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International Journal of Gynecology and Obstetrics 113 (2011) 229–234

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International Journal of Gynecology and Obstetrics j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j g o

CLINICAL ARTICLE

Genital tuberculosis among infertile women and fertility outcome after antitubercular therapy Vidushi Kulshrestha a, Alka Kriplani a,⁎, Nutan Agarwal a, Urvashi B. Singh b, Tanu Rana b a b

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

a r t i c l e

i n f o

Article history: Received 13 August 2010 Received in revised form 3 December 2010 Accepted 24 February 2011 Keywords: Conception DNA polymerase chain reaction Genital tuberculosis Infertility Laparoscopy

a b s t r a c t Objective: To compare modalities for diagnosing genital tuberculosis (GTB) and to assess fertility outcome after antitubercular therapy (ATT). Methods: Infertile women underwent endometrial aspiration (EA) and peritoneal washing (PW) for histopathologic examination, PCR, and acid-fast bacilli (AFB) smear and culture of Mycobacterium tuberculosis; laparoscopy and hysteroscopy were also performed. Women with a positive laboratory test and/or laparoscopic finding classified as definitive/probable received ATT for 6 months. Results: Of 196 women recruited, 187 underwent laparoscopy. Genital tuberculosis was diagnosed in 118 (60.2%). In 41.3%, EA PCR was positive; PW PCR was positive in 7.6%. The remaining laboratory tests were positive in a small number. Laparoscopy indicated definitive GTB in 9.1% and probable GTB in 37.4%. Among the 118 women treated for GTB, 22.9% conceived without in vitro fertilization; of these women, 74.1% had a positive EA PCR and 59.3% had a positive laparoscopy finding. A quarter of the women received ATT solely on the basis of the PCR result and 31.0% of these women conceived. Conclusion: No single test can detect all instances of GTB. A combination of tests is needed to increase the detection rate. Treatment given solely on the basis of a positive PCR result can result in conception. © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction Female genital tuberculosis (GTB) is a common cause of infertility, as first shown by Malkani et al. [1]. The incidence of GTB varies and can be as low as 0.69% in Australia or as high as 19% in India [2]. The incidence of tubal-factor infertility is even higher (48%) [3]. Infertility is the most common presentation of GTB, with up to 58% of women with GTB being affected [4,5]. An early diagnosis is important to prevent adverse sequelae. The criteria for a definitive diagnosis of GTB by demonstration of Mycobacterium tuberculosis are hardly ever met in people with paucibacillary GTB [6], because microscopy for acid-fast bacilli (AFB) requires the presence of at least 10 000 bacilli/mL of specimen and culture requires at least 100 bacilli/mL [7]. Because there is no gold standard, the diagnosis of GTB presents a dilemma to clinicians and there remains a high index of suspicion. The molecular diagnosis by polymerase chain reaction (PCR) has become a useful adjunct [8] to conventional diagnostic techniques because PCR detects less than 10 organisms/mL. Polymerase chain reaction can also be applied to sterile fluids such as peritoneal fluid, where culture is difficult because the bacterial load is low [9]. Laparoscopy is now increasingly being ⁎ Corresponding author at: Room 3081, 3rd floor, Teaching Block, Department of Obstetrics and Gynecology, All India Institute of Medical Sciences, Ansari Nagar East, New Delhi, India. Tel.: + 91 11 26 594933; fax: + 91 11 26 588641. E-mail address: kriplanialka@gmail.com (A. Kriplani).

used for the early detection of GTB because it offers the dual advantage of pelvic organ visualization and sample collection from inaccessible sites [10,11]. There is a wealth of literature on GTB and infertility, with many studies having been performed in low-income countries, where GTB has a tremendous impact on reproductive health. However, prospective studies comparing various diagnostic modalities are lacking. The present clinical trial was undertaken to evaluate the rate of diagnosis of GTB by various diagnostic modalities, with a special emphasis on the correlation among these modalities. In addition, the study ascertained the diagnostic value of DNA PCR and its correlation with laparoscopy, and determined the effect of antitubercular therapy (ATT) on conception. 2. Materials and methods The present prospective study was conducted from February 1, 2006, to January 31, 2009, after ethics clearance had been obtained from the Ethics Committee of the All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India. All participants provided informed consent. The study included all women who, during the study period, presented with infertility to the gynecological outpatient department of the investigator at the All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India. Detailed histories were taken and the following investigations were performed: hemogram including erythrocyte sedimentation rate, Mantoux test, semen analysis, chest

