Original Research ajog.

org

GYNECOLOGY
Genital tuberculosis screening at an academic fertility
center in the United States
Reshef Tal, MD, PhD; Tiwadeye Lawal, BS; Emily Granger, BS; Michael Simoni, MD; Pei Hui, MD, PhD; Natalia Buza, MD;
Lubna Pal, MD

BACKGROUND: Infertility is a common presentation of female genital Goldepositive population had a higher incidence of both recurrent
tuberculosis in endemic areas. Female genital tuberculosiserelated pregnancy loss (28% vs 7%; P¼.003) and Asherman syndrome (8% vs
maternal and neonatal complications have increased in recent years 0.3%; P<.001). Among those with a positive test result for QuantiFERON-
after assisted reproductive technology treatments. Despite rising TB Gold, chest x-ray was abnormal in only 2 patients (8.0%). Endometrium
emigration rates to the United States, guidelines to identify those with evaluation revealed abnormalities in 2 patients (8.0%), in whom chest
latent tuberculosis or female genital tuberculosis in fertility centers do x-ray was normal, with 1 showing evidence of female genital tuberculosis.
not exist. This was indicated by histology consistent with chronic granulomatous
OBJECTIVE: This study aimed to characterize the prevalence of female endometritis and positive endometrial testing for tuberculosis by poly-
genital tuberculosis in infertile patients at our academic fertility center. merase chain reaction, acid-fast bacilli smear, and culture for Mycobac-
STUDY DESIGN: This is a prospective cohort study. All patients pre- terium tuberculosis.
senting for infertility evaluation between January 2014 and January 2017 CONCLUSION: Although the prevalence of female genital tuberculosis
were assessed for risk factors for latent tuberculosis. Patients at risk for in infertile women in the United States seems to be low, this study indicates
latent tuberculosis underwent screening using QuantiFERON-TB Gold that it can be underdiagnosed without utilization of multiple diagnostic
serum assay. QuantiFERON-TB Goldepositive patients underwent further modalities including endometrial sampling. Given the potential for serious
testing for female genital tuberculosis consisting of endometrial biopsy maternal and neonatal morbidity in affected patients utilizing assisted
with histopathologic examination by a clinical pathologist, polymerase reproductive technology, we propose that all at-risk women seeking
chain reaction for tuberculosis, and culture for acid-fast Mycobacterium infertility care in the United States be screened for latent tuberculosis. In
tuberculosis. patients who screen positive, endometrial biopsy should be obtained for
RESULTS: Twenty-five of 323 infertility patients (7.7%) screened for evaluation by histology, polymerase chain reaction, and culture for
latent tuberculosis had positive QuantiFERON-TB Gold results. A greater Mycobacterium tuberculosis to rule out female genital tuberculosis before
number of patients with a positive test result for QuantiFERON-TB Gold infertility treatments are initiated.
were foreign born than those with a negative test result for QuantiFERON-
TB Gold (92% vs 29%; P<.001). Of note, the QuantiFERON-TB Key words: fertility, genital tuberculosis, latent TB, PCR, screening

