{"paper_id":"6c7bbfed-0b35-4646-ada0-af059f816ed4","body_text":"Endometriosis is a common gynecological pathology\nthat can cause pelvic pain ( 1 ) and reproductive failure ( 2 )\nand can be asymptomatic in some cases ( 3 ). Infertility is\na significant concern in endometriosis, with a reported\nprevalence of over 50% in women with infertility ( 4 - 6 ),\nand 30-50% of patients with endometriosis experiencing\ninfertility ( 6 ,  7 ). The mechanism of infertility is not clear\n( 6 ,  8 ); however, the increased intra-peritoneal inflammation, anatomical disturbances due to adhesions ( 9 ), the\nreduction in oocyte and embryo quality, and disruption of\nthe uterine-tubal transport pathway have been implicated\nin endometriosis-associated infertility ( 10 ,  11 ). Endometriotic lesions in all three forms of endometriosis, i.e.,\nsuperficial endometriosis, deep infiltrating endometriosis\n(DIE) lesions located greater than 5 mm below the peritoneal surface, and endometriomas of the ovary ( 12 ), can\nlead to infertility ( 13 ). Women with infertility are more\nlikely to have moderate to severe endometriosis ( 14 ), and\nthe severity of anatomical involvement can affect fertility\n( 6 ,  15 ).\nThe most common locations of DIE are in the rectovaginal wall, uterosacral ligaments (USLs), pararectal fossae, rectum, and uterovesical fold. Medical treatment of endometriomas can reduce the size of lesions\nand alleviate pain; however, it does not affect fertility.\nLaparoscopic surgery is the standard treatment for endometriosis ( 16 ). Nevertheless, there is insufficient information regarding the effect of DIE nodule surgery\non subsequent pregnancy rates, and the guidelines for\nsurgery in individuals with infertility and DIE nodules\nare inconsistent ( 15 ,  17 ) and the risk of severe surgery\ncomplications should be considered ( 15 ). In this regard,\nthe European Society of Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) suggest that laparoscopic\nsurgery for stage 1 and 2 endometriosis can increase\npregnancy rates. However, due to the lack of evidence,\nthere is no definitive recommendation for surgery in\nstage 3 and 4 endometriosis ( 15 ,  17 ). Besides, there is no\nsufficient study on the outcome of laparoscopic surgery\nfor advanced endometriosis on the pregnancy success of\naffected, infertile patients in the Iranian population. This\nstudy aims to study the effect of laparoscopic surgery for\nadvanced endometriosis on spontaneous pregnancy rates\nand ARTs in patients with endometriosis.\n\nThis retrospective study was conducted at Arash Women’s\nHospital. This study was approved by the Ethics Committee of Tehran University of Medical Sciences (IR.TUMS.\nMEDICINE.REC.1402.069). All participants signed written informed consent before the surgery. The medical records of women with complaints of infertility and diagnosis of endometriosis who had been referred to the Laparoscopy Clinic of Arash Women’s Hospital for endometriosis\nlaparoscopy between March 2017 and March 2021 were\nevaluated. Women with ages less than 42 years, infertility\ncomplaints, endometriosis diagnosis based on histological\nfindings, endometrioma or DIE diagnosis based on transvaginal sonographic and clinical findings, and normal semen analysis reports according to World Health Organization criteria were included in the study. Patients who do\nnot desire to conceive, patients with a previous history of\nendometriosis, patients with other causes of infertility, e.g.,\nabnormal male factor, uterine, cervical, and vaginal anomalies, or patients with a history of previous surgery for endometriosis, or patients with masses other than endometriosis\nin the pathology report were excluded from this study.\nIn the laparoscopic surgery department of the hospital, all patients with infertility who are referred to this\ncenter are routinely referred to the infertility clinic. In\nthis unit, they first consult with infertility specialists,\nand both couples are evaluated for the causes of infertility. The male factor is studied using semen analysis\nreports and hormonal tests (thyroid, prolactin, and androgen tests in case of symptoms of increased androgen). Along with hormonal disorders, the anomalies of\nthe uterus, cervix, and vagina are examined.\nAfter ruling out other causes of infertility, patients with severe endometriosis and\ninfertility at a young age, severe pelvic pain, large endometriomas, obstructive symptoms,\nand narrowness of the intestinal area, endometriomas suspected in sonography,\nhydrosalpinx, or  in vitro  fertilization (IVF) failure will be candidates\nfor laparoscopic surgery. The patients are introduced to the infertility clinics and\nundergo ovarian puncture and their embryos will be frozen. Besides studying the serum\nlevels of CA-125 and anti-müllerian hormone (AMH), patients undergo transvaginal and\ntransabdominal color Doppler sonography, and if necessary, transrectal sonography, which\nis performed by two radiologists specialized in endometriosis. During sonography, the size\nof the uterus, the presence of adenomyosis, the presence or absence of endometrioma in one\nor both ovaries, the size of the ovaries, deep nodules of endometriosis, and the size and\nlocation of the USL, rectovaginal, urinary system (bladder or ureter), and ovarian fossa\nnodules are studied.