Laparoscopic evaluation of female genital tuberculosis in infertility: An observational study

Tuberculosis (TB) continues to be a global problem but more so in developing nations, with drug-resistant TB compounding the problem1,2. Although pulmonary TB remains the most common type of TB globally, the incidence of extrapulmonary TB (EPTB) is on the rise, especially due to co-infection with HIV, and this accounts for about 20 per cent of cases3. Female genital tuberculosis (FGTB) is observed in about 5-30 per cent of infertility cases3. The prevalence of FGTB varies in different countries and in different parts of India being 45.1 per cent of the patients per 1,00,000 population in the Andaman Islands to about 1-19 per cent in infertile patients being higher (about 16%) in tertiary referral centres and are still higher (up to 41%) in patients coming for in vitro fertilization with tubal factor infertility (up to 48.5%)4-7.

FGTB may be asymptomatic or manifest with menstrual abnormalities especially oligomenorrhoea, hypomenorrhoea, abdominopelvic pain and pelvic mass5-8.

Conventionally, diagnosis of genital TB is made by Mycobacterium tuberculosis (MTB) on microscopic examination or BACTEC culture or mycobacteria growth indicator tube (MGIT) culture or presence of epithelioid granuloma on endometrial or peritoneal biopsy. These are infrequently present and may lead to missing the diagnosis in majority of patients5,7.

Polymerase chain reaction (PCR) is a sensitive test but has high rate of false positivity and hence, should not be used to start treatment5,8,9. Gene Xpert is specific and has been endorsed by the World Health Organization but has low sensitivity to detect FGTB10,11. Unlike pulmonary TB, diagnosis of EPTB, including FGTB, is difficult due to its paucibacillary nature. Dosanjh et al12 tried to combine various methods of diagnosis of detection of tuberculosis which is a type of composite reference standard (CRS). Later, other authors formed CRS for FGTB also along with the other types of FGTB13.

Composite Reference Standard (CRS) has become popular in the detection of genital TB and takes into consideration demonstration of Mycobacterium on microscopic examination or culture of endometrial/peritoneal biopsy or epithelioid granuloma on histopathology or positive Gene Xpert and definite findings (beaded tubes/caseous nodules/tubercles) or probable findings (ascites, white areas, pelvic/abdominal/perihepatic adhesions, distended tubes, pyosalpinx and tubo-ovarian masses) on laparoscopy13.

Laparoscopy by direct visualization of the abdomen and pelvis can detect most cases of FGTB missed by traditional tests and can be a part of CRS thus, can show a definite or probable finding of FGTB and also help in prognostication of infertility in addition to plan further treatment5,9,12-14. Although previous smaller studies of short duration have observed laparoscopy to be useful in the detection of FGTB, a bigger study with large sample size is needed for confirmation of findings of the prior studies.

Hence, the present study was done to report the laparoscopic observations in FGTB over a nine-year period, to help the clinicians in their day-to-day practice.

Material & Methods

This study was carried out at the department of Obstetrics and Gynaecology All India Institute of Medical Sciences, New Delhi, after seeking approval by the Institute Ethical Committee. An informed written consent was also taken from all the participants prior to the start of the study.

Study design: This was a cross-sectional study on 374 consecutive cases of diagnostic laparoscopy (pelviscopy) performed on FGTB with infertility as shown in Figure for nine years (July 2010 to July 2019) in an apex tertiary referral institute between 20 and 40 years. Inclusion criteria included infertile patients who were willing to participate in the study and had FGTB on CRS as in Figure which was formed for FGTB taking into consideration the study of Dosanjh et al12 in 2008. Exclusion criteria included women with malignancy or any other gynaecological disease and who were not willing to participate.

Complete medical/obstetric history and history of TB was taken from all participants. General physical and gynaecological examinations including bimanual examination for uterine size and adnexal mass and tenderness were performed on all the participants.

Laboratory investigations and microbiological tests: Baseline investigations such as complete haemogram, Mantoux test, blood sugar, X-ray chest and ultrasound or computed tomography (CT) scan where abdominal or pelvic lump was palpable were performed on all participants. Endometrial biopsy/aspirate was taken from all the participants between day 21 and 24 of the menstrual cycle with no. 4 Karman’s cannula in gynaecological outpatient minor operation theatre under all aseptic conditions; one part of the sample was sent in saline for detection of M. tuberculosis on microscopy and for culture, PCR and GeneXpert test. The second part of the sample was kept in formaldehyde solution for detection of tuberculous granuloma on histopathology.

Laparoscopy: Diagnostic laparoscopy was performed in all the cases under short general anaesthesia using no. 10 mm laparoscope (Karl Storz, Germany) as part of the infertility workup, and for findings of TB and for prognostication and treatment planning for infertility. During laparoscopy, the whole of the pelvis and abdomen along with their contents was meticulously examined for any definite or probable findings of FGTB. The laparoscopic findings were analyzed in two time periods (July 2010 to December 2014 and January 2015 to July 2019) to see changing patterns in laparoscopic findings and complications over time.

