Gai et al.

BMC Infect Dis (2021) 21:913

https://doi.org/10.1186/s12879-021-06564-z

RESEARCH ARTICLE Open Access

Acute miliary tuberculosis in pregnancy

after in vitro fertilization and embryo transfer:
a report of seven cases
Xiaoyan Gai1†, Hongbin Chi2,5,6,7†, Wenli Cao3†, Lin Zeng4, Lixue Chen2,5,6,7, Weixia Zhang1,
Donghong Song2,5,6,7, Ying Wang2,5,6,7, Ping Liu2,5,6,7, Rong Li2,5,6,7* and Yongchang Sun1*

Abstract
Background: While miliary tuberculosis (TB) in pregnancy is rare after in vitro fertilization and embryo transfer (IVF-
ET), it poses a serious threat to the health of pregnant women and their fetuses. The present study aimed to describe
the clinical features of miliary TB and pregnancy outcomes of patients after IVF-ET.
Methods: Data of infertile patients who received IVF-ET at Peking University Third Hospital between January 2012 to
December 2017 were retrospectively analyzed. Patients who developed miliary TB during pregnancy were identified,
and clinical characteristics of miliary TB were described.
Results: Out of 62,755 infertile women enrolled, 7137 (11.4 %) showed signs of prior pulmonary TB on chest X-ray
(CXR). Among the 15,136 women (mean age: 33.2 ± 5.0 years) who successfully achieved clinical pregnancy, seven
patients aged 28–35 years had miliary TB during pregnancy, with two patients having a complication of TB meningitis.
All these patients presented with fever. Notably, old TB lesions were detected on CXR in six patients before IVF-ET;
nevertheless, no anti-TB therapy was administered. Furthermore, salpingography revealed oviduct obstruction in all
patients (7/7). Patients received anti-TB therapy following a diagnosis of miliary TB and were clinically cured. However,
pregnancy was terminated due to spontaneous (4/7) and induced (3/7) abortion.
Conclusions: TB reactivation, mostly as miliary TB and TB meningitis, is severe in pregnant women after IVF-ET and
deleterious to pregnancy outcomes. Signs of prior TB on CXR may be risk factors for TB reactivation during pregnancy.
Keywords: Miliary tuberculosis, Infertility, In vitro fertilization, Embryo transfer

Background suffer from clinical TB each year [2]. Pregnancy-related

Tuberculosis (TB) remains a major public health prob- TB endangers the health of both women and their fetuses
lem globally and poses a considerable threat to human and is considered an important cause of morbidity and
health [1]. Globally, approximately 3.2 million women mortality [3–5]. TB more rapidly progresses in preg-
nant women than in nonpregnant ones [5] and can lead
to miscarriage [3–5]. Furthermore, women who survived
*Correspondence: roseli001@sina.com; suny@bjmu.edu.cn from TB are often dissuaded from having children or,
†
Xiaoyan Gai,Hongbin Chi and Wenli Cao are joint first authors even worse, can no longer conceive again.
1
Department of Respiratory and Critical Care Medicine, Peking University Acute miliary TB, a more serious and potentially lethal
Third Hospital, 49 N Garden Rd, Haidian District, Beijing 100191, China
2
Center for Reproductive Medicine, Department of Obstetrics form of the disease, results from massive hematogenous
and Gynecology, Peking University Third Hospital, 49 N Garden Rd, dissemination of Mycobacterium tuberculosis. The miliary
Haidian District, 100191 Beijing, China pattern in the lungs has been radiologically described as
Full list of author information is available at the end of the article

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or
other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this
licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecom-
mons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Gai et al. BMC Infect Dis (2021) 21:913 Page 2 of 9