T uberculosis (TB) is a major public

health burden with an estimated
worldwide incidence of 10 million in
almost 9% of all extrapulmonary cases of
TB and is an important cause of female
infertility in certain endemic areas of the
mortality.10 Furthermore, TB in preg-
nant women with HIV increases the risk
of maternal and infant mortality by
2018.1 In fact, nearly one-third of the world.3,5,6 In cases of genital TB, access nearly 300%.9
world population is infected with of TB bacilli to the genital tract is hy- Clinical presentation of FGTB can be
Mycobacterium tuberculosis (M tubercu- pothesized to occur through 4 plausible varied, ranging from infertility, menstrual
losis), 10% of which are known to routes: hematogenous dissemination, abnormalities, and chronic pelvic pain to
progress to clinical disease.2,3 TB exists gastrointestinal spread, lymphatic pregnancy loss; however, many who are
as either pulmonary or extrapulmonary spread, and rarely as primary infection of affected may remain entirely asymptom-
TB.4 Depending on the localization of M the genitalia through sexual trans- atic.4,11,12 In the early stages, the genital
tuberculosis in an organ, a wide spectrum mission.7 Adverse effects of FGTB on the organs may seem normal. However, as
of tubercular manifestations are encountered. reproductive anatomy and physiology FGTB progresses, the fallopian tubes are
Female genital TB (FGTB) is a form of can be devastating especially when not involved in 95%e100% of cases.4,13,14
extrapulmonary TB that accounts for treated early.8 Although FGTB can affect Furthermore, FGTB can involve the
women of any age, 75% of clinical cases uterine endometrium (in 50%e60% of
occur in women of reproductive age cases) wherein endometritis, endometrial
Cite this article as: Tal R, Lawal T, Granger E, et al. (20e45 years).4 TB among mothers is ulceration, caseous necrosis, and hemor-
Genital tuberculosis screening at an academic fertility associated with a 6-fold increase in rhage have been noted in advanced
center in the United States. Am J Obstet Gynecol perinatal deaths and a 2-fold risk of cases.15 Less frequently, the ovaries (in
2020;XX:x.exex.ex.
premature birth and low birthweight.9 20%e30% of cases), cervix (in 5%e15%
0002-9378/$36.00 In the developing world, TB during of cases), uterine myometrium (in 2.5%
ª 2020 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.ajog.2020.05.045
pregnancy is one of the leading non- of cases), and the vagina and the vulva (in
obstetrical causes of maternal 1% of cases) can be involved.15 As the

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Drug Administration (FDA)emandated

AJOG at a Glance testing for donors of human cells and
Why was this study conducted? tissues, which applies to reproductive
This study aimed to characterize the prevalence of female genital tuberculosis tissue donation.27 Furthermore, guide-
(FGTB) in infertile patients in the United States at an academic fertility center in lines to identify those with latent TB or
the Northeast. with FGTB are nonexistent. An accruing
body of evidence suggests that IVF-
Key findings related interventions in the setting of
Of 323 infertility patients at risk for TB, 7.7% screened positive for latent TB by untreated FGTB and ensuing pregnancy
QuantiFERON-TB Gold (QFT) testing. A greater number of patients with a may actually jeopardize maternal and
positive test result for QFT were foreign born than those with a negative test result fetal well-being. Therefore, it is impera-
for QFT (92% vs 29%). Of note, the QFT-positive population had a higher tive to elucidate the burden of FGTB in
incidence of both recurrent pregnancy loss (28% vs 7%) and Asherman syndrome infertile women seeking fertility care
(8% vs 0.3%). Endometrial evaluation in QFT-positive patients revealed abnor- within the United States. This study
malities in 2 patients (8.0%), with 1 showing evidence of FGTB. aimed to characterize the prevalence of
FGTB in infertile patients seeking
What does this add to what is known? fertility care at our fertility center after
Although the prevalence of FGTB in infertile women in the United States seems the implementation of enhanced FGTB
to be low, this study indicates that it can be underdiagnosed in women presenting screening guidelines.
to infertility clinics without utilization of multiple diagnostic modalities including
endometrial sampling. Given the potential for serious maternal and neonatal Materials and Methods
morbidity in affected patients using assisted reproductive technology, we propose Study population and screening
that all at-risk women seeking infertility care in the United States be screened for algorithm
latent TB, followed by comprehensive endometrial diagnostic testing in those A prospective cohort study was per-
who test positive. formed as a quality improvement initia-
tive at the Yale Fertility Center (YFC), an
academic fertility center in New Haven,
disease progresses, clinical presentation of higher burden, with 56%e78% of CT, between January 2014 and January
FGTB may be mistaken for other condi- infertile women in India having M 2017. This study was exempt from insti-
tions such as ovarian and endometrial tuberculosisepositive endometrial tis- tutional review board (IRB) approval;
malignancy, pelvic abscess, Meigs syn- sues and menstrual blood.21,22 Although however, approval from Yale IRB was
drome, and carcinoma of the vulva, va- FGTB is often associated with tubal obtained for publication of this work. A
gina, or cervix.16,17 factor infertility, advances in assisted screening algorithm was employed to
Infertility is common and may be the reproductive technology (ART) and stratify patients into at-risk groups based
only manifestation in asymptomatic increasing access to in vitro fertilization on the likelihood of FGTB infection
women with FGTB.11,18 Infertility is seen (IVF) technology globally have made it (Figure 1). Patients presenting to YFC for
in up to 40%e80% of cases of FGTB. possible for many affected women to infertility evaluation underwent risk
Distortion and obstruction of fallopian conceive.23 However, recent years have quantification for latent TB based on the
tubes, involvement of the endometrium witnessed an alarming increase in re- World Health Organization (WHO)
with resulting disorders of endometrial ports of FGTB-related maternal and screening guidelines for latent TB2
receptivity, destruction of normal neonatal complications after fertility (Table 1). Patients who were found to
endometrium and resulting intrauterine treatments, particularly in the setting of be from TB-endemic areas or otherwise
synechiae, defective ovarian function IVF, including life-threatening dissemi- at risk (n¼323) underwent screening for
caused by involvement of the ovaries in nated miliary TB, pregnancy loss, and latent TB using QuantiFERON-TB Gold
tubo-ovarian inflammatory phlegmon congenital TB (CTB).23e25 These un- (QFT) blood test. Patients with a positive
formation, and destruction of normal derscore that timely detection and test result for QFT were referred for chest
ovarian tissues with resulting compro- treatment of FGTB before IVF hold x-ray (CXR) and pulmonary infectious
mise to ovarian reserve have all been benefit for the mother and child. disease consultation. In addition, all
described as mechanisms contributing Despite a high prevalence of TB in at- QFT-positive patients underwent further
to FGTB-related infertility.19 The re- risk communities, the rising emigration diagnostic testing for FGTB with endo-
ported prevalence of FGTB in infertile rates to the United States from TB- metrial biopsy (EMBx); the collected tis-
women in the United States is 1%, endemic areas, and improved access to sue was evaluated by routine
whereas it is as high as 20% in India and fertility care, TB testing is neither histomorphologic assessment, endome-
Pakistan.19,20 Recent studies using sen- included in the standard diagnostic trial TB PCR testing, and culture for acid-
sitive molecular diagnostic techniques evaluation of infertile women in the fast M tuberculosis. Any patient who had
and multiple samples revealed an even United States26 nor in the US Food and evidence of FGTB based on endometrial

