Dr. J. B. Sharma MD, DNB, FRCOG (London), PhD, MFFP FAMS, FICOG FIMSA, is a Professor in Department of Obstetrics and Gynecology, All India Institute of Medical Sciences, New Delhi. Before that he has worked as Professor in Maulana Azad Medical College, New Delhi. He is the recipient of the Dr. B C Roy award for Research in 2015. He is the Chairperson of the FOGSI Urogynaecology society (2020–2022). He has over 400 publications and has 250 peer reviewed articles in various journals of national and international repute. He is currently Editor in chief of Indian Obstetrics and Gynecology, Journal of Paediatrics, Obstetrics and Gynecology (JPOG) and Associate Editor of International Journal of Gynecology and Obstetrics, India. He has edited three books and has been awarded many times by Royal College of Obstetricians and Gynaecologists (RCOG), London. His special areas of interest include female genital tuberculosis, urogynecology and anemia in pregnancy.
Female genital tuberculosis (FGTB) is an important cause of significant morbidity and infertility.
Gold-standard diagnosis by demonstration of acid fast bacilli on microscopy or culture or detection of epithelioid granuloma on histopathology of endometrial or peritoneal biopsy is positive in only small percentage of cases due to its paucibacillary nature. Use of gene Xpert on endometrial or peritoneal biopsy has improved sensitivity of diagnosis. Composite reference standard (CRS) is a significant landmark in its diagnosis in which combination of factors like AFB on microscopy or culture, positive gene Xpert, epithelioid granuloma on endometrial or peritoneal biopsy, demonstration of definite or probable findings of FGTB on laparoscopy or hysteroscopy. There have been many advances and changes in management of FGTB recently. The program is now called National Tuberculosis Elimination Program (NTEP), and categorization of TB has been stopped. Now, patients are divided into drug-sensitive FGTB for which rifampicin (R), isoniazid (H), pyrazinamide (Z) and ethambutol (E) are given orally daily for 2 months followed by three drugs (rifampicin, isoniazid and ethambutol (RHE) orally daily for next 4 months. Multi-drug-resistant FGTB is treated with shorter MDR TB regimen of 9–11 months or longer MDR TB regimen of 18–20 months with reserved drugs. In vitro fertilization and embryo transfer have good results for blocked tubes and receptive endometrium, while surrogacy or adoption is advised for severe grades of Asherman’s syndrome.
Keywords : Female genital tuberculosis , Drug-sensitive tuberculosis , Drug-resistant TB , Composite reference standard ,Laparoscopy , Hysteroscopy
Tuberculosis remains a major public health problem globally [1]. Female genital tuberculosis (FGTB) is a chronic infectious disease of female genital tract due to Mycobacterium tuberculous (rarely Mycobacterium bovis from unpasteurized infected milk) [2, 3]. It causes significant morbidity, especially irregular menstruation, pelvic pain, tubo-ovarian mass and infertility particularly in South East Asia and Africa [4–9]. The disease is making a comeback even in the developed countries like Europe and USA due to more liberal migration, concomitant immunocompromising diseases like human immunodeficiency virus coinfection, diabetes mellitus, chronic kidney and other systemic diseases [8–10]. FGTB is usually secondary to pulmonary TB through hematogenous route or lymphatic route but can occur through contagious spread from adjacent ileocaecal TB and rarely through infected semen from tuberculous orchitis in males [5, 6]. FGTB can cause permanent damage to female genital tract in advanced stages. Hence, early diagnosis and treatment in subclinical stage can prevent permanent damage and sequelae of female genital tract with successful pregnancy outcome [11, 12]. A high index of suspicion is needed for diagnosis which includes past or family history of TB or anti-tubercular therapy [4]. There have been recent changes in diagnosis and treatment of all types of TB including FGTB [13, 14]. Although FGTB is a paucibacillary disease, still all efforts should be made to arrive at a microbiological diagnosis and to do drug sensitivity test as treatment of TB including FGTB is now drug sensitivity test (DST) based using oral daily 4 drugs (rifampicin, isoniazid, pyrazinamide and ethambutol, RHZE for 2 months) followed by three drugs (RHE) daily orally for next 4 months. For drug-resistant TB, MDR drug regimens (shorter and longer) are used [2, 13–15].