0020-7292/$ – see front matter © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2010.12.014


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X-ray, pelvic ultrasound, hormone profile if the clinical features suggested polycystic ovary syndrome, and postmenstrual hysterosalpingography (HSG). Women who were infertile because of male infertility factors were excluded, as were those with anovulatory infertility and patent tubes on HSG who had undergone a trial of ovulation induction prior to laparoscopy. After the basic work-up, a premenstrual endometrial aspirate was obtained for histopathologic examination (HPE), acid-fast bacilli (AFB) smear, mycobacterial culture (performed with the Bactec 460TB System; Becton, Dickinson and Company, Towson, MD, USA), and in-house DNA PCR. Peritoneal wash fluid was also sent for PCR analysis. A 240-bp region of the mpt64 gene was amplified by PCR. Appropriate positive and negative controls were included. The laboratory personnel were kept blinded to the patient details. Diagnostic laparoscopy and hysteroscopy were performed. The laparoscopic findings were arbitrarily classified into 5 groups: definitive tuberculosis (presence of tubercles, caseation, or beaded tubes); probable tuberculosis (presence of straw-colored fluid in the pouch of Douglas, extensive dense pelvic and/or peritubal/periovarian adhesions, hydrosalpinx, tubo-ovarian mass, thick fibrosed tubes, midtubal block, perihepatic adhesions, hyperemia of the tubes/blue uterus on chromotubation); possible tuberculosis (mild/flimsy adhesions, dilated tortuous tubes, cornual/fimbrial block, fimbrial agglutination/phimosis); incidental (fibroid, polycystic ovary syndrome, endometriosis with patent tubes and no suggestion of GTB); and normal findings. In the initial part of the study, endometrial aspiration was performed before menstruation, whereas laparoscopy was performed after menstruation, which is in line with the algorithm proposed by Schaefer [12] and Jindal [13]. However, many women were lost to follow-up during the period between endometrial aspiration and laparoscopy, so in the later part of the study endometrial aspiration and diagnostic laparoscopy/hysteroscopy were performed in 1 sitting (after menstruation) to minimize loss to follow-up. The diagnosis of GTB was made if the laparoscopy result was classified as definitive or probable, or if any of the laboratory tests (i.e. AFB smear, culture, histopathology, DNA PCR of endometrial aspirate or peritoneal wash fluid) was positive, even if the laparoscopy revealed no pathology. Women who met these criteria for GTB received ATT for 6 months. Hysteroscopy findings suggestive of GTB were noted, but ATT was not instituted on the sole basis of such a finding. Antitubercular therapy consisted of isoniazid, rifampicin, ethambutol, and pyrazinamide given for 2 months, followed by isoniazid and rifampicin for the subsequent 4 months. Modern ATT has a low risk of teratogenicity, so women were not advised to use contraception during treatment. Women were followed up for at least 6 months after ATT. STATA 9 (StataCorp, College Station, TX, USA) was used for statistical analysis of data. The rates of diagnosis by laboratory tests and laparoscopy were compared with the McNemar test. The χ2 test was used to compare conception rates; P b 0.05 was considered to be statistically significant. Assuming an incidence of GTB of 15% (based on our hospital data) among infertile women in India and adopting a margin of error of 5% (95% confidence interval), the required sample size was calculated to be 204. If a drop-out rate of 20% was taken into account, the required sample size was estimated to be 244. 3. Results In total, 244 women presented with infertility and 196 were recruited into the study after providing informed consent (Fig. 1). The mean age of the participants was 28.3 ± 4.2 years; the duration of infertility ranged from 12 months to 20 years. Overall, 83 (42.3%) women had symptoms other than infertility that were suggestive of tuberculosis (Table 1), the most prevalent symptom being scanty periods in 34 (17.3%) women. The erythrocyte

