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INVITED REVIEW ARTICLE
Year : 2015  |  Volume : 2  |  Issue : 1  |  Page : 14-25

In vitro fertilization and embryo transfer in female genital tuberculosis


Department of Obstetrics and Gynecology, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication15-Jun-2015

Correspondence Address:
Dr. Jai B Sharma
Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2348-2907.158735

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  Abstract 

Female Genital Tuberculosis is a common cause of infertility in Asia and Africa due to tubal, endometrial and ovarian factors. In-vitro fertilization and embryo transfer is the only hope in women having tubal blockage but receptive endometrium. However, surrogacy or adoption may be needed if endometrium is also involved.

Keywords: Female Genital Tuberculosis, In vitro fertilization, Embryo transfer


How to cite this article:
Sharma JB. In vitro fertilization and embryo transfer in female genital tuberculosis. IVF Lite 2015;2:14-25

How to cite this URL:
Sharma JB. In vitro fertilization and embryo transfer in female genital tuberculosis. IVF Lite [serial online] 2015 [cited 2021 Aug 3];2:14-25. Available from: http://www.ivflite.org/text.asp?2015/2/1/14/158735


  Introduction Top


Tuberculosis (TB) remains a major public health problem globally with about 9.4 million new TB cases annually out of which about two million die. [1],[2],[3] The main burden is in developing countries especially in Asia and in Africa with 75% patients in the most economically productive age group (15-54 years) causing great economic burden on the family and the nation. [1],[2],[3],[4],[5] Co-infection with human immunodeficiency virus (HIV) and more liberal immigration due to globalization has been responsible for increased incidence worldwide. Multidrug-resistant (MDR) and extreme drug resistant TB are a matter of real concern.

Pulmonary TB (PTB) is the commonest and most infectious from of TB, but extra PTB is becoming more rampant. [2],[5] Female genital TB (FGTB) causes significant morbidity, short and long-term sequelae, especially infertility for the affected women due to fibrosis and scarring occurring as a part of healing. Early diagnosis and timely appropriate treatment may prevent permanent damage to the endometrium and  Fallopian tube More Detailss avoiding infertility and other stigmata of the disease. [5],[6],[7]


  Epidemiology of Female Genital Tuberculosis Top


The precise incidence of FGTB is difficult to ascertain as it is underreported due to asymptomatic cases and lack of reliable confirmatory investigations. [5],[7] The reported incidence varies in different countries from 1% in infertility clinics of USA, 3.1% gynecological admissions in Malaysia, 3.5-23% in Pakistan 0.8%, 2% in tubal factor in Italy, 4.2% in infertility patients in Saudi Arabia, 16.7% in Nigeria and 6.15-21.1% in South Africa, 1-19% in various parts of India. [7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22] Females with genitourinary TB constitute about 0.5% of all TB cases out if which about 50% are genital TB cases. [11] In infertility patients incidence of FGTB varies from 3% to 16% in India with higher incidence being from apex institutes like All India Institute of Medical Sciences, New Delhi where prevalence of FGTB in women of infertility was 26% and incidence of infertility in FGTB to be 42.5%, which may be due to referral of difficult and intractable cases to this apex hospital from all over India especially from states like Bihar where prevalence of TB is very high, [5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15] Similarly, incidence of FGTB is also very high in women seeking assisted reproduction being 24.5% overall, but as high as 48.5% with tubal factor infertility as reported by Singh et al. [20] Genital TB was found on autopsy in 1-12% of women dying with PTB. [7] The prevalence of genital TB in infertility practices and infertility in various countries, including in India by a different author is shown in [Table 1]a and [Table 1]b. [7],[8],[9],[10],[11],[12],[13],[14],[15],[20],[21],[22],[23],[24],[25],[26],[27],[28] The age of presentation of FGTB is lower in developing countries with the range being 20-40 years whereas in developed nations it is usually diagnosed in premenopausal women over the age of 40 years. [7],[10],[23] It may be due to younger age at marriage and childbearing in developing countries as compared to western world. FGTB is less common in postmenopausal women as the atrophic endometrium in them offers a poor mileu for the growth of the bacillus. [6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22] There has been 5-fold increase in overall incidence of TB in countries with high prevalence of HIV due to impaired immunity in them. HIV infects macrophages especially CD4 + T cells causing their depletion and dysfunction with rapid progression of TB. [21]
Table 1