Epidemiology
FGTB is an important variety of EPTB which causes significant morbidity, especially menstrual dysfunction and infertility (both primary and secondary) in affected women [2–6]. The prevalence of FGTB in infertility patients varies from country to country being only 0.72% in Portugal, 1% in USA and Europe to 20% in Pakistan and 6–25% in India being more in tertiary referral centers and in assisted reproduction centers [16–20]. It also causes significant infertility in other south East Asian countries like Indonesia [21] FGTB is observed in younger age group (20–40 years) in South East Asia and Africa as compared to older (premenopausal) age group in Europe and USA possibly due to early child bearing in the developing countries [2, 5, 6, 10]. Genital tuberculosis has significantly impacted both male and female reproduction in India [22, 23]. HIV coinfection has fueled the epidemic of TB all over the world with risk of TB in 10–20% [24, 25]. Now, the COVID-19 pandemic has exerted deleterious effect on control of TB including EPTB and FGTB [26–28]. People ill with COVID-19 and pulmonary TB show similar symptoms such as cough, fever and difficult breathing, and both are transmitted through droplets infection. WHO has observed 25% global reduction in TB detection due to less attention to TB as all the resources went into control of COVID-19. It may be responsible for 26% increase in TB deaths in near future. WHO has advised all member nations to urgently maintain continuity of essential services for people affected with TB during the COVID-19 pandemic [27, 28].
WHO estimates that TB may have caused more than double the number of death of COVID-19 in 2020 but yet has not received much attention or funding. In fact, COVID-19, tuberculosis and poverty may be a potential destructive synergism causing a storm like situation [27, 28].
Etiopathogenesis
FGTB is caused by Mycobacterium tuberculosis but can also be rarely caused by Mycobacterium bovis due to consumption of unpasteurized milk in villages [2, 4]. Genital infection is usually secondary to pulmonary TB or intestinal TB through hematogenous or lymphatic route and is more common in immunocompromised people or with chronic medical diseases including HIV and COVID-19 [2, 5, 6, 24–28]. Among the various sites, fallopian tubes are mostly affected (90–100%) followed by uterus (70%), ovaries (30%), cervix (10%) and rarely vulva and vagina (1% each) [2, 5, 6, 29]. Abdomino-pelvic TB may cause peritoneal adhesions, nodules and ascites and may simulate ovarian cancer [30]. Similarly, cervical TB may mimic cervical cancer causing abnormal vaginal discharge or vulval and vaginal ulcer or cancer [31].
Tuberculous of vulva may present as vulvul tumor or hypertrophic TB, while vaginal or vulval TB can present as genital fistula [2, 32].
In abdomino-pelvic TB, we have observed various types of adhesions on laparoscopy as TB is notorious to cause thick and vascular adhesions which may make laparoscopy and laparotomy hazardous with more risk of injury to the bowel [4]. We have described perihepatic adhesions with hanging gall bladder sign in abdomino-pelvic TB [33]. We have also observed Sharma’s ascending colon adhesion, Sharma’s sigmoid colonic adhesive band, Sharma’s compartmentalization sign in abdomino-pelvic TB [34–36]. We have described Sharma’s parachute sign in abdomino-pelvic TB with ascending colon being adherent to anterior abdominal wall making putting second port of laparoscope risky and hazardous on right side [37]. Abdomino-pelvic TB may sometimes be coexistent with malignancies or endometriosis [38, 39].
Symptomatology
The clinical features of FGTB vary as per involvement of different genital organs and are shown in Table 1 [2–6]. It is important to know that up to 10–12% of women may be asymptomatic or may have no obvious signs on clinical examination. As in Table 1, commonest symptoms are menstrual dysfunction and infertility (both primary and secondary).
Causes of Infertility
1. Fallopian tubes are involved in almost all cases of FGTB. It is often bilateral causing exosalpingitis and endosalpingitis with tubal blockage.
2. Uterus: TB affects endometrial receptivity with damage of endometrium and formation of intrauterine synechiae (Asherman’s syndrome). Latent FGTB can cause recurrent implantation failure and recurrent miscarriages due to endometrial hostility through increased TNF alpha (tumor necrosis factor alpha) and interleukin 2 (IL-2) levels [17]. It also shifts T helper cells response from T1 to T2.
3. TB causes oophoritis with poor ovarian reserve and increased need of gonadotrophins for ovulation induction. It can also destroy ovaries [8, 9].
1. World Health Organization. Global Tuberculosis Report-2019. https:// apps. who. int/ iris/ bitst ream/ handle/ 10665/ 329368/ 97892 41565 714- eng. pdf? Accessed 1 Aug 2020.
2. Sharma JB, Sharma E, Sharma S, et al. Genital tb-diagnostic algorithm and treatment. Indian J Tuberc. 2020;67(4S):S111–8.
3. Munne KR, Tandon D, Chauhan SL, et al. Female genital tuberculosis in light of newer laboratory tests: a narrative review. Indian J Tuberc. 2020;67(1):112–20.
