Effect of prior anti-tuberculosis treatment on assisted reproductive outcomes in infertile women: a retrospective cohort study.

Infertility is a common health issue affecting many childbearing period females worldwide, with a global prevalence of 9%–25%. In China, the prevalence of infertility has increased from 2.5% to 3% in 1993 to approximately 18% in 2020. 1 3 Tuberculosis (TB) is one of the leading causes of female infertility. 4 Genital TB (GTB) can result in tubal obstruction, ovulatory dysfunction and decreased endometrial receptivity, all of which impair reproductive function. 2 5 The incidence of GTB in developing countries is approximately 3%–16% approximately, with 80%–90% of cases occurring in women aged 20–40 years during their reproductive years. In some cases, infertility is the only presenting symptom. 6 9 In vitro fertilisation-embryo transfer (IVF-ET) is an effective technique for treating infertility. 8 Clinically, chest radiography (CXR) is routinely performed before assisted reproductive treatment (ART) to screen for active pulmonary TB (PTB). Our team’s previous research found that 10.4% of infertile patients who underwent ART had prior TB lesions on CXR, and 83.3% of them had never received anti-TB treatment. 1 The clinical pregnancy rate and live birth rate after ART in untreated patients with prior PTB lesions on CXR were significantly lower than those in patients without TB lesions. 1 However, it remains unclear whether prior PTB after completion of anti-TB treatment has an effect on ART outcomes. In previous studies, Mingming Lin et al at our centre analysed pregnancy outcomes in infertile women after ART, comparing those with fully treated endometrial TB to those without TB. They found that the cumulative live birth rate was lower and the rate of spontaneous miscarriage was higher in the TB group than in the non-TB group. 10 For patients with prior TB on CXR, there are currently no published data on pregnancy outcomes after anti-TB treatment. This study using a retrospective cohort analysis aimed to compare ART outcomes, including clinical pregnancy rate, live birth rate and miscarriage rate, among infertile patients with TB who have undergone standardised anti-TB treatment, prior PTB without anti-TB treatment and non-PTB groups. These findings may provide a theoretical basis for infertile patients in clinical management.

This retrospective cohort study included infertile patients (20–50 years old) who underwent ART at Peking University Third Hospital, between 1 January 2017 and 31 December 2017. 1 Infertile patients aged 20–50 years with prior TB lesions on CXR or with normal radiographic findings were included. Patients were categorised into three groups based on CXR findings and prior anti-TB treatment: (1) treated prior-PTB group: infertile patients showing radiographic evidence of prior tuberculous lesions with a history of anti-TB treatment; (2) untreated prior-PTB group: infertile patients showing radiographic evidence of prior tuberculous lesions without any history of anti-TB treatment and (3) non-PTB group: infertile patients without radiographic evidence of prior tuberculous lesions and no history of anti-TB treatment. Patients with active TB (including active PTB or GTB) were excluded from undergoing ART. The patient enrolment process is summarised in figure 1 , with detailed procedures provided in online supplemental data 1 and online supplemental figure 1 . The criteria for diagnosing prior PTB on CXR, such as the presence of fibrotic nodules, calcified lesions and fibrous bands, were consistent with those used in previous studies. 1 11 12 CXR results were jointly interpreted by a radiologist and a respiratory doctor. Detailed information on infertile patients who underwent ART at our reproductive centre, including age, body mass index (BMI), duration of infertility and baseline endocrine hormone levels, was acquired from a case registration research database. The infertility factors for each patient were documented and categorised into 10 major groups on the basis of the classifications used in our previous studies. 1 12 13 Use of the controlled ovarian hyperstimulation (COH) protocol and pregnancy outcomes were also recorded. COH was performed in accordance with the routine-assisted reproduction protocol at our centre. 1 13 On days 2–3 of the menstrual cycle, four sex hormones (follicle-stimulating hormone, luteinising hormone, oestradiol and progesterone) and the antral follicle count were detected. After embryo transfer, routine luteal support was provided with daily vaginal administration of 90 mg progesterone gel. Blood human chorionic gonadotropin (HCG) levels were measured 14 days after the transfer to confirm pregnancy. For patients with confirmed pregnancies, blood HCG levels were measured again 21 days after transfer, and ultrasonography was performed 30 and 37 days after transfer to assess the gestational sac and fetal heartbeat. The primary outcome was the live birth rate. Clinical pregnancy and miscarriage rates were the secondary outcomes. The definitions and calculation formulas for clinical pregnancy rate, miscarriage rate and live birth rate were consistent with those used in previous studies. 