“a collection of tiny discrete pulmonary opacities that are physician contacted the seven patients via phone call and
generally uniform in size and widespread in distribution, reviewed the medical records. Live birth was defined as
each of which measures 2 mm or less in diameter” [6, the delivery of a living fetus (or living fetuses) beyond 28
7]. If untreated, miliary TB is uniformly fatal. Relative to weeks of gestation, whereas miscarriage was defined as
all forms of TB, the incidence of miliary TB ranges from pregnancy loss before 28 weeks of gestation.
0.15 to 10 % [1, 6, 7]. Additionally, approximately 15–30 % This study was approved by the Ethics Committee
of patients with pulmonary TB during pregnancy exhibit of Peking University Third Hospital [batch number:
hematogenous dissemination and have miliary TB [8]. (2019)327-02]. The retrospective nature of the study
Because clinical symptoms such as fever and cough are resulted in a waiver regarding the signing of the informed
nonspecific and chest X-ray (CXR) and chest computed consent form.
tomography (CT) scan during pregnancy are associated
with a risk of radiation exposure, the diagnosis of miliary IVF‑ET protocol
TB during pregnancy is often delayed. IVF-ET was performed as previously described
With the increasing application of in vitro fertilization [15]. Briefly, controlled ovarian hyperstimulation was
and embryo transfer (IVF-ET), the incidence of TB dur- achieved, oocytes were fertilized, and ETs were sub-
ing pregnancy has gradually increased, posing a serious sequently performed [15]. Among seven patients who
threat to the health of pregnant women and fetuses [1, 9, developed TB during pregnancy, one had undergone
10]. There have been occasional case reports of TB with a frozen cycle transfer, whereas the remaining six had
hematogenous dissemination, miliary TB, and/or menin- undergone fresh cycle transfer. After ET, 60 mg of pro-
gitis during pregnancy after IVF-ET, leading to abortion, gesterone was injected intramuscularly for 14 days. Blood
fetal malformation, or increased risk of mortality [10, human chorionic gonadotropin concentration was moni-
11]. Therefore, correct and timely diagnosis and manage- tored at 2 weeks after transplantation, and the status of
ment of TB during pregnancy are important. Therefore, the embryo sac was examined by ultrasonography at 4
in this study, we aimed to describe the clinical features weeks after transplantation.
of TB and its impact on pregnancy outcomes after IVF-
ET. We retrospectively analyzed the data of patients who Statistical analysis
underwent IVF-ET and showed clinical signs of miliary Continuous variables are expressed as mean ± standard
TB during pregnancy between January 2012 and Decem- deviation or as median with interquartile range. Statisti-
ber 2017 at the reproductive center of our hospital. Addi- cal analysis was performed using SPSS version 23 (IBM
tionally, we summarized the clinical manifestations and Corp., Armonk, NY).
pregnancy outcomes of these patients.
Results
Methods Patients’ baseline data
This was a retrospective study of patients who under- A total of 62,755 infertile patients (mean age: 33.1 ± 5.1
went IVF-ET for infertility between January 1, 2012, and years, range: 20–50 years) were identified from our data-
December 31, 2017, at Peking University Third Hospi- base to have been referred to the reproductive center of
tal, a tertiary referral hospital in Beijing, China. Data on our hospital between January 1, 2012, and December 31,
patients undergoing IVF-ET, including causes of infertil- 2017. Of these patients, 11.4 % (7137/62,755) exhibited
ity, serum hormone concentrations, the controlled ovar- signs of prior pulmonary TB prior to IVF-ET based on
ian hyperstimulation protocol, and CXR results, were their CXR results. Furthermore, 37,854 out of all 62,755
recorded. CXR was routinely performed for each patient, patients underwent ET, whereas the remaining 24,901
and active TB cases were excluded before IVF-ET was patients failed because they had no ovum that could be
started. A medical team was assigned to follow up the obtained or had no embryo to transfer or due to some
pregnancy outcomes. other reasons. Finally, 15,136 (mean age: 33.2 ± 5.0 years)
During the 6-year period, 62,755 patients, who were all out of 37,854 patients succeeded in achieving clinical
HIV-negative, had received IVF-ET at our center. Among pregnancy. Among these 15,136 patients, seven had acute
these patients, seven with active TB during pregnancy miliary TB during pregnancy. Hence, the prevalence rate
were identified. Active TB was diagnosed according to was 7/15,136 (i.e., 4.6/10,000) (Fig. 1).
the national guidelines [12]. Miliary TB was diagnosed
based on the size, distribution, and density of miliary-like Baseline data of the seven patients with active TB
nodules that were bilaterally distributed on CXR or chest during pregnancy
CT scan [13, 14]. Baseline data and CXR and laparos- Among the seven cases, four occurred in 2012, two in
copy results before IVF-ET were retrieved. A respiratory 2016, and one in 2017. These pregnant women were
Gai et al. BMC Infect Dis (2021) 21:913 Page 3 of 9

