Tuberculosis (TB) remains a significant global public health issue (1). Among infertile patients, TB is a common cause of infertility (2, 3), particularly in high-burden countries, accounting for 20–30% of infertility cases. TB can lead to infertility through tubal obstruction, endometrial involvement, and decreased ovarian function (4).

In vitro fertilization and embryo transfer (IVF-ET) are effective for managing infertility, and routine chest radiography is recommended before undergoing IVF-ET (3). “Inactive” pulmonary TB lesions, like calcified nodules, observed on chest imaging, are often overlooked. In our previous retrospective cohort study, patients with untreated inactive pulmonary TB lesions experienced significantly lower clinical pregnancy and live birth rates following IVF-ET compared to those without such lesions (5). Additionally, our research team reported seven cases of miliary TB during pregnancy following IVF-ET, identifying primary infertility, inactive TB lesions visible on chest radiographs, and tubal obstruction as common risk factors (6). Therefore, patients experiencing infertility and showing inactive TB lesions on chest radiographs should receive comprehensive TB screening prior to IVF-ET, coupled with careful management during pregnancy (7).

Latent tuberculosis infection (LTBI) is characterized by a sustained immune response to Mycobacterium tuberculosis antigens without progression to active TB disease (8–10). Treating LTBI is crucial for the “End TB Strategy” (10). LTBI is usually diagnosed using a positive tuberculin skin test (TST) or interferon-gamma release assay (IGRA). The TST may yield false positives due to prior Bacillus Calmette–Guérin (BCG) vaccination, while IGRA demonstrates higher specificity (9). Guidelines recommend preventive anti-TB treatment for individuals at high risk of TB, including those with acquired immunodeficiency syndrome, those on corticosteroids or immunosuppressive therapy, and organ transplant recipients (11). However, the impact of LTBI on pregnancy outcomes following IVF-ET remains unclear (12, 13), and there are no established guidelines or expert consensus on whether patients with infertility and LTBI should receive preventive anti-TB treatment.

Therefore, this study aimed to address two key scientific questions: (1) What proportion of infertile women with untreated inactive TB lesions on chest radiographs are IGRA-positive? (2) Does IGRA positivity affect pregnancy outcomes following IVF-ET? The results of this study could provide valuable evidence to guide clinical practice (Clinical Trial: NCT 04443283). This study was registered as a clinical trial (NCT 04443283) in 2019, and the protocol has been published elsewhere (12).

This study investigated whether IGRA positivity affects pregnancy outcomes in women with infertility and untreated “inactive” TB lesions seen on chest radiographs, a population that has been mostly overlooked. Our cohort study showed that patients who were IGRA positive had a significantly higher cumulative miscarriage rate. Additionally, a trend toward a higher miscarriage rate in the first fresh cycle was observed in the IGRA-positive group, although this difference was not statistically significant. These findings suggest that LTBI may increase the risk of miscarriage in women undergoing IVF-ET.

Previous studies have indicated that LTBI may impact pregnancy outcomes through mechanisms such as impaired ovarian function, difficulties in embryo implantation, or altered immune responses (3, 18). LTBI has also been associated with chronic low-grade systemic inflammation and dysregulation of cytokine networks, including alterations in the balance of immune cell subsets, such as Th1, Th2, and Th17 cells (19). Disruptions in the endometrial immune microenvironment may further contribute to adverse pregnancy outcomes (20). Further research is needed to elucidate these underlying mechanisms in this population.

Currently, no guidelines recommend routine LTBI screening for patients with infertility and untreated “inactive” TB lesions seen on chest radiographs. In our previous study, 10.4% of patients with infertility seeking assisted reproduction had untreated “inactive” TB lesions on chest radiographs (5). In the present study, the IGRA positivity rate was 42.5% in this population, significantly higher than the LTBI prevalence of 18.1% in the general rural Chinese population (9) and higher than the 28.6% rate in individuals with radiographically inactive TB who lacked a history of TB treatment in rural China (21). Previous studies have reported a latent risk of reactivation associated with untreated inactive TB in the general population (22–24). Patients with infertility, in particular, should be closely monitored for potential TB reactivation during pregnancy (5, 25).

