The Prevalence and Reproductive Outcome of Infertile Women With Genital Tuberculosis (TB-PRIME)

The Prevalence of Genital Tuberculosis and the Impact on Reproductive Outcomes in Infertile Women: a National Multicenter Prospective Cohort Study

Female genital tuberculosis infection (FGTB) is an important cause of female infertility in TB-endemic areas. The pregnancy rate of assisted reproductive treatment (ART) in the infertile women with FGTB is still unsatisfied even after receiving standard anti-tuberculosis treatment. Moreover, recent years have witnessed an alarming increase in reports of FGTB-related maternal and neonatal complications after fertility treatments. These underscore that timely detection and treatment of FGTB before ART hold benefit for the mother and child.

Study Overview

• Status: Recruiting
• Conditions: Infertility, Female; Genital Tuberculoses, Female
• Intervention / Treatment: Diagnostic test: QuantiFERON-TB test & endometrial pathology & endometrial tissue GeneXpert Ultra

Detailed Description

This project aims to recruit infertile female with high risk of tuberculosis infecton who need assisted reproductive treatment in multiple reproductive centers. The infertility-related medical history and laboratory examination results were recorded according to clinical routine, and other essential information such as tuberculosis symptoms, tuberculosis-related history and other health conditions were also recorded, and the pregnancy outcomes of these patients were followed up.

According to the results of clinical screening, they were divided into four cohorts: non-tuberculosis (non-TB) group, latent tuberculosis infection (LTBI) group, subclinical genital tuberculosis infection (SGTB) group and female genital tuberculosis infection (FGTB) group.

Non-TB group: QuantiFERON-TB test (QFT) negative, continue assisted reproductive treatment; LTBI group: QFT positive. Excluded active pulmonary tuberculosis, patients have negative endometrial histopathology, acid-fast bacilli (AFB) microscopy, Mycobacterium tuberculosis (Mtb) culture, or GeneXpert MTB/RIF Ultra test results. Then assisted reproductive treatment can be continued, but follow-up for tuberculosis-related symptoms is required; SGTB group: QFT positive. Excluded active pulmonary tuberculosis, patients have negative endometrial histopathology, AFB microscopy, Mtb culture, but GeneXpert MTB/RIF Ultra positive test results. They are recommended to receive 6-month first-line standard anti-tuberculosis treatment (ATT) regimen; FGTB group: QFT positive. Excluded active pulmonary tuberculosis, regardless of GeneXpert MTB/RIF Ultra results, at least one of these test results, including endometrial histopathologiy, AFB microscopy, Mtb culture is positive, they will receive 6-month ATT.

Patients diagnosed with SGTB and FGTB will receive 6-month first-line standard ATT before ART, and follow up their anti-tuberculosis drug-related adverse reactions (TB-ARs) according to clinical routine to prevent the occurrence of grade 3-4 adverse drug reactions.

All cohorts will be followed up for pregnancy outcomes after entering the assisted reproduction cycle, and the pregnancy outcomes of all subjects after the first assisted reproduction after enrollment were recorded. Follow-up nodes included the 2nd, 4th, 10th weeks and 37th weeks of gestation. Follow-up content includes pregnancy status. Follow-up subjects will be terminated when adverse pregnancy outcomes such as ectopic pregnancy and miscarriage occurred; follow-up of pregnant participants will be extended to 2 weeks postpartum. Participants from the SGTB or FGTB group achieve pregnant naturally after drug withdrawal, the follow-up of the natural pregnancy outcome will be started as well.

