{"paper_id":"d120cb34-12c7-48a9-a8d9-9c03b66d3f33","body_text":"Infertility is one of the major issues in the personal and social lives of approximately\n10-15% of couples, affecting them during their reproductive age. Infertility is defined as\nnot becoming pregnant after one year of unprotected intercourse at reasonable intervals.\nAmong the different categories of infertility, unexplained infertility (UI), is a type of\ninfertility with a prevalence of 15-50%. A diagnosis of UI is confirmed when ovulation,\ntubal patency, and spermogram fail to show an underlying factor as a cause of normal\nconception ( 1 ). Management of UI is a debated issue. Various treatments have been suggested\nto cure this problem. For instance, Custers et al. ( 2 ) have recommended a six-month\nexpectant management in women with UI. Some studies suggest performing diagnostic\nlaparoscopy in patients with UI to determine the optimal management plan ( 3 - 7 ).\nAlternatively, other studies recommend laparoscopy only in women with UI and a history of\nchronic pelvic pain, previous surgery that causes significant pelvic adhesions, previous\npelvic infection, or a history of ectopic pregnancy (EP) ( 3 ,  4 ). Some investigators and\nclinicians explain that laparoscopy could be postponed until three courses of ovarian\nstimulation and intrauterine insemination (IUI) had been done and found to be ineffective in\nachieving a successful pregnancy ( 5 ). In contrast, others suggest that ovarian stimulation\nand IUI, as well as switching to  in vitro  fertilization (IVF) should rather\nbe considered in the case of infertility. In their perspective, laparoscopy is not essential\nin determining the etiology of UI because an increased live birth rate is faster reachable\nby IVF than laparoscopy ( 6 ). Thus, a universal management protocol for UI has not yet been\nestablished.\nPelvic pathologies such as minimal and mild\nendometriosis, pelvic and periadnexal adhesions, and\nfalse negative reports of hysterosalpingography (HSG)\ncompatible with tubal patency may be missed, while each\nof these pathologies may be the cause of UI ( 7 ). They have\ndifferent prevalences in various countries, ranging from\n3% ( 8 ) to 80% ( 9 ). Fertility treatments may be enhanced\nby performing laparoscopy, diagnosis, and in some cases\nsurgical correction of these pathologies ( 10 ).\nCurrently, the epidemiology of such abnormalities in\nIranian women with UI is yet to be evaluated; hence,\nwe decided to assess the findings of laparoscopy and\nhysteroscopy in selected patients with UI to determine\nthe incidence of various related pathological conditions,\nin order to apply the best management method for them.\n\nThe current cross-sectional study was conducted on\n96 women who had attended the infertility clinic at the\neducational hospitals of Isfahan University of Medical\nSciences from March 2018 to February 2020, after\napproval of the committee of research ethics (IR.MUI.\nMED.REC.1398.486). A written consent was taken\nfrom every participant. Inclusion criteria were: woman\naged 20-40 years, infertility duration >6-12 months\ndepending on female age, spontaneous ovulatory cycles\n[confirmation by methods such as serial transvaginal\nultrasonography (TVS), serum luteinizing hormone (LH)\nsurge or mid-luteal progesterone], normal hormonal assay\non day three of the cycle [follicle-stimulating hormone\n(FSH), estradiol], and normal TVS. All participants had\nunilateral or bilateral tubal patency on HSG. Spermograms\nwere normal according to the World Health Organization\n(WHO) criteria. Participants included in the study had one\nor more of the following items: failed to become pregnant\nafter 2-3 cycles of ovulation induction with clomiphene\ncitrate and IUI, history of pelvic infection, history of\npelvic surgery (high probability of pelvic adhesion), or\nhistory of EP.\nLaparoscopic surgery was performed under general anesthesia. A 10-mm port in an umbilical\narea and 2 or 3 additional 5-mm accessory ports were used. Exact pelvic and abdominal\nexploration was carried out, and tubal patency was checked with chromopertubation.