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ajog.org GYNECOLOGY Original Research

testing was counseled to defer infertility

FIGURE 1
treatment until completion of anti-TB
Genital TB screening algorithm
treatment course. In addition, a detailed
chart review was performed to charac-
terize demographic details and clinical
parameters in all QFT-tested patients.

Risk stratification questionnaire

In an attempt to identify patients at high
risk for latent TB, a risk stratification
questionnaire was administered to
women presenting for fertility care at
YFC. The questionnaire was in accor-
dance with the WHO screening guide-
lines for latent TB (Table 1)2 and included
information on history of TB exposure or
positive purified protein derivative test in
the patient or her partner, history of HIV
infection in the patient or her partner,
occupation, country of origin, excessive
smoking, alcohol consumption, or illicit
drug use. A positive screening test on any
of the specified WHO risk factors for
latent TB prompted further screening by
QFT blood test.

Screening test—QuantiFERON-TB
Gold
Screening for latent TB was based on
QFT (QIAGEN) blood test, performed
by commercial laboratories (Quest).
This FDA-approved test is an interferon
gamma release assay (IGRA) used for the
diagnosis of latent or active TB. The
assay is an enzyme-linked immunosor-
bent assayebased whole-blood test that
uses peptides from 3 TB antigens (ESAT-
6, CFP-10, and TB7.7) in an in-tube
format. The result is reported as quan-
tification of interferon gamma (IFNg) in
international units (IUs) per mL. An
individual is considered positive for M
tuberculosis infection if the IFNg
response to TB antigens is above the
commercial laboratoryespecified test
cutoff value (0.35 IU/mL).

