Acute Miliary Tuberculosis in Pregnancy After in Vitro Fertilization and Embryo Transfer: Report of Seven Cases and Systemic Review

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. 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 identied, and clinical characteristics of miliary TB were described. The keywords “infertility,” “in vitro fertilization and embryo transfer,” and “tuberculosis” were used to search for articles published from 1980 to 2019 in PubMed, Medline, and EMBASE databases. oviduct obstruction in following oviduct on a for dissemination. of extrapulmonary a of infertility in women after IVF-ET, especially in those with signs of prior pulmonary TB on CXR. The coexistence of primary infertility, untreated prior pulmonary TB, and fallopian tube obstruction is a high risk factor for TB dissemination. Patients with miliary TB had poor pregnancy outcomes; therefore, clinicians should be aware of the signs of TB before administering a course of IVF-ET treatment to ensure the health of the patient and for successful outcome of a subsequent pregnancy. Prospective studies are needed to determine the rate of and risk factors for reactive TB in infertile patients with prior pulmonary TB after IVF-ET and whether anti-TB therapy is benecial for pregnancy outcomes is these patients.


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 identi ed, and clinical characteristics of miliary TB were described. The keywords "infertility," "in vitro fertilization and embryo transfer," and "tuberculosis" were used to search for articles published from 1980 to 2019 in PubMed, Medline, and EMBASE databases.

Results
Of 62,755 enrolled women, 7137 (11.4%) showed signs of prior pulmonary TB on chest X-ray (CXR). Seven patients aged 28-35 years had miliary TB during pregnancy, with two patients complicated by TB meningitis. All of 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. Previous literature indicates that signs of prior TB on CXR and oviduct obstruction on laparoscopy are risk factors for TB reactivation during pregnancy, which displayed a trend for hematogenous dissemination.
Conclusions TB reactivation, mostly as miliary TB and TB meningitis, is severe in pregnant women after IVF-ET and deleterious to pregnancy outcomes. The coexistence of primary infertility, untreated prior pulmonary TB, and fallopian tube obstruction is a risk factor for TB dissemination.

Background
Active tuberculosis (TB) is rare in pregnancy after in vitro fertilization and embryo transfer (IVF-ET) in infertile patients. However, with the increasing application of assisted reproductive technology, the incidence of TB in pregnancy has gradually increased, posing a serious threat to the health of pregnant women and fetuses [1,2]. As clinical symptoms such as fever and cough are nonspeci c and chest X-rays (CXR) during pregnancy are associated with the risk of radiation exposure, pulmonary TB in pregnancy is often under-diagnosed. There have been occasional case reports of TB with hematogenous dissemination and miliary TB and/or meningitis during pregnancy after IVF-ET, leading to abortion, fetal malformation, or increased risk of mortality [3,4]. Therefore, correct and timely diagnosis and management of TB in pregnancy is important.
Thus, this study aimed to describe the clinical features of miliary TB and its impact on pregnancy outcomes after IVF-ET. We retrospectively analyzed the data of patients who underwent IVF-ET and showed clinical signs of miliary TB during pregnancy between January 2012 and December 2017 at the reproductive center of our hospital. We also conducted a literature search for TB after IVF-ET and summarized clinical manifestations and pregnancy outcomes of these patients.