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  Pathogenesis Top


The genital organs involved are fallopian tubes (90-100%) uterus (50-80%), ovaries (20-30%), cervix (5-15%), vagina and vulva (1-2%) cervical cases. [4],[5],[6],[7] The site of involvement in primary genital TB can be cervix, vagina or vulva. [4],[5],[6],[7] The spread of TB from lungs and other sites is usually by hematogenous or lymphatic route. Less commonly, direct contiguous spread from nearby abdominal organs like intestines or abdominal lymph nodes can cause genital TB. The fallopian tubes are involved in 90-100% cases with congestion, military tubercles, hydrosalpinx, pyosalpinx and tubo-ovarian masses. [4],[5],[6],[7]


  Pathology Top


Fallopian tubes

Fallopian tubes are involved in almost all (>90%) women with genital TB and the involvement is usually bilateral. Various types of TB salpingitis can be TB endosalpingitis, TB exosalpingitis, interstitial TB salpingitis and salpingitis isthmica nodosa [1],[4],[5],[6],[7] In tuberculous endosalpingitis, the infection starts from endosalpinx and is usually through hematogenous route of spread. The fallopian tube is thickened, enlarged and tortuous. Sometimes unilateral or bilateral pyosalpinx may be formed due to caseation in the tubal wall and the collection of the cheesy material in the lumen with blockade of both ends of fallopian tubes due to fibrosis. [4],[5],[6],[7] Dense pelvic adhesions are often formed around the tubes though some women may have tubo-ovarian mass without adhesions. [4],[5],[6],[7] Rarely a persistent fistula may form spontaneously or iatrogenically due to surgical drainage and may fail to heal. Intestinal obstruction can occur due to adhesions. Endosalpinx may sometimes be hyperplastic or edematous and may be totally destroyed, or there may be a fusion of papillae in the endosalpinx making women more prone to ectopic pregnancy and infertility. [4],[5],[6],[7] Sometimes granulomatous lesion with chronic inflammatory infiltrate with or without caseation may be seen in the tube. [4],[5],[6],[7]

In tuberculous exosalpingitis, there is the direct spread of the disease from intestines with disease starting in the muscularis mucosa of the tube. Initially, there is congestion of fallopian tubes, ovaries and peritoneum of the pouch of Douglas with flimsy adhesions and miliary tubercles on their surface. In later stages, there are beaded tubes with calcification and tubal blockade, tubo-ovarian masses due to peri-oophoritis, hydrosalpinx, pyosalpinx or massive adhesion formation. [4],[5],[6],[7] Thick and vascular plastic adhesions are formed between tubes and adjacent pelvic organs especially in adhesive or plastic type of peritonitis. In more severe cases, there may be multiple adhesions in the peritoneal cavity with an obliterated pouch of Douglas (Frozen pelvis). [4],[5],[6],[7] In interstitial tuberculous salpingitis there is inflammation in the interstitial part of the tube with thickening of the tube while in salpingitis isthmica nodosa, there is nodular thickening of the tube due to proliferation of tubal epithelium within the hypertrophied muscle layer as diagnosed on hysterosalpingography as small diverticulum. [1],[4],[5],[6],[7]