Fig. 1 Flow of protocol and outcomes

between 28 and 34 years of age, and the duration of ET: three had twin pregnancies and three had singleton
infertility ranged from 1 to 12 years. Their body mass pregnancies.
index was 20.1–27.3 kg/m2. All seven patients had pri-
mary infertility due to unilateral or bilateral oviduct
obstruction, as assessed using salpingography. Four Clinical manifestations and diagnosis of active TB
patients also underwent laparoscopy and showed tubal during pregnancy
obstruction and adhesion consistent with TB; how- All seven patients had fever at 7–14 weeks of preg-
ever, the pathology failed to reveal features of TB. One nancy. Among them, six had moderate-to-high fever,
patient had suffered from TB at the age of 16, and the with the highest body temperatures recorded at 38.5–
local hospital administered anti-TB therapies for over 40 °C, whereas one had low-grade fever (37.5 °C). All
6 months at that time. The other six patients had no seven patients had mild cough and a small amount of
clinical history of TB and had not received anti-TB sputum with (1/7) or without blood (6/7). CXR and
treatment. Among the seven patients, six showed signs CT scans were performed on all seven patients, which
of old pulmonary TB lesions on CXR before IVF-ET. showed diffuse miliary nodules in both lungs, consist-
Tuberculin skin test (TST) was performed in three ent with acute miliary TB (Fig. 2). Two patients with
patients before IVF-ET, with induration diameters of complaints of significant headache were confirmed by
10–20 mm, thus confirmed as positive (+ +) cases. lumbar puncture to have TB meningitis (Table 1).
However, this test was not performed in the other four Five patients underwent an interferon gamma release
patients. None had active TB before IVF-ET, and IVF- assay (IGRA) test after fever onset and showed posi-
ET was performed as scheduled (Fig. 2; Table 1). tive results. One patient underwent the TST, which was
One patient underwent frozen ET and had a singleton positive (+ + +).
pregnancy. The remaining six patients underwent fresh
Gai et al. BMC Infect Dis (2021) 21:913 Page 4 of 9

Fig. 2 Chest imaging in a 32-year-old infertile woman. a Posteroanterior chest radiograph showing a scarring nodule in the left upper lobe (arrow)
at screening before IVF-ET. b Chest computed tomography showing multiple miliary nodules of uniform density, size, and distribution. c A scarring
nodule in the left upper lobe and calcification of the left hilar lymph nodes. IVF-ET, in vitro fertilization and embryo transfer

Outcomes of TB and pregnancy outcomes of the seven et al. reported the first case in 1988 [10]. Since then, more
patients cases have been described, the majority of which were
After the diagnosis of TB, four patients had spontane- from developing countries, [17–21, 24]. The results from
ous abortion, whereas three patients underwent induced our study and from these previous studies indicated that
abortion (Table 2). All seven patients recovered after women with TB during pregnancy after IVF-ET were
anti-TB therapy. At follow-up, two patients achieved prone to hematogenous dissemination.
pregnancy after second IVF-ET. TB activation and dissemination may be related to
latent infection, IVF-ET intervention, and immune dys-
regulation in pregnancy [25]. Studies have shown that
Discussion estrogen, progesterone, and human chorionic gonado-
In this retrospective study, we identified seven cases of tropin have a direct inhibitory effect on T-cells [26, 27].
active TB during pregnancy from 62,755 cases of IVF- High estrogen levels are conducive to the proliferation
ET carried out at our hospital. All of these seven cases of M. tuberculosis. Increased vascular permeability after
were diagnosed with acute miliary TB, with two cases pregnancy may also facilitate bacterial spread throughout
complicated by TB meningitis. Notably, signs of prior the body, resulting in hematogenous dissemination [28].
TB on CXR were detected in 11.4 % of our study popula- The prognosis of miliary TB during pregnancy after IVF-
tion (7137/62,755), and six out of the seven patients with ET was poor and may have caused the spontaneous abor-
acute miliary TB had prior TB signs identified on CXR tion or may have resulted in premature delivery. More
before IVF-ET. seriously, respiratory failure and even acute respiratory
Our data indicated that TB in pregnancy after IVF-ET distress syndrome might occur in pregnant women [14,
mostly occurred during the first 8–12 weeks of preg- 16]. Furthermore, fetuses might suffer from intrauter-
nancy. Fever was the main symptom, and the time inter- ine growth retardation or be stillborn due to hypoxia,
val between fever onset and definitive diagnosis was 2–4 or acquire infection via hematogenous dissemination or
weeks or more. An important finding of our study was aspiration of contaminated amniotic fluid [11]. Moreover,
that all seven patients with active TB during pregnancy those with miliary TB during pregnancy were less likely
after IVF-ET developed hematogenous dissemination, to achieve pregnancy, even with IVF-ET.
which is the most serious condition of TB. Two out of the Identifying patients at high risk for TB activation
seven patients had tuberculous meningitis as a complica- should be an important evaluation before IVF-ET,
tion. This finding is consistent with the result of a previ- especially in regions with a high TB burden. From
ous report. We conducted a literature review on patients our observation, we speculate that the coexistence
with TB during pregnancy after IVF-ET using the key- of primary infertility, untreated prior pulmonary
words “infertility,” “in vitro fertilization and embryo TB, and fallopian tube obstruction may be a risk fac-
transfer,” “tuberculosis,” and “pregnancy” to search for tor for active TB during an IVF-ET pregnancy. Signs
articles published from 1980 to 2019 in PubMed, MED- of fibrotic scarring, calcified nodules, and/or pleu-
LINE, EMBASE, and Chinese Wanfang databases. ral thickening on CXR indicate previous infection
Furthermore, we summarized 37 cases of TB during with M. tuberculosis [29–31]. In our series, among
pregnancy after IVF-ET [10, 16–24] (Table 3). Addis the 7137 patients who had “old TB” lesions on CXR,
 Gai et al. BMC Infect Dis

