{"paper_id":"cd9244cc-028a-4e0a-ab88-e7609e3f111c","body_text":"https://doi.org/10.1177/2284026518784236\nJournal of Endometriosis and  \nPelvic Pain Disorders\n2018, Vol. 10(3) 158 –173\n© The Author(s) 2018\nArticle reuse guidelines: \nsagepub.com/journals-permissions\nDOI: 10.1177/2284026518784236\njournals.sagepub.com/home/pev\nJEPPD\nJournal of\nEndometriosis and \nPelvic Pain\nDisorders\nEndoART: A proposed randomized \ncontrolled trial on endometriomas in \nassisted reproductive technologies, \ncomparing the effect of no intervention, \nsurgery, and prolonged GnRH \ndownregulation on pregnancy rates\nCarla Tomassetti1,2, David Adamson3, Aydin Arici4, Michel \nCanis5,6, Peter Hompes7, Lone Hummelshoj8, Ben-Willem Mol9, \nLuciano Nardo10, Luk Rombauts11 and Thomas D’Hooghe2\nAbstract\nBackground: Clinical management of endometriomas, prior to starting treatment with assisted reproductive \ntechnologies (ART), has since long been a matter of debate. Whereas cystectomy has been advocated in the past, \nrecently more evidence has emerged on the potential negative effect of surgery on ovarian reserve. Parallel to this, \nprolonged downregulation with GnRH-a (gonadotropin-releasing hormone agonists) has been described to improve \nART pregnancy rates in women with endometriosis. However, none of these strategies have been assessed in a \nlarge randomized controlled trial. The aim of the EndoART study is to assess whether ovarian surgery or prolonged \nGnRH-a downregulation result in higher pregnancy rates after ART compared to no intervention in women with \nendometrioma(s).\nMethods/design: A parallel randomized multi-center trial has been designed to compare ART pregnancy rates in three \ndifferent treatment groups: no intervention, ovarian surgery, and prolonged hormonal suppression by GnRH-a prior to \nART. The primary outcome measure studied is the clinical pregnancy rate with fetal heart-beat within 6 months after \ninitiation of a fresh ART cycle. Secondary outcome measures studied include live birth rate after one initiated fresh ART \ncycle, cumulative clinical pregnancy rate with fetal heart-beat and live birth rates (after one fully completed ART cycle: \ninitiated fresh + eventual associated frozen embryo transfer cycles), ART–specific data (e.g. number of oocytes, number \nof good quality embryos), complications, pelvic pain, and quality of life.\nConclusion: This trial may answer the most frequently asked questions by both women with endometriosis and \nphysicians: how do you treat endometrioma in women prior to treatment with ART?\n1 Department of Obstetrics and Gynaecology, Leuven University \nFertility Center, University Hospitals Leuven, Leuven, Belgium\n2 Department of Development and Regeneration, Organ Systems, KU \nLeuven, Leuven, Belgium\n3 Palo Alto Medical Foundation Fertility Physicians of Northern \nCalifornia, East Palo Alto, CA, USA\n4 Division of Reproductive Endocrinology and Infertility, Department of \nObstetrics, Gynaecology and Reproductive Sciences, Yale University \nSchool of Medicine, New Haven, CT, USA\n5 Department of Gynaecological Surgery, CHU Estaing, Clermont-\nFerrand, France\n6 CICE (Centre International de Chirurgie Endoscopique), Faculty of \nMedicine, Clermont-Ferrand, France\n7 Vrije Universiteit Medical Center, Center for Reproductive Medicine, \nAmsterdam, The Netherlands\n8 World Endometriosis Research Foundation, London, UK\n9 The Robinson Research Institute, School of Medicine, University of \nAdelaide, The South Australian Health and Medical Research Institute, \nAdelaide, SA, Australia\n10 Reproductive Health Group, Manchester, UK\n11 Monash University, Melbourne, VIC, Australia\nCorresponding author:\nCarla Tomassetti, Department of Obstetrics and Gynaecology, Leuven \nUniversity Fertility Center, University Hospitals Leuven, Herestraat 49, \n3000 Leuven, Belgium. \nEmail: carla.tomassetti@uzleuven.be\n784236 PEV0010.1177/2284026518784236Journal of Endometriosis and Pelvic Pain DisordersT omassetti et al.\nresearch-article2018\nClinical Trial Protocol\n\n\nTomassetti et al. 159\nKeywords\nEndometriosis, ovarian cyst, ART, operative surgical procedures, gonadotropin-releasing hormone agonist, randomized \ncontrolled trial\nDate received: 24 January 2018; accepted: 30 May 2018\nIntroduction: literature background\nEndometriosis is a disease characterized by the presence of \nendometrium-like epithelium and stroma outside the endome-\ntrium and myometrium. Intrapelvic endometriosis can be \nlocated superficially on the peritoneum (peritoneal endome-\ntriosis), can extend 5 mm or more beneath the peritoneum \n(deep endometriosis) or can be present as an ovarian endome-\ntriotic cyst (endometrioma).\n1 Ovarian endometriotic cysts are \nrarely solitary, and are mostly found in association with \nadnexal endometriosis adhesions, deep and/or peritoneal \nendometriosis. Such disease is classified as moderate or severe \nendometriosis.\n2 Endometriosis (including endometrioma) \nmay cause infertility due to a combination of factors, including \npelvic adhesion formation compromising ovum pick up mech-\nanism, impaired ovarian function, impaired oocyte quality, \nendometrial dysfunction, peritoneal inflammation, immuno-\nlogical dysfunction, and potential other factors.\n3\nThere is now molecular, histological, and morphologi-\ncal evidence to suggest that endometriosis is detrimental to \nthe ovaries: toxic content from an endometrioma may lead \nto unfavorable events such as increased oxidative stress, \nincrease fibrosis, loss of cortex-specific stroma, smooth \nmuscle cell metaplasia, vascularization defect, and, later, \nreduced follicular maturation.\n4 Whether this vicious cycle \nof damage can be ameliorated by surgical treatment before \nin vitro fertilization/intracytoplasmic sperm injection \n(IVF/ICSI) is still controversial.\n5\nEffect of endometriosis on assisted reproductive \ntechnologies pregnancy rates\nThe influence of endometriosis on the pregnancy rates of \nassisted reproductive technologies (ART) is equivocal. In \nan older meta-analysis study, the pregnancy rates after \nART were reported to be up to 56% lower in women with \nstage III–IV endometriosis as compared with those with \ntubal factor, due to a lower number of retrieved oocytes, a \nlower fertilization rate, and a lower implantation rate.\n6 A \nmore recent meta-analysis confirmed that women with \nstage III–IV endometriosis have inferior fertility out-\ncomes, but that there is insufficient evidence to recom-\nmend surgery routinely before undergoing ART.\n7 Of note, \nother studies and some large databases show that a diagno-\nsis of endometriosis does not adversely affect pregnancy \nrates (e.g. the Society for Assisted Reproductive \nTechnology (SART) and the Human Fertilization and \nEmbryology Authority (HFEA)).