  Uterus Top


The endometrium is usually involved secondary to fallopian tubes involving 50-80% (mean 70%) cases of FGTB. Gross endometrial appearance may be unremarkable due to repeated menstruation reducing the severity of the disease. Initially, there is no macroscopic disease but caseation and ulceration occur later with the progression of TB and in advanced stages, there is a distortion of the cavity, varying from slight distortion to complete obliteration due to adhesions. Total destruction of the endometrium may result in Asherman's syndrome like picture resulting in amenorrhea secondary to end organ failure. In fact genital, TB is an important cause of Asherman's syndrome in India leading on to secondary amenorrhea and infertility with poor prognosis for treatment. [4],[5],[6] Microscopically, TB granulomas with or without caseation, epitheloid cells, and Langhans cells may be seen, especially in the premenstrual phase and close to the surface of the endometrium. However, typical granulomas may not always be seen due to repeated sheddings at the time of menstruation. Some authors have suggested that even in the absence of typical granulomas, endometrial TB may be diagnosed in the presence of a focal collection of lymphocytes with or without the presence of dilated glands and destruction of the epithelium. [4],[5],[6] Some women may present with pyometra due to the collection of caseating material in the uterus with constricted cervix, especially in postmenopausal women. [4],[5],[6]


  Ovaries Top


Isolated TB oophoritis is rare. It is more often seen as part of TB peritonitis or with TB of other genital organs (tubes or endometrium) usually by direct extension. Depending upon the severity and stage of disease, there may be tubercles on the ovary, adhesions, caseation, tubo-ovarian cyst or mass formation. Sometimes ovary may be completely destroyed by the disease. [4],[5],[6]


  Peritoneum Top


Tuberculosis may involve pelvic or abdominal peritoneum, which can be disseminated TB with tubercles all over the peritoneum, intestines, and omentum and may cause ascites and abdominal mass. It may masquerade as ovarian cancer as even CA 125 levels are raised in peritoneal TB with computed tomography scan and magnetic resonance imaging also giving similar picture and diagnosis may be made only on laparotomy done for suspected ovarian cancer. [5],[24] In such cases, ascitic fluid tapping for bio-chemical analysis and peritoneal biopsy may confirm the diagnosis of TB and thus avoiding a needless laparotomy. On laparotomy, there may be vague masses without a line of cleavage with adherent loops of bowel or omental masses mimicking secondaries from ovarian cancer. [5],[24] In advanced disease pelvic and abdominal organs are densely matted together with tubercles, foci of caseation, and calcified plaques on the peritoneal surface. There is a very high prevalence of perihepatic adhesions (Fitz-Hugh-Curtis Syndrome). [25],[26]


  Cervix Top


The cervix may be involved in 3-7% cases of genital TB usually as a downward extension of endometrial TB, but may rarely be a primary disease transmitted by the partner through infected semen. It may present as velvety polypoidal growth or ulceration or destruction of the surface epithelium and simulate cervical cancer necessitating biopsy for confirmation of diagnosis. Microscopic examination will differentiate between the two conditions showing granulomatous inflammation in TB. [4],[5],[6],[7] It may be diagnosed by Papanicolaou smear by the presence of multinucleated giant cells, histiocytes, and epithelioid cells. [4],[5],[6],[7]


  Vagina and Vulva Top


Their involvement is rare (1-2%) and is usually secondary to the extension from endometrium or cervix, but may rarely be primary due to transmission from an infected partner with tubercular epididymitis. There may be a hypertrophic lesion or a non-healing ulcer on the vulva or vagina simulating malignancy. Biopsy and histopathological examination are usually needed to confirm the diagnosis and to rule out malignancy and other causes like syphilis, lymphogranuloma venereum, etc., Rarely TB of the vagina can cause involvement of Bartholin's glands, vesicovaginal and rectovaginal fistula formation.