sedimentation rate was raised above 20 mm/hour in 61 (31.1%) women and the Mantoux test was positive in 51 (26.0%). Radiologic evidence of pulmonary tuberculosis was seen in 5 (2.6%) women, revealing fibrotic opacities in 2 (1.0%), calcified granuloma in 2 (1.0%) and patchy pneumonitis in 1 (0.5%) patient. Hysterosalpingography was performed in 169 (86.2%) women, with tuberculosis suspected in 124 (73.4%). Unilateral/bilateral tubal block was found in 99 (58.6%) women, with beading in 11 (6.5%), extravasation in 12 (7.1%), outpouchings in 1 (0.6%), calcification in 3 (1.8%), hydrosalpinx in 23 (13.6%; bilateral hydrosalpinx in 10 [5.9%]), dilated tubes in 20 (11.8%), irregular uterine cavity in 23 (13.6%), and small tubular uterine cavity in 6 (3.6%) women. In 1 (0.6%) woman, extreme extravasation occurred while attempting HSG and the procedure was abandoned. Incidental findings included an arcuate uterus in 4 (2.4%) women and a uterine septum in 2 (1.2%). Overall, 118/196 (60.2%) women were diagnosed with tuberculosis by at least 1 of the diagnostic modalities employed (Table 2). Laparoscopy was performed in 187 (95.4%) women. Nine (4.6%) women did not undergo laparoscopy because the GTB diagnosis was already established prior to laparoscopy (4 women had a positive HPE and 3 women had a positive AFB smear) or because the HSG showed extreme extravasation typical of GTB (n = 2). Tables 2 and 3 show the correlation between the laparoscopic findings and PCR results. According to the McNemar test, the diagnostic rates by laboratory tests and by laparoscopy were comparable (P = 0.71). In total, 118 women met the study criteria for GTB (Tables 2 and 3) and received ATT. Laparoscopy revealed pelvic adhesions and extensive damage to both tubes in 39 (19.9%) of these women, who were advised to undergo in vitro fertilization (IVF) and embryo transfer (ET) or to consider an adoption. The remaining women were encouraged to try spontaneous conception for 6 months, after which ovulation induction was given for the subsequent 6 months if required. Conception occurred in 27/118 (22.9%) women with GTB without the aid of IVF (Table 3). The length of time to conception varied, with 22 (81.5%) women conceiving within 6 months of starting ATT; 13 (48.1%) women conceived within 3 months. The median time from ATT initiation to conception was 4 months. Among the 27 women with GTB who conceived, the duration of infertility ranged from 1.5 to 15 years, with 11 (40.7%) women having been infertile for more than 5 years. Fifteen (55.6%) women had a normal menstrual cycle, 7 (25.9%) had menorrhagia, and 5 (18.5%) had scanty periods. The Mantoux test was positive in 4 (14.8%), 1 (3.7%) had a past history of TB, and the chest X-ray was normal in all. The DNA PCR of endometrial aspirate was positive in 20 (74.1%) women who conceived and that of peritoneal wash fluid was positive in 7 (25.9%). In 2 (7.4%) women, the endometrial aspirate samples tested positive both by AFB smear and by culture, but no woman who conceived had a positive HPE. The laparoscopy findings were positive in 16 (59.1%) women who conceived. Two (7.4%) women had extensive extravasation on HSG. On laparoscopy, 6 (22.2%) women who conceived had strawcolored fluid in the pouch of Douglas, 5 (18.5%) had a unilateral tubal block, 2 (7.4%) had a bilateral fimbrial block, 4 (14.8%) women had perihepatic adhesions, and 4 (14.8%) women had peritubal adhesions. None of the women who conceived had tubercles/caseation, beaded or tortuous tubes, or a hydrosalpinx greater than 5 cm. Of the women with GTB, 56/109 (51.3%) undergoing laparoscopy underwent a reconstructive procedure during laparoscopy, and 15 (26.8%) of these women conceived; among them, 6 (40.0%) women underwent fimbrioplasty alone, 4 (26.7%) underwent adhesiolysis, 3 (20.0%) underwent fimbrioplasty with adhesiolysis, 1 (6.7%) underwent hysteroscopic cannulation, and 1 (6.7%) underwent mere forceful dye instillation during chromotubation. There was no difference in the conception rate of women with primary versus secondary infertility (P = 0.119), women with scanty, normal, or heavy flow (P = 0.092), or women with or without GTB