\n8 When focusing on \nwomen with intact endometrioma undergoing ART com-\npared to women without endometriosis, a recent system-\natic review concluded that they had similar reproductive \noutcomes (live birth, clinical pregnancy, and miscarriage \nrate) compared with those without the disease, although \ntheir cycle cancelation rate was nearly three times higher \nand they had a lower number of oocytes retrieved;\n5 this \nwas only based on the information from maximally five \nstudies (of which none were randomized for obvious rea-\nsons). This review further concluded that of all evidence \nfound regarding endometrioma and ART, the majority of \nthe 33 studies included were not randomized (except \nthree). Furthermore, the authors highlighted the paucity of \ndata available for analysis and their high heterogeneity and \nrecommend that future studies should be carried out to \nexamine adverse events, including cancelation rates.\nEffect of endometrioma surgery on  \novarian reserve\nLaparoscopic excision of endometriotic cysts is superior \ncompared to drainage and coagulation or laser vaporiza-\ntion of the cyst wall with respect to both spontaneous preg-\nnancy rate and cyst recurrence rate.\n8,9 However, it is not \nclear if excision of endometriotic cysts prior to ART is \nbeneficial in terms of fertility outcome, pain symptoms, \nrecurrence rates, and complication rates when compared to \nexpectant management. More recent systematic reviews, \nconcerning the effect of endometrioma surgery on ovarian \ndamage and reserve, also come to conflicting conclusions, \ndepending on outcome measures that were studied. A sys-\ntematic review and meta-analysis by Somigliana et al.\n10 \nshowed—although heterogeneity was high—a statistically \nsignificant decline in postoperative anti-Müllerian hor -\nmone (AMH) serum levels after endometrioma cystec-\ntomy, attributed to the surgery itself, suggesting that this \ntechnique should be used with caution. A systematic \nreview by Muzii et al.,\n11 however, concluded that ovarian \nreserve evaluated with antral follicle count (AFC) is not \nreduced after surgical treatment of an endometrioma, and \na lower AFC is present for the affected ovary both before \nand after surgery. Less invasive techniques, such as the \ncombined technique (combination of partial cystectomy \nand subsequent CO\n2-laser ablation near the hilus12 or abla-\ntion of the cyst wall with low-energy sources such as \nplasma energy\n13 appear to cause less damage to the ovarian \ncortex, although there are no large randomized series that \ndraw firm conclusions). On these two surgical techniques \n\n160 Journal of Endometriosis and Pelvic Pain Disorders 10(3)\nper se (cystectomy versus (bipolar) ablation), only limited \nnon-randomized comparative evidence exists regarding \ntheir effect on the ovarian reserve. Three studies point \ntoward an advantage of (bipolar) ablation over classical \ncystectomy on ovarian reserve testing: one study uses AFC \nas an ovarian reserve marker,\n14 and the other two studies \nassess ovarian reserve by AMH. 15–16 Although both abla-\ntion and cystectomy had a negative effect on ovarian \nreserve, none of these studies were performed in a pre-\nART setting. A small study on ART patients where women \nwith endometriosis who underwent plasma energy abla-\ntion for the endometrioma(s) prior to ART were compared \nto women without endometriosis undergoing ART\n17 con-\ncluded that ovarian endometrioma ablation using plasma \nenergy is followed by good IVF/ICSI outcomes and sug-\ngested that this surgical procedure spares underlying ovar-\nian parenchyma. However, this does not directly relate to \nthe subject of the study as outlined in this article, since this \nis not a true comparison between treated and untreated \nendometrioma(s).\nThe effect of endometrioma treatment on \novarian response in ART\nThe effect of endometriotic ovarian cysts and of their surgi-\ncal or medical treatment on ovarian response during ART is \nequally controversial. Regarding surgical treatment, a ret-\nrospective analysis has shown that the number of oocytes \nand embryos obtained was not significantly decreased by \nlaparoscopic cystectomy of cysts larger than 3 cm, suggest-\ning that in experienced hands, this procedure might be a \nvaluable surgical tool for the treatment of large ovarian \nendometriomas.\n18 Several other studies, however, suggest \nthat cystectomy for endometrioma(s) is followed by a \nreduced ovarian response during ovarian stimulation for \nART, resulting in higher gonadotropin use when compared \nto patients without ovarian surgery for endometriomas \nbefore ART.\n19 Unilateral excision or drainage and coagula-\ntion or laser vaporization of endometriomas before ART \nhas also been reported to result in reduced responsiveness \nof the operated ovary during ART-stimulation.\n20 In view of \nexisting evidence that reduced ovarian responsiveness is \npresent in women with non-operated endometriomas\n21,22 \nespecially when larger than 30 mm,23 even though the \noocyte developmental competence per se is not affected,24 \nit is not clear to what extent surgical treatment of ovarian \nendometriotic cysts reduced ovarian response is caused by \nthe presence of the cysts and/or by the damage caused by \nthe surgical procedure. In the only randomized controlled \ntrial (RCT) addressing this clinical question,\n25 women with \novarian cystectomy for endometriomas followed by intra-\ncytoplasmatic sperm injection (ICSI) required a higher \ndose of gonadotropins and a longer duration of ovarian \nstimulation and still had fewer oocytes than women with \nendometriomas, who were treated directly with ICSI \nwithout ovarian cystectomy. This was also confirmed in a \nsystematic review by Hamdan et al.:\n5 compared to women \nwithout the disease, women with endometrioma require \nhigher follicle-stimulating hormone (FSH) dosage for ovar-\nian stimulation and have a lower AFC, suggesting that their \novarian reserve is diminished prior to ART. The authors \nfurther stated that surgical treatment of endometrioma prior \nto ART could exert a detrimental effect on ovarian reserve \nand that therefore a dogmatic recommendation on whether \nor not to perform surgery cannot be made.\nThe use of medical treatment with prolonged pituitary \ndownregulation before ART in patients with endometriosis \nin an older study is reported to cause no difference in total \ndose of gonadotropins used or days of stimulation when \ncompared to classical pituitary downregulation,\n26 but these \ndata are hampered by small sample sizes and do not spe-\ncifically focus on patients with endometriomas.