  Genital Tuberculosis and Infertility Top


Infertility both primary and secondary is fairly common in FGTB (40-80% among FGTB cases). Various causes of infertility in FGTB can be as follows:

  • Tubal factors
    1. Blockage of fallopian tubes
    2. Loss of tubal function due to ciliary damage causing infertility and ectopic gestation
    3. Perisalpingitis causing adhesions and tubo-ovarian mass formation
    4. Tubercular hydrosalpinx with or without obstruction occurs in 46% cases of FGTB can have an adverse impact and embryonic implantation and ovarian function. [27],[28],[29] In in vitro fertilization (IVF) treatment women with tubercular hydrosalpinx, have very low pregnancy rate, which is worse with bilateral (12%) as compared to unilateral hydrosalpinx (24%). Clinical pregnancy rates can be increased with salpingectomy. As Inflammatory reaction within the ovarian cortex provokes production of macrophage-mediated harmful cytokines and growth factors within the intrafollicular fluid adversely a ffecting the development of the oocyte. [29] However, routine pre-IVF salpingectomy in all women with ultrasonologically visible hydrosalpinx is not recommended but is done if aspirated hydrosalpingeal fluid can be tested for toxin by mouse-embryo assay. [29]
  • Defective ovarian function due to the tubo-ovarian mass formation, adhesions, anovulation and poor ovarian reserve. [27],[28],[29]
    1. Endocrine disruption
    2. In proven genital TB, chronic anovulation has been observed in FGTB
    3. Mycobacterium tuberculosis has antigonadotropic effect: Necessitating more ampoules of gonadotropins in IVF cycle
    4. Women with genital TB have higher day 3 follicle-stimulating hormone (FSH) level and relatively lower peak E2 level, thus requiring higher number of gonadotropin ampoules than controls
    5. Mycobacteria inhibit the basal production of progesterone and antagonize the stimulatory effect of hCG on corpus luteum causing a luteal phase defect, implantation failure, lower pregnancy rates and higher miscarriage rates
    6. In genital TB quality of embryo tends to be poor due to "intrinsic oocyte factor" defect. The harmful interleukins (ILs) induced by immune modulation or by the direct effect of toxins of mycobacteria adversely affect the oocyte development within the follicle.
  • Endometrial damage occurs in TB as follows: [29],[30],[31]
    1. Effect of genital TB on endometrial receptivity
      1. Adverse effect on endometrial markers which are essential to make the endometrium receptive for embryonic implantation [29]
      2. Defective vascularization of the endometrium
        • Activation of antiphospholipid antibodies in the endometrium
        • Reduced subendometrial blood flow due to the involvement of basal layer of endometrium in FGTB with defection endometrial vascularization
        • Through immunomodulation with the production of enzyme procoagulase causing vascular thrombus formation.
      3. Endometrial atrophy and synechiae formation: It occurs due to involvement of endometrium by caseous or fibrocaseous lesion of FGTB causing Asherman's syndrome which is common in endometrial TB: We observed through hysteroscope various grades of intrauterine adhesions in FGTB as: Grade 1 20.8%, Grade 2 28.5%, Grade 3 28.5%, Grade 4 17.5% [Figure 1] and [Figure 2]. with other findings of TB like tubercles, and shaggy cavity with caseation on hysteroscopy. [31] We observed increased difficulties and complications encountered during hysteroscopy in women with genital TB like inability to distend the cavity, excessive bleeding uterine perforation and flare-up of genital TB [32] Hysterosalpingographic findings in our study were a normal uterine cavity in 57.1% an irregular cavity in 18.5%, a shrunken cavity in 2.8% and an irregular filling defect in 18.5% and synechiae in 17.1% of women. [33]
        Figure 1: Fludeoxyglucose positron emission tomography-computed tomography (FDG PET/CT) image with secondary infertility left sided TO mass in genital tuberculosis. FDG PET/CT image with secondary infertility left sided TO mass

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        Figure 2: Hysterosalpingography in genital tuberculosis. HSG showing uterine cavity is small with contour irregularity. A filling defect noted in the right side of the uterine cavity suggests synechiae. There is also a left cornual block and right fimbrial block

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      4. Failure of implantation in FGTB.


It occurs in the following ways: [29]

  • There is the release of harmful cytokines and growth factors (IL-2, IL-8, TNF-α) in the endometrium
  • There is production of symmetric antibodies
  • There is production of natural killer cells
  • There occur lymphocyte activated killer cells
  • There is T-helper-1 cell (response) with leads on to implantation failure instead, or T-helper-2 cell response needed for successful implantation.