Table 1 Baseline characteristics of the seven cases of miliary TB

Case Type of infertility Infertility Infertility factor Past history CXR before IVF-ET Salpingography Laparoscopy Pathology ESR
duration
(years)

1 Primary infertility 12 Fallopian tubal ovula- Denial of TB history Fibrotic scars in upper Bilateral oviduct Extensive pelvic adhe- Peritoneal fibrous 8
(2021) 21:913

tion left lung obstruction sion, bilateral ovarian nodules complicated

adhesion. Yellow by hyaline degenera-
hard neoplasm tion
could be seen at the
umbrella end of the
right oviduct and
the mesentery; Pel-
vic adhesiolysis and
salpingostomy;
2 Primary infertility 4 Fallopian tubal ovula- Denial of TB history Left pleural thickening Bilateral oviduct Bilateral oviduct Endometritis 6
tion and adhesion umbrella end adhe- obstruction, after
sion laparoscopic reca-
nalization
3 Primary infertility 9 Fallopian tubal ovula- Denial of TB history Fibrotic scars in upper Bilateral oviduct NA NA 6
tion right lung obstruction
4 Primary infertility 7 Fallopian tubal ovula- Denial of TB history Fibrotic scars in upper Bilateral oviduct Bilateral oviduct manifestation of secre- 6
tion left lung obstruction obstruction; Bilateral tive phase
salpingoplasty
5 Primary infertility 5 Fallopian tubal ovula- Denial of TB history No abnormality Left oviduct obstruc- Bilateral oviduct Endometritis 5
tion; PCOS tion; Right oviduct obstruction
unsmooth;
6 Primary infertility 1 Fallopian tubal ovula- Denial of TB history; Left pleural thickening Left oviduct obstruc- NA NA 5
tion One IVF-ET failed tion; Right oviduct
history; unsmooth;
7 Primary infertility 3 Fallopian tubal ovula- Pulmonary TB at the Fibrous scars in the Bilateral oviduct NA NA 6
tion age of 16 upper right lung; Left obstruction
pleural thickening
and adhesion
CXR chest X-ray, IVF-ET in vitro fertilization and embryo transfer, TB tuberculosis, ESR erythrocyte sedimentation rate
Page 5 of 9
 Gai et al. BMC Infect Dis
(2021) 21:913

Table 2 Clinical manifestations and pregnancy outcomes of the seven cases of miliary TB during pregnancy
Case IVF-ET cycle type IVF-ET outcomes Vaginal Gestational weeks Fever Gestational TST after IGRA after Pregnancy outcomes Follow-up
bleeding with bleeding (w) weeks with fever fever
fever (w) onset onset

1 Fresh ET Singleton + 7 + 12 NA NA Spontaneous abortion Received ET again and gave birth 3

years later after TB.
2 Fresh ET Twin + 17 + 14 NA + Spontaneous abortion Underwent two rounds of ET 3 years
later, yet both failed.
3 Fresh ET Singleton − − + 9 NA + Induced abortion No pregnancy since.
4 Fresh ET Twin − − + 7 NA + Induced abortion Underwent ET 3 years later yet failed.
No pregnancy since.
5 Frozen ET Singleton + 8 + 10 +++ + Spontaneous abortion No pregnancy after three rounds of ET.
6 Fresh ET Twin + 14 + 12 NA + Spontaneous abortion Underwent fresh ET and two rounds of
frozen ET 5 years later, yet all failed.
No pregnancy since.
7 Fresh ET Singleton + 8 + 9 NA NA Induced abortion Experienced one failed frozen ET 6
years later; got pregnant and gave
birth after another ET 7 years later.
IVF-ET in vitro fertilization and embryo transfer, TB tuberculosis, ET embryo transfer, TST tuberculin skin test, IGRA​interferon gamma release assay, NA not available
Page 6 of 9
Table 3 Summary of reported cases of TB during pregnancy after IVF-ET
Cases Age (years) Onset time (week) TB history Clinical Diagnosis Pregnancy Outcomes for fetus Country References
manifestations outcomes for
pregnant women
Gai et al. BMC Infect Dis

