis, described as patients according to their microbiologic profiles. Patients
multiple 1–2 mm protrusions or polyps arising from the en- with Gram-negative and Gram-positive bacteria were
dometrium with associated endometrial stromal thickening treated with ciprofloxacin 500 mg twice daily for 10 days
and oedema, found normally in 11% patients on routine and amoxicillin-clavulanic acid combination 2 g once a day
hysteroscopy and present in 50 to 67% of women with for 8 days. Patients with Mycoplasma or Ureaplasma infec-
infertility having either recurrent pregnancy loss (RPL) or tion were administered josamycin 2 g per day for 12 days,
repeated implantation failure (RIF) with tissue diagnosis while minocycline 200 mg per day for 12 days was given

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 Endometritis and impact on fertility - Singh, N. 543

to resistant cases. Chronic Endometritis has been found in ATT. Therefore, early detection of tubercular endometritis
25% of patients even after three courses of oral antibiotic is very important. Early ATT improved menstrual cycle, en-
therapy, which indicates reasonable efficacy of oral antibi- dometrial thickness, and reduced incidence of grade I ad-
otic therapy for chronic endometritis. Cicinelli et al. (2015) hesions, an indication that it may improve the reproductive
also reported that clinical pregnancy rate and eventually outcomes of these patients. Individuals with advanced dis-
live birth rate in IVF patients was significantly higher in pa- ease do not improve with ATT and have poor reproductive
tients showing response to oral antibiotic treatment (65% outcomes (Bhagwan Sharma et al., 2016). Another study
and 60.8%, respectively) than in patients with persistent by Sharma and Singh et al. looked into the differences in
chronic endometritis (33% and 13.3%, respectively). efficacy of 6-month or 9-month ATT in patients with gen-
Few authors have described a correlation between an- ital tuberculosis and found that there was no difference
tibiotic administration and IVF outcomes in patients with in complete cure, recurrence, or pregnancy rates between
chronic endometritis. Vitagliano et al. (2018) conducted a 6-month and 9-month ATT administration (Sharma et al.,
meta-analysis to study the effects of antibiotic treatment 2016).
for chronic endometritis on the outcome of IVF in patients
with recurrent implantation failure. Patients having cured 2.6 Chronic Endometritis and Reproductive Out-
chronic endometritis showed higher clinical pregnancy comes
rates (OR, 4.02), live birth rates (OR, 6.81), and implan- If chronic endometritis is not diagnosed in a timely
tation rates (OR, 3.24) than patients with persistent endo- and systematic manner, it may become one of the factors
metrial infection (Vitagliano et al., 2018). leading to recurrent IVF failure. Recurrent IVF failure be-
Sfakianoudis et al. (2018) published a retrospective cause of chronic endometritis causes psychological stress,
case series and found three patients with repeated implan- frustration, and a financial burden for couples, potentially
tation failures (RIF) and unsuccessful treatment of chronic leading to higher risk complications.
endometritis. Based on antibiogram results, accurate an-
tibiotic treatment was prescribed. Patients with chronic Assisted reproduction in females with genital
endometritis after oral antibiotic treatment were given an tuberculosis
infusion of intrauterine antibiotic. Two of the three patients Patients with genital tuberculosis have a high incidence
reported on-going, complication-free pregnancies at 19 of infertility despite ATT, with conception rates of only 19.2
weeks and 20 weeks. Studies with animal models have de- per cent (Tripathy & Tripathy, 2002). Patients with blocked
scribed decreased presence of microbes in the uterine cav- tubes but a normal endometrium submitted to IVF-ET en-
ity and enhanced local immune defence in subjects treated joy better fertility outcomes (Parikh et al., 1997; Jindal et
with intrauterine infusion of antibiotics. Treatment resulted al., 2012). A study by Parikh et al. (1997) documented a
in the restoration of the endometrium (Sfakianoudis et al., pregnancy rate of 16.6% after IVF-ET and ATT in patients