Endometrial biopsy
All patients who had positive QFTresults
were offered to undergo EMBx to screen
for FGTB. Endometrial sample was ob-
tained by office-based aspiration biopsy
CXR, chest x-ray; EMBx, endometrial biopsy; ID, infectious disease; IVF, in vitro fertilization; PCR, polymerase chain reaction; TB,
using pipelle. Tissue sample aliquots tuberculosis.
underwent (1) routine histopathologic Tal et al. Genital TB in infertile women in the United States. Am J Obstet Gynecol 2020.
examination by a clinical pathologist, (2)

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span of 8 weeks in solid media (Löw-

TABLE 1
enstein-Jensen) before determination.
WHO high-risk groups for latent TB
Third, the specimen was cultured on a
WHO high-risk groups for latent TB 7H11 agar-based media for 8 weeks.
1 Adult and child TB contacts Finally, the specimen was identified with
a TB AccuProbe test.31
2 Healthcare workers and students
3 People living with HIV Statistical analysis
4 Patients receiving dialysis Data are expressed as meanstandard
deviation. Data were assessed for normal
5 Immigrants from high TB-burden countries
distribution with the Shapiro-Wilk test
6 Patients initiating anti-TNF therapy using GraphPad Prism 8 software
7 Illicit drug users (GraphPad Software, La Jolla, CA).
8 Prisoners Comparison of mean values between the
2 groups was performed using Student t-
9 Homeless people
test or Mann-Whitney U test, as appro-
10 Patients receiving organ and hematologic priate. Proportions between the 2 groups
transplantation were compared using the z-test. All sig-
11 Patients with silicosis nificance tests were 2 tailed, and P<.05
12 Patients with diabetes was considered statistically significant.
13 People with harmful alcohol use
Results
14 Tobacco smokers A total of 323 patients with infertility
15 Underweight people were deemed to be at risk for latent TB
TB, tuberculosis; TNF, tumor necrosis factor; WHO, World Health Organization. according to WHO guidelines and were
Tal et al. Genital TB in infertile women in the United States. Am J Obstet Gynecol 2020. further screened for latent TB by QFT
IGRA testing (Figure 1). None of these
patients had a history of being diagnosed
TB PCR, and (3) culture for acid-fast M are assay-specific nuances that can create or treated for TB. Twenty-five of these
tuberculosis. rare opportunities for false-positive and patients (7.7%) had positive QFT results,
false-negative results. Rare strains of M indicating the existence of latent TB,
Endometrial polymerase chain tuberculosis lack the IS6110 transposon whereas 298 patients had negative QFT
reaction for tuberculosis and will therefore not be detected in this results (92.3%). Infertility etiologies and
IS6110 is a transposon element of M test (false negative). Conversely, IS6110 other patient characteristics are listed for
tuberculosis present in varying numbers is found in some mycobacterial species both groups in Table 2.
of copies and at variable sites within the other than M tuberculosis, such as A significantly greater number of in-
M tuberculosis genome.28 Detection of M Mycobacterium bovis, creating a situation dividuals with positive test results for
tuberculosis was performed by real-time of false-positive result.28 QFT were born outside of the United
PCR using the Bio-Rad CFX96 plat- States than those with a negative test
form (Bio-Rad, Hercules, CA) with a Acid-fast bacilli smear and culture result for QFT (92% vs 29%; P<.001) and
primer set targeting IS6110 (upstream An acid-fast bacilli (AFB) smear and were originally from WHO-identified
primer -50 GGG TAG CAG ACC TCA culture was performed to confirm the TB-endemic areas (56% vs 26%;
CCT ATG and downstream primer-50 presence of M tuberculosis in the endo- P¼.001) (Figure 2). Those with a positive
AGC GTA GGC GTC GGT GAC 30 ) and metrial tissue according to standard test result for QFT were from the
a detection probe (50 6FAM-TCG CCT techniques29 by the Clinical Microbi- following regions outlined by the WHO:
ACG TGG CCT TT-TAMRA 30 ). ology Laboratory at Yale School of Southeast Asia (36%), Western Pacific
Amplification of a control gene (IGF) Medicine. After decontamination of the (20%), African (16%), Eastern Mediter-
was used to confirm amplifiable DNA collected tissue sample with exposure to ranean (12%), Americas (12%), and Eu-
with a primer set targeting IGF (up- sodium hydroxide for 15 minutes, the ropean (4%) (Figure 3). Those with a
stream primer - 50 TGG AGA CAG GGG specimen was neutralized with buffer negative test result for QFT were from the
CTT TTA TT and downstream primer - followed by examination by smear mi- following regions: Americas (73%),
50 ACT CCC TGC GGT TGT AAA TC) croscopy.30 The specimen was then Eastern Mediterranean (8%), Southeast
and a detection probe (50 FAM-CCT inoculated on 3 types of media. First, the Asia (9%), Western Pacific (6%), African
CCC TCT CAA TGT GCT CAA- specimen was processed with a Myco- (2%), and European (2%). Of note, the
TAMRA 30 ). Positive and negative con- bacteria growth indicator tube for 6 QFT-positive population had a higher
trols were evaluated in parallel. Notable weeks. Next, it was cultured over the incidence of both recurrent pregnancy