\n8,27 A recent \nRCT evaluating GnRH-a (gonadotropin-releasing hor -\nmone agonists) versus no intervention prior to ART in \nwomen with surgically treated peritoneal endometriosis \nonly showed no difference in terms of the number of meta-\nphase II (MII) oocytes obtained per cycle, but did find a \nsignificantly higher dose of FSH and a longer stimulation \nperiod to reach adequate follicle maturation in the GnRH-a \ngroup.\n28\nThe effect of endometrioma with or without \ntreatment on ART pregnancy rates\nThe effect of endometriotic ovarian cysts and of their sur -\ngical or medical treatment on pregnancy rates after ART is \nagain controversial. A Cochrane review evaluating sur -\ngery, medical treatment, combination therapy, or no treat-\nment for improving reproductive outcomes among women \nwith endometriomas prior to undergoing ART could not \ndetect any evidence of an effect in the included trials (but \nonly four trials were included).\n29 According to a review \npaper including six retrospective controlled studies, the \npregnancy rate after ART was either similar or reduced in \nwomen who previously underwent endometrioma surgery \nprior to ART, when compared to non-operated controls.\n20 \nIn the only RCT addressing this clinical question, 25 preg-\nnancy rates after ART were similar after cystectomy and \nafter expectant management. A systematic review and \nmeta-analysis\n30 concluded that surgical management of \nendometriomas has no significant effect on pregnancy \nrates compared to no treatment and that there is insuffi-\ncient evidence to suggest superiority of one treatment \nstrategy over another. This was confirmed in the review by \nHamdan et al.\n5\nThe effect of prolonged pituitary downregulation with \nGnRH-agonists (3–6 months) prior to ART has been sum-\nmarized by a Cochrane review including only three small \nRCTs.\n26,27,31,32 Although it was found to increase live birth \nrate by nearly four-fold compared to no pretreatment, the \n\nTomassetti et al. 161\nstrength of this evidence is hampered by the small sample \nsize and by the lack of data analysis in the subgroup of \nwomen with endometriomas. Potential adverse effects of \nthe intervention (miscarriage, multiple pregnancy, and \nectopic pregnancy) were not addressed in the included \nstudies.\nInternational guidelines on management of \nendometrioma prior to ART\nBased on the lack of clear evidence in the literature on what \nto do with an endometriotic cyst prior to starting an ART \ntreatment, clinicians mainly rely on guideline statements to \nmake clinical decisions in these patients. However, a lack \nof evidence (or knowledge gap) does not imply a lack of \npotential benefit, and therefore, surgery is often chosen as a \npossible strategy. This is reflected by a survey on clinical \npractices in endometriomas detected prior to ART, which \nconcludes that they are often operated on\n33 as there is the \nintuitive feeling that the presence of an endometrioma \nreduces the success rate and increases the risks of treatment \nwith ART, as many clinicians have experienced problems \nwith an endometrioma complicating oocyte aspiration.\nOn surgical treatment of endometriomas prior to ART, \nthe World Endometriosis Society (WES) consensus on cur-\nrent management of endometriosis\n34 states that—taking \ninto account the lack of evidence that surgical treatment of \nendometriosis improves pregnancy rates through ART, the \npossible damage of the endometrioma and/or surgery itself \nto the ovary, and the possible complications of endometrio-\nmas during ART—laparoscopic cystectomy may some-\ntimes be recommended for women with endometriomas \nlarger than 3 cm diameter. According to the European \nSociety for Human Reproduction and Embryology \n(ESHRE) Guideline on the management of women with \nendometriosis,\n8 it is recommended to clinicians that in \nwomen with endometrioma larger than 3 cm, cystectomy \nshould only be considered prior to ART to improve endo-\nmetriosis-associated pain or the accessibility of follicles (in \ncontrast to the recommendations in the previous version of \nthe guideline that recommended cystectomy in cysts larger \nthan 4 cm).\n35 They further recommend that clinicians coun-\nsel women with endometrioma regarding the risks of \nreduced ovarian function after surgery, the possible loss of \nthe ovary, and consider that the decision to proceed with \nsurgery should be taken carefully if the woman has had pre-\nvious ovarian surgery. Furthermore, the ASRM Practice \nCommittee on Endometriosis and Infertility\n36 concluded in \n2012 that in each case, the benefits (prevention of possible \ncyst rupture in large cysts, facilitation of oocyte retrieval, \ndetection of occult malignancy, avoidance of contamina-\ntion of follicular fluid with endometrioma content, and pre-\nvention of progression of endometriosis) and the risks \n(surgical trauma and complications, economic costs, poten-\ntial decreased ovarian response, and lack of evidence for \nimproved ART results) should be balanced by clinicians \nand that therefore surgery should be considered if the endo-\nmetrioma is larger than 4 cm.\nOn medical treatment prior to ART, no specific state-\nments exist on endometriosis cysts per se. With respect to \nguidelines on medical pretreatment prior to ART for endo-\nmetriosis in general, both the WES consensus\n34 and the \nESHRE guidelines 8 state that clinicians can prescribe \nGnRH-a for a period of 3–6 months prior to treatment with \nART (level B evidence). The opinion of the ASRM Practice \nCommittee on Endometriosis and Infertility (2012) is less \npositive toward prolonged downregulation with GnRH-a \nprior to ART, as they acknowledge that results described in \nthe literature are difficult to extrapolate to other popula-\ntions due to very high reported pregnancy rates and that it \nis unclear whether this therapy is equally beneficial for \nmild and severe stages of endometriosis and what the \nmechanisms might be.\n36\nStudy objectives\nAs described above, current statements on how to manage \nwomen with endometrioma(s) prior to ART cannot be \nmade based on the available literature; clearly, more stud-\nies are needed to address this important clinical question. \nThe aim of this study is to provide an answer by conduct-\ning a large international multi-center randomized clinical \ntrial comparing the effect of three different treatment strat-\negies on the rate of clinical pregnancy with fetal heartbeat \n(CPHB) after ART (no intervention, prolonged GnRH-a \ndownregulation, and surgical treatment) prior to starting \nART in women with at least one endometrioma with a \ndiameter of 3 cm or more. Apart from CPHB, we want to \nevaluate further the effect of these three strategies on live \nbirth rate, cumulative pregnancy rate, complications, qual-\nity of life (QOL), ovarian reserve and specific ART param-\neters (such as number of oocytes and embryo quality).