4. Sharma JB, Sharma E, Sharma S, et al. Female genital tuberculosis: revisited. Indian J Med Res. 2018;148(Supp):S71–83.
5. Grace A, Devaleenal B, Natarajan M. Genital tuberculosis in females. Indian J Med Res. 2017;145(4):425–36.
6. Sharma JB. Current diagnosis and management of female genital tuberculosis. J Obstet Gynaecol India. 2015;65:362–71.
7. Rajaram S, Gupta P, Gupta B, et al. Laparoscopy in the diagnosis of tuberculosis in chronic pelvic pain. Int J Mycobacteriol. 2016;5:318e323.
8. Tal R, Simoni M, Pal L. Latent and genital tuberculosis in the infertile population in US—experience at an academic fertility center in the north east underscores a need for vigilance. Fertil Steril. 2017;108:117e118.
9. Tal R, Lawal T, Granger E, et al. Genital tuberculosis screening at an academic fertility center in the United States. 2020.
10. Reis-de-Carvalho C, Monteiro J, Calhaz-Jorge C. Genital tuberculosis role in female infertility in Portugal. Arch Gynecol Obstet. 2021;6:66.
11. Mahajan N, Naidu P, Kaur SD. Insight into the diagnosis and management of subclinical genital tuberculosis in women with infertility. J Hum Reprod Sci. 2016;9(3):135–44.
12. Malhotra N, Singh UB, Iyer V, et al. Role of laparoscopy in the diagnosis of genital TB in infertile females in the era of molecular tests. J Minim Invasive Gynecol. 2020;27(7):1538–44.
13. Central TB Division of Ministry of Health and Family Welfare under Government of India. National Strategic Plan for Tuberculosis: 2017–2025, Elimination by 2025 [Internet]. 2017. https:// tbcin dia. gov. in/ Write ReadD ata/ Natio nalSt rateg icPla n2017- 25. pdf. Accessed 3 Aug 2020.
14. World Health Organization Guidelines for treatment of drugsusceptible tuberculosis and patient care. Treatment Tuberculosis World Health Organisation, geneva 2017 Update.
15. World Health Organization. WHO consolidated guidelines on tuberculosis: module 4: treatment: drug-resistant tuberculosis treatment. World Health Organization; 2020. https:// apps. who. int/ iris/ handle/ 10665/ 332397. Accessed 1 Aug 2020.
16. Langer AJ, Navin TR, Winston CA, et al. Epidemiology of tuberculosis in the United States. Clin Chest Med. 2019;40(4):693–702.
17. Zahoor D, Bhat MM, Kanth F, et al. Prevalence of genital tuberculosis in infertile women; a study from a Tertiary Care Center in North India. IJCMR. 2019;6(6):F1–3.
18. Agarwal S, Chauhan J, Vachhani A, et al. A study on co-relation of infertility and female genital tuberculosis. Natl J Med Res. 2016;6(2):151–4.
19. Sharma D, Depan A, Yadav K, et al. Prevalence of female genital tract tuberculosis in suspected cases attending Gynecology OPD at tertiary centre by various diagnostic methods and comparative analysis. Int J Reprod Contracept Obstet Gynecol. 2019;8(6):2286–92.
20. Sharma JB, Dharmendra S, Agarwal S, et al. Genital tuberculosis and infertility. Fertil Sci Res. 2016;3:6–18.
21. Djuwantono T, Permadi W, Septiani L, et al. Female genital tuberculosis and infertility: serial cases report in Bandung, Indonesia and literature review. BMC Res Notes. 2017;10(1):683.
22. Malik S. Genital tuberculosis and its impact on male and female infertility. US Endocrinol. 2020;16(2):97–103.
23. Symptom Export and Treatment www. webmed. com World Health Organization Tuberculosis and HIV. Who Geneva 2015.
24. Bruchfeld J, Correia-Neves M, Källenius G. Tuberculosis and HIV coinfection. Cold Spring Harb Perspect Med. 2015;5(7):a017871.
25. Oberoi S, Khaira R, Rai SK. Aetiology of infertility: an epidemiological study. Nat J of Comm Med. 2017;8(1):17–20.
26. WHO information note. Tuberculosis and COVID-19 www. WHO. Int. Accessed 15 Dec 2020.
27. Saunders MJ, Evans CA. COVID-19, tuberculosis and poverty: preventing a perfect storm. Eur Respir J. 2020;56(1):2001348.
28. Hogan AB, Jewell BL, Sherrard-Smith E, et al. Potential impact of the COVID-19 pandemic on HIV, tuberculosis, and malaria in low-income and middle-income countries: a modelling study. Lancet Glob Health. 2020;8(9):e1132–41.