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TABLE 2
Characteristics of QFT-tested infertile female patients
Parameter QFT positive (n¼25) QFT negative (n¼298) P values
Age (y) 35.35.5 (23e43) 32.94.8 (21e44) .038
2
BMI (kg/m ) 27.56.4 (19.3e44.7) 27.77.0 (17.3e56.1) .865
AMH (ng/mL) 4.26 (0.13e11.46) 3.483.7 (0e35.2) .463
Non-US born 92 29 <.0001
Born in TB-endemic country 56 26 .001
Primary infertility 48 55 .496
Secondary infertility 52 45 .496
Infertility etiology:
Male factor 8 10 .750
Anovulatory or PCOS 32 28 .667
Tubal 16 13 .667
Endometriosis 4 4 1
Asherman syndrome 8 0.3 <.0001
Unexplained 24 19 .542
Diminished ovarian reserve 0 5 .254
Other 8 10 .749
Mixed 0 10 .097
Abnormal menstruation 52 36 .112
History of RPL 28 7 .003
Abnormal endometrial histology 8 N/A N/A
Positive TB PCR test 4 N/A N/A
Positive TB culture 4 N/A N/A
Abnormal chest x-ray 8 N/A N/A
Values are presented as meanSD (range) or percentage.
AMH, antimüllerian hormone; BMI, body mass index; N/A, not applicable; PCOS, polycystic ovarian syndrome; PCR, polymerase chain reaction; QFT, QuantiFERON-TB Gold; RPL, recurrent pregnancy
loss; SD, standard deviation; TB, tuberculosis; US, United States.
Tal et al. Genital TB in infertile women in the United States. Am J Obstet Gynecol 2020.

loss (28% vs 7%; P¼.003) and Asherman positive result for TB by PCR and had a screening algorithm to characterize the
syndrome (8% vs 0.3%; P<.001) than the positive AFB smear and culture, but prevalence of latent TB and FGTB in
QFT-negative population. Tubal infer- notably had a negative CXR. The patient the at-risk infertile female population
tility and other infertility etiologies were was counseled regarding anti-TB treat- presenting to our fertility center.
not different between the 2 groups. ment and deferral of IVF until Although only 1 of 323 at-risk patients
Interestingly, CXR examination had completion of therapy. She was treated was confirmed as having FGTB based
abnormal findings in only 2 (8.0%) of with isoniazid, rifampin, pyrazinamide, on positive endometrial histology and
the 25 patients who tested positive for and ethambutol daily for 6 months. confirmation of M tuberculosis infec-
QFT. Histologic evaluation of endo- Fertility treatment was resumed after tion by PCR and culture, almost 8% of
metrial tissue in this population the completion of TB treatment and our patients considered to be at a
revealed abnormal histology in 2 pa- only after a repeat EMBx confirmed full higher risk for TB had positive results
tients (8.0%). One patient had evidence resolution of endometrial pathology. for latent TB. This study indicates that
of nonspecific chronic endometritis, FGTB can be underdiagnosed in
whereas the other patient had evidence Comment women presenting to infertility clinics
of chronic granulomatous endome- Principal findings without utilization of multiple diag-
tritis, consistent with endometrial TB In this study, we utilized a newly nostic modalities such as endometrial
(Figure 4). This patient also had a implemented comprehensive TB sampling.