1 33 10 Denial of TB history Fever, cough, short- Miliary TB (1/1) Cured Spontaneous abortion U.K. Addis et al. [10]
ness of breath
5 25–33 5–9 Denial of TB history; Fever (5/5) Miliary TB (5/5) Cured Spontaneous abortion China Wei et al. [16]
Laparoscopy showed (5/5)
bilateral oviduct
obstruction (5/5)
(2021) 21:913

4 NA 5–15 Denial of TB history Fever (4/4) Miliary TB (4/4); ARDS Died (1/4); Cured (3/4) Spontaneous abortion China Wei et al. [17]
(1/4) (4/4)
1 29 11 Denial of TB history; Fever, shortness of Miliary TB (1/1) Cured Spontaneous abortion China Liu et al. [18]
laparoscopy showed breath
bilateral oviduct
obstruction
6 27–32 6–9 One case had a history Fever (6/6), slight Miliary TB (6/6) Cured Spontaneous abortion China Gao et al. [19]
of tuberculous pleu- cough and expecto- (5/6); induced abor-
ritis, and 1 case had a ration (6/6) tion (1/6)
history of pelvic TB
11 26–36 6–14 Denial of TB history Fever (11/11) Miliary TB (11/11); TB Cured Spontaneous abortion China Jin et al. [20]
meningitis (4/11) (8/11); induced
abortion (3/11)
6 29–39 5–16 (5/6); 26 (1/6) One case had a history Fever, cough, short- Miliary TB (6/6); TB Cured Spontaneous abortion China Ye et al. [21]
of TB, one case had ness of breath (6/6); meningitis (1/6) (3/6); induced abor-
no history of TB, but Headache (1/6) tion (3/6)
chest radiograph
showed sclerotic
calcification in the
lung(s), and the
other 4 cases had no
manifestation of TB
1 38 14 Denial of TB history, Fever, cough Miliary TB with TB Cured Spontaneous abortion Israel Gull et al. [22]
and laparoscopy meningitis (1/1)
showed bilateral
oviduct obstruction
1 NA 8 Denial of TB history; Fever, cough Miliary TB (1/1) Cured Spontaneous abortion Belgium Jacquemyn et al. [23]
Laparoscopy showed
bilateral oviduct
obstruction
1 31 8 Denial of TB history; Fever, cough Miliary TB (1/1) Cured Premature delivery China Fan et al. [24]
Laparoscopy showed
bilateral oviduct
obstruction
TB tuberculosis, IVF-ET in vitro fertilization and embryo transfer, ARDS acute respiratory distress syndrome
Page 7 of 9
Gai et al. BMC Infect Dis (2021) 21:913 Page 8 of 9

