{"paper_id":"f1874ca1-3b8d-4371-92f0-9321416b4696","body_text":"During the last decade, infertility has had an increasing\nimpact onthe health of Western countries’ populations.\nThe most accepted definition of infertility is failure to\nconceive after 12 months or more of regular unprotected\nsexual intercourses ( 1 ).\nDuring the last 20 years, multiple factors have been\naddressed as causes of reduced spontaneous conception,\namong which intrauterine pathologies might play a\ncrucial role. According to this, several treatments have\nbeen proposed to overcome infertility due to the presence\nof intrauterine affections. In this context, hysteroscopy is\ncurrently considered the gold standard for both assessment\nand management of intrauterine factors. Indeed, it allows\na more precise diagnosis of endometrial abnormalities\ncompared to non-invasive techniques such as transvaginal\nsonography (TVS), hysterosalpingography (HSG) and\nsonohysterography; above all, it allows for simultaneous\ntreatment of an intrauterine pathology ( 2 ).\nThe present study is a systematic review on the efficacy\nof diagnostic and/or operative hysteroscopy in improving\nreproductive outcomes for specific conditions in infertile\nwomen.\n\nWe systematically reviewed the literature from 2000 to 2020 by searching in PubMed, Embase,\nand the Cochrane Libraryby using the following keywords: infertility, hysteroscopy,\npregnancy rate (PR), miscarriages, live birth rates (LBR), uterine malformations and\nmetroplasty. In general, randomised controlled trials (RCT) were selected; if they were not\navailable on a specific subject, less relevant studies were chosen. The patients included in\nthis review were infertile women with or without endometrial abnormalities who sought\nspontaneous conception or required  in vitro  fertilization/ intracytoplasmic\nsperm injection (IVF/ICSI). The type of intervention analysed is diagnostic and/or operative\nhysteroscopy performed during the infertility evaluation and/or prior IVF/ICSI compared to\nno hysteroscopy in similar groups of patients.\nWe divided the studied population according to indication\nand efficacy of hysteroscopy in improving reproductive\noutcomes. As result, we obtained the following four\ngroups: group A: initial work-up of asymptomatic patients\nwith negative ultrasound findings; group B: women with\nendometrial abnormalities at the TVS with or without\nabnormal uterine bleeding (AUB); group C: patients with\ngenital tract malformations and/or recurrent abortions; and\ngroup D: women with negative ultrasound findings who\nrequired assisted reproductive technology (ART), IVF or ICSI.\nThe primary outcome was clinical PR (CPR), which was\ndefined by at least TVS visualization of the gestational\nsac. The secondary outcome was miscarriage rate (MR),\nwhich was defined as pregnancy loss before 20 weeks of\ngestation.\n\nAtotal of 28 records were considered in the study\nselection process. After removing three duplicates and\nexcluding four studies due to incomplete outcomes,\n21 full-text articles wereconsidered suitable for the\nsystematic review ( Fig.1 ).\nPrisma flow chart ( 3 ).\nSubdivisions of the selected articles according to groups A,\nB, C or D, and their results, are described as follows. Only two\nstudies, one retrospective and one prospective, were included\nin group A, which showed that a consistent percentage\nof women (79 and 33%, respectively) had hysteroscopic\nabnormalities ( Table 1 ). Group B comprised four studies- two\nprospective, one RCT, and one retrospective cross-sectional.\nThe outcomes reported that 65% of patients achieved\npregnancy after hysteroscopy with only one intrauterine\ninsemination (IUI), and the PR was significantly higher after\nhysteroscopic removal of submucous myomas. Malignancy\nor atypia did not occur in the subsequent 12 months of followup after the hysteroscopy, and the uterine cavity was restored\nin 93.6% of women, respectively ( Table 2 ). Group C had\nfive studies, three prospective and two retrospectives. The\nresults revealed significantly higher PR and LBR in patients\nwho underwent hysteroscopic treatment of uterine septum\n( Table 3 ). A total of nine RCT studies were assigned to group\nD. This group had significantly higher PR, CPR, LBR and\nimplantation rate (IR) in the selected categories of patients\nwho underwent hysteroscopy before ICSI ( Table 4 ). Tables\n1-4 display the aforementioned groups in extensive details.\nCharacteristics of the two studies included in group A\nTVS; Transvaginal sonography, HSG; Hysterosalpingography, and PR; Pregnancy rate.\nCharacteristics of the five studies included in group B\nEP; Endometrial polyp, SM; Submucosal fibroid, IM; Intramural fibroid, SS; Subserosal fibroid, SM-IM; Submucosal-intramural fibroid, IM-SS; Intramural-subserosal fibroid, IUA; Intrauterine adhesion, IUI; Intrauterine insemination, MR; Miscarriage rate, LBR; Live birth rate, CR; Conception rate, CS; Caesarean section, PAUB; Postmenstrual uterine bleeding, PR;\nPregnancy rate, and RCT; Randomised controlled trial.