Methods
This was a retrospective study of patients who underwent IVF-ET for infertility between January 1, 2012, and December 31, 2017, at Peking University Third Hospital, a tertiary referral hospital in Beijing, China. Data on patients undergoing IVF-ET, including causes of infertility, serum hormone concentrations, the controlled ovarian hyperstimulation protocol, and CXR results, were recorded. CXR was routinely taken for each patient, and active TB cases were excluded before IVF-ET was started. A medical team was assigned to follow the pregnancy outcomes.
During the 6-year period, 62,755 patients, who were all HIV-negative, had received IVF-ET at our center, and among them, seven patients with active TB during pregnancy were identi ed. The diagnosis of active tuberculosis was in accordance with national guidelines [5]. The diagnosis of miliary TB was made based on the equality of the size, distribution, and density of miliary-like nodules bilaterally diffused on CXR or chest computed tomography (CT) scan [6,7]. Baseline data, CXR, and laparoscopy results before IVF-ET were retrieved. A respiratory physician contacted the seven patients through the phone and reviewed the medical record. This study was approved by the Ethics Committee of Peking University Third Hospital (batch number: (2019)327-02). The retrospective nature of the study resulted in a waiver regarding the signing of the informed consent form.
IVF-ET protocol IVF-ET was performed as previously described [8]. In brief, controlled ovarian hyperstimulation was achieved, oocytes were fertilized, and then embryo transfers were performed [8]. For the seven patients who developed TB during pregnancy, one had undergone a frozen cycle transfer, while the remaining six had undergone fresh cycle transfer. After embryo transfer, 60 mg of progesterone was injected intramuscularly for 14 days. Blood human chorionic gonadotropin concentration was monitored at 2 weeks after transplantation, and the status of the embryo sac was examined by ultrasonography at 4 weeks after transplantation.
Literature retrieval and analysis ofpatients with TB during pregnancy after IVF-ET We used the keywords "infertility," "in vitro fertilization and embryo transfer," and "tuberculosis" to search for articles published from 1980 to 2019 in PubMed, MEDLINE, and Wanfang databases and summarized the clinical manifestations and pregnancy outcomes of the identi ed cases.

Patient baseline data
Between January 1, 2012, and December 31, 2017, a total of 62,755 women (mean age, 33.1 years; range, 20-50 years) who had been referred to the reproductive center were enrolled in this study. Based on the CXR results before IVF-ET, 11.4% of patients (7137/62,755) were found to exhibit signs of prior pulmonary TB. From the total population, seven patients with acute miliary TB during pregnancy were identi ed.
Baseline data of the seven patients with active TB during pregnancy Among the seven cases, four occurred in 2012, two in 2016, and one in 2017. These pregnant women were between 28 and 34 years of age, and the duration of infertility ranged 1-12 years. The body mass index was 20.1-27.3 kg/m 2 . All seven patients had primary infertility due to unilateral or bilateral oviduct obstruction, assessed by salpingography; four patients also underwent laparoscopy, with manifestations of tubal obstruction and adhesion consistent with TB, but the pathology failed to reveal features of TB. One patient had suffered from TB at the age of 16, and the local hospital administered anti-TB therapies for over 6 months at that time. The other six patients had no clinical history of TB and had not received anti-TB treatment. Among the seven patients, six showed signs of old pulmonary TB lesions on CXR before IVF-ET. Tuberculin skin test (TST) was performed in three patients before IVF-ET, with induration diameters of 10-20 mm, thus con rming them as positive (++) cases. However, this test was not performed in the other four patients. None had active TB before IVF-ET, and IVF-ET was performed as scheduled (Table 1). CXR chest X-ray, IVF-ET in vitro fertilization and embryo transfer, TB tuberculosis, ESR erythrocyte sedimentation rate One patient underwent frozen ET and had a singleton pregnancy. The remaining six patients underwent fresh ET: three had twin pregnancies and three had singleton pregnancies.
Clinical manifestations and diagnosis of active TB during pregnancy All seven patients had fever at 7-14 weeks of pregnancy. Among them, six had moderate-to-high fever, with the highest body temperatures recorded at 38.5-40 °C, whereas one had low-grade fever (37.5 °C). All seven patients had mild cough and a small amount of sputum with (1/7) or without blood (6/7). CXR and CT scans were performed on all seven patients, which showed diffuse miliary nodules in both lungs, consistent with acute miliary TB (Fig. 1). Two patients with signi cant headache were diagnosed with TB meningitis using lumbar puncture (Table 2). 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 Five patients underwent an interferon gamma release assay (IGRA) test after fever onset and showed positive results. One patient underwent a TST, which was positive (+++).

Outcomes of TB and pregnancy outcomes of the seven patients
After the diagnosis of TB, four patients had spontaneous abortion, whereas three patients underwent induced abortion ( Table 2). All seven patients recovered after anti-TB therapy. At follow-up, two patients achieved pregnancy after second IVF-ET.

