|Year : 2020 | Volume
| Issue : 2 | Page : 123-127
Acute miliary tuberculosis and pelvic tuberculosis after In vitro fertilization
Li-Juan Fan1, Ting-Ting Ma2, Shan Liu1, Yun Qi2
1 Assisted Reproduction Center of Northwest Women's and Children's Hospital, Xi'an 710000, China
2 Department of Gynecology and Pediatric Tuberculosis, Xi'an Chest Hospital, Xi'an 710100, China
|Date of Submission||04-Nov-2019|
|Date of Decision||21-Feb-2020|
|Date of Acceptance||02-Apr-2020|
|Date of Web Publication||26-Jun-2020|
Department of Gynecology and Pediatric Tuberculosis, Xi'an Chest Hospital, No. 127, South Chang'an Road, Xi'an 710100
Source of Support: None, Conflict of Interest: None
Nearly one-fourth of the world's population is infected with Mycobacterium tuberculosis (MTB). Female genital tuberculosis (TB) is a common cause of infertility in both developing and undeveloped countries. Furthermore, assisted reproduction treatments and pregnancy potentially increase the risk of TB infection and reactivation. In this study, we present the case of a 28-year-old infertile female without a history of TB who developed an acute miliary TB and pelvic TB after in vitro fertilization–embryo transfer (IVF-ET). Elevated serum estrogen levels during controlled ovarian hyperstimulation and T-lymphocyte function inhibition during pregnancy are the risk factors for MTB infection and reactivation. In her 7th week of gestation, the patient developed fever and spontaneously aborted. Her chest computed tomography images revealed classical miliary TB. Uterine curettage tissue and vaginal secretion samples as well as Gene X-pert MTB/rifampicin (RIF) and TB-RNA test results were positive for MTB. Histological examination of the uterine curettage tissue confirmed the diagnosis of endometrial TB. Treatment with isoniazid, RIF, pyrazinamide, amikacin, and levofloxacin was selected based on the patient's diagnosis, complications, and test results. Currently, the patient is undergoing anti-TB treatment, and her condition is stable. It is important to rule out the presence of TB in infertile patients before performing IVF-ET to avoid TB dissemination during pregnancy.
Keywords: Acute Miliary Tuberculosis; In vitro Fertilization; Pelvic Tuberculosis; Pregnancy
|How to cite this article:|
Fan LJ, Ma TT, Liu S, Qi Y. Acute miliary tuberculosis and pelvic tuberculosis after In vitro fertilization. Reprod Dev Med 2020;4:123-7
| Introduction|| |
Nearly one-fourth of the world's population is infected with Mycobacterium tuberculosis (MTB), and the infection progresses to clinical disease in only 10% of the infected individuals. A strong relationship has been reported between female genital tuberculosis (FGTB) and infertility, with FGTB being a common cause of infertility in both developing and undeveloped countries. Genital organs, including the fallopian tubes, uterine endometrium, and ovaries, can be affected by MTB, resulting in infertility. Latent MTB may get reactivated during assisted reproduction treatment and pregnancy.
Pregnancy is a known risk factor for TB. Increased estrogen levels during pregnancy may inhibit T-lymphocyte function; therefore, there is a high chance for MTB infection or reactivation when the immune response is decreased. Meanwhile, estrogen promotes an increase in paracellular permeability and vasodilation. During controlled ovarian hyperstimulation (COH), serum estrogen levels rapidly rise. Therefore, COH has been suggested as a risk factor for MTB infection and reactivation.,
In 2008, Annamraju et al. reported one case of pelvic TB reactivation by anin vitro fertilization (IVF) egg collection procedure. Furthermore, in 2015, Liu et al. reported one case of miliary TB after IVF–embryo transfer (IVF-ET). The above two reports described the features of TB illnesses and treatments, without a comprehensive analysis of IVF and TB. We present the case of a patient with acute miliary TB, pelvic TB, and missed abortion following pregnancy after IVF-ET. We have comprehensively analyzed the entire IVF treatment protocol and anti-TB treatment in this case report.
| Case Report|| |
This case was reported after obtaining approval from the local ethics committee and consent from the patient. The patient was a 28-year-old female who got married in 2015. Hysterosalpingography performed in 2015 showed a normal shape of the patient's uterus and patency of both her fallopian tubes. Furthermore, in the same year, a left salpingectomy was performed for a left tubal pregnancy. After the surgery, the patient was unable to conceive. The test results of her husband's seminal fluid were normal. On the basis of her anamnesis, she was diagnosed with secondary infertility.