\nMethods\nStudy hypothesis and design\nThe WERF EndoART study is designed as a parallel-group \nmulti-center randomized controlled clinical trial to test the \nhypothesis that in women with at least one endometriotic \novarian cyst with a diameter of 3 cm or more, the CPHB rate \nafter one initiated fresh ART cycle differs according to the \ntreatment received before the start of the ART cycle. Women \nwill be randomized into three different treatment groups: the \nDirect ART Group (no other treatment as preparation prior \nto the start of ART), the Surgery Group (surgical treatment \nof the ovarian endometrioma(s) prior to the start of ART), \nand the Ultra Long Group (prolonged (3–6 months) down-\nregulation with GnRH-a prior to the start of ART).\nThis trial is an effectiveness trial: as opposed to an effi-\ncacy trial, it evaluates whether an intervention with proven \n\n162 Journal of Endometriosis and Pelvic Pain Disorders 10(3)\nefficacy does more good than harm in the normally com-\nplex clinical setting.37 The goal is to measure the impact of \nreal-time clinical practice in real patients in a realistic set-\nting of clinical practice. In view of inherent heterogeneity, \nthis trial cannot be an efficacy trial. In a surgical interven-\ntion, it is impossible to completely standardize all intraop-\nerative procedure, as every operation is different. \nFurthermore, due to international and multi-center recruit-\nment, there will undoubtedly be variability in center-spe-\ncific practices of ART, surgery, and hormonal suppression \nwith GnRH-a, which cannot be tolerated in an efficacy \ntrial. However, in order to achieve as much standardization \nas possible, the methodology of an efficacy trial will be \napplied where possible. Furthermore, this study will take \nplace as a superiority trial, as outlined further below.\nSample size calculation\nSample size is estimated based on the primary outcome: \nCPHB rate per randomized patient 6 months after initiation \nof one fresh ART cycle (= per-protocol analysis). Sample \nsize is based on the baseline pregnancy rate expected in con-\ntrols, the clinically important difference that might be \nexpected with the surgical treatment and appropriate levels \nof alpha and beta error. With respect to the baseline preg-\nnancy rate, two retrospective studies and one prospective \ncontrolled but non-randomized trial have assessed surgical \ntreatment versus no treatment of endometriomas prior to \nART.\n38–40 Although the treatments were different, the con-\ntrol groups all received only ART treatment. The pregnancy \nrates were 20%, 23%, and 20%, respectively, in the three \nstudies, resulting in an average pregnancy rate of about \n21%. This trial is designed as a superiority trial, that is, to \ntest the hypothesis that there is a significant difference in the \nprimary outcome variable between three groups. Based on \nclinical grounds (patient burden, risks, and costs of surgery), \nit is reasonable to argue that unless the relative difference is \nas much as 33%, it may not be worthwhile to consider sur-\ngery. Given a baseline assumption of 21% of CPHB among \npatients with an endometrioma after one fresh ART cycle, it \nis reasonable to expect that the results should improve to \n28% (i.e. 33% increase) if ART is preceded by surgery.\nThe hypothesized effect size of prolonged downregula-\ntion in this study should be at least equal to the above \nhypothesized effect of surgery, taking into account addi-\ntional cost and patient burden (side effects and treatment \ndelay) as well as literature data suggesting a possible four-\nfold increase of odds for pregnancy.\n27 Given a baseline \nCPHB rate of 21%, a relative difference of 33% for the \nSurgery and the Ultra Long Groups, with the usual 5% \nalpha error (probability to wrongly reject the null hypoth-\nesis; type I error; ‘significance level’) and 20% beta error \n(probability to wrongly retain the null hypothesis; type II \nerror; ‘power’) assumptions, the number of patients needed \nwould be 563 per group using a chi-square test. To account \nfor 5% losses to follow-up after randomization, it is pru-\ndent to aim for a total sample size of 1800 patients (600 per \ngroup). These assumptions are conservative and allow for \nthe use of life table analysis and multivariate regression. \nNo stratification by endometriosis stage will be used, as \nthis decreases the sample per stratum and will make statis-\ntical analysis more complex. In addition, no stratification \nper center will be used, as including the trial center as a \nvariable in the proportional hazards analysis should be suf-\nficient to allow for the center effect (or clustering). It is \neven questionable whether within centers there is no vari-\nation among surgeons and reproductive endocrinologists \nwith respect to clinical techniques used (there probably is). \nTherefore, no sample size adjustments will be made to \navoid clustering effects.\nRecruitment and study sites\nPatient recruitment will cover a period of three full years, \nand the follow-up of the last recruited patient is estimated \nto be completed 15 months later, with a possible extension \nof 6 months to be able to record the follow-up of all live \nbirth rates.\nThis study will be conducted worldwide, matching the \nglobal research goals of the World Endometriosis Research \nFoundation (WERF). Only infertility centers/networks \nwith combined high-volume output and excellence in ART \nand in laparoscopic reproductive surgery for endometrio-\nsis (including experience and availability of techniques to \nperform ovarian sparing surgery) will be included. It is \naccepted that within the participating centers, women are \ntreated surgically by a different (i.e. adequately experi-\nenced) physician than for ART, on the condition that at the \nstart of the trial in each center, a list is provided of partici-\npating physicians, stating their specific expertise (surgery, \nART, or both).\nEligible centers worldwide can apply for study partici-\npation to the WERF EndoART consortium if they meet the \nfollowing eligibility criteria:\n•• Quality assurance in ART;\n•• At least 250 fresh ART cycles per year;\n•• Existence of a quality monitoring system, prefera-\nbly with external validation;\n•• Quality assurance in surgery;\n•• At least 12 endometrioma surgeries per year;\n•• Demonstrated ability to surgically treat all stages of \nendometriosis at the same surgery at which the \nendometrioma is diagnosed and treated;\n•• Video of surgical technique used for treatment of \nendometrioma to be submitted to the WERF \nEndoART Consortium;\n•• Ability to recruit at least 20 randomized patients \nduring a study period of 3 years; this is an essential \ncondition to qualify for co-authorship.