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231

Presented with infertility (n=244)

Excluded (n=48) • Lost to follow-up while awaiting laparoscopy (n=7) a • No follow-up after basic investigations (n=11) • Male factor infertility (n=10) • Other confirmed cause of infertility with patent tubes on HSG; received ovulation induction before laparoscopy (n=14) - PCOS (n=10) - Endometriosis (n=2) - Hyperprolactinemia, pituitary microadenoma (n=2) • ATT was taken within 1 year of presenting to outpatient department (n=2) • Unfit for surgery because of uncontrolled diabetes mellitus; later unwilling to receive infertility treatment (n=1) • Did not give consent for diagnostic laparoscopy (n=3) b

Recruited after complete work-up (n= 196) No evidence of GTB (n=78) (39.8%)

Diagnosed with GTB and received ATT (n=118) (60.2%)

Conceived 27/118 (22.9%) Fig. 1. Flow diagram of the participants. Abbreviations: ATT, antitubercular therapy; GTB, genital tuberculosis; HSG, hysterosalpingography; PCOS, polycystic ovary syndrome. a Recruited in the initial part of the study, when endometrial aspiration was performed before menstruation; patients were then given a date for surgery, as was the routine at the study institution. b Includes 1 patient who was PCR-positive and did not consent to laparoscopy without ATT and who conceived more than 2 months after initiation of ATT.

(P = 0.128). The conception rate was significantly higher in women without a previous history of tuberculosis (P = 0.004). The conception rates in women with or without a reconstructive procedure during laparoscopy did not differ significantly (P = 0.32). Of the 118 women with GTB, 29 (24.5%) were diagnosed solely by DNA PCR of the endometrial aspirate, with other tests being negative for GTB. These women received ATT on the sole basis of the DNA PCR result, and 9 (31.0%) of them conceived. In 35 (29.6%) women with GTB, all laboratory tests were negative and the diagnosis was based on the laparoscopic findings only. Of these women, 3 (8.6%) conceived. The overall fertility outcome was a full-term live birth in 16 (13.6%) women and a preterm birth in 3 (2.5%). Seven (5.9%) women had an abortion and 1 (0.8%) woman had an ectopic pregnancy. 4. Discussion Although a wide variety of investigations and effective drug treatment are available, GTB during the reproductive years is still a worrisome entity. The crux to effective management is an early diagnosis before damage to the reproductive organs has occurred. The lack of a gold standard despite an armamentarium of tests is one of the impediments to the successful management of GTB. There is universal

agreement that multiple samples may increase the diagnostic yield [14]. In the present study, infertile women underwent a whole battery of tests for GTB. In most instances, GTB was detected either by DNA PCR of endometrial aspirate (41.3%) or by laparoscopy (46.5%). However, onequarter of women in whom the endometrial aspirate was culturepositive and three-quarters of women in whom the endometrial aspirate smear was AFB-positive had a negative DNA PCR result. Women with a positive AFB smear were culture-negative and HPE-negative and vice versa. However, 1 woman with GTB was diagnosed because the peritoneal wash fluid was culture-positive, with all other tests being negative. This inconsistency among the various laboratory tests signifies the need for multisampling for multiple tests. Furthermore, despite the low detection rates, HPE, Bactec culture, and AFB smear should not be omitted in the infertility work-up. The availability of DNA PCR has revolutionized the diagnosis of paucibacillary GTB because it enables the detection of less than 10 pg of DNA (approximately 3 genome equivalents) with a sensitivity of more than 90% and a specificity of 70–92% [15]; it is especially useful if the bacillary load is low [6]. Nevertheless, the role of PCR is controversial because of the high rate of false positives, and most studies advocate the commencement of ATT in women with a positive PCR result only if there is also evidence of GTB on clinical examination