Previous studies on LTBI and pregnancy outcomes following IVF-ET have shown mixed results. One study reported no significant differences in pregnancy or neonatal outcomes between the TST-positive and TST-negative groups (26). Another retrospective study found that the IGRA-positive group had lower biochemical pregnancy rates, lower clinical pregnancy rates, and lower live birth rates than the IGRA-negative group, indicating a trend toward reduced outcomes, although no statistically significant differences (13). Further, a small cohort study in the United States involving 323 women with infertility found that 7.7% (25/323) of them were diagnosed with LTBI via blood IGRA and that the rates of recurrent spontaneous abortion (28% vs. 7%) and Asherman syndrome (8% vs. 0.3%) were significantly higher in women with LTBI than in those without (27). Inconsistent results across studies may stem from variations in LTBI diagnostic methods and the small sample sizes of ET studies. Our research uniquely focused on patients with untreated, “inactive” TB lesions seen on chest radiographs. We found an increased cumulative miscarriage rate as well as a trend toward higher single-cycle miscarriage rates in the IGRA-positive group than in the IGRA-negative group. However, IGRA was not identified as an independent factor in multivariate analysis,; this may be due to the small number of miscarriage events. Given the limited total miscarriage cases and analysis of multiple factors (including age, BMI, infertility factors, ovarian stimulation protocol, IGRA status, endometrial thickness, and high-quality embryo rate), false-negative results may have been produced. Therefore, further studies with larger sample sizes are needed to confirm these findings.

Furthermore, in the present study, two patients in the IGRA-positive group experienced miliary TB during pregnancy following IVF-ET, underscoring the potential risk of TB reactivation and its profound implications for maternal and fetal health, including miscarriage, stillbirth, or low birth weight. Women undergoing IVF-ET experience immune modulation due to hormonal stimulation and the immune-suppressive environment required for embryo implantation. These alterations in immune function may compromise the body’s ability to contain latent TB infections, thereby increasing the risk of reactivation during pregnancy (10). Preventive anti-TB treatment for such patients with infertility may therefore offer benefits by reducing the risk of TB reactivation.

Some experts in the United States and Canada have recommended that members of the general population with nodular or fibrotic lesions consistent with old TB are high-priority candidates for preventive anti-TB treatment of LTBI after active TB disease is excluded (22–24). However, a recent randomized controlled trial in the general population in rural China found that a 6-week preventive treatment regimen for 677 individuals with IGRA positivity and radiographically inactive TB lesions did not significantly reduce the incidence of active TB (21). Studies specifically focused on populations with infertility remain limited.

The global incidence of infertility among women is as high as 10–15%, and an increasing number of reports of TB during pregnancy have recently emerged in high TB burden in countries, such as China (5, 25), and also in developed countries, primarily among immigrants from countries with high TB prevalence (28). A study in India on latent female genital TB found that after anti-TB treatment, the implantation and clinical pregnancy rates were higher in the latent TB group than in the non-TB group. In contrast, the miscarriage rate was lower (29). However, preventive anti-TB treatment may delay assisted reproduction, which is particularly problematic for older women. Freezing embryos and preserving fertility before initiating preventive anti-TB treatment, followed by thawed ET, could offer a solution. In clinical practice, the side effects of anti-TB medications, including liver toxicity and potential adverse effects on the fetus, also need to be considered. Therefore, neither the international guidelines on LTBI nor the guidelines on infertility diagnosis and treatment currently recommend preventive anti-TB treatment before IVF-ET (30). However, a recent expert consensus in China suggested that LTBI screening and preventive anti-TB treatment for patients with infertility undergoing assisted reproduction may be helpful to improve pregnancy outcomes (31). Future randomized controlled trials are needed to assess the risks and benefits of preventive anti-TB treatment, thereby providing evidence-based guidance for the development of guidelines.

This study has several limitations. First, this was a single-center study; however, as the National Clinical Research Center for Obstetrics and Gynecology and one of the largest reproductive centers in China, our center serves a diverse patient population nationwide, enhancing the representativeness of the sample. Additionally, the IGRA testing and IVF-ET treatment protocols at our center are homogeneous and subject to strict quality control. Second, we only analyzed the impact of IGRA results on pregnancy outcomes, not of the TST results, although the TST is more commonly used in primary care. However, because TST results can be affected by the Bacillus Calmette–Guérin vaccination, IGRA is regarded as a more accurate measure of LTBI. Finally, while we excluded patients with active TB, routine laparoscopy was not performed for all participants, leaving the possibility of latent genital TB undetermined.

This study demonstrated that, among Chinese women with infertility and untreated “inactive” TB lesions seen on chest radiographs undergoing IVF-ET, the IGRA positivity rate reached 42.5%, with a higher cumulative miscarriage rate following IVF-ET observed among patients who were IGRA positive. These results underscore the importance of considering LTBI screening and management in clinical practice, particularly in regions with high TB prevalence. Future research should prioritize larger, multicenter studies to investigate further the effectiveness of preventive anti-TB treatment in improving fertility treatment success rates.