Original Article

Evaluating Chronic Endometritis in Women with Recurrent

Implantation Failure and Recurrent Pregnancy Loss by Hysteroscopy
and Immunohistochemistry
Mahvash Zargar, MD, PhD, Mehri Ghafourian, MD, PhD, Roshan Nikbakht, MD, PhD,
Vahideh Mir Hosseini, MD, PhD, and Parastoo Moradi Choghakabodi, MD, DVM
From the Fertility, Infertilty and Perinatology Research Center, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
(Drs. Zargar, Ghafourian, Nikbakht, and Hosseini), Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran (Dr. Zargar), and Research Center for
Thalassemia and Hemoglobinopathy, Ahvaz, Iran (Dr. Choghakabodi)

ABSTRACT Study Objective: The identification of less invasive methods with acceptable diagnostic value for evaluating intrauterine
abnormalities can improve the satisfaction of patients and physicians. Although hysteroscopy plus biopsy has favorable pre-
dictive and diagnostic values, limited studies have evaluated its value, and the exact value of this method is not completely
understood. The aim of this study was to evaluate the prevalence of chronic endometritis in patients with recurrent implanta-
tion failure (RIF) and recurrent pregnancy loss (RPL) by hysteroscopy and immunohistochemistry.
Design: A cross-sectional study.
Setting: An infertility clinic at Jundishapur University Hospital, Ahvaz, Iran.
Patients: Women with RIF after IVF and RPL.
Interventions: Hysteroscopy on the third to fifth day after finishing the menstruation cycle and then a biopsy for immuno-
histochemistry by a specific monoclonal antibody against the CD138 marker.
Measurements and Main Results: In total, 85 patients with a mean age of 36.08 § 5.76 years underwent hysteroscopy on
the third to fifth day after finishing the menstruation cycle. At the end of hysteroscopy, a biopsy was taken and assessed
using immunohistochemistry by a specific monoclonal antibody against the CD138 marker. Immunohistochemical staining
findings of >5 plasma cells per 20 high-power fields were considered the gold standard. The prevalence of chronic endome-
tritis (CE) in both groups and the diagnostic value of hysteroscopy were evaluated. All data were analyzed using the Fisher
exact test and analysis of variance. The prevalence of RIF-related CE was 23.4% (11); 21.3% (10) of the cases were diag-
nosed by hysteroscopy. The prevalence of RPL-related CE was 36.8% (14) and 31.6% (12) based on hysteroscopy and
immunohistochemistry staining, respectively. Subsequently, 10 patients (RIF/RPL-related CE with a positive hysteroscopic
outcome) were selected randomly for in vitro fertilization therapy, and 3 (30%) of them eventually became pregnant. The
sensitivity, specificity, and positive and negative predictive values of hysteroscopy in diagnosing CE were 86.36%, 87.30%,
70.37%, and 94.82%, respectively.
Conclusion: Hysteroscopy is a reliable diagnostic technique in patients with RIF after in vitro fertilization and RPL that can
reliably diagnose chronic endometritis. Journal of Minimally Invasive Gynecology (2020) 27, 116−121. © 2019 Published
by Elsevier Inc. on behalf of AAGL.
Keywords: Hysteroscopy; Immunohistochemistry; Endometritis; Recurrent implantation failure

Recurrent pregnancy loss is an important pregnancy

Dr. Mahvash Zargar has received research grants from Ahvaz Jundishapur
University of Medical Sciences.
Supported by Ahvaz Jundishapur University of Medical Sciences (ethical
code IR.AGUMFREC.1396.495).
Corresponding author: Mahvash Zargar, MD, PhD, Department of Fertility,
Infertility and Perinatology Research Center, Ahvaz Jundishapur University
of Medical Sciences, Ahvaz, Iran.
E-mail: dr.zargar199@gmail.com
Submitted August 11, 2018, Revised February 27, 2019, Accepted for publi-
cation February 28, 2019.
Available at www.sciencedirect.com and www.jmig.org
complication that affects 3% to 5% of couples. Moreover,
the exact cause of RPL in 30% to 40% of cases is unknown,
but studies have reported that RPL has multifactorial
etiologies [1,2].
Recurrent implantation failure (RIF) patients are groups
of patients with diverse clinical problems who need accu-
rate evaluations. This situation is attributed to cases with
over 2 to 3 in vitro fertilization (IVF) failures or failure
after the cumulative transfer of over 10 embryos with

1553-4650/$ — see front matter © 2019 Published by Elsevier Inc. on behalf of AAGL.
https://doi.org/10.1016/j.jmig.2019.02.016