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Table 1 Demographic profile and presenting symptoms other than infertility. Symptom

Table 3 Laparoscopic findings, PCR results, and rate of conception in women treated with ATT.a

Number of patients (%) (n = 196)

Age, y 20–29 30–39 Infertility Primary Secondary Socioeconomic status Low Middle High Past history of tuberculosis Contact history Symptoms Scanty periods Irregular cycles Oligomenorrhea Loss of appetite Vaginal discharge Menorrhagia Weight loss Lower abdominal pain Dyspareunia Dysmenorrhea Malaise Constipation

138 (70.4) 58 (29.6) 64 (32.7) 83 (42.3) 49 (25.0) 53 (27.0) 9 (4.6) 34 (17.3) 17 (8.7) 14 (7.1) 13 (6.6) 12 (6.1) 12 (6.1) 10 (5.1) 8 (4.1) 8 (4.1) 3 (1.5) 1 (0.5) 1 (0.5)

Table 2 Rate of diagnosis of GTB by diagnostic modality.a

Endometrial aspirate HPE c DNA PCR

Positive result

Concurrent diagnosis by DNA PCR (endometrial aspirate)

Concurrent diagnosis by laparoscopy b

7/196 (3.6) 81/196 (41.3)

3/7 (42.9) d Not applicable

4/196 (2.0) 4/196 (2.0)

3/4 (75.0) 1/4 (25.0)

3/7 (42.9) e 39/81 (48.1) (7 definitive) 4/4 (100%) 0/1 (0.0) e

f

Bactec culture AFB smear Peritoneal wash fluid DNA PCR Bactec g culture AFB smear Hysteroscopy

15/187 1/187 0/187 74/187

(8.0) (0.5) (0.0) (39.6)

11/15 (73.3) 0/1 (0.0) 0/0 (0.0) 57/74 (77.0)

5/15 (33.3) 0/1 (0.0) 0/1 (0.0) 43/74 (58.1) (9 definitive)

Laparoscopy Definitive GTB Probable GTB Definitive and probable GTB

17/187 (9.1) 70/187 (37.4) 87/187 (46.5)

7/17 (41.2) 32/70 (45.7) 39/87 (44.8)

Not applicable

f

Abbreviations: AFB, acid-fast bacilli; GTB, genital tuberculosis; HPE, histopathologic examination; PCR, polymerase chain reaction. a Values are given as number (percentage). b Definitive and probable TB. c Epithelioid granuloma with necrosis/caseation. d Bactec culture and AFB smear were negative. e Laparoscopy was not done in 4 women. f AFB/Bactec was negative. g Bactec 460TB System (Becton, Dickinson and Company, Towson, MD, USA).

PCR results

PCR positive

123 (62.8) 73 (37.2)

or if the hysteroscopic or laparoscopic findings are suggestive of GTB [16,17]. However, in the present study, even women diagnosed solely by PCR were given ATT, based on the assumption that other tests were negative because the disease was still in the early stages. In a previous study [18] in women with repeated IVF failure, PCR was positive in 77.7% of participants and up to 20% of women conceived with IVF after the initiation of ATT on the basis of the positive PCR result. This finding indicates that the detection of latent GTB requires the use of molecular tests such as PCR. However, the

Diagnostic modality

Laparoscopic Number finding of patients (n = 187)

Definitive GTB

17 (9.1)

Probable GTB b

70 (37.4)

Possible GTB

34 (18.2)

Incidental findings

21 (11.2)

Normal findings d

45 (24.1)

Laparoscopy not done e

9/196 (4.6)

8 (47.1) EA: 7 (41.2) PW: 1 (5.9) 32 (45.7) EA: 32 (45.7) PW: 3 (4.3) c 12 (35.3) EA: 9 (26.5) PW: 3 (8.8) 9 (42.9) EA: 9 (42.9) PW: 2 (9.5) c 21 (46.7) EA: 20 (44.4) PW: 6 (13.3) c 4 (44.4) EA: 4 (44.4)