\nLaparoscopic findings were recorded. Endometriotic implants were ablated or excised, and\nblunt and sharp adhesiolysis were performed. Tubal surgery, including adhesiolysis and\nfimbrioplasty, was done if necessary. Adequate irrigation was carried out at the end of\nthe surgery. Hysteroscopy was performed in a low lithotomy position in the early\nfollicular phase in all the patients, and hysteroscopic findings were again recorded. If\nany pathology was revealed in hysteroscopy, it was corrected. An endometrial biopsy was\nperformed by fine curette to rule out endometritis upon finding no pathology.\nAfter data collection, each of the quantitative and\nqualitative data related to patients was entered separately\nin an Excel worksheet in the table of variables, and the\nnecessary categories were created. The data were then\nanalyzed by SPSS 23 (IBM Corp., Armonk, New York,\nUSA) using the absolute number, relative frequency,\nmean, standard deviation, t test, Fisher’s Exact test\nand Chi-Squared test. A significance level of 95% was\nconsidered.\n\nIn this study, 96 women with UI were included. Fiftynine (61.4%) women had primary infertility, while 37\n(38.6%) suffered from secondary infertility. The mean\nage, body mass index (BMI), infertility duration, and\nother demographic characteristics are presented in  Table\n1 . As can be seen, there were no statistically significant\ndifferences between the two groups of primary and\nsecondary infertility in terms of age (P=0.771), BMI\n(P=0.051), infertility duration (P=0.841), past medical\nhistory (P=0.202), and irregular menstrual cycles\n(P=0.392). However, the secondary infertility group had\na significantly higher number of previous laparoscopy\nor laparotomy (P=0.007). Infertility duration for the\nparticipants ranged from 2 to 10 years. Although there\nwere no differences between the two groups in duration\nof infertility, patients in the secondary infertility group\nwere older than the primary group. Hypertension (HTN)\nand diabetes mellitus (DM) were the common issues in\nthe patients (12.5 and 7.3%, respectively). Recurrent\nabortions and previous dilatation and curettage (D&C)\nwere seen in 6.3 and 5.2% of the patients, respectively.\nAmong the participants, 15.6% had previous cesarean\nsection procedures, 16.7% had previous laparotomy for\ngynecological causes, and 15.7% had irregular cycles. In\npatients with primary infertility, 25 out of the 59 patients\n(42.3%), and in patients with secondary infertility 16 out\nof the 37 patients (43.2%) had laparoscopic abnormalities.\nFinally, in the primary and secondary groups, 20 of the\n59 participants (33.8%) and 8 of the 37 participants\n(21.6%), respectively, had hysteroscopic abnormalities.\nEndometriosis (21.8%) followed by tubal pathology\n(13.5%) were the most common laparoscopy findings\nin both groups. Also, uterine septum (7.2%) followed by\nendometritis (6.2%) were the most common intrauterine\npathologies observed in the participants (Tables 2 ,  3 ).\nBaseline characteristics of participants with unexplained infertility\nData are presented as mean ± SD or n (%). BMI; Body mass index, DM; Diabetes mellitus, HTN; Hypertension, D&C; Dilatation and curettage, *; Independent sample t test, **; Fisher’s\nexact test, and ***; Chi-Square.\nFindings at laparoscopy\nData are presented as n (%). IM; Intramural, SS; Subserosal, **; Fisher’s exact test, and\n***; Chi-Square.\nFindings at hysteroscopy\nData are presented as n (%). **; Fisher’s exact test and ***; Chi-Square.\n\nIn the present study, we observed that abnormal\nlaparoscopic findings were more common than\nhysteroscopic ones in UI patients. The abnormal\nlaparoscopic results were about 26% in the primary\ninfertility group and 17% in the secondary infertility\ngroup. Endometriosis (21.8%) and tubal pathology\n(13.5%) were the most prevalent laparoscopy findings in\nboth primary and secondary infertility groups. Abnormal\nhysteroscopic findings were 20 and 8.3% in primary\nand secondary groups, respectively. Uterine septum\n(7.2%) and endometritis (6.2%) were the most prevalent\nintrauterine pathologies in both groups.\nMany studies have investigated similar issues in order\nto find optimal treatments for UI patients. For instance,\nFirmal et al. ( 11 ) showed pelvic abnormalities in 36.7%\nof women with UI. Their participants failed to conceive\nafter three or more cycles of ovulation induction and IUI.