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Zargar et al. Evaluating Chronic Endometritis in Women with Recurrent Implantation Failure 117

acceptable qualities [3]. In these couples, maternal, pater- Methods

nal, and embryonic factors should be evaluated [4].
This was a cross-sectional study of women with a history
Accurate evaluations are needed for endometrial factors
of RIF and RPL who referred to the infertility clinic at Jun-
that may affect RIF and unexplained RPL. Although previ-
dishapur University Hospital, Ahvaz, Iran, between Octo-
ous studies have indicated that ultrasonography and hyster-
ber 2016 and October 2017.
osalpingography are strongly required in order to find
The inclusion criteria were as follows: (1) a history
uterine-related abnormalities, some subtle abnormalities
of RIF after IVF or RPL, (2) a normal hysterosalpingog-
would not be found using these methods [5,6].
raphy, (3) a normal chromosomal karyotype, (4) normal
One of the etiologies of RIF and RPL is chronic
levels of lupus anticoagulant, anticardiolipin, antiphos-
endometritis (CE), which is defined as chronic inflam-
pholipid, and anti-beta 2 glycoprotein, and (5) a normal
mation of the endometrial linings. Patients with CE are
thyroid function test and prolactin. If patients were
usually asymptomatic, but it can present with chronic
smokers or alcohol consumers or did not continue this
pelvic pain, dyspareunia, abnormal vaginal bleedings, or
study, they were excluded.
vaginal discharges [7,8]. Recent studies have shown an
The study was completely explained for all participants,
increase in the prevalence of CE in patients with RIF
and an informed consent form was completed. RIF after
(30%) and RPL (13%) [4,9].
IVF was defined as the failure to achieve a clinical preg-
Scientific evaluations reported that CE is associated
nancy after 2 good-quality embryo transfers in fresh or fro-
with infertility capacity and poor pregnancy outcomes like
zen cycles. RPL was defined as 2 or more consecutive
preterm labor and abortion [4,10]. Routine methods like
pregnancy losses or 3 or more alternate pregnancy losses
ultrasonography and hysterosalpingography have been
(<20 weeks of gestational ages) [7]. Participants were
reported to not be powerful enough for the identification
selected using a nonrandomized method.
of small intrauterine lesions [5]. Hysteroscopy can be used
Considering the specific goal of determining the preva-
instead, and some studies have reported that hysteroscopy
lence of CE in women with a history of RIF after IVF, pre-
can identify 11% to 45% of these small intrauterine
vious studies [16], the researcher’s opinion, and the
lesions [11].
parameters of a = 0.05, p = 0.14, d = 0.1, the formula used
Hysteroscopy is a definite method for observation and
was as follows: n = pqz2/d2. The sample size in the RIF
evaluation of the uterine cavity. Indeed, hysteroscopy
group was estimated at 47.
along with biopsy has a favorable predictive value for
Considering the specific goal of determining the preva-
evaluating intrauterine inflammation and is considered
lence of CE in women with a history of RPL, previous stud-
the best method for diagnosing intrauterine abnormali-
ies [16], the researcher’s opinion, and the parameters of
ties [12]. A diagnosis of CE with hysteroscopy is based
a = 0.05, p = 0.27, and d = 0.15, the formula was as follows:
on direct observation of mucosal edema, focal or diffuse
n = pqz2/d2. The sample size in the RPL group was esti-
endometrial hyperemia, and the presence of micropolyps
mated at 55 considering a 10% churn rate.
(<1 mm) [9,13].
Hysteroscopy was performed for each participant 3 to
The gold standard for diagnosing CE is histologic identi-
5 days after menstruation. The medium for hysteroscopy
fication of plasma cells in endometrial stroma [11]. Using
was 0.9% saline solution (Karl Storz, with a 3.5-mm outer
immunohistochemistry (IHC) methods and identifying syn-
sheath diameter and 30˚ A 40211 A viewing angle). The
decan 1 (CD138), a proteoglycan in the surface of plasma
cervical canal, uterine cavity, and endometrium were evalu-
cells and keratinocytes, provides a more accurate diagnosis
ated. Diagnosing CE by hysteroscopy was based on the
of CE [14]. Pathological evaluation for diagnosing CE may
observation of focal or diffuse endometrial hyperemia,
encounter biases because of the normal presence of inflam-
stroma edema, and polyps with <1-mm sizes on the endo-
mation cells in the endometrium [15].
metrium [16]. At the end of hysteroscopy, a biopsy was
Generally, histologic evaluations need biopsy. Endo-
taken by a number 2 curette, and the biopsy specimen was
metrial biopsy is an invasive method for diagnosing dif-
fixed by formalin solution and sent to the laboratory for
ferent endometrial abnormalities. Patients and physicians
IHC staining evaluation using anti−sundecan-1 (CD138)
prefer to experience and use less invasive methods for
monoclonal antibodies. The process of CD138 evaluation
the diagnosis and treatment of diseases. Therefore, the
was similar to what was done by Bayer-Garner and Korour-
identification of less invasive methods with acceptable
ian [17]. All biopsy specimens were assessed by a target
diagnostic value can improve the satisfaction of patients
pathologist. A diagnosis of CE in IHC staining was based
and physicians. There are limited studies that have evalu-
on the presence of 5 or more plasma cells in the endometrial
ated the diagnostic value of hysteroscopy, but the exact
stroma in high-power fields (HPFs) (at least 5 plasma cells
value of this method is not completely understood. This
per 20 HPFs) [16]. The hysteroscopic findings and the IHC
study aimed to evaluate the prevalence of CE in patients
staining findings were recorded on special forms for each
with RIF and RPL by hysteroscopy and IHC and the
patient. Immunohistochemical staining findings of >5
diagnostic value of hysteroscopy for diagnosing CE in
plasma cells per 20 HPFs were considered the gold
these patients.

