Investigating The Rate of Pregnancy Success after Endometriosis Surgery in Infertile Patients with Advanced Endometriosis: A Retrospective Study

Endometriosis is a common gynecological pathology that can cause pelvic pain ( 1 ) and reproductive failure ( 2 ) and can be asymptomatic in some cases ( 3 ). Infertility is a significant concern in endometriosis, with a reported prevalence of over 50% in women with infertility ( 4 - 6 ), and 30-50% of patients with endometriosis experiencing infertility ( 6 , 7 ). The mechanism of infertility is not clear ( 6 , 8 ); however, the increased intra-peritoneal inflammation, anatomical disturbances due to adhesions ( 9 ), the reduction in oocyte and embryo quality, and disruption of the uterine-tubal transport pathway have been implicated in endometriosis-associated infertility ( 10 , 11 ). Endometriotic lesions in all three forms of endometriosis, i.e., superficial endometriosis, deep infiltrating endometriosis (DIE) lesions located greater than 5 mm below the peritoneal surface, and endometriomas of the ovary ( 12 ), can lead to infertility ( 13 ). Women with infertility are more likely to have moderate to severe endometriosis ( 14 ), and the severity of anatomical involvement can affect fertility ( 6 , 15 ). The 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 and alleviate pain; however, it does not affect fertility. Laparoscopic surgery is the standard treatment for endometriosis ( 16 ). Nevertheless, there is insufficient information regarding the effect of DIE nodule surgery on subsequent pregnancy rates, and the guidelines for surgery in individuals with infertility and DIE nodules are inconsistent ( 15 , 17 ) and the risk of severe surgery complications should be considered ( 15 ). In this regard, the European Society of Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) suggest that laparoscopic surgery for stage 1 and 2 endometriosis can increase pregnancy rates. However, due to the lack of evidence, there is no definitive recommendation for surgery in stage 3 and 4 endometriosis ( 15 , 17 ). Besides, there is no sufficient study on the outcome of laparoscopic surgery for advanced endometriosis on the pregnancy success of affected, infertile patients in the Iranian population. This study aims to study the effect of laparoscopic surgery for advanced endometriosis on spontaneous pregnancy rates and ARTs in patients with endometriosis.

In this study, information from 114 infertile women who underwent surgery and had a desire for fertility was evaluated. These women were followed up for 36 months after laparoscopy. 40 participants were excluded from the study (11 did not attempt to conceive, 17 had a history of previous endometriosis surgery, 6 had underlying diseases, 5 were divorced, and 1 used a rented uterus candidate). Finally, 74 women who desired pregnancy after laparoscopic surgery were included in the final analysis. Table 1 demonstrates the demographic, clinical, and surgical information of the included patients. It has been 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 in terms of BMI, CA-125 level, AMH level, infertility duration, duration of surgery, primary infertility rate, failed IVF rate, presence of endometriosis symptoms, stage of disease, chronic pelvic pain, history of surgery except endometriosis, adenomyosis, number of frozen embryos, type of cystectomy, the maximum size of the cyst, type of salpingectomy, type of DIE nodule, number of nodules, rectal nodules, size of rectum nodule, type of USL involvement, the maximum size of USL nodule, and presence of torus uterinus nodule (all P>0.05). Demographic, clinical, and surgical information on the pregnant and non-pregnant participants Data are presented as mean ± SD or n (%). Previous surgeries are cesarean section, appendectomy, cholecystectomy, cystectomy, cyst aspiration, and surgery for ectopic pregnancy. BMI; Body mass index, AMH; Anti-müllerian hormone, IVF; In vitro fertilization , DIE; Deep infiltrating endometriosis , and USL; Uterosacral ligament. In a follow-up of 3 years, 37 patients (50%) became pregnant. Out of the 37 pregnancies, 16 (43.24%) were conceived spontaneously, while 21 (56.76%) were benefited from ART. Patients who conceive spontaneously are significantly younger and have a lower duration of infertility compared with patients who used ARTs (P=0.046 and P=0.005, respectively). Also, patients who conceive spontaneously are less likely to have adenomyosis compared to patients who benefited from ARTs (P=0.017). However, there are no statistically significant differences between these two groups regarding the BMI, salpingectomy, chronic pelvic pain, interval between surgery to pregnancy, 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 is not statistically significant (P=0.087, Table 2 ). Demographic, clinical, and surgical information in participants based on type of pregnancy Data are presented as mean ± SD or n (%). BMI; Body mass index and ART; Assisted reproductive techniques.