\nCharacteristics of the five studiesincluded in group C\nCPR; Clinical pregnancy rate, MR; Miscarriage rate, AR; Abortion rate, LBR; Live birth rate, PR;\nPregnancy rate, IVF;  In vitro  fertilization, ICSI; Intracytoplasmic\nsperm injection, and NS; Not significant.\nCharacteristics of the nine studies included in group D\nRCT; Randomized controlled trial, PR; Pregnancy rate, TVS; Transvaginal sonography, HSG;\nHysterosalpingography, IR; Implantation rate, MR; Miscarriage rate, LBR; Live birth\nrate, OP; Ongoing pregnancy rate, ICSI; Intracytoplasmic sperm injection, IVF; \nIn vitro  fertilization, ART; Assisted reproductive technology, and CPR;\nClinical pregnancy rate.\n\nThe exploration of the uterine cavity as a routine\nprocedureduring the initial infertility work-up is still under\ndebate. With regards to our study results, only two studies\nwere included in the systematic review, which analysed\nthe role of hysteroscopy in asymptomatic infertile women.\nThe National Institute for Health and Clinical Excellence\n(NICE guidelines, 2014) stated that hysteroscopy should\nnot be offered during the initial infertility evaluation; on\nthe other hand, according to the Practice Committee of the\nAmerican Society for Reproductive Medicine (ASRM),\nhysteroscopy is a relatively expensive and invasive\nprocedure ( 2 ). In contrast, the guidelines of the Italian\nSociety of Gynaecological Endoscopy (SEGI), strictly\nrecommend hysteroscopy as a screening procedure for\nthe infertile couple as part of the primary work-up ( 24 ),\neven if a specific evidence of its usefulness in these\ncases is lacking. Similarly, the literature currently shows\nan increasing trend towards hysteroscopic evaluation\nfor women who struggle with unexplained infertility.\nMoreover, this kind of management could help todetect\nlesions that were not diagnosed by other tools. Indeed, it\nmayprovide definitive treatment of endocavitary lesions\nthat could impact women fertility ( 4 ).\nConversely, hysteroscopic exam of the uterine cavity\nis considered mandatory during the primary work-up of\ninfertile couples in presence endometrial abnormalities\ndetected at TVS, accompanied or notby bleeding. In\nthis context, the most common endometrial pathologies\nobserved by hysteroscopyare endometrial polyps and\nsubmucous fibroids. In general, their treatment by\noperative hysteroscopy improves PR and reproductive\noutcomes. Endometrial polyps are thought to interfere\nwith uterine receptivity and embryo implantation, and\nadversely impact fertility ( 25 ). Current evidence supports\nhysteroscopic resection of endometrial polyps prior to\nART in order to improve fertility ( 6 ,  25 - 27 ). There is a 50%\nviable PR obtained after polypectomy among subfertile\npatients ( 26 ). In cases with hysteroscopic polypectomy\nprior to IUI, hysteroscopic removal of polyps showed a\nsignificant improvement in clinical PR ( 27 ). Submucous\nfibroids should be also removed in infertile patients, especially if they significantly impact the endometrial\nline, regardless of the size or the presence of symptoms\n( 27 ,  28 ).\nInfertility may be associated with AUB, not only in\ncases of endometrial polyps and submucous myoma, but\nalso in cases of other endometrial pathologies such as\nadenomyosis, endometrial hyperplasia and endometrial\nmalignancy. In the latter cases, it is interesting to report\nthat small (<2 cm) intramucous endometrial cancer,\nwell-differentiated, may be removed by hysteroscopy,\npreserving fertility ( 29 ).\nAnother emerging cause of infertility associated with\nAUB is isthmocele or uterine scar defects following\ncaesarean section (CS). These may be defined as first,\nsecond, or third degree according tothe dimensions.\nHysteroscopic treatment of isthmocele is reported to be\nassociated with an increased PR ( 30 ).\nIntrauterine adhesions (IUA), occasionally associated\nwith Asherman syndrome, are caused by postsurgical or\ninfectious damage to the basalis layer of the endometrium.\nIUA, sometimes detected on ultrasound as endometrial\nthickening, may be responsible for infertility and recurrent\npregnancy loss (RPL) ( 31 ). In this context, hysteroscopy\nis considered the gold standard for both diagnosis and\ntreatment ( 32 ).\nHysteroscopic adhesiolysisis associated with improved\nfertility as well as reproductive outcomes as reported\nby Goldenberg et al. ( 33 ). Moreover, hysteroscopic\nevaluation of the uterine cavity is recommended in order\nto identify eventual congenital uterine abnormalities\nin patients with RPL ( 34 - 36 ). Indeed, women with a\nhistory of recurrent miscarriage or infertility have higher\nprevalence of congenital uterine anomalies compared\nwith those not having a history of recurrent miscarriage\nor infertility ( 37 ). However, it is important to highlight\nthat, among congenital uterine malformations, septate\nuterus is the most common structural uterine anomaly\nassociated with the highest incidence of reproductive\nfailure ( 28 ). In this context, the Thessaloniki ESHRE/\nESGE consensus on diagnosis of the female genital\nanomalies has recently established that the combination\nof gynaecologic examination and two-dimensional\n(2D)-TVS is recommended as the current standard for\nthe evaluation of asymptomatic women, while threedimensional (3D)-TV is recommended when genital\ntract anomalies are suspected. Thus, magnetic resonance\nimaging (MRI) and endoscopic evaluation are also\nindicated, but only in complex cases or in diagnostic\ndilemmas ( 38 ).