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118 Journal of Minimally Invasive Gynecology. Vol 27, No 1, January 2020

standard. Based on the antibiogram results, doxycycline Fig. 1

100 mg orally twice a day for 21 days was used to treat CE.
IHC with CD138 (syndecan 1). CE on endometrial biopsy. (a) CD56
Statistical Analysis mouse monoclonal antibody staining as an internal positive control,
which is the main marker of natural killer cells. (b) Plasma cells identi-
Eventually, all data were analyzed using the Fisher exact fied in brown by immunohistochemical CD138 staining.
test and analysis of variance. Results were reported as odds
ratios with 95% confidence intervals (SPSS Version 22;
IBM Corp, Armonk, NY). A P value <.05 was considered
statistically significant. For reporting quantitative and qual-
itative data, we used the mean § standard deviation and the
number or percent, respectively. The prevalence of CE in
both groups using 2 methods of diagnosing was calculated,
and the diagnostic value of hysteroscopy including the sen-
sitivity, specificity, positive predictive value (PPV), and
negative predictive value (NPV) were calculated based on
special formulas in the AUC system. This study was
approved by the Ahvaz Jundishapur University of Medical
Sciences Ethical Committee.

Results
In this study, 85 patients including 47 cases with a his-
tory of RIF and 38 cases with a history of RPL participated.
The mean age of the patients in RIF and RPL groups was
36.4 § 5.9 years (range, 25−41 years) and 35.7 § 5.6 years
(range, 20−40 years), respectively.
Hysteroscopic assessments showed the presentation of
CE among 29.4% of the total patients (n = 25), whereas this
rate was 25.88% (n = 22) using IHC (total = 47 [55.29%]).
The prevalence of RIF-related CE was 23.4% (n = 11);
21.3% (n = 10) of them were diagnosed by hysteroscopy.
The prevalence of RPL-related CE was 36.8% (n = 14) and
31.6% (n = 12) based on hysteroscopy and IHC staining,
respectively. Subsequently, 10 patients (RIF/RPL-related
CE with a positive hysteroscopy outcome) were selected
randomly for IVF therapy, and 3 (0.3) of them eventually
became pregnant.
The sensitivity, specificity, PPV, and NPV of hysteros-
copy in the diagnosis of CE were 86.36%, 87.3%, 70.37%,
and 94.82%, respectively. These diagnostic values in the RIF
group were 90.0%, 94.6%, 81.81%, and 97.22%, and in the technique as an alternative to IHC as the gold standard of
RPL group, they were 83.3%, 76.9%, 62.5%, and 90.9%. CE diagnosis [18]; it seems that the use of hysteroscopy
IHC with CD138 (syndecan 1) is shown in Figures 1 and plus other routine means such as ultrasonography and hys-
2. The correlation coefficients between the 2 methods of terosalpingography can help make an earlier diagnosis of
hysteroscopy and IHC in the diagnosis of RIF and RPL CE. Moreover, hysteroscopy can provide a better vision of
after IVF are shown in Figure 3. the small lesions responsible for RPL or RIF that would not
be found during the routine methods mentioned previously
[6,17].
Discussion
In this study, the exact diagnosis of CE was made based
The findings of our study showed the considerably high on the IHC staining method, although previous studies used
prevalence of CE among patients with a history of RIF after hematoxylin-eosin staining and hematoxylin phloxine saf-
IVF and among those with RPL. The efficacy of hysteros- fron stain. IHC has the following advantages in comparison
copy for the assessment of CE among these cases was with other staining methods: (1) IHC can increase the sensi-
examined, and its acceptable sensitivity and specificity was tivity of microscopic identification of plasma cells [19,20],
found. However, the overall accuracy of hysteroscopy for (2) IHC can decrease false-positive identification of plasma
the diagnosis of CE is not enough to introduce this cells although hematoxylin-eosin and hematoxylin phloxine