The results of the patient's all pre-IVF examinations were normal, including blood routine, coagulation, erythrocyte sedimentation rate, liver function, kidney function, hepatitis, syphilis serological, HIV serological, and serum sex hormone tests, including follicle-stimulating hormone, luteinizing hormone, estrogen, progestogen, testosterone, and prolactin; electrocardiographic examination; chest radiography; transvaginal ultrasonography (TVS); and hysteroscopy. The total number of bilateral ovarian antral follicles in the patient was nine. She was treated using the standard gonadotropin-releasing hormone agonist (GnRH-a) protocol. Pituitary downregulation was started during the luteal phase of her previous menstrual cycle with GnRH-a (triptorelin acetate, Ferring, Germany) at a dose of 0.1mg/day for 14days. The effect of pituitary downregulation was confirmed by TVS findings and serum sex hormone test results. Her serum sex hormone levels during the entire IVF process are shown in [Figure 1]. After pituitary downregulation, the ovaries were stimulated with an initial dose of 150 IU recombinant follicle-stimulating hormone (r-FSH, Gonal-F, Merck Serono) for 5days. On day 6 of ovarian stimulation (the patient's 12th day of menstruation), based on the TVS findings and serum sex hormone test results, the r-FSH dose was adapted according to the ovarian response, and 150 IU r-FSH was administrated for another day. Following that, 75 IU of urine-human menopausal gonadotropin (u-hMG, Urofollitropin for Injection, Livzon) and 75 IU of r-FSH were administrated for another 2 days. On day 9 of the ovarian stimulation (the 15th day of menstruation), the diameter of the leading follicle observed on ultrasound was 20mm. Another 75 IU of u-hMG was administrated that day to induce final oocyte maturation, and 10,000 IU of human chorionic gonadotropin (hCG, Chorionic Gonadotropin for Injection, Livzon) was administered that night. GnRH-a was administered until the day of hCG injection. The patient's serum estrogen and FSH levels reached peaks on the trigger day, with the levels being 1,725 pg/μL and 13.45 IU/μL, respectively. Oocyte retrieval was performed through transvaginal aspiration under ultrasound guidance 36 h following the hCG injection. Four oocytes were retrieved and three embryos developed on the 3rd day of IVF. All the three embryos developed into blastocysts on the 5th day of IVF. A good-quality blastocyst was selected for the fresh transfer. The patient's endometrial thickness was 7.8 mm before blastocyst transfer. The patient conceived after the fresh blastocyst transfer, but spontaneously aborted in the 8th week of her pregnancy. She did not send the villous tissue for chromosomal examination.
|Figure 1: Sexual hormone and endometrial thickness during in vitro fertilization–embryo transfer.|
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Two months after the spontaneous abortion, a natural cycle frozen blastocyst transfer was performed. TVS on menstruation day 5 showed that the diameter of the patients' leading follicle was 10 mm and her endometrium was 6 mm thick. To prevent the thinning of the endometrium, the patient was treated with 10 g of estradiol gel (Oestrogel, Besins) each day. On menstruation day 9, 2 mg of estradiol (Progynova, Bayer) was orally administered twice a day to increase the endometrial thickness.
On menstruation day 15, the diameter of the leading follicle reached 14 mm. u-hMG administration was initiated with 75 IU/day until the trigger day. On menstruation day 18, the diameter of the leading follicle reached 18.7 mm and the endometrial thickness reached 9.3 mm. hCG (10,000 U) was administered to trigger ovulation, and one blastocyst was transferred on the 5th day after ovulation.
Progesterone injections (60 mg) and 20 mg oral progesterone (Dydrogesterone, Abbott) were administered for luteal phase support beginning on the day of blastocyst transfer. Serum β-human chorionic gonadotropin was administered at 1,258 mIU/μL on day 12 after blastocyst transfer. TVS findings confirmed the presence of one gestational sac with fetal cardiac activity in the uterine cavity 26 days after blastocyst transfer. Thirty-three days after blastocyst transfer, a second TVS still showed one gestational sac with fetal cardiac activity in the uterine cavity.