• Study Type: Observational
• Enrollment (Anticipated): 3000

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200051
      • Recruiting
      • Shanghai first maternity and infant hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 43 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Probability Sample

Study Population

Infertile female patients with high risk factors for tuberculosis infection who intend to undergo assisted reproduction

Description

Inclusion Criteria:

• 1) Female, aged ≥20 years and <43 years old;
• 2) In line with conventional assisted reproduction indications;

• 3) Meet any of the following:

  1. with tuberculosis infection history;
  2. with a history of close contact to tuberculosis patients;
  3. exact positive IGRA results in the past or chest imaging indicated a past history of pulmonary tuberculosis;
  4. suspected symptoms of tuberculosis, including fever, night sweats, fatigue, cough and sputum;
  5. suspected symptoms of genital tuberculosis, including lower abdominal pain, abnormal menstruation, fallopian tube stenosis, obstruction, thickening, beading changes, uterine cavity adhesions, deformation, pelvic adhesions, etc.;
• 4) Voluntarily join the study and sign the informed consent

Exclusion Criteria:

• 1) Co-infection with HIV;
• 2) Chromosomal abnormalities;
• 3) suspected genital tuberculosis infection symptoms (participants meet inclusion criteria 3)e in Inclusion Criteria) known to be caused only by factors part from tuberculosis, such as endocrine factors, history of ectopic pregnancy, history of uterine curettage, chronic pelvic inflammatory disease, endometriosis, malignant tumors, etc.;
• 4) There are other serious physical or mental illnesses that are not suitable for selection;
• 5) Participate in other clinical studies that would affect this study at the same time.

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Non-TB Group; QuantiFERON-TB test (QFT) negative, continue assisted reproductive treatment	Diagnostic test: QuantiFERON-TB test & endometrial pathology & endometrial tissue GeneXpert Ultra; Endometrial biopsy is required to diagnose LTBI, SGTB and FGTB, which is an invasive operation and increases patients' economic burden. A screening method has been established that uses the interferon gamma release test as the primary screening test, and those who are positive undergo endometrial biopsy. Therefore, this project will use QFT to screen participants with Mtb infection, and further endometrium biopsy will be performed for QFT positive patients to diagnose LTBI, FGTB and SGTB. For participants with negative results for all diagnostic tests but QFT (defined as LTBI), close follow-up is necessary according to WHO guidelines.
Latent tuberculosis infection Group; QFT positive. Excluded active pulmonary tuberculosis, patients have negative endometrial histopathology, acid-fast bacilli (AFB) microscopy, Mycobacterium tuberculosis (Mtb) culture, or GeneXpert MTB/RIF Ultra test results. Then assisted reproductive treatment can be continued, but follow-up for tuberculosis-related symptoms is required	Diagnostic test: QuantiFERON-TB test & endometrial pathology & endometrial tissue GeneXpert Ultra; Endometrial biopsy is required to diagnose LTBI, SGTB and FGTB, which is an invasive operation and increases patients' economic burden. A screening method has been established that uses the interferon gamma release test as the primary screening test, and those who are positive undergo endometrial biopsy. Therefore, this project will use QFT to screen participants with Mtb infection, and further endometrium biopsy will be performed for QFT positive patients to diagnose LTBI, FGTB and SGTB. For participants with negative results for all diagnostic tests but QFT (defined as LTBI), close follow-up is necessary according to WHO guidelines.
Subclinical genital tuberculosis Group; QFT positive. Excluded active pulmonary tuberculosis, patients have negative endometrial histopathology, AFB microscopy, Mtb culture, but GeneXpert MTB/RIF Ultra positive test results. They are recommended to receive 6-month first-line standard anti-tuberculosis treatment (ATT) regimen	Diagnostic test: QuantiFERON-TB test & endometrial pathology & endometrial tissue GeneXpert Ultra; Endometrial biopsy is required to diagnose LTBI, SGTB and FGTB, which is an invasive operation and increases patients' economic burden. A screening method has been established that uses the interferon gamma release test as the primary screening test, and those who are positive undergo endometrial biopsy. Therefore, this project will use QFT to screen participants with Mtb infection, and further endometrium biopsy will be performed for QFT positive patients to diagnose LTBI, FGTB and SGTB. For participants with negative results for all diagnostic tests but QFT (defined as LTBI), close follow-up is necessary according to WHO guidelines.
Female genital tuberculosis Group; QFT positive. Excluded active pulmonary tuberculosis, regardless of GeneXpert MTB/RIF Ultra results, at least one of these test results, including endometrial histopathologiy, AFB microscopy, Mtb culture is positive, they will receive 6-month ATT	Diagnostic test: QuantiFERON-TB test & endometrial pathology & endometrial tissue GeneXpert Ultra; Endometrial biopsy is required to diagnose LTBI, SGTB and FGTB, which is an invasive operation and increases patients' economic burden. A screening method has been established that uses the interferon gamma release test as the primary screening test, and those who are positive undergo endometrial biopsy. Therefore, this project will use QFT to screen participants with Mtb infection, and further endometrium biopsy will be performed for QFT positive patients to diagnose LTBI, FGTB and SGTB. For participants with negative results for all diagnostic tests but QFT (defined as LTBI), close follow-up is necessary according to WHO guidelines.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical pregnancy rate of ART	the number of participants with gestational sacs seen by ultrasound examination 4-6 weeks after transplantation/the number of embryo transfer cycles in this group	2 years
Continued pregnancy rate of ART	the number of patients whose pregnancy was confirmed by repeat ultrasonography at 10th week of gestation/the number of embryo transfer cycles in this group	2 years
Prevalence of SGTB among infertile women	the number of SGTB participants/the total number of this project	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevalence of FGTB/LTBI among infertile women	the number of each group/the total number of this project	2 years
Abortion rate	number of abortions/number of clinical pregnancy in non-TB or LTBI or SGTB or FGTB group	2 years
Ectopic pregnancy rate	number of ectopic pregnancy/number of clinical pregnancy in non-TB or LTBI or SGTB or FGTB group	2 years
Preterm birth rate	the number of premature births/the number of clinical pregnancy in non-TB or LTBI or SGTB or FGTB group	2 years
Live birth rate	the number of live births/the number of clinical pregnancy in non-TB or LTBI or SGTB or FGTB group	2 years
Maternal mortality rate	the number of maternal mortality/the number of clinical pregnancy in non-TB or LTBI or SGTB or FGTB group	2 years
Neonatal mortality rate	the number of neonatal mortality/the number of clinical pregnancy in non-TB or LTBI or SGTB or FGTB group	2 years
Spontaneous pregnancy rate	number of Spontaneous pregnancy/number of subjects completed ATT in FGTB/SGTB group	2 years
The incidence of grade 3-4 adverse events	the number of patients with grade 3-4 adverse events during anti-tuberculosis treatment / the total number of in FGTB/SGTB group	2 years
The rate of drug discontinuation due to adverse drug reactions	the number of patients who discontinued in anti-tuberculosis treatment due to adverse drug reactions / the total number of patients with adverse reactions in FGTB/SGTB group	2 years
Treatment completion rate	number of patients who completed anti-tuberculosis treatment / total number of patients in this group × 100%	2 years
Incidence of active tuberculosis of LTBI group during 1 year after enrollment	the number of subjects who develop to active tuberculosis during 1 year after enrollment/the number of subjects of LTBI group	1 year

