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 identified 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 first 8–12 weeks of pregnancy. Fever was the main symptom, and the time interval from fever onset to definitive diagnosis was 2–4 weeks or more. An important finding 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, 9–17]. 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 fluid [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 fibrotic scarring, calcified nodules, and/or pleural thickening on CXR indicate previous infection with M. tuberculosis [21–23]. 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 nonspecific, and confirmation 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 [27–30]. 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 specificity 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.