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FIGURE 2
Prevalence of TB incidence by nation

TB, tuberculosis.
Tal et al. Genital TB in infertile women in the United States. Am J Obstet Gynecol 2020.

Clinical implications In this study, women with latent TB Pregnancy in women with FGTB used
The vast majority (92%) of patients who had a significantly greater frequency of to be an extremely rare occurrence
had positive QFT results in this study recurrent pregnancy loss (28% vs 7%) before the advent of ART because the
were born outside of the United States, and Asherman syndrome (8% vs 0.3%) condition most often affects the fallo-
with more than half (56%) being born in than women who had a negative QFT pian tubes, thereby resulting in tubal
a TB-endemic country. Consistent with result, respectively. Of note, genital TB factor infertility. ART has aided many
these findings, in most low-prevalence has been associated with recurrent women with FGTB-associated infertility
countries, most people diagnosed as pregnancy loss33 and recurrent implan- to conceive.34 However, there have been
having TB are foreign born.32 In partic- tation failure after IVF.21 M tuberculosis multiple alarming reports of women
ular, in the United States, 60%e70% of may reside in the basal endometrium who developed serious TB-related
TB cases are identified in foreign-born leading to impairment of the endome- maternal23,35,36 and neonatal24,37 mor-
individuals.32 FGTB is a common trial and subendometrial blood flow bidities after IVF. In the United States,
contributor to infertility in TB-endemic before developing into active tubercular the first case series of IVF-related CTB
countries.10 Approximately 5%e10% of endometritis.21 In more advanced stages, was reported in 2013, describing 5 neo-
infertile women around the world have there can be a distortion of the endo- nates (2 sets of twins and 1 singleton)
FGTB. This figure varies significantly metrial cavity, varying from slight born with CTB in New Jersey hospitals
according to geography and ranges from distortion to complete obliteration after being conceived through IVF.24 All
less than 1% in the United States to caused by adhesions, consistent with 3 pregnancies ended in preterm delivery.
approximately 18% in India.19,20 Asherman syndromeelike picture. In 3 of 5 CTB cases, the neonates

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ajog.org GYNECOLOGY Original Research

experienced failure to thrive, and ulti-

FIGURE 3
mately, there was 1 neonatal death.24 In
Region of origin of QFT-tested patients
these cases, all 3 mothers were American
residents who emigrated from India.
Remarkably, none of the women were REGION OF ORIGIN OF QUANTIFERON-
diagnosed as having TB before the birth NEGATIVE PATIENTS
of the CTB-positive infants; postnatal Western Pacific European African
testing revealed that all 3 mothers had 6% 2% 2%
TB-positive EMBx consistent with Southeast Asia
FGTB. Therefore, it is crucial that pa- 9%
tients at risk for FGTB presenting with Eastern
infertility undergo appropriate screening Mediterranean
8%
and diagnostic testing before undergoing
ART treatments. In this study, the pa-
tient diagnosed as having FGTB was also
an immigrant from India, an endemic
country with a high prevalence of FGTB.
She was given antitubercular treatment Americas
and her IVF treatment was delayed until 73%
treatment completion. Antitubercular
treatment in infertile patients with FGTB
diagnosed on the basis of endometrial
PCR has been found to result in favor-
REGION OF ORIGIN OF QUANTIFERON-
able reproductive outcomes3 and should POSITIVE PATIENTS
be offered to patients with FGTB before African Americas
pursuing IVF. 16% 12%
In the absence of professional guide- Eastern
European Mediterranean
lines regarding FGTB screening and 4%
evaluation in women seeking fertility 12%
treatment, many fertility clinics in the
United States use CXR to triage patients
who have positive results on TB screening
tests (tuberculin skin test [TST] or QFT) Western Pacific
to determine the need for further evalu- 20%
ation or antitubercular treatment. This is
based on general recommendations to
rule out active pulmonary disease in those Southeast Asia
having positive results on TB screening 36%
tests. However, most women with FGTB A pie chart showing the regional distribution (by percentage) of QFT-positive and QFT-negative
do not exhibit pulmonary symptoms and patients in our clinic.
many have negative CXRs. The American QFT, QuantiFERON-TB Gold.
Thoracic Society reported that approxi- Tal et al. Genital TB in infertile women in the United States. Am J Obstet Gynecol 2020.
mately 40%e75% of women with FGTB
have abnormal CXRs.38 However, other
studies found that less than 25% of a screening tool to clear infertile patients tertiary care facility in the Northeast of
women with FGTB had abnormal CXR with latent TB for proceeding with IVF the United States, our findings highlight
results.19,39 In this study, only 8% of our treatment. To confidently rule out the the importance of fertility specialists
patients with latent TB (QTB positive) existence of FGTB in infertile women being vigilant to the possibility of FGTB
had abnormal CXRs. Of note, these pa- who have positive results on M tubercu- as a mechanism for infertility in patients
tients had negative endometrial testing losis screening tests, endometrial sam- from geographic areas where TB is
for TB and no evidence of endometrial pling and multiple diagnostic tests should deemed endemic. Clinicians should
pathology, whereas the patients who had be used together, as utilized in our consider the possibility of FGTB in high-
abnormal endometrial histology had a population. risk patients presenting with evidence of
negative CXR study. Our experience un- Given the nearly 8% prevalence of tubal distortion, pelvic adhesive disease
derscores that in a high-risk population, a latent TB identified among at-risk of unclear etiology, and features of
negative CXR should not be used alone as women seeking infertility care at a chronic pelvic infection unresponsive to