The patient had fever in the 9th week of pregnancy. The highest temperature was 40°C, and she had no chills. She denied any complaints of cough, sputum, abdominal pain, diarrhea, urinary frequency, urgency of urination, urodynia, night sweats, or weight loss. Three days later, the patient experienced vaginal bleeding. TVS showed one gestational sac without fetal cardiac activity. A chest X-ray showed increased bronchovascular shadows [Figure 2]. The patient's enzyme-linked immunospot test result was positive. The computed tomography (CT) images [Figure 3] showed classic miliary TB. The patient's thoracic structure was symmetrical and normal. Both the lungs showed increased lung markings and diffuse, spot-like, light, and high-density shadows and miliary shadows. Streaky opacities were found in the upper lobe of the left lung. Meanwhile, spot calcification shadows were found in the upper lobe of the right lung. The mediastinum, bilateral hila, and pleural space were normal. No airway obstruction, pleural effusion, or enlarged lymph nodes were detected.
|Figure 2: Chest radiograph (posteroanterior view) showing classical miliary pattern. Brochovascular shadows are increased.|
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|Figure 3: Diffuse miliary nodular pattern was found in chest computed tomography images (Both lungs showed increased lung markings and diffuse, spot-like, lightly high-density shadow and miliary shadow. Streaky opacities were found in the upper lobe of the left lung. Meanwhile, spot calcification shadows were found in the right upper lobe lung).|
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As shown in [Figure 3], a diffuse miliary nodular pattern was observed on the patient's chest CT images. Laboratory tests results showed the following: hemoglobin, 91 g/L; albumin, 30 g/L; alanine aminotransferase, 70.4 U/L; aspartate aminotransferase, 69.8 U/L; serum sodium, 132.7 mmol/L; and potassium, 3.4 mmol/L. The patient was transferred to the Xi'an Chest Hospital for further treatment. She was diagnosed with acute miliary TB, missed abortion, mild anemia, and hypoproteinemia upon admission and underwent examinations for TB after her hospitalization. Her vaginal secretions showed positive results for both Gene X-pert MTB/rifampicin (RIF) and TB-RNA were both positive. No RpoB gene mutation was detected. Her cerebrospinal fluid chlorine level was 119 mmol/L, glucose level was 2.3 mmol/L, protein level was 0.19 g/L, and adenosine deaminase level was 2 U/L. The patient's craniocerebral magnetic resonance imaging findings were normal. Therefore, endometrial TB was added as a supplemental diagnosis. The patient was administered anti-TB treatment and uterine curettage. Treatment with isoniazid, RIF, amikacin, and levofloxacin (HRAmLfx) was selected on the basis of the patient's diagnosis, complications, and test results. Fetal villa tissues were sent for pathological examination. As shown in [Figure 4], granulomas were found in the endometrium. The MTB polymerase chain reaction and TB-RNA results of the uterine curettage tissue were positive. Nine days later, the patient's laboratory tests showed a normal liver function; pyrazinamide was added in her subsequent anti-TB treatment. Currently, the patient had finished her anti-TB treatment, and her condition is stable.
|Figure 4: The pathology of endometrial tissue (magnification 10 × 40) (uterine curettage showed granulomas in the endometrium, white arrow).|
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| Discussion|| |
The worldwide prevalence of FGTB is approximately 27% (range: 14%–41%)., However, the actual prevalence of FGTB cannot be estimated accurately, because in some cases, MTB infection may cause no significant clinical symptoms. The genital organs affected by MTB (in the descending order of frequency) are fallopian tubes (95%–100%), uterine endometrium (50%–60%), ovaries (20%–30%), cervix (5%–15%), uterine myometrium (2.5%), and vagina/vulva (1%).,
The rate of ectopic pregnancy is also high after FGTB. In advanced FGTB, adhesions may occur between the fallopian tubes and other pelvic organs with a loss of fimbrial structure. Consequently, the function of the fallopian tubes may get adversely affected after FGTB. In the present patient, the first chest radiograph obtained before COH showed normal findings, but the possibility of a TB infection and a pelvic TB infection could not be completely ruled out. The patient had a previous ectopic pregnancy naturally. Most genital MTB infections cause no significant clinical symptoms, so the possibility that the patient had FGTB at that time cannot be ruled out, and FGTB may have been the cause of her ectopic pregnancy.
