Effect of antitubercular treatment on the pregnancy outcomes and prognoses of patients with genital tuberculosis

Abstract

This retrospective study aims to demonstrate the effect of antitubercular treatment (ATT) on the pregnancy outcomes and prognoses of patients with genital tuberculosis (GTB) who had received laparoscopy and/or hysteroscopy. This study included 78 patients with infertility and who were diagnosed with GTB through laparoscopy and/or hysteroscopy over the period of November 2005 to October 2015. The recruited patients were divided into ATT and nonATT groups on the basis of ATT duration. The GTB recurrence rates, menstrual patterns, and pregnancy outcomes of the patients were determined at follow-up. Among the 78 patients, 46 received ATT and 32 did not receive ATT. The menstrual volumes of patients in the ATT group significantly decreased relative to those of patients in the nonATT group. GTB did not recur among all patients regardless of treatment. A total of 11 pregnancies (36.7%) in the ATT group and 19 pregnancies (63.3%) in the nonATT group were observed. Pregnancy rates significantly differed (P = 0.002) between the two groups. ATT may decrease the menstrual volume and pregnancy rates of patients who were diagnosed with GTB through laparoscopy and/or hysteroscopy. In addition, ATT did not improve the prognosis of patients with chronic GTB.

Keywords

antitubercular treatment / pregnancy / prognosis / genital tuberculosis

Introduction

Genital tuberculosis (GTB) is highly prevalent in developing countries, such as China [¹]. As first shown by Malkani, GTB infection may affect the Fallopian tubes, endometrium, and ovaries [²]. It is usually present as a primary to secondary infection in other sites and spreads through a hematogenous route from the initial source of infection to the Fallopian tubes. After the initial involvement of the Fallopian tubes, the infection spreads to the ovaries through direct extension. Thus, GTB may cause tubal blockage; pelvic, abdominal, and perihepatic adhesions; and frozen pelvis. GTB should be considered as a cause of menstrual irregularities, menstrual reduction, and infertility [³].

The clinical diagnosis of GTB is complicated. Laparoscopy and/or hysteroscopy are the most effective tools for the diagnosis of GTB [⁴,⁵]. These methods enable the observation of the disturbed structures of the Fallopian tubes, endometrial cavity, and pelvic cavity. These disturbances may be the cause of unexplained infertility. Laparoscopy and/or hysteroscopy can enable the collection of biopsy specimens, particularly from coarse and yellow nodules [⁶]. Tissue paraffin sections, which are the bases of histopathology diagnosis, can be used to confirm the presence of caseous necrosis.

Antitubercular treatment (ATT) is required after the surgical diagnosis of GTB. ATT consists of an initial treatment phase with isoniazid, rifampicin, ethambutol, and pyrazinamide, followed by treatment with isoniazid and rifampicin [⁷]. Given that these drugs have potentially teratogenic effects, women with GTB are advised to use contraception at least six months after receiving ATT. However, previous studies on the fertility-related effects of ATT were conducted on female patients with nonactive GTB. Some studies have shown that ATT does not alleviate pelvic or perihepatic adhesions, shrunken uterine cavity, and bilateral blocked tubes, which may cause infertility [⁸,⁹]. The necessity for ATT is a key problem for subsequent treatment. No literature about the effect of ATT on the pregnancy outcomes and prognoses of patients with GTB is available.

Hence, the objective of the present study is to demonstrate the effect of ATT on the pregnancy outcomes and prognoses of patients with GTB who had received laparoscopy and/or hysteroscopy.

Methods and statistical analysis

This retrospective study was performed in the Reproductive Medical Center of Tongji Hospital, Huazhong University of Science and Technology, Hubei Province, over the period of November 2005 to October 2015. This study was performed with the approval and support of the Ethics Institutional Review Board of Tongji Hospital, Huazhong University of Science and Technology, Hubei Province. We recruited 78 patients with infertility and who were diagnosed with GTB through laparoscopy and/or hysteroscopy. GTB was diagnosed on the basis of a pathology and/or biopsy specimen collected from the endometrium or pelvic cavity of the participating patient. The relevant institutional ethics committee approved the research protocol. All participants provided informed consent. Patient characteristics, detailed symptom history, menstrual history, presurgical condition, laparoscopy and/or hysteroscopy findings, and pelvic adhesions were noted.