[Table 2]">  Diagnosis: Various Clinical Symptoms and Sings of Female Genital Tuberculosis are Shown in [Table 2] Top
[4],[5],[6],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42]
Table 2: Symptoms and signs in FGTB[4-7]


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Early diagnosis of FGTB is crucial for timely treatment and prevention of fibrosis and infertility. A high index of suspicion is required. The diagnostic approach used is family history of TB or history of antituberculous therapy (ATT) in a close family member or a past history of TB or ATT in the patient may show recrudescence of TB in the genital region. History of HIV positivity is also important. Detailed general physical examination for any lymphadenopathy, any evidence of TB at any other site in body (bones, joints, skin etc.), chest examination (PTB), abdominal examination (abdominal TB), examination of external genitalia (vulvar or vaginal TB), speculum examination (cervical TB), bimanual examination (endometrial or fallopian tube TB) help in the diagnosis of genital TB. [5],[6]

All tests are not required for every single case of genital TB. [31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41] The tests will depend upon the site of TB and its clinical presentation and are shown in [Table 3]. [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9] and [Figure 10]
Table 3: Investigations in genital TB[4-7,31-41]


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Figure 3: Ultrasound findings in genital tuberculosis. Ultrasound showing a tuberculous mixed echogenic mass on right side of uterus

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Figure 4: Magnetic resonance imaging (MRI) findings in genital tuberculosis (TB). MRI Film showing bilateral tubo-ovarian masses in a confirmed case of genital TB

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Figure 5: Hysterosalpingography in genital tuberculosis. Hysterosalpingography shows an occluded right tube with "beaded" appearance. The left tube is occluded in mid ishmic portion. There is a smooth filling defect in the fundus which was caused by a fibroid

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Figure 6: Hysteroscopic findings in genital tuberculosis. Hysteroscopy showing pale cavity in proven genital tuberculosis

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Figure 7: Hysteroscopic findings in genital tuberculosis. Grade 3b uterine adhesions: Multiple firms adhesion connecting separate parts of uterine cavity with extensive scarring of uterine cavity with amenorrhoea

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Figure 8: Laparoscopic findings in genital tuberculosis. Laparoscopy showing multiple tubal block with beaded appearance in a proven case genital Koch

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Figure 9: Laparoscopic findings in genital tuberculosis. Laparoscopic findings showing large hydrosalphinx

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Figure 10: Laparoscopic findings in genital tuberculosis. Laparoscopic findings showing Fitz-Hugh-Curtis syndrome

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Treatment

Medical treatment

Treatment of latent genital TB detected only on positive polymerase chain reaction (PCR) is controversial due to high false positivity. Many antiretroviral treatment (ART) experts routinely treat positive PCR patients with better pregnancy outcome in those women treated with ATT than without treatment The logic of treating later TB is that in early stage, it can be treated without causing permanent damage to endometrium and other genital organs with much better outcome Jindal et al. [38] observed 30.8% pregnancy rate an TB PCR positive women with ATT while Kulshrestha et al. [43] also obtained 31% pregnancy rate on ATT in TB PCR positive women. Latent Genital TB has been found to be associated with repeated IVF failure in Indian clinical setting. [44] Even when Indian women migrate to western countries, they have a poor prognosis with IVF as compared to Caucasian women despite similar embryo quality, which could be due to latent FGTB in Indian women. [45] However, treating women with positive PCR is associated with risk of over treatment as many women without FGTB are then treated. Short course chemotherapy for 6-9 months has been found to be effective for medical treatment of FGTB. [2],[3],[4],[5],[6]

Directly observed treatment short course strategy treatment

Directly observed treatment short course (DOTS) is favored by WHO to prevent MDR and for better results. WHO in its recent guidelines has removed category 3 and recommend daily therapy of rifampicin (R), isoniazid (H), pyrazinamide (Z) and ethambutol (E) for 2 months, followed by daily 4 month therapy of rifampicin (R) and isoniazid (H). Alternatively 2 months intensive phase of RHZE can be daily, followed by alternate day continuation phase (RH) of 4 months. Three weekly dosing throughout therapy (2RHZE 4HR) can be given as DOTS provided every dose is directly observed, and the patient is not HIV positive or living in an HIV prevalent setting. [2],[3],[4],[5],[6]