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57.1% and a specificity of 100%, histo-

FIGURE 4
pathologic examination had a sensitivity
Endometrial biopsy showing chronic granulomatous endometritis
of 10.7% and a specificity of 90.5%, and
culture had a sensitivity of 7.1% and a
specificity of 100%.45 Although other
studies also corroborated the superiority
of the PCR test in detection of FGTB
compared with all other diagnostic
tests,43,46e48 TB culture can still detect
FGTB cases who have a negative result by
PCR.48 Therefore, performing TB his-
tology and culture tests on endometrial
biopsies in addition to PCR seems to
increase the diagnostic power for
A, Fragment of endometrium with several granulomas (arrows) within the endometrial stroma (100 detecting FGTB and is the diagnostic
original magnification). B, Higher magnification shows a necrotizing granuloma with multinucleated strategy that we chose in this study.
giant cells (arrow) (200 original magnification). However, despite using all of these
Tal et al. Genital TB in infertile women in the United States. Am J Obstet Gynecol 2020. diagnostic modalities, it is plausible that
there may still be QFT-positive patients
in this study who may have FGTB but
standard antibiotic regimens; in those studies on women from endemic areas were underdiagnosed. Further research
with unexplained infertility; and in cases with high TB burden in China, IGRA has is needed to develop more sensitive
presenting with menstrual irregularities, been found to have sensitivity of 86% diagnostic tests for FGTB.
postmenopausal bleeding, and persistent e94% and specificity of 70%e75% for
vaginal discharge.15 Laparoscopic evi- the diagnosis of FGTB.43,44 Of note, Lu Strengths and limitations
dence of pelvic adhesive disease and et al43 found that IGRA performed on Limitations of this study include the
tubal disease should prompt clinicians to pelvic effusion aspirates yielded higher relatively small number of patients
consider a possibility of FGTB; in such sensitivity for FGTB diagnosis than who had positive results for latent TB
situations, obtaining peritoneal biopsies conventional IGRA testing on peripheral and the fact that the results were from a
for evaluation of FGTB by PCR and blood (94% vs 72%, respectively). This single center, limiting the generaliz-
culture for TB should be considered in was associated with a higher number of ability of our findings to infertile
addition to routine histology. spot-forming cells in pelvic effusion populations seeking infertility care in
samples than peripheral blood, indi- other regions of the country. Rates of
Research implications cating that pelvic effusion may have a FGTB are bound to vary among infer-
Genital TB screening and diagnosis are higher concentration of TB tility clinics across the United States
challenging. In this study, we chose QFT antigenespecific effector T cells. depending on local rates of latent TB
testing as the preferred screening Although QFT has a relatively high and population dynamics. Our deci-
approach for latent TB because of its sensitivity for the detection of FGTB, sion to use QFT as the preferred
reported higher sensitivity than TST. there is no gold standard, and research to screening approach to latent TB was
The common TST for latent TB was re- develop optimized FGTB screening is based on the convenience of sampling
ported to have a sensitivity of only 55% needed. Further studies are warranted to (single blood test) and evidence of
and a specificity of 80% in women with investigate the sensitivity and specificity higher sensitivity than TST. However,
laparoscopically proven FGTB.40 Apart of IGRA testing in various pelvic bodily it is important to note that data on
from decreased sensitivity, TST has fluids (eg, menstrual blood, endometrial performance and validity of QFT in
further disadvantages as a screening aid aspirate, pelvic fluid aspirate) and comparison with TST, as a screening
for latent TB, which include its nonspe- whether these may be affected by the modality for FGTB, are lacking, and
cific false-positive results.41 These timing of sampling in relation to the future studies are needed to identify if
include infection by non-TB mycobac- menstrual cycle. either one is superior as a screening
teria and previous Bacillus Calmettee Currently, many of the tests that are tool over the other. According to our
Guérin vaccination administration. routinely used in the diagnosis of FGTB, screening algorithm, EMBx was ob-
With regard to the newer IGRA (QFT), a such as histopathologic examination and tained only from patients who had a
large meta-analysis of 20 studies with AFB smear and culture, lack sufficient positive QFT result and not all at-risk
1711 patients reported 72% and 82% sensitivity. Thangappah et al45 evaluated patients. Although this strategy is
pooled sensitivity and specificity, the sensitivity of conventional FGTB more practical from a clinic’s
respectively, for the diagnosis of extrap- diagnostic methods. The study reported perspective, it may have missed some
ulmonary TB.42 Moreover, in 2 recent that endometrial PCR had a sensitivity of cases of FGTB. Moreover, this study is