All patients with FGTB diagnosed by microscopy, culture, Gene Xpert, histopathology or laparoscopy were treated with anti-tubercular therapy as per the protocol of the hospital where laparoscopic evidence of FGTB is taken as evidence of FGTB and treatment is started even in the absence of microbiological and histopathological evidence. Participants were given full oral anti-tubercular therapy for six months (rifampicin, isoniazid, pyrazinamide and ethambutol daily for two months in intensive phase, followed by rifampicin, isoniazid and ethambutol daily for the next four months in continuation phase) through Directly Observed Treatment Short course (DOTS) strategy. The patients were kept on a regular follow up for compliance and any side effects of drugs. In the present study, diagnostic laparoscopy was performed for all suspected and confirmed cases of FGTB as part of research project and infertility protocol for tubal patency, confirmation of diagnosis and prognostication of the disease.

Criteria for the diagnosis of FGTB as per Composite Reference Standard (CRS): As per the study by Dosanjh et al12 in 2008, FGTB was diagnosed in the presence of positive AFB on microscopy or culture or positive Gene Xpert or positive epithelioid granuloma on histopathology of endometrial or peritoneal biopsy or definite or probable findings of FGTB on laparoscopy. PCR being non-specific was not taken as part of CRS. By combining various tests in CRS, most cases which otherwise would have been missed by traditional methods could be diagnosed and treated on time.

Statistical analysis: Data analysis was performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA) for continuous data using Kolmogorov–Smirnov test. Descriptive statistics (mean, standard deviation and range) were carried out for normally distributed data. Comparison of means across two groups was done using Student’s t independent test and comparison of categorical values was done by Chi-square/Fisher’s exact test.

Results

A total of 2258 patients screened for FGTB over a period of nine years, a total of 404 were suspected to have FGTB on histopathology taking, clinical examination, radiological imaging, microbiological and histopathological findings with the prevalence of FGTB. Out of the 404 cases, laparoscopy could not be done in 30 patients (9 patients were lost to follow up, 11 got pregnant while waiting for laparoscopy, and 10 refused laparoscopy; Figure).

Close

Figure

Diagnostic algorithm. FGTB, female genital tuberculosis

Export to PPT

Out of 374 women in whom laparoscopy was tried, findings were seen in 363 cases, as laparoscopy was abandoned in five patients and pelvis could not be seen due to adhesions in six patients. Hence, only 363 cases with proven FGTB on laparoscopy were taken, making the prevalence of FGTB in infertility to be 16 per cent. Another 110 patients not found to have FGTB also underwent laparoscopy for other reasons and were not included in the study.

The general characteristics of the participating women are shown in Table I, with mean age being 27.5±4.8 yr while mean parity was 0.29±0.12 and mean body mass index was 22.6±2.58 kg/m². History of tuberculosis was seen in 145 (38.77%), with pulmonary TB in 24.59 per cent and EPTB in 14.17 per cent of cases. Infertility was seen in all women, with a mean duration of infertility being 3.78±1.58 yr. Primary infertility was seen in 81.81 per cent of cases and secondary infertility in 18.18 per cent of cases. A total of 246 (65.77%) patients were from a lower socioeconomic status. History of Bacillus Calmette–Guérin (BCG) vaccine was observed in 84.49 per cent of cases.

The clinical features, examination findings and baseline investigations are depicted in Table II. Menstrual symptoms were most common, especially hypomenorrhoea in 27.80 per cent and oligomenorrhoea in 29.67 per cent of cases. Adnexal mass was palpable in 68 (18.18%) being unilateral in 46 (12.29%) and bilateral in 22 (5.8%) cases. Infectious Mantoux test (>10 mm) was observed in 142 (37.96%) cases, while erythrocyte sedimentation rate (ESR) ranged between 12 and 69, with a mean of 32.74±12.84 mm in the first hour. On X-ray chest, old healed lesions of tuberculosis were seen in 26 (6.95%) and enlarged thoracic lymph nodes were seen in 18 (4.81%) cases.

The numbers of patients based on methods of diagnosis of FGTB are shown in Table III. Positive MTB on microscopy of endometrial aspirate or biopsy was observed in 18 (4.81%) cases, 24 (6.41%) on culture, tuberculous granuloma on histopathology in 58 (15.50%) cases while on peritoneal biopsy, AFB microscopy or culture were seen in 14 (3.94%) cases, epithelioid granuloma was seen in 22 (5.88%) cases. Positive PCR on endometrial or peritoneal biopsy was seen in 314 (83.95%) cases. GeneXpert was positive in 31 (18.56%) cases out of 167 cases. If non-specific PCR was excluded, only 90 patients had definite evidence of FGTB on microscopy, culture, Gene Xpert or positive histopathology, with many patients having more than one positive finding. Hence, out of 363 cases, 273 were missed by traditional tests but diagnosed by laparoscopy. Definite findings of tuberculosis (tubercles, caseous nodules and beaded tubes) were seen in 164 (43.85%) cases, while probable findings of FGTB (straw-coloured fluid, pelvic adhesions, perihepatic adhesions, hyperaemic tubes, convoluted tubes, hydrosalpinx, pyosalpinx and shaggy areas) were seen in 210 (56.14%) cases.