The patient is first categorized to one of the treatment categories and is then given treatment as per guidelines for national programs by WHO [Table 4]. Genital TB is classified under category 1 being a seriously ill extrapulmonary disease. To ensure quality assured drugs in adequate doses a full 6 months course pack box is booked for an individual patient in the DOTS center with fixed drug combipack of isoniazid, rifampicin, pyrazinamide and ethambutol thrice a week for first 2 months (intensive phase) under direct observation followed by combination blister pack of isoniazid and rifampicin thrice a week for next 4 months (continuation phase).
Table 4: Category wise treatment regimens for tuberculosis including FGTB[2-6]


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Rarely FGTB cases can have relapse or failure categorizing them into category II [Table 4]. which includes 2 months intramuscular injections of streptomycin thrice weekly along with other four drugs (RHZE) of category I under direct supervision of DOTS center health worker for first 2 months followed by four drugs (RHZE) thrice a week for another month (Intensive phase), followed by continuation phase with three drugs isoniazid (H), rifampicin (R) and ethambutol (E) thrice a week for another 5 months.

Nondirectly observed treatment short course treatment

Patients are not opting for DOTS treatment must take daily therapy of RHZE for 2 months (intensive phase), followed by RH for 4 months (continuation phase). Convenient and economic combipacks are available in the market.

Treatment of chronic cases, drug resistant, and multi-drug resistant female genital tuberculosis

It is same as for pulmonary MDR with second-line drugs and is shown in [Table 4] and is needed for long duration (18-24 months).

Monitoring

The women should be counseled about the importance of taking ATT regularly and consumption of good and nutritious diet and should report in case of any side effects of the drugs. Liver function test is no longer done regularly unless there are symptoms of hepatic toxicity. Similarly, pyridoxine is not routinely prescribed with ATT unless there are symptoms of peripheral neuropathy with isoniazid. Rarely hepatitis can be caused by isoniazid, rifampicin and pyrazinamide and optic neuritis by ethambutol and auditory and vestibular toxicity by streptomycin in which case the opinion of an expert should be sought for restarting the ATT in a modified form.

Possible options for antiretroviral therapy in TB patients include:

  • Defer antiretroviral therapy until TB treatment is completed
  • Defer antiretroviral therapy until the end of the initial phase of treatment and use ethambutol and isoniazid in the continuation phase
  • Treat TB with a rifampicin-containing regimen and use efavirenz + 2 nucleoside reverse transcriptase inhibitors (NRTIs)
  • Treat TB with a rifampicin-containing regimen and use 2 NRTIs; then change to a maximally suppressive highly active antiretroviral therapy regimen on completion of TB treatment.


Surgical treatment

The medical therapy especially the modern short course chemotherapy consisting of rifampicin and other drugs is highly effective for the treatment of FGTB with the rare need of surgery. However, limited surgery like drainage from residual large pelvis or tubo-ovarian abscesses, pyosalpinx can be performed followed by ATT for better results

There are much higher chances of complications during surgery in women with genital TB in hysteroscopy, laparoscopy, and laparotomy. [32],[41],[42] There are excessive hemorrhage and nonavailability of surgical planes at the time of laparotomy with higher risks of injury to the bowel and other pelvic and abdominal organs. In a case of abdomino-pelvic TB, bowel loops may be matted together with no plane between them and uterus and adnexa may be buried underneath the plastic adhesions and bowel loops and are inapproachable. Even trying to perform a diagnostic laparoscopy or laparotomy in such cases can cause injury to bowel necessitating a very difficult laparotomy and resection of the injured bowel. It is better to take biopsies from the representative areas and close the abdomen without pelvic clearance in cases of laparotomy done for suspected pelvic tumors but found to be tubercular at laparotomy, followed by full medical treatment.