\n\nTomassetti et al. 163\nThe WERF EndoART Coordinating Committee will \nreview every application and reserves all rights to make a \nfinal decision regarding acceptance or not of the applying \ncenter, according to the formal list of conditions and \nquality assurance (see above). Only this committee can \njudge the expertise, quality and reputation of the apply-\ning center. After approval of the WERF EndoART \nCoordinating Committee, the applying center becomes a \nmember of the WERF EndoART Consortium. A partici-\npating center will be excluded from further participation \nin this study if no patients have been randomized at 1 year \nafter start of the study at the site.\nRandomization and blinding\nPatients who meet the study criteria and who have signed \nthe informed consent form (ICF) are randomized into three \ngroups with an equal distribution (1/3, 1/3, and 1/3): the \nDirect ART Group, the Surgery Group, or the Ultra Long \nGroup. The study starts at the moment of randomization, \nincluding data recording on history, current symptoms, and \nQOL by the use of questionnaires (endometriosis patient \nquestionnaire—minimum required (EPQ-M) World \nEndometriosis Research Foundation (WERF) Endometriosis \nPhenome and Biobanking Harmonization Project II \n(EPHect) Questionnaire,\n41 30-item Endometriosis Health \nProfile (EHP-30) Oxford questionnaire,42,43 and other rele-\nvant data as summarized in Table 1). Randomization will be \ndone by centralized computer assignment, ensuring that the \nallocation sequence is concealed from study personnel to \nminimize a possible allocation bias during recruitment. \nBlock randomization by study center will be used to ensure \nallocation of equal numbers of subjects in each group per \ncenter. Blinding is neither applicable nor possible in this \nTable 1. Baseline data to be recorded.\n1. WERF EPHect Questionnaire—Minimum (EPQ-M) 41\n2. EHP-30 Oxford Questionnaire for QOL.42,43\n3. Additional data\nHistory Age at randomization (male and female)\nDuration of infertility (months)\nFertility work-up Male factor\n Moderate/severe; yes/no\n Date—classification of sperm sample (WHO 44)\nOvulation factor\n Ovulatory\n Oligo/anovulation WHO types I–II\n Expected or proven poor ovarian response45\nImplantation—date of ultrasound/hysteroscopy (if performed)\n Normal\n Congenital abnormality (definition ESHRE/ESGE\n46)\n Large intramural fibroid (> 3 cm)\n Adenomyosis\nTubal factor\n Normal\n Blocked left/right/both sides\nKaryotype male and female: date—results\nOvarian reserve testing At randomization or maximum 6 months prior\n AMH (date—result—assay)\n FSH (date—result)\n Antral follicle count (date—result)\nEndometriosis N previous therapeutic surgeries for endometriosis\nN previous ovarian surgery\n For endometrioma left/right/both sides\n For non-endometriotic cyst left/right/both sides\nHistory of salpingectomy left/right/both sides\nEndometriotic cyst(s)\n Transvaginal ultrasound\n  Date\n  For each cyst: localization and mean diameter (mm)\nCurrent hydrosalpinx no/right/left/both sides\nSuspected peritoneal lesions (imaging, prior surgery): yes/no\nSuspected deep lesions (clinical exam, imaging): yes/no\nWERF: World Endometriosis Research Foundation; QOL: quality of life; ESGE: European Society of Gynaecological Endoscopy; ESHRE: European \nSociety of Human Reproduction and Embryology; WHO: World Health Organization; AMH: anti-Müllerian hormone; FSH: follicle-stimulating hor-\nmone.\n\n164 Journal of Endometriosis and Pelvic Pain Disorders 10(3)\nstudy, as neither surgery, GnRH-downregulation, nor ART \ncan be blinded (no placebo surgery with mock incisions and \nno placebo medical pretreatment). However, biases to this \nare expected to be minimal because the primary outcome \nmeasured is clear and unambiguous. In theory, an influence \non retention of participants in the trial may be present as a \nresult of communication of personal ideas of health-care \nproviders involved after patients have been randomized. To \nmonitor this, both the number of screened/eligible versus \nrandomized patients as well as the number of post-randomi-\nzation drop-outs versus randomized patients will be recorded \nper center.\nStudy population\nThe study population includes women with at least one ovar-\nian endometriotic cyst with a diameter of at least 30 mm and \nwho have an indication for treatment with ART.\nInclusion criteria\nIndication for ART: based on existing guidelines 8,34,36 \nand can be summarized as follows: if tubal function is \ncompromised, if there is male factor infertility, and/or \nother treatments have failed and/or prolonged infertility \nof more than 4 years.\nAge: from 18 until 40 years included at randomization \n(as from 40 years onwards, baseline success rates of \nART are considerably lower and will therefore make it \nmore difficult to observe a difference between both \nstrategies).\nUltrasound diagnosis of at least one ovarian endometri-\notic cyst with a diameter of 30 mm or more, performed by \nan experienced practitioner using advanced ultrasound \nequipment. All patients in the WERF EndoART study \nmust fit the International Ovarian Tumor Analysis \n(IOTA)-criteria for reliable diagnosis of endometriomas \nin premenopausal women\n47 (positive predictive value \n(PPV) of 88.6%, sensitivity of 67.9%, and specificity of \n97.8%): ground glass echogenicity of the cyst fluid, one \nto four locules, and no papillations with detectable blood \nflow (alternatively when no Doppler used: no solid parts). \nIf there is doubt about the differential diagnosis with a \nfunctional ovarian (corpus luteum) cyst, a new ultrasound \nis performed to confirm the diagnosis of an ovarian endo-\nmetriotic cyst 6–8 weeks after the initial ultrasound. The \ncyst diameter is the mean (in millimeter) of diameters \nmeasured in the three dimensions of the cyst. Diagnosis \nand ultrasound assessment of the cyst should be per -\nformed maximally 3 months prior to randomization.\nExclusion criteria\nRecent therapeutic surgery for ovarian endometriotic \ncysts defined as excisional or ablative surgery of ovar -\nian endometriotic cyst(s) with or without excision of all \nvisible endometriosis and endometriosis-related adhe-\nsions in a period of 6 months before randomization.\nWomen with significant pelvic pain requiring elective \nsurgery, who are therefore unable to undergo direct ART \nor ART with ultralong GnRH-a downregulation.\nART with sperm derived from testicular biopsy for non-\nobstructive azoospermia because of lower observed \nART pregnancy rates compared to obstructive azoo-\nspermia.\n48 The use of donor sperm is allowed but should \nbe recorded.\nThe use of donor oocytes.