Some patients with GTB were treated with ATT using isoniazid after surgery. The patients then received rifampicin, ethambutol, and pyrazinamide for 2 months, followed by isoniazid and rifampicin for the next 4–10 months. ATT could last for 6–12 months. The patients were divided into two subgroups (ATT and nonATT group) in accordance with ATT duration. A total of 46 patients received ATT, and 32 patients did not receive ATT. All patients were followed up to determine GTB recurrence, menstrual pattern, and pregnancy outcome.

Statistical analysis was performed using SPSS version 19.0, and two-sided hypothesis tests were conducted. Categorical data were presented as number and percentages and compared through the χ²-test. Given that all continuous variables were normally distributed, they were presented as mean±standard deviation and compared through Student’s t-test. P value<0.05 was considered statistically significant.

GTB in our center

We recruited 78 patients who were diagnosed with GTB through laparoscopy or hysteroscopy. The patients were divided into two subgroups (ATT and nonATT groups) in accordance with ATT duration. A total of 46 patients received ATT, and 32 patients did not receive ATT. The mean age of the ATT group was 27.8±2.9 years and that of nonATT group was 28.4±4.4 years.

The characteristics of the patients in each group are presented in Table 1. The baseline variables of patients in the two groups were comparable. The age range (P = 0.515), type of infertility (P = 0.669), number of patients with tuberculosis (TB)-positive endometrial biopsy (P = 0.598), number of patients with hydrosalpinx (P = 0.696), number of patients who underwent bilateral or unilateral salpingectomy (P = 0.914), number of patients with pelvic adhesions (P = 0.682), and number of patients with TB-positive chest X-ray results (P = 0.074) were similar and were not significantly different between the two groups.

The menstrual volumes and menstrual periods of patients in the two groups before and after ATT were compared (Table 2). Before ATT, the menstrual volume and menstrual period of patients in the ATT group were not significantly different from those of patients in the nonATT group (P = 0.447; P = 0.114). However, after ATT, the menstrual volumes of patients in the ATT group significantly decreased relative to those of patients in the nonATT group (P = 0.007). However, the menstrual periods of the patients in the two groups were similar (P = 0.192).

The prognoses and pregnancy outcomes of patients in the ATT and nonATT groups were compared (Table 3). GTB did not recur in all patients (46 patients in the ATT group and 32 patients in the nonATT group) regardless of treatment. A total of 11 pregnancies (36.7%) were recorded. Surprisingly, in the nonATT group, 19 patients (63.3%) became pregnant after laparoscopy or hysteroscopy. The pregnancy rates of the two groups were significantly different (P = 0.002). Only one patient in the ATT group (3.3%) reported spontaneous pregnancy, whereas 29 patients (96.7%) from the two groups became pregnant through in vitro fertilization or embryo transfer.

Conclusions

GTB is an important disease that is highly prevalent in developing countries, such as China. It may cause menstrual irregularities and infertility. More than 90% of female patients with GTB suffer from Fallopian tube blockage, calcification, hydrosalpinx, and adhesions. Furthermore, GTB infection results in the development of adhesions in the endometrial cavity, such as those observed in Asherman’s syndrome [¹⁰,¹¹]. GTB also induces the formation of thick and plastic adhesions between the ovaries and other pelvic organs. The presence of these adhesions may cause ovulation failure and hypo-ovarianism. Severe cases of GTB may lead to frozen pelvis as a result of the formation of multiple adhesions in the pelvic and peritoneal cavities. Such cases also exhibit nodular thickening, which can be attributed to epithelial proliferation [¹²].

Even though ultrasonographic examination, chest X-ray, hysterosalpingograms, and DNA PCR assays have provided diagnostic clues for GTB, tissue sampling for histopathological examination remains the golden standard for the diagnosis of GTB [¹³,¹⁴]. This method could reveal the presence of caseous necrosis. However, tissue collection from the endometrium, Fallopian tubes, and pelvic cavity is difficult. Laparoscopy is the most reliable tool among all surgical methods for the diagnosis of GTB. It could show the morphological abnormalities of organs in the pelvic cavity. When performed with hysteroscopy, laparoscopy could directly show the status of the endometrial cavity.