Sometimes even after a full 6 months course of ATT, women with genital TB with infertility do not conceive when laparoscopy and hysteroscopy may be repeated to see any remaining disease. The outcome for fertility in FGTB is only good when ATT is started in early disease. However, cases of advanced TB with extensive adhesions in pelvis and uterus are usually untreatable with very poor prognosis for fertility. Tuboplasty performed after ATT does not help much with chances of flare up of the disease and risk of ectopic pregnancy, should the women conceive [4],[6]


  In Vitro Fertilization and Embryo Transfer in Genital Tuberculosis Top
[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56]

Most women with genital TB present with infertility and have a poor prognosis for fertility in spite of ATT. The conception rate is low (19.2%) with the live birth rate being still low (7%). [13] IVF with embryo transfer (ET) appears to be the only hope for some of these women whose endometrium is not damaged with a pregnancy rate of 16.6% per transfer. [14],[38],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56] Jindal et al., [52] reported favorable infertility outcomes following antitubercular treatment prescribed on the sole basis of positive PCR, test for endometrial TB. Singh et al., [55] observed poor endometrial blood flow in women with FGTB undergoing IVF-ET. Malhotra et al. [56] studied peri-follicular Doppler blood flow before oocyte recovery in patients with or without genital TB. Although they observed a trend of poor ovarian blood flow in FGTB patients, there was no difference in other outcome variables like fertilization or cleavage rate in FGTB women undergoing IVF/intracytoplasmic sperm injection in their center. IVF-ET has been found to be most successful out of all ART modalities in genital TB patients with 17.3% conception rate in contrast to only 4.3% with fertility enhancing surgery. [47] Latent genital TB has been found responsible for repeated IVF failure in young Indian patients presenting with unexplained infertility with the apparently normal pelvis and nonendometrial tubal factors. [44] The pregnancy rates and take home baby rate could be improved by early detection when there are minimal damage and aggressive management of the disease. As already discussed in pathogenesis and pathology, women with FGTB have poor ovarian reserve with few quality embryos needing more gonadotropins, have poor endometrial receptivity or have endometrial synechae. The result of IVF and ET are poorer than in other indications. The results of IVF-ET in FGTB by various authors are shown in [Table 4] and pregnancy rate vary from 9.1% to 38.3% with many ending into abortion or ectopic pregnancy. Studies have shown the poor result with IVF in FGTB and the following observations have been made: [46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56]

  • Most patients are poor responders
  • Need high starting and maintenance dose of gonadotropins
  • Endometrium invariably is poorly developed, and even exogenous estrogen may not help
  • Oocyte and embryo quality is poor, and the pregnancy rate is poor.


In a retrospective analysis of 120 cases who underwent IVF at her center, Malik [48] showed a pregnancy rate of 38.2%, which is comparable to other indications. She attributed this to early diagnosis through molecular tests like PCR and aggressive management like that for active disease. ATT was given to the patients till the endometrial biopsy was negative, and this varied from 6 to 18 months. IVF was done only after the biopsy was negative. Maximum no. of pregnancies were achieved when treatment was given for 9 months (40%). No difference in pregnancy rate was noticed when patients were kept on or were taken off the ATT during the IVF cycle. Fertility outcome in FGTB with IVF-ET by various authors is given in [Table 5].
Table 5: Fertility outcome in FGTB with IVF and ET by various authors


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Hence, if after ATT their tubes are still damaged, but their endometrium is receptive (no adhesions or mild adhesions, which can be hysteroscopically resected), IVF-ET is recommended to these women. [5],[48] However, if they have endometrial TB causing damage to the endometrium with shrunken small uterine cavity with Asherman's syndrome, adoption or gestational surrogacy is advised to them.