\nART with preimplantation genetic testing (formerly \npreimplantation genetic screening (PGS) or preimplan-\ntation genetic diagnosis (PGD), viz. screening or diag-\nnosis),\n1 as the number of embryos suitable for transfer \nor cryopreservation is significantly lower compared to \nnormal ART.\n49\nHistory of unilateral oophorectomy or having an ovarian \nremnant, as in this case in clinical practice the threshold \nfor surgery on the remaining ovary will be higher, mak-\ning it unsuitable for randomization.\nSubject withdrawal. Withdrawal is defined as women leav-\ning the study after they have been randomized and does \nnot include mere screening failures. Women should not be \nrandomized until they have been screened and found to \nmeet the inclusion criteria.\nFollowing reasons will lead to subject withdrawal:\nWomen allocated to the Surgery Group whose histologi-\ncal tissue diagnosis at surgery did not confirm the pres-\nence of an endometrioma (e.g. corpus luteum cyst).\nWomen allocated to the Direct ART Group or Ultra \nLong Group undergoing ovarian surgery between rand-\nomization and the completion of the study period.\nWomen allocated to the Surgery Group who receive \nART treatment before they undergo surgery.\nParticipation in any other drug study during the dura-\ntion of the study.\nWithdrawal of consent.\nOther changes in medical condition that precludes con-\ntinuation in the study: must be clearly documented and \nmedically justifiable.\nStudy procedures\nThe study starts at the moment of randomization, and the \npatient ends the study when CPHB is diagnosed within \n6 months after initiation of the fresh ART cycle (i.e. \nfresh + associated frozen cycles) or when after one fresh \n\nTomassetti et al. 165\ncycle and its associated frozen embryo transfer (FET) \ncycles, no CPHB has been detected (until all frozen \nembryos have been used unless this follow-up time exceeds \n12 months after the initiated fresh cycle). Per patient, only \none fully completed ART cycle (fresh + associated frozen \ncycles within above-mentioned time frame) is performed \nwithin the study; in case an initiated fresh cycle is canceled, \nany subsequently initiated fresh cycles fall outside the \nscope of this study.\nAn initiated fresh cycle is defined as follows: an ART \ncycle in which the woman received specific medication for \novarian stimulation (i.e. start of gonadotropin administra-\ntion) with the intention to treat, irrespective of whether or \nnot follicular aspiration is attempted.\n1 All women, who \nachieved a CPHB within the study period, will be con-\ntacted 8–12 months later for follow-up on further preg-\nnancy outcome including live birth.\nART treatment (all groups). To avoid treatment bias, it is \nimportant that treatment with ART is standardized as \ndescribed in this section. All women will be treated with \nART according to routine practices in the participating \ncenters. Table 2 shows which ART procedures and varia-\nbles need to be recorded during this study.\nUse of GnRH-agonists. The use of cyclic or continu-\nous use of oral contraceptives or progestogens is allowed \nbefore the initiation of the fresh ART cycle and in between \nsubsequent frozen cycles, but has to be recorded. In both \nthe Direct ART Group and the Surgery Group, downregu-\nlation with GnRH-agonist should be used in a classical way \nand not last more than 28 days. More specifically, women \nrandomized to the Direct ART Group or the Surgery Group \nare not allowed to use GnRH-a for treatment of endome-\ntriosis in the 3 months prior to the start of the fresh ART \ncycle. Ultrasound-guided aspiration of persistent func-\ntional ovarian cysts before or during ovarian stimulation \nis only allowed if these cysts are clearly echolucent and \nunilocular and completely lack the typical endometrioma \ncharacteristics; aspiration of the endometrioma(s) is not \nallowed. Between the end of the fresh ART cycle and the \nend of the study period (in case frozen-thawed cycles are \nplanned), the use of GnRH-agonists is not allowed except \nas part of a hormonal replacement preparation for endome-\ntrium in a frozen-thawed cycle.\nOvarian stimulation protocols. For both fresh and fro-\nzen-thawed cycles, different stimulation protocols are \nallowed; for the fresh ART cycle, natural cycle or intended \nmild stimulation (= aiming at maximum 5 oocytes) is not \nallowed. The type of gonadotropin (highly purified, uri-\nnary, or recombinant) can be freely chosen by each center, \nas these products are equally effective with respect to clin-\nical pregnancy rate.\n50,51 As block randomization per center \nwill be used, it is expected that there will be no signifi-\ncant differences in ART protocols used in the three study \ngroups.\nOocyte retrieval. Oocyte retrievals (all study groups) \nwill be performed under intravenous antibiotic prophy-\nlaxis (cefazolin 2 g IV single dose or equal type and dose \nof other antibiotic) to prevent infection.\n52 During oocyte \nretrieval, ultrasound-guided puncture of the endometrioma \nshould be avoided in order to prevent infection and abscess \nformation; in case this accidentally happens, it must be \nrecorded and the content of the fluid must be sent for cyto-\nlogical examination. The cyst must not be drained if an \naccidental puncture happens.\nIVF and embryo transfer. Fertilization will be performed \nusing IVF or ICSI based on the routine practice of each \ncenter. Embryo culture is done using commercially avail-\nable culture media.\nThe main standardizing restriction in the ART treatment \nprotocol is the embryo transfer policy (cleavage or blasto-\ncyst stage, as per center routine practice):\n•• A maximum of two embryos in women of 36 years \nold or younger;\n•• A maximum of three embryos in women of 37 until \n39 years old inclusive;\n•• A maximum of four embryos in women of 40 years \nonwards.\nLuteal phase support. Luteal phase support regimen \nand duration are chosen freely by each center according \nto their standard practice, but should be documented. A \nnew egg aspiration cycle (i.e. after the end of the study \nperiod) is only initiated when all cryopreserved embryos \nhave been used.\nDirect ART group. Women in the Direct ART Group will \ninitiate their fresh ART cycle, without any intervention for \nthe endometrioma, within 6 months of randomization. \nObviously, prolonged downregulation with GnRH-a (other \nthan the short-term downregulation (maximum of 28 days) \nas in a classical agonist protocol) within 3 months before \nthe start of ART is not allowed in this group, as described \nabove. In case women are on GnRH-a treatment at the time \nof randomization, this means the use of GnRH needs to be \ndiscontinued and followed by a wash-out period of at least \n3 months before they can start ART.