1 13 Clinical pregnancy rate was defined as clinical pregnancy per embryo transfer; miscarriage rate was defined as miscarriages per clinical pregnancy; live birth rate was defined as live births per embryo transfer. 1 The primary outcome of this study was live birth rate. Based on our previous research, the anticipated live birth rate was 23.8% in the untreated prior-PTB group, with an expected 12% difference between the treated prior-PTB group and untreated prior-PTB group. Assuming a 1:4 ratio between the two groups (150 cases in the treated group vs 600 in the untreated group), the estimated statistical power would reach 83.3%. 1 Continuous variables are expressed as mean±SD or median (IQR), and independent sample t-tests or Mann-Whitney U tests were used as appropriate. Categorical variables, such as causes of infertility and COH protocol use, are presented as number and percentage, and group comparisons were conducted using the χ 2 test. To compare the means of continuous variables among multiple groups, analysis of variance was employed; Bonferroni correction was used when variances were equal, whereas the Tamhane T2 test was applied when variances were unequal. Multifactorial logistic regression was used to assess the impact of exposure factors on the primary and secondary outcomes. Pregnancy outcomes, including clinical pregnancy, miscarriage and live birth rates, were treated as dependent variables, whereas TB group status was included as an independent variable in the multifactorial logistic regression. Previous studies have identified several factors with substantial evidence of association with pregnancy outcomes, including age, BMI, endometrial thickness, number of good-quality embryos per cycle, causes of infertility and COH protocol. We included these variables in the multivariate analysis to control for potential confounding. These specific covariates were chosen because they consistently demonstrate the highest clinical predictive value for IVF-ET outcomes in infertile patients across multiple studies, including our institutional research. 1 13 The results are reported as adjusted ORs, 95% CIs and p values. Statistical analyses were performed using SPSS Statistics for Windows (V.25; IBM), and statistical significance was set at p<0.05.

In total, 8769 infertile patients aged 20–50 years old underwent ART and embryo transfer at our reproductive centre during the study period. Among them, 171 from the treated prior-PTB group, 791 from the untreated prior-PTB group and 7807 from the non-PTB group ( figure 1 ). The treated prior-PTB group had a moderate age (33.6±4.7 years vs 34.8±5.0 years vs 33.0±5.0 years), longer duration of infertility (5.1±4.4 years vs 4.6±4.0 years vs 4.3±3.7 years) and lower BMI (22.0±2.9 kg/m² vs 22.6±3.5 kg/m² vs 23.1±3.8 kg/m²) compared with the other two groups (all p<0.05; table 1 ). There were significant differences in infertility factors among the three groups, with fallopian tubal disease being the most common cause of infertility, occurring at the highest rate in the treated prior-PTB group (36.3%), which was significantly higher than those in the untreated prior-PTB group (23.4%) and the non-PTB group (20.3%). Compared with the non-PTB group, the treated prior-PTB group had a lower number of antral follicles (8.5±4.7 vs 10.3±5.7) and thinner endometrial thickness (10.39±1.66 mm vs 10.78±1.71 mm); among these three subgroups, the treated prior-PTB group had the highest number of retrieved oocytes (10.1±5.9 vs 9.3±4.9 vs 10.0±5.2) and the highest number of good-quality embryos (4.0 (2.0, 6.0) vs 3.0 (1.0, 5.0) vs 3.0 (2.0, 6.0)) (all p<0.05). p5 blastomeres, (2) a size difference of <20% and (3) fragmentation of <50%. AMH, anti-Müllerian hormone; BMI, body mass index; COH, controlled ovarian hyperstimulation; E2, oestradiol; ET, embryo transfer; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; IVF, in vitro fertilisation; LH, luteinising hormone; No., Number; P, prolactin; PCOS, polycystic ovary syndrome; PTB, pulmonary tuberculosis. Compared with the untreated prior-PTB group, the treated prior-PTB group had a significantly higher clinical pregnancy rate (41.5% vs 31.7%, p<0.05) and live birth rate (35.3% vs 23.8%, p<0.05). The miscarriage rate was lower in the treated group than in the untreated group (11.3% vs 19.1%, p=0.123), although the difference was not statistically significant ( table 2 ). p<0.05. Clinical pregnancy rate was defined as clinical pregnancy per embryo transfer. Miscarriage rate was defined as miscarriages per clinical pregnancy. Early miscarriage was defined as early miscarriages per clinical pregnancy. Late miscarriage was defined as late miscarriages per clinical pregnancy. Live