\nThey concluded that laparoscopy may be considered in\nthe work-up of a woman with UI. Tsuji et al. ( 9 ) indicated\nthat 80.7% of patients had abnormal pathology based\non laparoscopy results. They explained that women\nwith UI and normal HSG should undergo diagnostic\nlaparoscopy before ART. Our study showed abnormal\nlaparoscopic findings in about 43% of the UI cases. All\nof the participants in the present study failed to become\npregnant after 2-3 cycles of ovulation induction and IUI.\nTherefore, they underwent laparoscopy as they had one\nor more of the following conditions: a history of pelvic\ninfection, a history of pelvic surgery, or a history of EP.\nThe overall rate of endometriosis is 6-10% in the general\npopulation ( 12 ). In the current study, endometriosis was\nobserved in about 22% of the participants with UI. This\nhigh incidence reflects the high rate of endometriosis in\nwomen with UI. All women in this study had mild to\nmoderate endometriosis (not severe) that could easily be\nmissed in TVS ( 13 ), so laparoscopy helps to detect and concomitantly treat this pathology and may even promote\nconceiving spontaneously. Other studies reported\nendometriosis in laparoscopy in 2.7% ( 8 ) to 63% ( 9 )\nof women with UI. These differences in the prevalence\nof endometriosis studies are due to multifactorial of\nthe disease nature ( 12 ). Providing a database on the\nprevalence of endometriosis in each country may be\nhelpful in providing treatment plans for patients with UI.\nHSG is a screening test for evaluating tubes; however,\nit is recommended only in low-risk patients with tubal\ndiseases. Nonetheless, laparoscopy could be a better\noption for confirming tubal patency in high-risk women.\nIn addition, laparoscopy may correct some pathologies and\nincrease the rates of both spontaneous and ART-mediated\npregnancies ( 7 ). Therefore, HSG does not determine\nall tubal pathologies, as confirmed by previous studies.\nFirmal et al. ( 11 ) observed a 3.3% bilateral tubal block\nin laparoscopy in UI. Tsuji et al. ( 9 ) reported peritubal\nadhesion in 8.8% and tubal occlusion in 5.3% of women\nwith UI based on laparoscopy. Mahran et al. ( 4 ) have\nfound a 30% tubal factor in laparoscopy in women with\ninfertility. The current study showed tubal pathologies\nsuch as fimbrial agglutination and adhesion in 13.5% of\nthe UI cases. Therefore, laparoscopy detected and also\ntreated these pathologies missed by HSG.\nThe hysteroscope is considered the stethoscope for\nthe uterus. Intrauterine pathology can be identified with\nhysteroscopy and is likely to have an adverse effect\non reproductive outcomes. These pathologies include\nendometrial polyps, endometritis, intrauterine synechia,\nand mullerian anomalies ( 14 ).\nMakled et al. ( 15 ) showed that 86% of the abnormal\nfindings were in hysteroscopy in women with UI.\nEndometrial polyp (31%), endometrial hyperplasia\n(15%), endometritis (14%), and uterine septum (3%)\nwere the most frequent pathologies. They concluded\nthat hysteroscopy and endometrial biopsy are both\nrecommended for all women with UI. On the other hand,\nthe Cochrane Database in 2018 revealed no evidence in\nfavor of hysteroscopy as a tool in the basic fertility workup for screening women with UI in order to improve\ntheir reproductive success rates ( 16 ). Our data on\nabnormal hysteroscopy were 28.3% in women with UI,\nnamely uterine septum (7.2%) and endometritis (6.2%).\nAlthough they were the most prevalent pathologies in our\nstudy, they had a low prevalence rate. So, it seems that\nfurther investigation is required to recommend universal\nhysteroscopy to all women with UI unless there are issues\nin the patient history or on TVS and HSG images.\nMollo et al. ( 17 ) claim that hysteroscopic metroplasty\nimproves the fertility of women with septate uterus and\nUI. Bakas et al. ( 18 ) included 68 women with various\ndegrees of septate uterus and UI in their study and showed\nthat clinical pregnancy and live birth rates were 44 and\n36.8%, respectively, during a 12-month follow-up. They\nsuggest that hysteroscopic septum resection in women\nwith septate uterus and UI can postoperatively improve\nclinical pregnancy and live birth rate in women with UI.