The current study aimed to determine the impact of laparoscopic surgery for DIE on the success rate of pregnancy in infertile patients with endometriosis. In our study, the pregnancy rate after laparoscopic surgery was 50%. This study supports the use of surgical therapy to increase the fertility rate in women with endometriosis. The majority of studies indicate that the pregnancy rate following DIE ranges from 34 to 84.5% (95% CI=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 in the follicle content before ovulation, and alterations in the intraperitoneum that can affect fertilization and implantation ( 21 , 22 ). The combination of surgery followed by ARTs has been reported as a more effective approach to treating infertility in these cases. A recent systematic review study has shown that women who underwent initial surgery followed by ART have considerably higher cumulative live birth rates compared to those who received first-line ART only ( 23 ). Also, our results have indicated that patients with a younger age have a higher chance of conceiving. Our results are in line with the study conducted by Sun et al. ( 24 ). Gunardi et al. ( 25 ) have demonstrated that individuals aged 35 or younger are more likely to conceive after laparoscopic cystectomy in infertile women compared to those over the age of 35. In line with this, Adamson et al. ( 26 ) categorized age into three groups, i.e., under 35, 36-39, and over 40, with higher success rates observed in younger age groups. In our study, the number and size of endometriotic nodules do not have a significant correlation with pregnancy. This finding is consistent with the findings of Centini et al. ( 27 ). Small implants of peritoneal endometriosis can trigger inflammation and the infiltration of activated macrophages. These macrophages express high levels of cyclooxygenase and secrete increased levels of prostaglandin (PG) F2 alpha and PGE2, which play pivotal roles in the disease’s pathophysiology and clinical manifestations, such as pain and infertility. The inflammatory response and generation of reactive oxygen species increase the expression of inflammatory factors, such as interleukin 6, interleukin 8, and nuclear factor kappa B, which can lead to poor oocyte quality and infertility ( 28 ). Nevertheless, in our study, pregnant women did not significantly differ from 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 results are in line with previous studies ( 29 - 31 ). Zhang et al. ( 30 ) have reported that the pregnancy rate is higher in patients undergoing DIE surgery with multiple nodules who 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 those who conceived spontaneously. It has been reported that adenomyosis is present alongside DIE in 48.7% of cases ( 32 , 33 ). Our study was conducted in a retrospective manner, which is a limitation of our study. Additionally, the small sample size is another limitation. Collectively the results of this study provide valuable insight into the beneficial roles of laparoscopic surgery for advanced endometriosis on spontaneous pregnancy rates and ARTs in Iranian patients with endometriosis.

Our study has found that endometriosis surgery is associated with a high fertility rate. It is also important to note that patient age plays a significant role in the pregnancy rate of this population. Besides, adenomyosis is higher in individuals who achieved pregnancy with IVF. While this study can be used to advise patients on the impact of surgery, randomized clinical trials are needed to validate the obtained results.