Collaborators and Investigators

• Sponsor: Huashan Hospital
• Collaborators: The Second Hospital of Hebei Medical University; Tongji Hospital; The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School; The First Affiliated Hospital of Zhengzhou University; Tang-Du Hospital; General Hospital of Ningxia Medical University; Shanghai First Maternity and Infant Hospital; First Affiliated Hospital of Wenzhou Medical University; The First People's Hospital of Yunnan; Jiangxi Maternal and Child Health Hospital; Northwest Women's and Children's Hospital, Xi'an, Shaanxi; The 924th Hospital of Joint Logistics Support Force of Chinese People's Liberation; Shenzhen Zhongshan Urology Hospita

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 1, 2021
• Primary Completion (ANTICIPATED): June 1, 2023
• Study Completion (ANTICIPATED): August 1, 2023

Study Registration Dates

• First Submitted: January 21, 2022
• First Submitted That Met QC Criteria: March 27, 2022
• First Posted (ACTUAL): April 5, 2022

Study Record Updates

• Last Update Posted (ACTUAL): April 5, 2022
• Last Update Submitted That Met QC Criteria: March 27, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis, Urogenital; Infertility; Tuberculosis; Infertility, Female; Tuberculosis, Female Genital
• Other Study ID Numbers: KY2021-840

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No