PCR negative

Conception after ATT initiation (n = 118)

PCR status positive in women who conceived

9 (52.9) 1 (0.8)

0/1 (0.0)

38 (54.3) 9 (7.6)

6/9 (66.7)

22 (64.7) 4 (3.4)

4/4 (100.0)

12 (57.1) 4 (3.4)

4/4 (100.0)

24 (53.3) 8 (6.8)

7/8 (87.5)

5 (55.6) 1 (0.8)

0/1 (0.0)

Abbreviations: ATT, antitubercular treatment; EA, endometrial aspirate; GTB, genital tuberculosis; PCR, polymerase chain reaction; PW, peritoneal wash fluid. a Values are given as number (percentage). b Other test results: 4 patients had positive cultures (3 PCR-positive, 1 PCR-negative); 2 patients had a positive HPE (1 PCR-positive, 1 PCR-negative). c Concurrent endometrial PCR was also positive. d Other test results: 1 patient had a positive acid-fast bacilli smear (PCR was negative). e Other test results: 4 patients had a positive histopathologic examination (2 PCRpositive, 2 PCR-negative); 3 patients had a positive acid-fast bacilli smear (1 PCR-positive, 2 PCR-negative); 2 patients had a hysterosalpingography highly suggestive of GTB (1 PCRpositive, 1 PCR-negative).

authors advocate the use of PCR only in women with repeated IVF failure and not on a routine basis because of cost restraints. In the present study, 9 (31.0%) of the women who received ATT on the sole basis of a positive PCR result conceived, emphasizing the role of PCR even in the absence of other evidence of GTB. Because these women responded to ATT and conceived, it seems more likely that they had very early subclinical disease, without significant damage to the tubes and endometrium. Because the fertility outcome for women with GTB is good only when ATT is started early, it is imperative to diagnose tuberculosis early in women who present with infertility [17]. Therefore, we suggest DNA PCR testing of endometrial aspirates in all women with infertility who live in areas endemic for GTB, and we recommend the initiation of ATT in all women who test positive, even if no other evidence of GTB exists. The classification of laparoscopic findings indicative of tuberculosis varies in the literature; the findings have been classified as minimal/ advanced [12]; as definitive/probable/incidental/normal [14]; as early/ subacute/chronic [10], and as acute/chronic [17]. In the present study, the laparoscopic findings were arbitrarily grouped into 5 categories, adding “possible” GTB to the categories suggested by Bhanu et al. [14]. Fimbrial/cornual block, fimbrial agglutination or phimosis, mild/flimsy adhesions, and dilated tubes might also occur as a result of pelvic infection with Chlamydia or other organisms and were therefore kept in the “possible” category. Women with such findings do not warrant ATT if all other tests for tuberculosis are negative; hence, such women were grouped separately and were not given ATT if the other diagnostic tests were negative. One patient in this group had an ectopic pregnancy 3 months after laparoscopy, which was managed with methotrexate, and ATT was started at a later point in time. Bhanu et al. reported a 100% correlation between PCR findings and laparoscopic findings classified as “definitive” and a 60% correlation for laparoscopic findings classified as “probable” [14]. The present study showed positive PCR results in 47.1% of women with a definitive