Discussion
In this retrospective study, we examined seven cases of active TB during pregnancy from 62,755 cases of IVF-ET carried out at our hospital. All of these seven cases were diagnosed with acute miliary TB, with two cases complicated by TB meningitis. Of note, signs of prior TB on CXR in our study population were detected in 11.4% of patients (7,137/62,755), and six of the seven patients with acute miliary TB had prior TB signs identi ed on CXR before IVF-ET.
On the basis of our case presentations and characterizations as well as the literature review, TB in pregnancy after IVF-ET mostly occurred during the rst 8-12 weeks of pregnancy. Fever was the main symptom, and the time interval from fever onset to de nitive diagnosis was 2-4 weeks or more. An important nding of our study was that TB in pregnancy after IVF-ET was prone to hematogenous dissemination, which is the most serious condition of TB [3,[9][10][11][12][13][14][15][16][17]. TB dissemination may be related to latent infection, IVF-ET intervention, and immune dysregulation in pregnancy. Studies have shown that estrogen, progesterone, and human chorionic gonadotropin have a direct inhibitory effect on T-cells [18,19].
High estrogen levels are conducive to the proliferation of Mycobacterium tuberculosis. Increased vascular permeability after pregnancy may also facilitate bacterial spread throughout the body, resulting in hematogenous dissemination [20]. The prognosis of miliary TB during pregnancy after IVF-ET was poor and may have caused the spontaneous abortion or may have resulted in premature delivery. More seriously, respiratory failure and even acute respiratory distress syndrome might occur in pregnant women [9]. Furthermore, fetuses might suffer from intrauterine growth retardation or be stillborn due to hypoxia or they might be infected through hematogenous dissemination or absorption of contaminated amniotic uid [4]. Moreover, those with miliary TB during pregnancy were less likely to achieve pregnancy, even with IVF-ET.
Identifying patients at high risk of TB activation should be an important evaluation before IVF-ET, especially in regions with a high TB burden.
From our observation, we speculate that the coexistence of primary infertility, untreated prior pulmonary TB, and fallopian tube obstruction may be a risk factor for active TB during an IVF-ET pregnancy. Signs of brotic scarring, calci ed nodules, and/or pleural thickening on CXR indicate previous infection with M. tuberculosis [21][22][23]. In our series, among the 7137 patients who had old TB lesions on CXR, six developed miliary TB during pregnancy. Liu et al. reported a similar case in which untreated prior pulmonary TB developed into miliary TB during pregnancy [11]. Genital TB (GTB) is a form of extrapulmonary TB and a major cause of primary infertility among women in TB-endemic countries [24], with a prevalence rate of 28.4% in our hospital, as observed in previous studies [25,26]. GTB may cause fallopian tube obstruction, reduced endometrial receptivity, and ovarian dysfunction, leading to infertility. However, manifestations of GTB are nonspeci c, and con rmation of diagnosis relies on invasive procedures. Our seven patients showed unilateral or bilateral oviduct obstruction, which suggested chronic infections such as GTB.
Clinical diagnosis of TB in pregnant women is often delayed, largely because of the concern about radiation exposure. The IGRA is an important diagnostic method for detecting active TB and is safe for use in pregnancy [27][28][29][30]. Both the IGRA and TST have a high consistency of 77.3-88.0% [29]. The IGRA has a high sensitivity of 100% and a moderate speci city of 80.0% for detecting active TB during pregnancy [30], which is not affected by previous vaccination with Bacillus Calmette-Guérin. However, it remains unclear whether the IGRA and/or TST is required to assess latent TB infections before IVF-ET and whether preventive anti-TB therapy can improve the pregnancy outcomes of infertile women with latent TB or signs of prior pulmonary TB.
Our study has some limitations. First, this was a single-center study; however, as the largest reproductive center in China, we perform more than 10,000 cycles of IVF-ET annually on women from all over the country. Therefore, the population in this study was representative. Second, we inquired whether active TB had occurred during pregnancy through telephone follow-up of patients. This, however, could not rule out the possibility of missed diagnosis of TB during pregnancy.

Conclusions
Acute miliary TB rarely occurs in pregnant women after IVF-ET, especially in those with signs of prior pulmonary TB on CXR. The coexistence of primary infertility, untreated prior pulmonary TB, and fallopian tube obstruction is a high risk factor for TB dissemination. Patients with miliary TB had poor pregnancy outcomes; therefore, clinicians should be aware of the signs of TB before administering a course of IVF-ET treatment to ensure the health of the patient and for successful outcome of a subsequent pregnancy. Prospective studies are needed to determine the rate of and risk factors for reactive TB in infertile patients with prior pulmonary TB after IVF-ET and whether anti-TB therapy is bene cial for pregnancy outcomes is these patients. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.