Our study obtained reliable diagnostic results given that laparoscopy and/or hysteroscopy was performed to diagnose GTB. The data presented in Table 1 show that the most significant characteristic of GTB is pelvic adhesion (75/78, 96.2%), followed by primary infertility (73/78, 93.6%). PCR assay confirmed that the biopsied endometrial tissue were TB-positive (22/78, 28.2%). Laparoscopy and/or hysteroscopy detected the involvement of one or two involved Fallopian tubes (46/78, 59.0%) and hydrosalpinx (32/78, 41.0%). Some patients also exhibited positive chest X-ray films (28/78, 35.9%). The ATT and nonATT groups were not significantly different (P>0.05). This result showed that pelvic adhesion, which can be detected only through laparoscopy and/or hysteroscopy, may be the most important reason for GTB-associated infertility, especially primary infertility. Adhesion causes the formation of fibrotic lesions that may change the structure and function of organs in the pelvic cavity.

In our study, all patients with GTB did not exhibit obvious symptoms and were thus in the nonactive phase. We found that laparoscopy and/or hysteroscopy did not increase the risk of spreading Mycobacterium tuberculosis, especially in patients with chronic nonactive GTB.

The patients who were diagnosed with GTB through laparoscopy and/or hysteroscopy did not undergo ATT at our hospital. Instead, they were referred to special tuberculosis hospitals that can provide ATT for free. In China, different special tuberculosis hospitals are established in different provinces. Some hospitals believe that patients with nonactive GTB do not require ATT despite having positive biopsy results and that only patients in the active phase who exhibit symptoms, such as coughing, fever, and abdominal pain, should receive ATT. On the other hand, some patients who were diagnosed with GTB through laparoscopy and/or hysteroscopy at our hospital may not undergo ATT because they cannot afford treatment.

The initial clinical therapy for GTB is a multidrug approach that consists of isoniazid, rifampicin, streptomycin, pyrazinamide, and ethambutol. It is given for 6–12 months. ATT is necessary for patients with active GTB because it can relieve infection symptoms, such as coughing, fever, and abdominal pain and because it can block the spread of M. tuberculosis [¹⁵]. However, the necessity of ATT for patients with chronic nonactive GTB remains controversial. Based on literature reports, ATT has little effect on pelvic anatomy once sufficient agglutination or adhesion occurs. The poor tubal response to ATT can be attributed to the irreversible Fallopian tube damage caused by TB. ATT cannot alleviate advanced fibrotic lesions (pelvic adhesions and Fallopian tube blockage), which may be the most important reason for infertility in patients with GTB [⁷]. At the same time, a previous study showed that ATT improves menstrual cycles and endometrial thicknesses and reduces the incidence of grade 1 adhesions in patients with early-stage GTB. However, ATT does not improve the symptoms of patients with advanced GTB [⁸]. Furthermore, ATT does not improve the prognosis of patients with chronic nonactive GTB. The data shown in Table 3 indicated that GTB did not recur in patients regardless of treatment.

In this study, the patients who underwent laparoscopy and/or hysteroscopy were suffering from chronic and advanced GTB and exhibited the formation of thick adhesions. ATT may affect endometrial tissue, as indicated by the reduced menstrual volumes of patients who received ATT. The menstrual volumes of patients in the ATT and nonATT groups were not significantly different prior to treatment (P = 0.447). Treatment, however, significantly decreased the menstrual volumes of 22 patients (47.8%) in the ATT group and of 6 patients (18.8%) in the nonATT group. The result of the ATT group was significantly different from that of the nonATT group (P = 0.007). ATT did not affect the menstrual periods of patients in both groups. No significant difference was found in the two groups regardless of treatment (P = 0.114, P = 0.192).

On the other hand, the effect of ATT on pregnancy outcomes remains uncertain. A previous study suggested that extending ATT would improve the pregnancy outcomes of women with GTB [¹⁶]. By contrast, our study showed that ATT may decrease pregnancy rates among women with GTB. Conception occurred in only 11 out of 46 patients (36.7%) who had received ATT and in 19 out of 31 patients (63.3%) who did not receive ATT. The pregnancy rates of the two groups were significantly different (P = 0.002). ATT may negatively affect the pregnancy outcomes of patients with GTB for reasons connected to the effects of ATT on endometrial lesions. In the context of traditional Chinese medicine, the multidrug approach for ATT may cause a deficiency of qi and blood. This deficiency further damages endometrial tissue. The damaging effect of ATT on endometrial tissue may need further medical research.

In conclusion, our results indicated that ATT, which is widely applied for the clinical treatment of patients diagnosed with GTB through laparoscopy and/or hysteroscopy, may reduce menstrual volume and decrease pregnancy rates. In addition, ATT does not improve the prognosis of patients with chronic GTB.

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