\nSurgery group. To minimize post-randomization withdrawal \nof subjects, women in the Surgery Group need to receive \nsurgery within 2 months after randomization and initiate \ntheir fresh ART cycle within 6 months after surgery. Pri-\nmarily, a laparoscopic approach should be used (state-of-\nthe-art, to enhance patient recovery), while recording any \nconversions to laparotomy. The technique used for \n\n166 Journal of Endometriosis and Pelvic Pain Disorders 10(3)\nTable 2. ART procedures and variables.\nPretreatment None (natural cycle prior to ART)\nCombined oral contraceptives (COC; generic name, start + end date)\nProgestogens only (POP; generic name, start + end date)\nGnRH-a (generic name, injection dates, and only in Ultra-Long Group)\nOvarian stimulation Type protocol\n Long agonist (generic name, date start agonist)\n Short agonist (generic name, date start agonist)\n Antagonist (generic name, date start antagonist)\n Clomiphene citrate + gonadotropin + antagonist (generic name, date start antagonist)\nGonadotropin:\n Type, generic name, start date\n Start dose (min 75–max 450 IU/day), highest daily dose (IU)\n Total dose used (IU)a\nOHSS (ovarian hyperstimulation syndrome) risk present: yes/no\nCoasting performed—yes/no, if yes: N days coasting\nEstradiol and progesterone level on day of decision: LH/HCG trigger (mg/dL)\nEndometrial thickness (mm) on day of decision: LH/HCG trigger\nN mature follicles (>13 mm) on day of decision: LH/HCG trigger\nLH/HCG trigger: generic name, dose, and date\nOocyte aspiration Cancelation: yes/no\n  If yes, state reason why (OHSS risk, insufficient ovarian response, premature LH/progesterone rise, \nother medical reasons, non-medical reasons)\nAge male and female at cancelation or aspiration\nAntibiotic prophylaxis: generic name, dose, and type of administration\nDate of aspiration, N hours between LH/HCG and aspiration\nRepeat US measurement of endometrioma(s) during aspiration\nAccidental puncture of endometrioma: yes/no\n If yes, result of cytology to be reported\nN mature follicles (>13 mm) not aspirated\n If >0: state reason why (endometrioma interpositioning, inaccessible ovary due to other reason, other)\nN follicles aspirated\nN oocytes obtained in total\n N mature oocytes\na\n N immature oocytes—N postmature oocytes\nFertilization N mature oocytes for IVF/N mature oocytes for ICSI\nN 2pn from IVF/N 2 pn from ICSI\nFertilization rate = N 2pn/N mature oocytes for IVF/ICSIa\nN embryos from IVF/N embryos from ICSI\nEmbryo transfer (fresh) Stage (cleavage, blastocyst), date of embryo transfer\nTotal N embryos available\n N good quality embryos available per aspirationa/per N 2pna\n N embryos frozena, freezing method and date\nN embryos transferred\n N top quality embryos transferred\nEmbryo utilization ratea: (N embryos transferred + N embryos frozen)/total N of embryos available\nUltrasound guided: yes/no\nLuteal support (fresh \nand frozen-thawed)\nProgesterone intramuscular/oral/vaginal\nHCG subcutaneous/intramuscular\nEnd of luteal support (N days after LH/HCG trigger)\nFrozen-thawed embryo \ntransfer\nEndometrial preparation\n Clomiphene citrate\n Natural cycle ± HCG trigger\n Gonadotropins ± HCG trigger\n Substitution protocol with GnRH-agonist\n Substitution protocol without GnRH-agonist\nEndometrial thickness on day of decision of thawing\nDate of thawing and date of embryo transfer\nStage at embryo transfer, further cleaving after thawing: yes/no\nN embryos thawed—N embryos survived\nN embryos transferred\nUltrasound guided: yes/no\nTotal N embryo transfers performed (fresh + frozen)\na\n(Continued)\n\nTomassetti et al. 167\nthe surgical treatment of the endometrioma is aimed at \nsimultaneously treating the endometrioma while minimiz-\ning ovarian damage. Although direct comparison of the \neffect of different techniques on ovarian reserve is not pos-\nsible according to current literature, in this study, only those \ntechniques associated with minimal ovarian damage are \nallowed. This strategy is defendable since this study focuses \non ART success and not on long-term recurrence risk of the \ncyst(s). In case a complete cyst ablation is performed, it is \nmandatory to also biopsy the cyst wall to confirm the diag-\nnosis of endometriosis through histological examination. \nAny of the following surgical techniques may be used: the \ncombined technique (stripping of the peripheral capsule \nand CO\n2-laser ablation near the hilus 12 or complete cyst \nablation with micro-bipolar, CO2-laser, or plasma energy, \npreferably using the lowest energy source available).53 This \nvariation in surgical technique is allowed as there is a need \nfor an intervention where small variability will not matter. \nIf deemed necessary according to the size of the cyst (e.g. \nlarger than 6 cm), a two-step laparoscopic procedure can be \nperformed. During the first step, the cyst is drained. After \nthis step, ovarian suppression with combined oral contra-\nceptives, oral progestogens, or GnRH-agonists will be pre-\nscribed during 6–8 weeks before the second surgical step. \nDuring this second step, surgical treatment of the ovarian \nendometrioma is performed as mentioned above. Standard \ncomplete cystectomy and unipolar ablation are not allowed \ndue to the larger anticipated effect on ovarian tissue dam-\nage. Not only the ovarian endometriotic cyst(s) must be \ntreated, but also excision of all visible endometriosis and \nendometriosis-related adhesions must be performed. Since \nthere is no evidence that one surgical treatment is superior \nto another regarding peritoneal endometriosis (resection or \ndestruction/coagulation), deep lesions (in case of bowel \nendometriosis: partial or full thickness disk excision, seg-\nmental bowel resection), and related adhesions, all these \ntechniques can be used in this study but need to be reported \nspecifically. The details of surgery will be recorded in a \nstandard surgical form, merging information from the \nWERF EPHect Standard Surgical Form\n54 and the CORDES \nDeep Endometriosis Surgical Sheet 55 as summarized in \nTable 3.\nObviously, postoperatively prolonged downregulation \nwith GnRH-a (other than the short-term downregulation \n(maximum of 28 days) as in a classical agonist ART-\nstimulation protocol) is not allowed in this group, as \ndescribed above. In case women are on GnRH-agonist \ntreatment at the time of randomization, this means the use \nof GnRH needs to be discontinued and followed by a \nwash-out period of at least 3 months before they can start \nART. Preoperative use of GnRH-a is allowed (in case of a \ntwo-step surgical approach also between the first and the \nsecond interventions), but again in that case patients will \nneed a wash-out period of 3 months postoperatively before \nthey can start ART treatment.