Pregnancy suppresses the T-helper 1 proinflammatory response, which may mask symptoms while increasing susceptibility to new infections and reactivating TB., The enhancement of vascular permeability during pregnancy increases the accessibility of pathogens to the blood and increases their subsequent spread., Two studies from large London teaching hospitals reported TB incidence estimates in pregnant women to be three to five times higher than the respective local background rate (153–252/100,000 maternities).,, The reactivation of pelvic TB has been reported after IVF egg collection. In follicular phase, serum estrogen levels reach a peak, about 200–400 pg/μL, several hours before ovulation. The serum estrogen peaks in IVF patients are several times, and even dozens of times, higher than natural cycle serum estrogen peaks due to multiple follicle development. The COH protocol used in this patient is the standard GnRH-a protocol. Her estrogen reached a peak of 1,725 pg/μL during the COH period. We speculate that the patient's estrogen peak during the COH period may have been a factor in TB infection and dissemination.
The endometrium is affected in 60%–90% of genital TB cases, and uterine enlargement may be a possible result due to it being filled with caseous material. The uterine changes due to TB may have specific features, such as a collar-stud abscess, a T-shaped uterus, and a pseudounicornuate uterus. It may also have nonspecific features such as synechiae formation, uterine contour distortion, uterine cavity obliteration, and endometrium thickening. Chronic infection may lead to extensive destruction of the endometrium and myometrium, resulting in complete narrowing of the uterine cavity, called Netter syndrome. The endometrial and uterine damage caused by TB could decrease endometrial receptivity. We could not conclude that the patient's first embryo transfer failure was caused by endometrial TB. She had undergone TVS and hysteroscopy at our hospital before her COH, and both TVS and hysteroscopy findings were normal. Furthermore, because the shape of the patient's uterine cavity was normal, we did not perform endometrium curettage during hysteroscopy.
Progesterone have an effect on the immune system, which can inhibit proinflammatory cytokine expression in immune cells expressing the respective receptor., Luteal support treatment was started after embryo transfer among IVF-ET patients. The dose of progesterone added to IVF-ET patients was much higher than that of general threatened abortion patients. The added progesterone may increase the risk of TB infection or reactivation.
The fetus can be infected with TB in utero via the umbilical cord. Various reports have described different perinatal outcomes with increased abortion rates, high fetal distress levels in utero, and fetal growth restriction., Our patient's vaginal secretions showed positive results in both the Gene X-pert MTB/RIF and TB-RNA tests. In addition, the pathological examination confirmed the presence of granulomas in the endometrium. TB DNA and RNA were also detected in the aborted tissue. We speculate that the invasion of trophocytes accelerated TB dissemination and finally resulted in fetal abortion and maternal acute miliary TB.
There are some limitations in this study that are worth discussing. IVF-ET and pregnant may increase the incidence rate and reactivation rate of TB, but the incidence remains unclear. Pregnant TB mainly found in developing countries and underdeveloped countries, there is no universal data about the incidence of TB after IVF-ET.
| Conclusion|| |
The incidence of TB is high in both developing and underdeveloped countries. It is important to rule out the presence of TB in infertile patients before performing IVF-ET to avoid TB dissemination during pregnancy.
Declaration of patient consent
The authors certify that they have obtained all appropriate consent forms from the patient. The patient consented to the use of her images and other clinical information in this report and subsequent publication. The patient understood that neither her name nor initials would be published and every effort would be made to conceal her identity; however, her anonymity could not be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Houben RM, Dodd PJ. The global burden of latent tuberculosis infection: A re-estimation using mathematical modelling. PLoS Med 2016;13:e1002152. doi: 10.1371/journal.pmed.1002152.