\nSurgery is performed under general anesthesia in\nthe lithotomy position. After creating the pneumoperitoneum, any existing adhesions are freed, and salpingectomy is performed in the case of hydrosalpinx.\nThen, visible ovarian cysts are placed under excisional\ncystectomy. After hemostasis is established with forceps bipolar, the ovarian bed is sutured with 2-0 Vicryl,\nif there is a need to explore more of the cold-sack to\nbreak the ureters and remove the nodule of the USL or\nthe rectum, the ovaries are suspended on the abdominal\nwall. All deep nodules of the USL, pelvis, and torus\nuterinus are removed. If there is a bowel nodule, it is\nremoved by the shaving method, discoid, or anastomotic resection. Then, washing is done and the dren is\nfixed inside the abdomen and the duration of the surgery is recorded.\nPatients undergoing laparoscopic endometriosis surgery are classified according to the size, number, and\nlocation of DIE lesions, the size of one or both endometriomas, and the involvement of the fallopian tubes\nbased on the revised American Society for Reproductive Medicine (rASRM). After the surgery, the patients\nwere immediately encouraged to conceive on their\nown, or the patients with bilateral salpingectomy were\nreferred to infertility clinics to benefit from ARTs.\nThe checklist includes demographic information,\npatient age, body mass index (BMI), primary or secondary infertility, duration of infertility, endometriosis\nsymptoms (dysmenorrhea, dyschezia, dyspareunia),\nand previous surgery history. Cyst size, number, size, and type of nodules were recorded based on the pathology reports. At least 6 months after surgery and up to 3\nyears, the patients are contacted by phone to evaluate\nthe success rate of pregnancy in patients and by which\napproach they were convinced, i.e., naturally, ovulation induction, or using ARTs. Spontaneous pregnancy\nis investigated in patients who did not undergo bilateral salpingectomy. Pregnancy is defined as a positive\nserum beta-hCG test and confirmation of pregnancy\ninside the uterus by abdominal sonography. Then, the\nimpact of age, CA-125 level, adenomyosis, primary\nor secondary infertility, duration of infertility, stage\nof endometriosis, duration of surgery, size of endometriomas, unilateral or bilateral salpingectomy, and the\nnumber, size, and location of DIE nodules on the pregnancy success rate are investigated.\nThe statistical analyses were conducted using the\nGraphPad Prism V 8.3.4 (GraphPad Software, San Diego,\nCA, USA). For comparing the mean of the continuous\nvariables between the two groups, the Shapiro-Wilk test\nwas performed to study the normality of data. Based on\nthe normality of data, the t test or Mann-Whitney were\nperformed to study the statistical difference between the\ntwo groups. For the nominal variables, the Fisher exact\ntest to utilized to investigate the statistical difference between groups. P<0.05 was considered as the level of statistical significance.\n\nIn this study, information from 114 infertile women\nwho underwent surgery and had a desire for fertility\nwas evaluated. These women were followed up for 36\nmonths after laparoscopy. 40 participants were excluded\nfrom the study (11 did not attempt to conceive, 17 had\na history of previous endometriosis surgery, 6 had underlying diseases, 5 were divorced, and 1 used a rented\nuterus candidate). Finally, 74 women who desired pregnancy after laparoscopic surgery were included in the\nfinal analysis.\nTable 1 demonstrates the demographic, clinical, and\nsurgical information of the included patients. It has\nbeen shown that patients who became pregnant are significantly younger than the patients who did not become pregnant (P=0.016). However, there are no statistically significant differences between these two groups\nin terms of BMI, CA-125 level, AMH level, infertility\nduration, duration of surgery, primary infertility rate,\nfailed IVF rate, presence of endometriosis symptoms,\nstage of disease, chronic pelvic pain, history of surgery except endometriosis, adenomyosis, number of\nfrozen embryos, type of cystectomy, the maximum size\nof the cyst, type of salpingectomy, type of DIE nodule, number of nodules, rectal nodules, size of rectum\nnodule, type of USL involvement, the maximum size\nof USL nodule, and presence of torus uterinus nodule\n(all P>0.05).\nDemographic, clinical, and surgical information on the pregnant\nand non-pregnant participants\nData are presented as mean ± SD or n (%). Previous surgeries are cesarean section, appendectomy,\ncholecystectomy, cystectomy, cyst aspiration, and surgery for ectopic pregnancy. BMI;\nBody mass index, AMH; Anti-müllerian hormone, IVF;  In vitro \nfertilization , DIE; Deep infiltrating endometriosis , and USL; Uterosacral\nligament.