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diagnosis of GTB on laparoscopy and in 45.7% of women with a probable diagnosis of GTB on laparoscopy. Normal findings occurred in 24.1% of infertile women undergoing laparoscopy, a percentage that is lower than the 43% reported in the literature [4]. This could be explained by the fact that the present study was conducted in a tertiary care center to which women were referred from all over the country. None of the previous studies of GTB compared the results from different diagnostic tests. Few studies have reported the role of messenger RNA (mRNA) PCR in the diagnostic evaluation of pulmonary tuberculosis. In a previous study, the value of mRNA PCR on endometrial aspirate/peritoneal wash specimen was evaluated—with the authors concluding that mRNA PCR was positive only if the culture was also positive [18]. Given that GTB is a paucibacillary condition, the utility of mRNA PCR in this context seems to be limited. The rate of conception in women with GTB is very poor, and when conception does occur, the pregnancy is more likely to be ectopic or result in a spontaneous abortion. In women with advanced GTB who have extensive tubal damage and extensive adhesions in the pelvis and uterus, the reason for the poor fertility prognosis is obvious. Also, such women are usually not amenable to reconstructive surgery and IVF and ET is the only therapeutic option [12]. In another subgroup of women with GTB, the fertility prognosis is poor even though they have patent tubes. These women may have endometrial and tubal ciliary damage, which prevents a normal conception and implantation. Yet another reason for poor fertility is a diminished ovarian reserve because of GTB [19]. There is even a role for latent GTB in infertility because dormant mycobacteria present in the basal endometrium may impair the endometrial and subendometrial blood flow [19]. Overall, the conception rate among women with GTB varies from 10% to 20% throughout the world, with the rate in the present study being 22.9%. Many studies have evaluated the role of ATT in IVF settings. In a series of 117 women with GTB, Parikh et al. [20] achieved a 16.6% pregnancy rate in 30 women who received ATT and underwent IVF and ET. Gurgan et al. [21] found a pregnancy rate of only 9.1% (4/44 IVF cycles) among 24 women treated for GTB, compared with a pregnancy rate of 21.3% (78/366 IVF cycles) in 274 women with tuboperitoneal infertility unrelated to GTB. Jindal [13] reported a conception rate of 17.3% with assisted reproductive techniques, compared with a rate of 4.3% with fertility-enhancing surgery alone. De Vynck et al. [22] reported a pregnancy rate of 38% among 34 women with GTB who received ATT, with 5/13 women conceiving after IVF. The rates of live birth, ectopic pregnancy, and abortion were 8.8%, 17.6%, and 11.8%, respectively, in this study [22]. Six intrauterine pregnancies (28.6% success rate) have been reported after 21 IVF treatment cycles in 13 women with histologically proven GTB [23]. A pregnancy rate of up to 20% after ATT has been reported in women with repeated IVF failure [19]. Frydman et al. [24] suggest that IVF is the only effective treatment for tuberculous infertility. In non-IVF settings, Tripathy and Tripathy [5] reported a pregnancy rate of 19.6% (with 7.2% live births, 5.1% ectopic pregnancies, and 7.2% abortions) in a prospective study of 97 women with GTB on receiving ATT, 73 of whom were diagnosed via laparoscopy. In this study, PCR was not included as a diagnostic test for GTB. The pregnancy rate was highest in the group of women with a menstrual blood culture negative for tuberculosis. In a series by Mondal and Dutta [25], 8 of 9 women who conceived after ATT had a spontaneous abortion. In the present study, a comparable proportion (22.9%) of GTB patients receiving ATT conceived, all without the aid of IVF; 13.6% had a full-term live birth, 2.5% had a preterm birth, 5.9% had an abortion, and 0.8% had an ectopic pregnancy. The median length of time to conception after initiation of ATT was 4 months, stressing the role of ATT in conception in women with GTB. None of the women with histopathologic evidence of GTB conceived, even though they received ATT, indicating that irreversible damage to the endometrium had occurred. The fact that the pregnancy rate in the