\nAbnormal development of the septal endometrium can\ncorroborate incomplete differentiation and maturation\nof the endometrium covering the septum. Interestingly,\npartial uterine septum might be ignored in HSG reports by\nradiologists, and it might be mis-reported and considered\nas an arcuate uterus. Therefore, it is recommended that\ngynecologists review the HSG photos In fact, seven cases\nwith uterine septum in our study were not reported by\nradiologists.\nOther studies have reported a relationship between\nchronic endometritis (CE) and recurrent implantation\nfailure (RIF), suggesting a robust correlation between\nCE and defects in implantation and embryo development\n( 19 ). Recent studies have investigated the relationship\nbetween CE and UI. Cicinelli et al. ( 19 ) showed a CE\nprevalence of 56.8% in the hysteroscopy of women with\nUI, which was also confirmed by histology. The abovementioned diagnosis and treatment of CE improve\nspontaneous pregnancy and live birth rate in such patients.\nIn the study of Ghahiri et al. ( 20 ), the prevalence of\nendometritis in the UI group was 34%, while it was 21%\nin the anovulatory group, emphasizing the importance of\nendometritis evaluation in women with UI. They obtained\nthe endometrial tissue using a pipelle. Endometritis was\ndetected in 6.2% of the women with UI in the present\nstudy, which was lower than other studies. Still, it was\nthe second abnormal result after uterine septum and was\ntreated by prescribing antibiotics.\nNowadays, different studies suggest different therapies\nfor women with UI, including early laparoscopy\nprocedures when UI is first diagnosed or performing late\nlaparoscopy only in cases with three failed experiences of\nIUI, a history of pelvic pain, a history of pelvic surgery,\nand a history of pelvic infection. Additionally, some\nstudies even recommend disregarding laparoscopy and\nswitching to ART after three failures in IUI and ovarian\nstimulation ( 21 ). It seems that several factors influence\ndecision-making on this issue. Female demographics\nsuch as age, infertility duration, history of pelvic pain,\nsurgery, infection, surgeon expertise for performing\nlaparoscopy, the clinical protocols in the country where\nthe patient lives, cultural factors, the regional prevalence\nof endometriosis and the history of tubal and peritubal\ndiseases are factors to be considered when selecting the\nbest management plan for women with UI ( 22 - 24 ).\nSuperficial endometriosis is only detected by\nlaparoscopy, and ablation or excision of these problematic\nsections may help women with UI to become pregnant\nspontaneously. Still, even these effects are small and\ninsignificant ( 25 ). In the current study, the prevalence of\nsuperficial endometriosis was three times more than the\ngeneral population, so eliminating laparoscopy from the\nscope of UI seems futile.\nFurther investigation will need to be conducted on\nperforming hysteroscopy for women with UI. According\nto our study, uterine septum and endometritis were the most prevalent pathologies; however, the prevalence rates\nof these pathologies were not high enough to recommend\nuniversal hysteroscopy along with laparoscopy. Therefore,\ndecisions should be made on a case-by-case basis.\nNevertheless, laparoscopy has some complications\nsuch as vessel, bladder, and bowel injuries ( 26 ). Also,\nhysteroscopy has side effects like uterine perforation,\nbowel injury, and fluid deficit ( 27 ). So, it is necessary to\nschedule the patients with definitive indications for these\nprocedures.\nThe strength of the current study is evaluating the\nincidence of laparoscopic and hysteroscopic findings in\nwomen with UI, revealing that endometriosis was the most\nprevalent pathology. The limitation of the current study is\nthat we had no follow-up and outcomes of laparoscopy\nand hysteroscopy of the patients with UI.\n\nBased on the findings of the present study, laparoscopic\nsurgery is recommended in UI cases after three failed IUI\nand ovarian stimulation, a history of pelvic pain, pelvic\nsurgery, and pelvic infection. however, it seems that\nfurther investigation is required to recommend universal\nhysteroscopy to all women with UI.","source_license":"public-domain-us","license_restricted":false}