six developed miliary TB during pregnancy. Liu et al. Conclusions

reported a similar case in which untreated prior pul- Acute miliary TB occurs in pregnant women after IVF-
monary TB developed into miliary TB during preg- ET, particularly in those exhibiting signs of prior pul-
nancy [18]. Our previous study revealed that the monary TB on CXR. Patients with miliary TB have
clinical pregnancy and live birth rates were signifi- poor pregnancy outcomes. The coexistence of primary
cantly lower in infertile patients with untreated prior infertility, untreated prior pulmonary TB, and fallopian
pulmonary TB than in those without signs of prior TB, tube obstruction is a high-risk factor for TB dissemina-
highlighting the adverse effects of TB in this specific tion. Therefore, clinicians should be aware of the signs
patient population [32]. of TB before administering a course of IVF-ET treat-
Genital TB (GTB) is a form of extrapulmonary TB ment. Prospective studies are warranted to determine the
and a major cause of primary infertility among women incidence of and risk factors for reactive TB in infertile
in TB-endemic countries [33], with a prevalence rate patients with prior pulmonary TB after IVF-ET and to
of 28.4 % in our hospital, as observed in previous stud- clarify whether anti-TB therapy is beneficial for preg-
ies [34, 35]. GTB may cause fallopian tube obstruction, nancy outcomes in these patients.
reduced endometrial receptivity, and ovarian dysfunc-
tion, leading to infertility. However, manifestations
Abbreviations
of GTB are nonspecific, and confirmation of diagno- CT: Computed tomography; CXR: Chest X-ray; GTB: Genital TB; IGRA​: Interferon
sis relies on invasive procedures. Our seven patients gamma release assay; IVF-ET: In vitro fertilization and embryo transfer; TB:
showed unilateral or bilateral oviduct obstruction, Tuberculosis; TST: Tuberculin skin test.
which suggested chronic infections such as GTB. Fur- Acknowledgements
ther studies are required to clarify whether the IGRA Not applicable.
test and TST are necessary for the assessment of latent
Authors’ contributions
TB infection prior to IVF-ET and whether preven- RL and YS jointly conceived and directed this work, and RL is the leading
tive anti-TB therapy can improve the pregnancy out- corresponding author. XG, HC, and WC had full access to all data in the study
comes of infertile women with latent TB infection or and take responsibility for the integrity of the data and the accuracy of data
analysis. XG, HC, WC, LZ, LC, WZ, DS, YW, and PL participated in the acquisition,
untreated prior pulmonary TB on CXR. Moreover, analysis, or interpretation of the data. XG and HC wrote the report. YS and RL
screening for latent TB infection during pregnancy can were involved in manuscript editing. The final version has been reviewed and
provide an excellent opportunity for prevention. approved by all authors. All authors read and approved the final manuscript.
Imaging plays a pivotal role in the diagnosis of pul- Funding
monary diseases, including TB [31, 36]. Clinical diag- This research was funded by the National Natural Science Foundation [No.
nosis of active TB in pregnant women is often delayed, 81400041 and 81871212] and the National Natural Science Foundation of
China Youth Fund Project [No. 81400038]. The sponsors of the study had
which is largely attributable to the concern about no role in study design, data collection, data analysis, data interpretation, or
radiation exposure from chest radiography. The IGRA writing of the report. The corresponding author confirms that she had full
test is an important diagnostic method for active TB access to all data in the study and had the final responsibility for the decision
to submit for publication.
detection and is safe for use during pregnancy [37–40].
Both the IGRA test and TST have a high consistency Availability of data and materials
of 77.3–88.0 % [39]. TheIGRA test has a high sensi- The datasets used and/or analyzed during the current study are available from
the corresponding author on reasonable request.
tivity of 100% and a moderate specificity of 80.0% for
detectingactive TB during pregnancy [40], which are
Declarations
not affected by previous vaccination withbacillus Cal-
mette–Guérin. Further studies on the use of the IGRA Ethics approval and consent to participate
test for TB detectionduring pregnancy, particularly This study was approved by the Ethics Committee of Peking University Third
Hospital [batch number: (2019)327-02]. The retrospective nature of the study
in high-risk patients from TB-endemic regions, are resulted in a waiver regarding the signing of the informed consent form.
warranted.
Our study has some limitations. First, this was a sin- Consent for publication
Written informed consent was obtained from the seven patients for publica-
gle-center study; however, as the largest reproductive tion of their cases.
center in China, we perform more than 10,000 cycles
of IVF-ET annually on women from all over the coun- Competing interests
The authors declare that they have no competing interests.
try. Therefore, the population in this study was repre-
sentative. Second, we inquired whether active TB had Author details
1
occurred during pregnancy through telephone follow- Department of Respiratory and Critical Care Medicine, Peking University
Third Hospital, 49 N Garden Rd, Haidian District, Beijing 100191, China. 2 Center
up, which might have led to an underdiagnosis of the for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking
disease. University Third Hospital, 49 N Garden Rd, Haidian District, 100191 Beijing,
Gai et al. BMC Infect Dis (2021) 21:913 Page 9 of 9