\nIn a follow-up of 3 years, 37 patients (50%) became\npregnant. Out of the 37 pregnancies, 16 (43.24%) were\nconceived spontaneously, while 21 (56.76%) were benefited from ART. Patients who conceive spontaneously\nare significantly younger and have a lower duration of infertility compared with patients who used ARTs (P=0.046\nand P=0.005, respectively). Also, patients who conceive\nspontaneously are less likely to have adenomyosis compared to patients who benefited from ARTs (P=0.017).\nHowever, there are no statistically significant differences\nbetween these two groups regarding the BMI, salpingectomy, chronic pelvic pain, interval between surgery to\npregnancy, and number of frozen embryos (P>0.05). Although there is a trend in which stage 4 endometriosis patients become pregnant with the help of ARTs, this trend\nis not statistically significant (P=0.087,  Table 2 ).\nDemographic, clinical, and surgical information in participants\nbased on type of pregnancy\nData are presented as mean ± SD or n (%). BMI; Body mass index and ART; Assisted\nreproductive techniques.\n\nThe current study aimed to determine the impact of\nlaparoscopic surgery for DIE on the success rate of\npregnancy in infertile patients with endometriosis. In\nour study, the pregnancy rate after laparoscopic surgery was 50%. This study supports the use of surgical\ntherapy to increase the fertility rate in women with endometriosis.\nThe majority of studies indicate that the pregnancy rate following DIE ranges from 34 to 84.5% (95%\nCI=65.1%-71.9%) ( 18 - 20 ). The development of infertility associated with DIE is due to various factors, including an increase in inflammatory mediators, changes\nin the follicle content before ovulation, and alterations\nin the intraperitoneum that can affect fertilization and\nimplantation ( 21 ,  22 ). The combination of surgery followed by ARTs has been reported as a more effective\napproach to treating infertility in these cases. A recent\nsystematic review study has shown that women who underwent initial surgery followed by ART have considerably higher cumulative live birth rates compared to\nthose who received first-line ART only ( 23 ). Also, our\nresults have indicated that patients with a younger age\nhave a higher chance of conceiving. Our results are in\nline with the study conducted by Sun et al. ( 24 ). Gunardi\net al. ( 25 ) have demonstrated that individuals aged 35 or\nyounger are more likely to conceive after laparoscopic\ncystectomy in infertile women compared to those over\nthe age of 35. In line with this, Adamson et al. ( 26 ) categorized age into three groups, i.e., under 35, 36-39, and\nover 40, with higher success rates observed in younger\nage groups. In our study, the number and size of endometriotic nodules do not have a significant correlation\nwith pregnancy. This finding is consistent with the findings of Centini et al. ( 27 ).\nSmall implants of peritoneal endometriosis can trigger\ninflammation and the infiltration of activated macrophages. These macrophages express high levels of cyclooxygenase and secrete increased levels of prostaglandin\n(PG) F2 alpha and PGE2, which play pivotal roles in the\ndisease’s pathophysiology and clinical manifestations,\nsuch as pain and infertility. The inflammatory response\nand generation of reactive oxygen species increase the\nexpression of inflammatory factors, such as interleukin 6,\ninterleukin 8, and nuclear factor kappa B, which can lead\nto poor oocyte quality and infertility ( 28 ). Nevertheless,\nin our study, pregnant women did not significantly differ\nfrom non-pregnant individuals in terms of multiple-location DIE, BMI, cancer antigen 125 (CA-125), AMH, history of IVF failure, history of surgery, adenomyosis status, endometriosis symptoms, or type of infertility. These\nresults are in line with previous studies ( 29 - 31 ). Zhang\net al. ( 30 ) have reported that the pregnancy rate is higher\nin patients undergoing DIE surgery with multiple nodules\nwho became pregnant compared to those who did not become pregnant. In our study, adenomyosis is higher in individuals who achieved pregnancy with IVF compared to\nthose who conceived spontaneously. It has been reported\nthat adenomyosis is present alongside DIE in 48.7% of\ncases ( 32 ,  33 ).\nOur study was conducted in a retrospective manner,\nwhich is a limitation of our study. Additionally, the small\nsample size is another limitation. Collectively the results\nof this study provide valuable insight into the beneficial\nroles of laparoscopic surgery for advanced endometriosis\non spontaneous pregnancy rates and ARTs in Iranian patients with endometriosis.\n\nOur study has found that endometriosis surgery is associated with a high fertility rate. It is also important to note\nthat patient age plays a significant role in the pregnancy\nrate of this population. Besides, adenomyosis is higher in\nindividuals who achieved pregnancy with IVF. While this\nstudy can be used to advise patients on the impact of surgery, randomized clinical trials are needed to validate the\nobtained results.","source_license":"CC0","license_restricted":false}