29. Meenu S, Ramalingam S, Sairam T, et al. Comparison of polymerase chain reaction (PCR), microbiological and histopathological observations in the diagnosis of endometrial tuberculosis. J Obstet Gynaecol India. 2020;70(6):510–5.
30. Cruz RP, Duarte M da R, Bianchi AR, et al. Pelvic tuberculosis masses mimicking advanced ovarian cancer: case report and literature review. J Gynecol Surg. 2020. https:// doi. org/ 10. 1089/ gyn. 2020. 0082.
31. Kumari R, Vaishya V, Khanna G, et al. Tuberculosis of the cervix: an uncommon cause of vaginal discharge in a post-menopausal woman. Nath Med J. 2018;31:140–50.
32. Sharma JB, Gupta S, Kriplani A, et al. Hypertrophic tuberculosis vulva an unusual case report. J Ind Med Assoc. 2021;119(2):41–2.
33. Sharma JB. Sharma’s hanging gall bladder sign: a new sign for abdomino-pelvic tuberculosis: AN observational study. IVF Lite. 2015;2:94–8.
34. Sharma JB. Sharma’s ascending colonic adhesion: a new sign in abdomino-pelvic tuberculosis with infertility. IVF Lite. 2016;3:18–22.
35. Sharma JB. Sharma’s sigmoid colonic adhesive band—a new laparoscopic sign in female genital tuberculosis. Indian J Tuberc. 2020;67(3):327–32.
36. Sharma JB. Sharma’s abdominal compartmentalization sign: a new laparoscopic sign for abdomino-pelvic tuberculosis. Indian J Tuberc. 2020;67(4):578–85.
37. Sharma JB. Sharma’s parachute sign a new laparoscopic sign in abdomino pelvic tuberculosis. Indian J Tubercul. 2019. https:// doi. org/ 10. 1016/j. ijtb. 2019. 06. 004.
38. Gupta A, Gupta S, Manaktala U, et al. Coexisting genital malignancies with tuberculosis: a case series with review of literature. J Midlife Health. 2016;7(4):159–62.
39. Sharma JB, Goyal M, Kumar S, et al. Concomitant female genital tuberculosis and endometriosis. Indian J Tuberculosis. 2017;64(3):173–7.
40. Sharma JB, Dharmendra S, Jain S, et al. Evaluation of Gene Xpert as compared to conventional methods in diagnosis of female genital tuberculosis. Eur J Obstet Gynecol Reprod Biol. 2020;255:247–52.
41. Chaudhary R, Dhama V, Singh M, et al. Comparison of diagnostic accuracy of bactec culture, gene-xpert and histopathology in the diagnosis of genital tuberculosis in women with infertility. Int J Reprod Contracept Obstet Gynecol. 2020;9(4):1614–21.
42. Sethi S, Dhaliwal L, Dey P, et al. Loop-mediated isothermal amplification assay for detection of Mycobacterium tuberculosis complex in infertile women. Indian J Med Microbiol. 2016;34(3):322–7.
43. Jeanes C, O’Grady J. Diagnosing tuberculosis in the 21st century— dawn of a genomics revolution? Int J Mycobacteriol. 2016;5(4):384–91.
44. Gupta S, Gupta P. Etiopathogenesis, challenges and remedies associated with female genital tuberculosis: potential role of nuclear receptors. Front Immunol. 2020;11:02161.
45. Mala YM, Prasad R, Singh N, et al. Role of laparoscopy in diagnosing genital tuberculosis in suspected women: a cross-sectional study from a tertiary care hospital in Northern India. Indian J Tuberc. 2018;65(1):23–9.
46. Sharma JB. Sharma’s python sign: a new tubal sign in female genital tuberculosis. J Lab Phys. 2016;8(2):120–2.
47. Sharma JB. Sharma’s kissing fallopian tubes sign: a new tubal sign in female genital tuberculosis. J Obstet Gynaecol India. 2017;67(3):227–9.
48. Ministry of Health and Family Welfare, Government of India and World Health Organization. INDEX TB Guidelines: guidelines on extra-pulmonary tuberculosis for India. New Delhi: MOHFW; 2016.
49. Sharma JB, Kriplani A, Sharma E, et al. Multi drug resistant female genital tuberculosis: a preliminary report. Eur J Obstet Gynecol Reprod Biol. 2017;210:108–15.
50. Korma W, Mihret A, Chang Y, et al. Antigen-specific cytokine and chemokine gene expression for diagnosing latent and active tuberculosis. Diagnostics. 2020;10(9):716.