2018). with normal endometria. Jindal et al. (2012) observed a
population of women with tuberculosis and found a preg-
Treatment of chronic granulomatous endometritis nancy rate of 17.3% in IVF-ET as compared to only 4.3%
or tubercular endometritis is anti-tubercular therapy after fertility enhancing surgery for tubal block. Gesta-
(ATT) tional surrogacy is an option for patients with a normal
All new cases that are drug sensitive and are either ovarian reserve and intrauterine adhesions (endometrium
diagnosed clinically or confirmed microbiologically should destroyed with genital tuberculosis). Studies have docu-
receive combination therapy. Medical therapy with an- mented a viable delivery rate of 50 per cent with gesta-
ti-tubercular drugs for 6-9 months is effective for cases of tional surrogacy (Sharma et al., 2018). Adoption is advised
genital tuberculosis (Arora et al., 1992). In a randomized if ovaries are destroyed with diminished ovarian reserve
controlled trial, six months of ATT was found to be equally (Neonakis et al., 2011; Sharma, 2015).
effective as nine months therapy for genital tuberculosis The reasons of infertility due to chronic endometritis
(Sharma et al., 2016). include decreased endometrial receptivity due to direct
Directly observed treatment short course strategy effect of microbes, presence of lymphocyte subtypes in
(DOTS) is recommended by the WHO and is the preferred the endometrium leading to an abnormal micro-environ-
mode of treatment. Four drugs – isoniazid (H), rifampicin ment milieu which hampers endometrial receptivity, local
(R), pyrazinamide (Z) and ethambutol (E) – are given for immune response, abnormal milieu in the endometrium
two months (HRZE), followed by H, R and E (HRE) daily for for the recruiting circulating B cells, along with increased
four months. Daily treatment is given under direct super- levels of inflammatory markers in the endometrium. Dis-
vision. A 60 kg adult should receive the following dosage eased endometria of patients with chronic endometritis do
of the respective drugs: isoniazid 300mg/day, rifampicin not respond to ovarian steroid treatment, which is given
600mg/day, pyrazinamide 1600mg/day, and ethambutol to patients during IVF cycles to improve endometrial re-
1200mg/day. Patients may also take prescription combina- ceptivity (Kimura et al., 2019). Patients with chronic en-
tion kits without direct supervision (non-DOTS treatment) dometritis due to tuberculosis with advanced intrauterine
(Sharma et al., 2016). adhesions/Asherman’s syndrome do not respond to estra-
Sharma et al. (2016) evaluated the effects of anti-tu- diol for endometrial preparation before embryo transfer.
bercular therapy on the endometrium of females with Singh et al. (2020) conducted a revolutionary study in pa-
genital tuberculosis and found that patients resumed tients with Asherman’s syndrome (AS) and evaluated the
having regular menstrual cycles. On histopathology, AFB role of BM-derived autologous stem cell therapy in endo-
and epithelioid granulomas disappeared. On USG evalu- metrial regeneration and restoration of menstruation and
ation, endometrial thickness improved from 7mm to 7.5 fertility in refractory cases of AS and endometrial atrophy
mm. On hysteroscopy, post ATT patients had better-look- (EA). BM-derived mononuclear stem cells were instilled
ing cavities and less pale-looking cavities. Prevalence of into the sub-endometrial zone of 25 patients followed by
intrauterine adhesions/Asherman’s syndrome was 62% oral oestrogen therapy for 3 months. Menstrual flow and
before treatment with ATT and decreased to 28.7% af- endometrial thickness (ET) were evaluated at intervals
ter treatment with ATT. The endometrial cavity improved of 3, 6, and 9 months and 5 years. Mean ET (mm) be-
mainly in patients with grade I adhesions, from 34% to fore stem cell transfer was 3.3±1.0 mm. At the end of 3
2.1%, (p<0.001). There was no improvement in higher months, there was a significant increase in ET (mm) to
grade intrauterine adhesions/Asherman’s syndrome with 5.1±1.9 (p=0.001), but there was no significant change at

JBRA Assist. Reprod. | v.26 | no3| July-Aug-Sept/ 2022

Review 544

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