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ajog.org GYNECOLOGY Original Research

inherently limited by lack of an existing including TB PCR has false-negative re- tuberculosis: a case series. Iran J Reprod Med
gold standard for FGTB diagnosis. sults, and it is challenging to avoid un- 2013;11:519–24.
15. Grace GA, Devaleenal DB, Natrajan M.
derestimation of FGTB diagnosis. Larger Genital tuberculosis in females. Indian J Med
Conclusion studies to assess the prevalence of FGTB Res 2017;145:425–36.
There is a concerning potential for dis- in infertile population in the United 16. Chow TW, Lim BK, Vallipuram S. The mas-
ease exacerbation if IVF is pursued in the States in different geographic areas are querades of female pelvic tuberculosis: case
setting of existing FGTB, with resulting needed together with research efforts reports and review of literature on clinical pre-
sentations and diagnosis. J Obstet Gynaecol
risks for maternal and neonatal well- aimed at the development of more sen- Res 2002;28:203–10.
being in the event of IVF success. This sitive screening and diagnostic tests for 17. Kulchavenya E, Kholtobin D. Diseases
study illustrates that FGTB can be FGTB. n masking and delaying the diagnosis of urogenital
underdiagnosed in women presenting to tuberculosis. Ther Adv Urol 2015;7:331–8.
infertility clinics without utilization of 18. Mathad JS, Gupta A. Tuberculosis in preg-
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Genital tuberculosis is common among females June 1, 2019. From the Departments of Obstetrics, Gynecology, and
with tubal factor infertility: observational study. 42. Fan L, Chen Z, Hao XH, Hu ZY, Xiao HP. Reproductive Sciences (Dr Tal, Ms Lawal, Ms Granger,
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tion of latent genital tuberculosis during in vitro release assay for the diagnosis of female genital This work was presented in part as an abstract at the
fertilisation and pregnancy. Int J Tuberc Lung Dis tuberculosis in Northwest China. J Clin Lab Anal 73rd annual meeting of the American Society for
2009;13:921. 2019;33:e22621. Reproductive Medicine, San Antonio, TX, Oct. 28eNov.
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tuberculosis after in vitro fertilization: suggestion interferon-g release assays for the diagnosis of Corresponding author: Reshef Tal, MD, PhD. reshef.
for tuberculosis tests in infertile women in female genital tuberculosis in a tertiary referral tal@yale.edu

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