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Zargar et al. Evaluating Chronic Endometritis in Women with Recurrent Implantation Failure
Fig. 2
IHC with CD138 (syndecan 1) after treatment of CE on endometrial
biopsy.
saffron incorrectly diagnose plasmocytes and mononuclear
as plasma cell in stroma [17], (3) IHC can increase the
speed of plasma cell counting and decrease false-negative
cases, and (4) IHC is not completely dependent on the
pathologist [21].
Despite all the advantages of IHC, it has not been used
widely for diagnosing CE. Also, there are limited studies
that have evaluated this method in patients with a history of
RIF and RPL. Most of these studies were retrospective and
showed that the prevalence of CE in patients with RIF was
30% to 37%, and in patients with RPL, it was 13% to 56%
[4,20−22].
The prevalence of CE was lower in patients with a his-
tory of RIF than those with a history of RPL. This finding is
in consistent with Bouet et al.’s study [16]. Based on the
Fig. 3
Correlation coefficients (p value) between 2 methods of hysteroscopy and IHC in the diagnosis of RIF and RPL after the IVF process.
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119
findings of Cicinelli et al’s study [3], the prevalence of CE
in women with RIF was 66.0%, which was about triple
compared with our study (23.4%). Because Cicinelli et al
considered unexplained infertility and a history of RIF as
inclusion criteria, this discordance could be because of the
more exclusive criteria used in our study.
There are a variety of definitions used for RPL and RIF
and the sample sizes in other studies, that may have been
responsible for their different outcomes compared with our
study. On the other hand, among those studies that used
IHC for the diagnosis of CE, the definition of CE based on
the number of plasma cells found in every HPF might be
different [18,23]. This study showed a high sensitivity and
specificity for hysteroscopy in the diagnosis of CE in
patients with RPL and RIF.
In a recent study, Bouet et al [16] tried to assess the val-
ues of hysteroscopy for the diagnosis of CE among those
with a history of RIF and RPL. They found a sensitivity
and specificity of 40% and 80% for hysteroscopy. These
rates were considerably lower than ours, especially for sen-
sitivity [16]. These differences may have occurred because
of the variety of definitions considered for CE in IHC or the
different degrees of diagnostic skills among the patholo-
gists or gynecologists.
Another study on 142 patients with a history of spontane-
ous miscarriage in 2011 showed that the sensitivity, specific-
ity, PPV, and NPV of hysteroscopy were 98.4%, 56.23%,
63.5%, and 97.82%, respectively [24]. The sensitivity of
their study was superior to ours but not the specificity.
Studies on women with different uterine diseases
showed that hysteroscopy had 55.4% sensitivity and 99.9%
specificity for the diagnosis of underlying diseases of the
uterus [10]. These findings showed that although hysteros-
copy is an appropriate means for confirmation of the pri-
mary diagnosis, it has some inadequacies for ruling out
diagnoses.
120
Different studies regarding evaluating the diagnostic
value of hysteroscopy showed different findings. Some
studies reported a favorable diagnostic value for hysteros-
copy. However, there are studies that showed a low sensi-
tivity of this test. Another factor that may affect these
findings is individual errors of the gynecologist or patholo-
gist for identifying CE criteria in patients, and studies with
more skillful specialists may present more reliable findings.
One of the forte of this study was using IHC staining for
the histological evaluation of endometrial biopsies, which
this method is more reliable than previous method. One of
the main limitations of our study was its small sample size.
Another limitation of the study was the absence of a control
group because of ethical issues.
Various studies have confirmed that hysteroscopy before
intrauterine insemination or assisted reproductive technol-
ogy can improve the chances of conception in infertile
women and pregnancy rates [25−27]. In this regard, our
study merely followed up the pregnancy rates in RIF/RPL-
related CE patients with a positive hysteroscopy without
comparing their results with the results of with a negative
hysteroscopy.
Future studies should be planned with greater sample
sizes and considering all confounding factors that may
affect study findings. CE may be an important factor in RIF
after IVF and RPL. In addition, treating CE can improve
fertility outcomes.
In this regard, the quality of endometrial scratching
method during intrauterine insemination in CE patients is
questionable. Although the efficacy of this method is still
under question even in large systematic reviews [28], the
endometrial status among CE patients can answer this ques-
tion better because their endometrium inflammatory status
is responsible for their recurrent pregnancy losses and IVF
failure [28−30].
In conclusion, hysteroscopy is a valid and reliable tech-
nique in patients with RPL and RIF to detect traces of CE.
Further evaluations in order to improve their reproducibility
are recommended.
Acknowledgment
We would like to express our appreciation to the Center
for Reproductive Medicine Mahzyar and Ahvaz Jundisha-
pur University of Medical Sciences for their help in com-
pleting this research.
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