Annamraju H, Ganapathy R, Webb B. Pelvic tuberculosis reactivated byin vitro
fertilization egg collection? Fertil Steril 2008;90:2003.e1-3. doi: 10.1016/j.fertnstert.2008.02.147.
Bonds RS, Midoro-Horiuti T. Estrogen effects in allergy and asthma. Curr Opin Allergy Clin Immunol 2013;13:92-9. doi: 10.1097/ACI.0b013e32835a6dd6.
Hongbo L, Li Z. Miliary tuberculosis afterin vitro
fertilization and embryo transplantation. Afr Health Sci 2015;15:701-4. doi: 10.4314/ahs.v15i2.50.
Djuwantono T, Permadi W, Septiani L, Faried A, Halim D, Parwati I. Female genital tuberculosis and infertility: Serial cases report in Bandung, Indonesia and literature review. BMC Res Notes 2017;10:683. doi: 10.1186/s13104-017-3057-z.
Golden MP, Vikram HR. Extrapulmonary tuberculosis: An overview. Am Fam Physician 2005;72:1761-8. doi: 10.1016/j.pop.2005.09.005.
Grace GA, Devaleenal DB, Natrajan M. Genital tuberculosis in females. Indian J Med Res 2017;145:425-36. doi: 10.4103/ijmr.IJMR_1550_15.
] [Full text]
Das P, Ahuja A, Gupta SD. Incidence, etiopathogenesis and pathological aspects of genitourinary tuberculosis in India: A journey revisited. Indian J Urol 2008;24:356-61. doi: 10.4103/0970-1591.42618.
] [Full text]
Zenner D, Kruijshaar ME, Andrews N, Abubakar I. Risk of tuberculosis in pregnancy: A national, primary care-based cohort and self-controlled case series study. Am J Respir Crit Care Med 2012;185:779-84. doi: 10.1164/rccm.201106-1083OC.
Villa A, Vegeto E, Poletti A, Maggi A. Estrogens, neuroinflammation, and neurodegeneration. Endocr Rev 2016;37:372-402. doi: 10.1210/er. 2016-1007.
Nowicki S, Selvarangan R, Anderson G. Experimental transmission of Neisseria gonorrhoeae
from pregnant rat to fetus. Infect Immun 1999;67:4974-6. doi: 10.1111/j.1574-695X.1999.tb01365.x.
Ren Y, Wang H, Qin H, Yang J, Wang Y, Jiang S, et al
. Vascular endothelial growth factor expression in peripheral blood of patients with pregnancy induced hypertension syndrome and its clinical significance. Pak J Med Sci 2014;30:634-7. doi: 10.12669/pjms.303.4558.
Kothari A, Mahadevan N, Girling J. Tuberculosis and pregnancy-results of a study in a high prevalence area in London. Eur J Obstet Gynecol Reprod Biol 2006;126:48-55. doi: 10.1016/j.ejogrb.2005.07.025.
Llewelyn M, Cropley I, Wilkinson RJ, Yang J. Tuberculosis diagnosed during pregnancy: A prospective study from London. Thorax 2000;55:129-32. doi: 10.1136/thorax.55.2.129.
World Health Organization. Manual of Diagnostic Ultrasound. Geneva: World Health Organization; 2013.
Ahmadi F, Zafarani F, Shahrzad GS. Hysterosalpingographic Appearances of Female Genital Tract Tuberculosis: Part II: Uterus. Int J Fertil Steril 2014;8:13-20.
Malhamé I, Cormier M, Sugarman J, Schwartzman K. Latent tuberculosis in pregnancy: A systematic review. PLoS One 2016;11:e0154825. doi: 10.1371/journal.pone.0154825.
Erbay G, Senol G, Anar C, Riza Meral A, Tuzel O. Relationship between tuberculosis and female hormone levels in post-menopausal women. Southeast Asian J Trop Med Public Health 2016;47:78-83.
Bishara H, Vinitsky O, Salim R, Keness Y, Chazan B, Miron D. Tuberculosis in pregnancy and puerperium. Harefuah 2013;152:381-4, 435.
Mathad JS, Gupta A. Tuberculosis in pregnant and postpartum women: Epidemiology, management, and research gaps. Clin Infect Dis 2012;55:1532-49. doi: 10.1093/cid/cis732.
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