China. 3 Tuberculosis Department, Beijing Geriatric Hospital, 102699 Beijing, 21. Ye R, Wang C, Zhao L, Wu X, Gao Y, Liu H. Characteristics of miliary tubercu-
China. 4 Clinical Epidemiology Research Center, Peking University Third Hos- losis in pregnant women after in vitro fertilisation and embryo transplanta-
pital, 100191 Beijing, China. 5 National Clinical Research Center for Obstetrics tion. Int J Tuberc Lung Dis. 2019;23:136–9.
and Gynecology, 100191 Beijing, China. 6 Key Laboratory of Assisted Reproduc- 22. Gull I, Peyser MR, Yaron Y, Jaffa AJ, Amit A, Lessing JB. The effect of an in-vitro
tion (Peking University), Ministry of Education, 100191 Beijing, China. 7 Beijing fertilization pregnancy on a woman with genital tuberculosis. Hum Reprod.
Key Laboratory of Reproductive Endocrinology and Assisted Reproductive 1995;10:3052–4.
Technology, 100191 Beijing, China. 23. Jacquemyn Y, Van Casteren C, Luijks M, Colpaert C. Disseminated
tuberculosis in pregnancy unknown to doctors in Western Europe case
Received: 19 August 2020 Accepted: 12 August 2021 presentation: ‘part of the routine study in infertility’. BMJ Case Rep. 2012;
2012:bcr2012006227.
24. Fan XL, Chen ZJ, Li CY, Ma L. Analysis of a case of miliary tuberculosis in both
lungs and premature delivery after in vitro fertilization and embryo trans-
plantation pregnancy. Chin J Obstet Gynecol. 2003;38:637–8 In Chinese.
References 25. Singh N, Perfect JR. Immune reconstitution syndrome and exacerbation of
1. World Health Organization. Global TB report. 2020. https://​www.​who.​int/​ infections after pregnancy. Clin Infect Dis. 2007;45:1192–9.
teams/​global-​tuber​culos​is-​progr​amme/​tb-​repor​ts. Accessed 3 Nov 2020. 26. Aghaeepour N, Ganio EA, Mcilwain D, Tsai AS, Tingle M, Van Gassen S, et al.
2. Sugarman J, Colvin C, Moran AC, Oxlade O. Tuberculosis in pregnancy: an An immune clock of human pregnancy. Sci Immunol. 2017;2:eaan2946.
estimate of the global burden of disease. Lancet Glob Health. 2014;2:e710-6. 27. Saito S, Nakashima A, Shima T, Ito M. Th1/Th2/Th17 and regulatory T-cell
3. Zumla A, Bates M, Mwaba P. The neglected global burden of tuberculosis in paradigm in pregnancy. Am J Reprod Immunol. 2010;63:601–10.
pregnancy. Lancet Glob Health. 2014;2:e675-6. 28. Yu N, Yang J, Guo Y, Fang J, Yin T, Luo J, et al. Intrauterine administration
4. Sulis G, Pai M. Tuberculosis in pregnancy: a treacherous yet neglected issue. of peripheral blood mononuclear cells (PBMCs) improves endometrial
J Obstet Gynaecol Can. 2018;40:1003–5. receptivity in mice with embryonic implantation dysfunction. Am J Reprod
5. Bates M, Ahmed Y, Kapata N, Maeurer M, Mwaba P, Zumla A. Perspectives on Immunol. 2014;71:24–33.
tuberculosis in pregnancy. Int J Infect Dis. 2015;32:124–7. 29. Uzorka JW, Kroft LJM, Bakker JA, van Zwet EW, Huisman E, Prins C, et al.
6. Sharma SK, Mohan A, Sharma A. Miliary tuberculosis: a new look at an old Abnormalities suggestive of latent tuberculosis infection on chest
foe. J Clin Tuberc Other Mycobact Dis. 2016;18:13–27. radiography; how specific are they? J Clin Tuberc Other Mycobact Dis.
7. Sharma SK, Mohan A. Miliary tuberculosis. Microbiol Spectr. 2017. https://​doi.​ 2019;15:100089.
org/​10.​1128/​micro​biols​pec.​TNMI7-​0013-​2016. 30. Uzorka JW, Wallinga J, Kroft LJM, Ottenhoff THM, Arend SM. Radiological
8. Sobhy S, Babiker Z, Zamora J, Khan KS, Kunst H. Maternal and perinatal signs of latent tuberculosis on chest radiography: a systematic review and
mortality and morbidity associated with tuberculosis during pregnancy meta-analysis. Open Forum Infect Dis. 2019;6:ofz313.
and the postpartum period: a systematic review and meta-analysis. BJOG. 31. Nachiappan AC, Rahbar K, Shi X, Guy ES, Barbosa EJM Jr, Shroff GS, et al.
2017;124:727–33. Pulmonary tuberculosis: role of radiology in diagnosis and management.
9. Li Q, Song Y, Chen H, Xie L, Gao M, Ma L, et al. Retrospective analysis of 28 Radiographics. 2017;37:52–72.
cases of tuberculosis in pregnant women in China. Sci Rep. 2019;9:15347. 32. Gai XY, Chi HB, Zeng L, Cao WL, Chen LX, Zhang C, et al. Untreated prior