  Gestational Surrogacy in Genital Tuberculosis Top


In gestational surrogacy, another women's uterus is used for implantation while ovum belongs to this women and sperm belongs to her husband. She is this genetic mother of the fetus. The most important prerequisite for surrogacy in FGTB is a normal ovarian reserve with normal basal FSH (<10 IU/ml) level, ovarian volume (>3 ml) and basal antral follicular count of 4 or more. [57]

The indications of surrogacy in FGTB in India are as follows: [57]

  • Moderate to severe intrauterine adhesions not amenable to hysteroscopic adhesiolysis
  • Atrophy of the basal layer of endometrium not responding to hormonal therapy
  • Grossly reduced endometrial thickness (<7 mm) in spite of estrogen supplementation with high resistance subendometrial blood flow in the proliferative phase in repeated cycles
  • Dense pelvic adhesions causing to repeated IVF failure
  • Unexplained repeated IVF failure with endometrium showing the persistence of TB granuloma or PCR positivity despite adequate antitubercular chemotherapy
  • MDR genital TB.


Surrogate host can be a family member or stranger but a forced friendship, must be established between the host and the commissioning couple in surrogacy.

In their experience of surrogacy in FGTB at Institute of Reproductive Medicine in Kolkata on 14 women with uterine synechiae, poor endometrial development or repeated IVF failure, Samanta et al. [57] could achieve a viable delivery rate of 50%.

New tuberculosis research

There has been a renewed interest in research in TB globally with the development of new drugs and vaccines. Newer diagnostic tests including Gene Xpert are being developed. [58],[59] New drugs, effective against strains that are resistant to conventional drugs and requiring a shorter treatment regimen are being developed. There may be the role of stem cell therapy in endometrial atrophy (Asherman's syndrome) in FGTB to help regenerate the endometrium and tubal mucosa. IVF-ET if performed on time has a good success rate. There is a need to improve pregnancy outcome by IVF-ET in FGTB. Gestational surrogacy has a role in some women.


  Summary and Conclusion Top


  • FGTB is in the important cause of infertility being responsible for up to 16% cases of infertility in developing countries while infertility is seen in up to 40-50% cases of genital TB
  • FGTB can cause destruction of ovaries, tubo-ovarian masses or poor ovarian reserve with poor quality of embryos and need of a high dose of gonadotropins
  • Endometrial TB causes poor endometrial receptivity, endometrial adhesions, and recurrent implantation failure
  • Diagnosis is by good history taking, thorough clinical examination and judicious use of investigations especially endometrial sampling for acid-fast bacilli culture, PCR, and histopathological testing. Laparoscopy and hysteroscopy may be helpful in early diagnosis and to see the severity of disease for prognostication for fertility
  • Medical treatment using DOTS strategy under direct observation and using quality assured drugs in appropriate dosage and for the adequate time is the mainstay of treatment
  • Surgical treatment is rarely required and should only be done in exceptional circumstances and should be in the form of limited surgeries like laparoscopy, hysteroscopy and drainage of abscess, etc., as surgery in genital and peritoneal TB can be difficult and hazardous
  • The prognosis for fertility is poor. However, for tubal disease in absence of endometrial disease, ART especially IVF-ET may give good results if performed on time after giving full course of ATT and in fact may be the only hope for such women
  • There is the role of gestational surrogacy in women with Asherman's is syndrome due to endometrial TB with a viable pregnancy rate of about 50%
  • Stem cell therapy may play a role in the regeneration of endometrium and tubal mucosa in FGTB in future.


 
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  Authors Top


Dr. J B Sharma MD, FRCOG, FAMS is working as an Additional Professor in Obstetrics & Gynaecology at All India Institute of Medical Sciences New Delhi, India. He has 330 publications in Index and non-index Journals including 115 in peers reviewed indexed international and national Journals. He is the author of "Textbook Of Obstetrics" and "Midwifery and Gynecological nursing "and edited 2 books. He is involved with research projects with OXFORD University, Indian Council of Medical Research and Central TB division and Ministry of Health and Family Welfare Govt. of India. His research areas are Genital Tuberculosis, Anemia in pregnancy and Urogynaecology.


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