birth rate was defined as live births per embryo transfer. ART, assisted reproductive treatment; PTB, pulmonary tuberculosis. When compared with the non-PTB group, the treated prior-PTB group exhibited similar pregnancy outcomes ( table 3 ). The graphical abstract of this article is seen in figure 2 . The definition of pregnancy outcomes is consistent with the above. ART, assisted reproductive treatment; PTB, pulmonary tuberculosis. In the untreated prior-PTB group, one patient experienced fever at 12 weeks’ gestation, and CT imaging revealed diffuse miliary nodules in both lungs, leading to a diagnosis of acute miliary TB. The pregnancy was terminated because of spontaneous abortion. The mother’s condition improved after anti-TB treatment, and she stopped taking the medication after >1 year of treatment. After adjusting for age, BMI, causes of infertility and other confounders, multivariable regression confirmed significantly higher live birth rate in the treated prior-PTB group compared with the untreated prior-PTB group (aOR: 1.69, 95% CI: 1.01 to 2.83, p=0.045). Moreover, the treated prior-PTB group demonstrated pregnancy outcomes comparable to those of the non-PTB group ( table 4 and online supplemental table 1 ). Factors were adjusted for age, body mass index, causes of infertility, COH protocol use, endometrial thickness and number of good-quality embryos per cycle. The definition of pregnancy outcomes is consistent with the above. Data on BMI, endometrial thickness were missing for 88 and 1457 patients, respectively, in the whole research population. p<0.05 aOR, adjusted OR; BMI, body mass index; COH, controlled ovarian hyperstimulation; PTB, pulmonary tuberculosis. No significant association was observed between infertility causes and pregnancy outcomes in patients undergoing ART ( online supplemental table 2 ).

This study was based on our established cohort of 8769 patients undergoing ART. Here, we analysed the pregnancy outcomes of patients with prior PTB lesions who had a history of completing standardised anti-TB treatment. The results indicated that patients with a history of standardised anti-TB treatment had similar clinical pregnancy rate, miscarriage rate and live birth rate after ART as those in the normal CXR group. And when compared with the untreated prior-PTB group, the treated prior-PTB group had a significantly higher live birth rate after adjusting for multivariables. These research findings suggest that patients with TB who have undergone anti-TB treatment have similar pregnancy outcomes after ART to those without TB. This finding indicates that anti-TB treatment can substantially improve pregnancy outcomes in infertile patients with prior PTB undergoing ART. After TB infects the human body, it may appear as PTB, GTB, bone TB or TB affecting other organs. Certain investigations have focused on the pregnancy outcomes of patients with GTB following anti-TB treatment. Pregnancy outcomes after ART in patients with cured uterine TB showed that the cumulative live birth rate was lower and the spontaneous abortion rate was higher in the treated TB group than in the non-TB group. 10 Another study in China analysed pregnancy outcomes after ART in 155 patients with GTB following anti-TB treatment, including 130 patients with tubal TB and 25 patients with uterine TB. The results indicated that the pregnancy outcomes for the tubal TB group were similar to those of the non-TB group, whereas the fertilisation, implantation and pregnancy rates for the uterine TB group were significantly lower than those of the non-TB group. 14 A recent systematic review analysing pregnancy outcomes in patients with GTB indicated that for patients with TB with structural damage, for example, tubal obstruction, the clinical pregnancy rate after anti-TB treatment remained lower than that in the non-TB group. However, for patients with TB without structural damage, a 6-month course of anti-TB treatment did not show a significant effect on pregnancy outcomes. The authors noted that the evidence was uncertain because of the limited number of included studies, with only three studies contributing to the data. 15 TB screening before ART is of the utmost importance in patients with infertility. The rapid advancements in ART have enabled an increasing number of infertile patients to fulfil their desire to conceive. 16 However, there have been a growing number of reports of pregnancies complicated by active TB, primarily presenting as miliary PTB or tuberculous meningitis. 15 17 In a summary of >80 000 patients who underwent ART for infertility at our hospital, 7 cases of active TB during pregnancy were identified, characterised by acute haematogenous disseminated PTB (7/7) and tuberculous meningitis (2/7). Ultimately, four cases resulted in spontaneous abortion, while three cases ended in elective abortion. 