Various abdominopelvic findings of TB on laparoscopy are shown in Table IV. The laparoscopy was abandoned or failed due to umbilical adhesions in five (1.377%) women and there was inability to see the pelvis due to adhesions in another six women. Of the definite findings, tubercles were seen mostly on uterus in 123 (33.68%) women (

Of the probable findings, the most common adhesions were seen as pelvic adhesions in 198 (54.54%), abdominal adhesions in 88 (24.24%) while, perihepatic adhesions (

Various probable fallopian tube findings of FGTB are shown in Table IV including unilateral hydrosalpinx (

Further analysis of data between two the time periods (July 2010 to December 2014 and January 2015 and July 2019 was done (Table IV). It was found that bilateral beaded tubes which were more common in the second half (P=0.05) and abdominal adhesions which were more common (29.12%) in the first half, than in the second half (19.45%) (P=0.03) and bilateral tubal block was more common in the first half (49.45%) than in the second half of time (32.43%; P=0.001). There was no significant difference in various laparoscopic findings across the two time periods.

Discussion

Female genital tuberculosis (FGTB) is a type of extrapulmonary tuberculosis (EPTB) and is a significant cause of infertility, especially in developing countries3-7. Being a paucibacillary disease, its diagnosis remains a dilemma as the gold standard method of diagnosis like AFB positivity on microscopy or culture or positive Gene Xpert or epithelioid granuloma on endometrial and peritoneal biopsy are positive in selected cases and may miss the diagnosis in most cases5,7,9. The use of PCR picks up more cases but has a high false-positive rate and alone is not advisable to diagnose FGTB or to start anti-tuberculous therapy5,7,9.

The role of radiological methods such as ultrasound, computed tomography (CT) scan, magnetic resonance imaging and positron emission tomography is more for tubercular tubo-ovarian masses and to differentiate between abdominopelvic TB and ovarian cancer, while hysterosalpingography can detect uterine and tubal pathophysiology15-18. Molecular tests like nucleic acids have been used for the diagnosis of pleural TB, a variant of EPTB and can be used for FGTB also19.

In the present study also, CRS was used for diagnosis of FGTB as it can pick up more cases which can be missed by gold standard culture and histopathology but avoid diagnosing FGTB by non-specific and highly false-positive tests like PCR.

Laparoscopy can detect more cases of genital TB and abdominal TB by direct viewing of the abdomen and pelvis for various TB findings. Definite findings like beaded tubes, caseous nodules or tubercles or probable findings such as encysted ascites, pelvic, abdominal or perihepatic adhesions, hydrosalpinx, pyosalpinx or tubo-ovarian masses and tubal blockage are seen5,6,9,13,14.

Laparoscopy in suspected cases of FGTB should be done by an experienced gynaecologist after proper counselling of the patients due to complications in surgery20. All patients are treated with six months of anti-tubercular drugs as has been recommended by the WHO1, National TB Elimination Program of India2 and a previous randomized controlled trial21, which confirmed that six-months therapy was equally effective to nine month therapy. Rarely, multidrug-resistant FGTB can be there, necessitating longer treatment (18-24 months) therapy with reserved drugs in consultation with infectious disease experts22. Various other studies have also proven the utility of diagnostic laparoscopy alone or in combination with other molecular methods in better and early detection of FGTB23-30.

Tuberculosis has a major impact on both female and male fertility, but there are many controversies and pitfalls in its diagnosis29,30. However, laparoscopy appears to be a useful diagnostic modality in the diagnosis of FGTB along with other tests.

The strength and novelty of the study is the large sample size of successful cases of laparoscopy in FGTB patients diagnosed on CRS with the observation of various laparoscopic findings in abdominopelvic TB.

Furthermore, laparoscopy could detect most cases of FGTB missed by traditional methods for timely treatment to prevent permanent damage and sterility. The limitations of the study are dependence on CRS for diagnosis as laparoscopy may overdiagnose some cases, inability to do testing for pelvic infections like chlamydia or gonorrhoea due to financial and logistics constraints and also lack of long-term follow up data of these patients regarding improvement in fertility outcome with anti-tuberculous therapy.

In the current study, diagnostic laparoscopy was performed for all suspected and confirmed cases of FGTB as part of a research project and infertility protocol which is also a limitation as anti-tubercular treatment can be started on the basis of these tests without subjecting the patients to laparoscopy.

Overall, although laparoscopy is a useful method in diagnosing FGTB and abdominopelvic TB and, for prognostication of infertility, it should not be done in isolation, it should be combined with conventional methods as part of CRS for increased detection of FGTB for timely treatment.