\nHysteroscopy, as well as HSG, cannot differentiate\nseptate from bicorporal uterus, due to their inability to\nassess the contour of the uterus; therefore, both procedures\nhave a limited diagnostic value in the evaluation of\ngenital tract malformations. Conversely, hysteroscopy\ncompared to HSG, may be more useful to investigate the\nrelationship between the cervix (single or double) and the\nvaginal canal, and analyse the vaginal, the cervical and\nthe uterine intracavitary morphology ( 39 ).\nWhen infertility is associated with the presence of a\nuterine septum, operative hysteroscopy is a valuable tool\nthat offers resolutive management. Bakas et al. ( 14 ) have\nproposed that hysteroscopic metroplasty in patients with\nseptate uterus and unexplained infertility is a method to\nimprove CPR and LBR. Grimbizis et al. ( 40 ) reported\n6.1% of LBR in untreated women with uterine septum\ncompared with 82% in those who underwent hysteroscopic\nmetroplasty. To date, RCTs with the aim to evaluate the\neffectiveness and possible complications of hysteroscopic\nmetroplasty have not been published ( 41 ). Furthermore, it\nseems that hysteroscopy with biopsy may be a valid tool\nin patients with RPL and recurrent implantation failure\n(RIF) in order to detect chronic endometritis, as reported\nby Zargar et al. ( 42 ).\nIn ART, the role of hysteroscopy is even more\nimportant. In the clinical practice, hysteroscopy is\ncommonly performed before IVF in all patients, including\nwomen with normal TVS and/or HSG findings, because\na significant percentage may have a misdiagnosed\nuterine disease that might negatively affect the success\nof the fertility treatment ( 43 ). Hysteroscopy reveals the\npresence of intrauterine lesions in almost 28% of infertile\npatients with negative TVS results undergoing ART. This\ndemonstrates that TVS hasa low sensitivity in diagnosis\nof several intrauterine alterations ( 44 ).\nMoreover, the RCT by Elsetohy et al. ( 16 ), reported\nthat 43.3% of women with negative ultrasounds showed\nabnormal hysteroscopic findings prior to ICSI. Similarly, an\nimproved IR and CPR, after office hysteroscopy and before\nundergoing ICSI, was observed, especially in patients whose\nuterine abnormalities were corrected ( 20 ,  45 ).\nEl-Toukhy et al. ( 19 ) reported significant improvement in\nPR when hysteroscopy was performed in the cycle before\nIVF, regardless of intrauterine abnormalities. Possible\nexplanations include possible reliance on irrigation of the\ncavity with saline, which mechanically removes harmful\nantiadhesive glycoprotein molecules ( 46 ); probing of the\ncervical canal, which makes the embryotransfer procedure\neasier ( 23 ); and mechanical endometrial injury, which\nmay enhance receptivity by modulating the expressions\nof gene encoding factors required for implantation ( 47 -\n 52 ). Finally, a screening hysteroscopy is recommended\nprior to ART and highly recommended after two or more\nfailed IVF cycles.\nThe strength of our study relies on its design. This\nsystematic review included a large sample size of infertile\nwomen with or without endometrial abnormalities who\nsought spontaneous conception or required IVF/ICSI.\nDespite our robust methodological approach, risk of bias\ninherent to the nature of the study itself should be taken\ninto consideration when interpreting the results. Larger,\nprospective randomised studies are warranted to draw\nfirm conclusions.\n\nHysteroscopy represents the gold standard for diagnosis\nand treatment of abnormal uterine findings that are\npresent in approximately 25% of infertile women. These\nlesions can interfere with spontaneous and assisted\nreproduction, and may remain undiagnosed with the\nuse of TVS, SIS/GIS or HSG. Although spontaneous\nor assisted reproductive conception is possible, even in\nthe presence of the small intrauterine abnormalities that\nrepresent only 2-3% of infertility causes, their treatment\nby operative hysteroscopy may help improving the IR\nand CPR. However, it has to be considered that treatment\nof intrauterine lesions may not always be synonymous\nwith restoration of fertility. Diagnostic and, if required,\noperative hysteroscopy prior to ART in infertile women\nwith or without intrauterine abnormalities, may contribute\nto increase reproductive outcomes.","source_license":"CC-BY-4.0","license_restricted":false}