10. Addis GM, Anthony GS, d’A Semple P, Miller AW. Miliary tuberculosis in an pulmonary tuberculosis adversely affects pregnancy outcomes in infertile
in-vitro fertilization pregnancy: a case report. Eur J Obstet Gynecol Reprod women undergoing in vitro fertilization and embryo transfer: a large retro-
Biol. 1988;27:351–3. spective cohort study. Biomed Environ Sci. 2021;34:130–8.
11. Samedi V, Field SK, Al Awad E, Ratcliffe G, Yusuf K. Congenital tuberculosis in 33. Bhanothu V, Theophilus JP, Reddy PK, Rozati R. Occurrence of female genital
an extremely preterm infant conceived after in vitro fertilization: case report. tuberculosis among infertile women: a study from a tertiary maternal
BMC Pregnancy Childbirth. 2017;17:66. health care research centre in South India. Eur J Clin Microbiol Infect Dis.
12. Diseases Prevention and Control Department of China Health and Family 2014;33:1937–49.
Planning Commission. Guidelines for implementing the National Tubercu- 34. Zhang LZ, Wei ZX, Liu P. Factors affecting the clinical pregnancy rate in an
losis Control Program in China. Beijing: Peking Union Medical College Press; in vitro fertilization and embryo transfer program. Chin J Obstet Gynecol.
2008. 1998;33:727–30 In Chinese with English abstract.
13. Ray S, Talukdar A, Kundu S, Khanra D, Sonthalia N. Diagnosis and manage- 35. Li MM, Li R. Progress in diagnosis and treatment of female genital tuberculo-
ment of miliary tuberculosis: current state and future perspectives. Ther Clin sis induces infertility. Chin J Obstet Gynecol. 2015;50:954–6 In Chinese.
Risk Manag. 2013;9:9–26. 36. Razek AAKA, El Badrawy MK, Alnaghy E. Interstitial lung fibrosis imaging
14. Deng W, Yu M, Ma H, Hu LA, Chen G, Wang Y, et al. Predictors and outcome reporting and data system: what radiologist wants to know? J Comput
of patients with acute respiratory distress syndrome caused by miliary Assist Tomogr. 2020;44:656–66.
tuberculosis: a retrospective study in Chongqing, China. BMC Infect Dis. 37. Gupta RK, Kunst H, Lipman M, Noursadeghi M, Jackson C, Southern J, et al.
2012;12:121. Evaluation of QuantiFERON-TB Gold Plus for predicting incident tuberculosis
15. Wang H, Gao H, Chi H, Zeng L, Xiao W, Wang Y, et al. Effect of levothyroxine among recent contacts: a prospective cohort study. Ann Am Thorac Soc.
on miscarriage among women with normal thyroid function and thyroid 2020;17:646–50.
autoimmunity undergoing in vitro fertilization and embryo transfer: a 38. Abubakar I, Drobniewski F, Southern J, Sitch AJ, Jackson C, Lipman M, et al.
randomized clinical trial. JAMA. 2017;318:2190–8. Prognostic value of interferon-g release assays and tuberculin skin test
16. Wei Y, Wen E, Zhao YY, Wang LN, Qiao J. In vitro fertilization and embryo in predicting the development of active tuberculosis (UK PREDICT TB): a
transplantation pregnancy complicated by acute miliary tuberculosis in five prospective cohort study. Lancet Infect Dis. 2018;18:1077–87.
cases. Chin J Perinat Med. 2010;13:324–6 In Chinese. 39. Lighter-Fisher J, Surette AM. Performance of an interferon-gamma release
17. Wei Y, Zhao YY, Wang YQ. The clinic analysis of four cases of pregnancy of assay to diagnose latent tuberculosis infection during pregnancy. Obstet
women with miliary tuberculosis after in vitro fertilization and embryo Gynecol. 2012;119:1088–95.
transfer. Int J Gynecol Obstet. 2009;107:545. 40. Chen Q, Guo X, Wang X, Wang M. T-SPOT.TB in detection of active tuber-
18. Liu HB, Zhao L. Miliary tuberculosis after in vitro fertilization and embryo culosis during pregnancy: a retrospective study in China. Med Sci Monit.
transplantation. Afr Health Sci. 2015;15:701–4. 2016;22:57–60.
19. Gao HJ, Hu YJ, Zhu YM, Huang HF. Retrospective analysis of 6 cases of miliary
tuberculosis in pregnant women after in vitro fertilization and embryo
transplantation. Chin J Tuberc Respir Dis. 2007;30:848–50 In Chinese with
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub-
English abstract.
lished maps and institutional affiliations.
20. Jin C, Mi Z, Sun LF. Clinical characteristics of pulmonary tuberculosis in
pregnant women after in vitro fertilization embryo transfer. Chin J Clin Infect
Dis. 2014;7:137–9 In Chinese with English abstract.