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present study was better than that in previously reported studies, even without assisted reproduction, could be explained by the detection of early disease. There may be concerns that reconstructive procedures result in a flare-up of disease [26]. However, none of women in the present study who underwent reconstructive surgery had a flare-up in the postoperative period. Antitubercular therapy was started 1 day after surgery in these women. Female GTB poses as a diagnostic dilemma. The present study emphasizes that in endemic areas, a single diagnostic test may not be sufficient to detect GTB. Hence, an infertile woman should undergo all available diagnostic investigations in 1 sitting, so as not to miss the diagnosis. Through inclusion of DNA PCR on endometrial aspirate in the routine work-up for infertility, more cases of early GTB can be detected, especially because other tests are usually negative at this stage because GTB is paucibacillary. In low-income countries where IVF is costly, ATT may be started even on the basis of positive DNA PCR result alone and can result in a good fertility outcome. Peritoneal-fluid DNA PCR helps in detecting cases missed by PCR on endometrial aspirate specimen. Larger randomized trials may be planned in the future to evaluate the effect of ATT in PCR-positive women with patent tubes on laparoscopy. Acknowledgments The Indian Council of Medical Research funded this project (grant number IRIS ID No. 2004–05330). Conflict of interest The authors have no conflicts of interest. References [1] Malkani PK, Rajni CK. Pelvic tuberculosis. Obstet Gynecol 1959;14:600–11. [2] Sutherland AM. The changing pattern of tuberculosis of the female genital tract: a thirty-year survey. Arch Gynecol 1983;234(2):95–101. [3] Singh N, Sumana G, Mittal S. Genital tuberculosis: a leading cause for infertility in women seeking assisted conception in North India. Arch Gynecol Obstet 2008;278(4):325–7. [4] Saracoglu OF, Mungan T, Tanzer F. Pelvic tuberculosis. Int J Gynecol Obstet 1992;37(2):115–20. [5] Tripathy SN, Tripathy SN. Infertility and pregnancy outcome in female genital tuberculosis. Int J Gynecol Obstet 2002;76(2):159–63. [6] Katoch VM. Newer diagnostic techniques for tuberculosis. Indian J Med Res 2004;120(4):418–28. [7] Bates JH. Diagnosis of tuberculosis. Chest 1979;76(6 Suppl):757–63. [8] Baum SE, Dooley DP, Wright J, Kost ER, Storey DF. Diagnosis of culture-negative female genital tract tuberculosis with peritoneal involvement by polymerase chain reaction. J Reprod Med 2001;46(10):929–32. [9] Eisenstein BI. The polymerase chain reaction. A new method of using molecular genetics for medical diagnosis. N Engl J Med 1990;322(3):178–83. [10] Merchant R. Endoscopy in the diagnosis of genital tuberculosis. J Reprod Med 1989;34(7):468–74. [11] Gupta N, Sharma JB, Mittal S, Singh N, Misra R, Kukreja M. Genital tuberculosis in Indian infertility patients. Int J Gynecol Obstet 2007;97(2):135–8. [12] Schaefer G. Female genital tuberculosis. Clin Obstet Gynecol 1976;19(1):223–39. [13] Jindal UN. An algorithmic approach to female genital tuberculosis causing infertility. Int J Tuberc Lung Dis 2006;10(9):1045–50. [14] Bhanu NV, Singh UB, Chakraborty M, Suresh N, Arora J, Rana T, et al. Improved diagnostic value of PCR in the diagnosis of female genital tuberculosis leading to infertility. J Med Microbiol 2005;54(Pt 10):927–31. [15] Roy H, Roy S, Roy S. Use of polymerase chain reaction for diagnosis of endometrial tuberculosis in high risk subfertile women in an endemic zone. J Obstet Gynecol India 2003;53:260–3. [16] Rozati R, Sreenivasagari R, Rajeshwari CN. Evaluation of women with infertility and genital tuberculosis. J Obstet Gynecol India 2006;56:423–6. [17] Sharma JB. Tuberculosis and obstetric and gynaecological practice. In: Studd J, Tan SL, Chervenak FA, editors. Progress in Obstetrics and Gynecology. 18th edition. Edinburgh, UK: Elsevier; 2008. p. 395–427. [18] Rana T, Singh UB, Kulshrestha V, Kaushik A, Purwal C, Agarwal N, et al. Utility of reverse transcriptase PCR and DNA-PCR in the diagnosis of female genital tuberculosis. J Med Microbiol 2011;60:486–91. [19] Dam P, Shirazee HH, Goswami SK, Ghosh S, Ganesh A, Chaudhury K, et al. Role of latent genital tuberculosis in repeated IVF failure in the Indian clinical setting. Gynecol Obstet Invest 2006;61(4):223–7.


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