This retrospective study was conducted at Arash Women’s Hospital. This study was approved by the Ethics Committee of Tehran University of Medical Sciences (IR.TUMS. MEDICINE.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 laparoscopy between March 2017 and March 2021 were evaluated. Women with ages less than 42 years, infertility complaints, endometriosis diagnosis based on histological findings, 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 not desire to conceive, patients with a previous history of endometriosis, patients with other causes of infertility, e.g., abnormal male factor, uterine, cervical, and vaginal anomalies, or patients with a history of previous surgery for endometriosis, or patients with masses other than endometriosis in the pathology report were excluded from this study. In the laparoscopic surgery department of the hospital, all patients with infertility who are referred to this center are routinely referred to the infertility clinic. In this unit, they first consult with infertility specialists, and both couples are evaluated for the causes of infertility. The male factor is studied using semen analysis reports and hormonal tests (thyroid, prolactin, and androgen tests in case of symptoms of increased androgen). Along with hormonal disorders, the anomalies of the uterus, cervix, and vagina are examined. After ruling out other causes of infertility, patients with severe endometriosis and infertility at a young age, severe pelvic pain, large endometriomas, obstructive symptoms, and narrowness of the intestinal area, endometriomas suspected in sonography, hydrosalpinx, or in vitro fertilization (IVF) failure will be candidates for laparoscopic surgery. The patients are introduced to the infertility clinics and undergo ovarian puncture and their embryos will be frozen. Besides studying the serum levels of CA-125 and anti-müllerian hormone (AMH), patients undergo transvaginal and transabdominal color Doppler sonography, and if necessary, transrectal sonography, which is performed by two radiologists specialized in endometriosis. During sonography, the size of the uterus, the presence of adenomyosis, the presence or absence of endometrioma in one or both ovaries, the size of the ovaries, deep nodules of endometriosis, and the size and location of the USL, rectovaginal, urinary system (bladder or ureter), and ovarian fossa nodules are studied. Surgery is performed under general anesthesia in the lithotomy position. After creating the pneumoperitoneum, any existing adhesions are freed, and salpingectomy is performed in the case of hydrosalpinx. Then, visible ovarian cysts are placed under excisional cystectomy. After hemostasis is established with forceps bipolar, the ovarian bed is sutured with 2-0 Vicryl, if there is a need to explore more of the cold-sack to break the ureters and remove the nodule of the USL or the rectum, the ovaries are suspended on the abdominal wall. All deep nodules of the USL, pelvis, and torus uterinus are removed. If there is a bowel nodule, it is removed by the shaving method, discoid, or anastomotic resection. Then, washing is done and the dren is fixed inside the abdomen and the duration of the surgery is recorded. Patients undergoing laparoscopic endometriosis surgery are classified according to the size, number, and location of DIE lesions, the size of one or both endometriomas, and the involvement of the fallopian tubes based on the revised American Society for Reproductive Medicine (rASRM). After the surgery, the patients were immediately encouraged to conceive on their own, or the patients with bilateral salpingectomy were referred to infertility clinics to benefit from ARTs. The checklist includes demographic information, patient age, body mass index (BMI), primary or secondary infertility, duration of infertility, endometriosis symptoms (dysmenorrhea, dyschezia, dyspareunia), and 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 years, the patients are contacted by phone to evaluate the success rate of pregnancy in patients and by which approach they were convinced, i.e., naturally, ovulation induction, or using ARTs. Spontaneous pregnancy is investigated in patients who did not undergo bilateral salpingectomy. Pregnancy is defined as a positive serum beta-hCG test and confirmation of pregnancy inside the uterus by abdominal sonography. Then, the impact of age, CA-125 level, adenomyosis, primary or secondary infertility, duration of infertility, stage of endometriosis, duration of surgery, size of endometriomas, unilateral or bilateral salpingectomy, and the number, size, and location of DIE nodules on the pregnancy success rate are investigated. The statistical analyses were conducted using the GraphPad Prism V 8.3.4 (GraphPad Software, San Diego, CA, USA). For comparing the mean of the continuous variables between the two groups, the Shapiro-Wilk test was performed to study the normality of data. Based on the normality of data, the t test or Mann-Whitney were performed to study the statistical difference between the two groups. For the nominal variables, the Fisher exact test to utilized to investigate the statistical difference between groups. P<0.05 was considered as the level of statistical significance.