18 It is also crucial to maintain immune balance in the context of latent or active TB. 19 There are three factors that influence the success of implantation and pregnancy, including uterine receptivity, endometrial regeneration and cytokine regulation. Immune factors associated with latent genital tuberculosis infection (LGTB) may play a role in the implantation process by altering endometrial receptivity. 2 20 21 Women undergoing ART may be at a higher risk of TB infection and associated with poorer perinatal outcomes. 22 Therefore, TB screening in patients with infertility before ART is of paramount importance. Additionally, in this study, the multivariate analysis of pregnancy outcomes revealed that age, BMI, COH protocol use and causes of infertility were significantly associated with pregnancy outcomes. Patients aged <30 years had a higher clinical pregnancy rate and live birth rate, along with a lower miscarriage rate than their older counterparts, which is consistent with age-related reproductive trends. 23 Moreover, a higher BMI was associated with reduced clinical pregnancy rate, increased miscarriage rate and significantly lower live birth rate, adversely affecting pregnancy outcomes, which is consistent with findings in the existing literature. 24 26 Furthermore, the results indicated that infertility has varying effects on pregnancy outcomes. Infertility due to male factors, for example, oligospermia or asthenospermia, leads to poorer pregnancy outcomes than other causes. However, the small number of male factor infertility cases in the treated prior-PTB group (n=12) may have introduced a potential bias. Building on previous research, this study further demonstrates that anti-TB treatment can significantly improve ART pregnancy outcomes in infertile patients with radiographic evidence of prior PTB, achieving comparable results to those without TB history. However, current clinical practice lacks consensus regarding the necessity of TB screening and preventive anti-TB treatment for infertile patients. Therefore, our findings provide important clinical guidance for implementing systematic preoperative TB screening and determining the need for preventive anti-TB treatment in this patient population. Our study has several limitations. First, this was a single-centre study; however, as the largest reproductive centre in China, our cohort of >10 000 reproduction cycles annually reflects a broad population base. Moreover, the single-centre setting enabled standardised treatment protocols and consistent follow-ups, ensuring high data quality. Second, the diagnosis of prior TB lesions was based on CXR findings, which may not have fully captured the presence of latent TB infection or accurately distinguished between prior and latent TB. Third, the patients with active GTB were excluded, but it remains uncertain whether latent GTB was present in women. Future studies may benefit from incorporating more advanced diagnostic methods, such as CT and molecular testing, to ensure a more comprehensive assessment of TB infection status. Fourth, while our data were collected from 2017, the biological impact of TB on infertility and the fundamental principles of anti-TB treatment remain unchanged, supporting the continued relevance of our pregnancy outcome findings to current practice.

In infertile patients with CXR showing prior TB lesions who have received anti-TB treatment, ART outcomes, including clinical pregnancy rate, live birth rate and miscarriage rate, are comparable to those of patients with normal CXR findings. Additionally, clinical pregnancy and live birth rates were significantly better than those in patients with untreated prior TB lesions on chest CXR. These findings underscore the potential benefits of anti-TB treatment in this TB patient population. However, the risks associated with untreated patients with prior TB lesions warrant clinical attention and further research. Currently, no published data exist on pregnancy outcomes after anti-TB treatment in patients with prior TB on CXR. This study addressed this gap by evaluating pregnancy outcomes after ART in such patients who have undergone standardised anti-TB treatment. Our study demonstrated that infertile patients with prior TB lesions on CXR who have completed anti-TB treatment achieved ART outcomes similar to those with normal CXR findings. ART outcomes in infertile patients with prior TB lesions on CXR who completed anti-TB treatment are markedly better than patients with untreated prior TB lesions. This finding indicates that anti-TB treatment can substantially improve pregnancy outcomes in infertile patients with prior PTB undergoing ART, providing valuable guidance for clinical management. ART outcomes in infertile patients with prior TB lesions on CXR who completed anti-TB treatment are markedly better than patients with untreated prior TB lesions. This finding indicates that anti-TB treatment can substantially improve pregnancy outcomes in infertile patients with prior PTB undergoing ART, providing valuable guidance for clinical management.