\nUltra long group. Within 2 months of randomization, \nGnRH-a pretreatment (triptorelin, goserelin, and leupro-\nlide) should be started and continued during a minimum of \n3 months and a maximum of 6 months prior to commence-\nment of gonadotropin stimulation for ART. Add-back with \nlow-dose estrogens, with or without progesterone, or tibo-\nlone is allowed but needs to be documented. Patients will \nstart the ART treatment within 6 months of randomization. \nDue to the treatment allocation, the stimulation protocol \nwill invariably be an agonist protocol.\nParticipants flow. The participants flow within the WERF \nEndoART study is summarized in Figure 1.\nTrial monitoring and patient visits. Follow-up visits will be \nplanned (with local principal investigator (PI) or investiga-\ntor) in each center and are part of routine clinical care and \ntherefore will not add a significant burden to either patients \nor clinicians:\nOne visit at screening and initiation of the trial (study \ninformation, completion of ICF, and randomization).\nOne visit after (each) surgery for patients in the Surgery \nGroup.\nSevere adverse events No ovarian response in fresh cycle (no follicle development)\nInability to puncture mature follicles\nSignificant bleeding following oocyte aspiration\n  Requiring in-patient hospitalization ± blood transfusion ± surgical intervention\nSignificant pelvic infection within 14 days of oocyte aspiration\n  Raised temperature (>38°C), lower abdominal pain, biochemical signs of infection (elevated white cell \ncount, elevated C-reactive protein)\n Requiring in- or out-patient antibiotic treatment\nOvarian abscess ± surgical intervention\nOHSS requiring in-patient hospitalization\nART: assisted reproductive technologies; GnRH-a: gonadotropin-releasing hormone agonists; LH: luteinizing hormone; HCG: human chorionic \ngonadotropin; OHSS: ovarian hyperstimulation syndrome; IVF: in vitro fertilization; ICSI: intracytoplasmic sperm injection.\naSecondary outcome variables.\nTable 2. Continued\n\n168 Journal of Endometriosis and Pelvic Pain Disorders 10(3)\nOne visit after the first initiated ART cycle, regardless \nof its outcome (i.e. with or without oocyte aspiration or \nembryo transfer) and (if applicable) its associated fro-\nzen-thawed embryo transfer cycle, in any case at the \nend of the study period if no CPHB is obtained.\nIn case the primary outcome is reached (CPHB), a study \nvisit is optional and may be replaced by a visit to the \nobstetrician who will follow the pregnancy; in the latter \ncase, a formal written report with confirmation of \nCPHB by ultrasound is necessary.\nOutcome measures\nPrimary outcome. The primary outcome studied is CPHB. \nThis outcome parameter is a suitable and realistic surrogate \noutcome.37 More specifically, the CPHB rate per rand-\nomized patient within 6 months after initiation of the fresh \nART cycle (= per-protocol analysis) is the main outcome \nstudied, upon which also power and sample size calcula-\ntions are based. As explanatory information, it will be \nrecorded how these CPHBs were achieved (pregnancy after \nART in fresh or frozen-thawed cycle, escape intrauterine \ninsemination (IUI), and spontaneous pregnancy after \ncancelation of the cycle or between cycles). The CPHB \nshould be documented by a written report in the patient \nrecord (a copy of the ultrasound image is not compulsory).\nSecondary outcomes. The secondary outcome measures \nrelated to reproductive outcome include CPHB rate per \nfully completed (= fresh + all associated frozen-thawed \nTable 3. Surgical procedure: variables, work-up, staging, and adverse events.\n1. WERF EPHect Standard Surgical Form (EPHect SSF)54\n2. If deep endometriosis is present: CORDES Deep Endometriosis Surgical Sheet55\n3. Other information to be recorded:\nGeneral information Surgeon\nDate of (second step) surgery\nPreoperative work-up Hormonal treatment between randomization and surgery\n None (natural cycle prior to ART)\n COC (generic name, start + end date)\n POP (generic name, start + end date)\n GnRH-a (generic name, injection dates)\nPresumed diagnosis apart from endometrioma(s):\n Peritoneal endometriosis: yes/no\n Deep endometriosis lesion: yes/no\nSurgical procedure summary Endometrioma surgery\n Two-step procedure: yes/no\n If yes: date of first intervention (marsupialization)\n Per cyst: describe side and diameter and technique used:\n Ablation only or combined resection/ablation near hilus\n Energy source\n  Ultrasound\n  Bipolar (unipolar ablation not allowed!)\n  Laser CO\n2\n  Other laser\n  Plasma energy\n Ovarian reconstruction (suture used)\n Ovariectomy performed: yes/no\n Picture of each ovary before and after intervention\n Histology result: endometrioma confirmed: yes/no\nSalpingectomy: no/left/right/both sides\nNon-endometriotic cyst removed: yes/no (histology result)\nOther endometriotic lesion treatment as in CORDES\nConversion to laparotomy and reason why (bleeding, bowel resection, ureter reimplantation, other)\nSevere adverse events Within 6 weeks after surgery\n Classification according to Clavien-Dindo56\n Specification of the problem\n Bleeding\n Pelvic infection\n Rectovaginal fistula\n Thrombo-embolic complications\nPostoperative premature ovarian failure (amenorrhea and hypergonadotropic hypogonadic state)\nWERF: World Endometriosis Research Foundation; ART: assisted reproductive technologies; COC: combined oral contraceptives; POP: progesto-\ngens only; GnRH-a: gonadotropin-releasing hormone agonists.\n\nTomassetti et al. 169\ncycles) ART cycle, cumulative live birth delivery rate per \ninitiated fresh ART cycle and per fully completed ART \ncycle, and CPHB rate and live birth delivery rate per patient \nduring the study period, including also eventual expectant \nfertility management pregnancies or after escape-IUI \n(intention-to-treat analysis) with reporting of the mode of \npregnancy. ART-specific outcome data for fresh and associ-\nated frozen cycles, more detailed pregnancy outcomes \n(Table 4), and QOL and adverse events will be recorded \nand analyzed. Since, after randomization, women in the \nSurgery and Ultra Long Groups are expected to start later \nwith their fresh ART cycle than women in the Direct ART \nGroup, also the time to pregnancy of any CPHB detected \nduring the study period will be reported. Next to this, the \ntime interval between randomization and the start of the \nfirst ART cycle will also be recorded in all three groups, \nsince the time factor (waiting period before start of ART) is \na relevant variable for women.\nIn order to quantify the effect of no intervention, sur -\ngery, and prolonged GnRH-agonist downregulation on \novarian function, ovarian reserve tests will be done at ran-\ndomization (or not more than 6 months prior) and at base-\nline (maximum 1 week before the start of gonadotropin \nstimulation for the fresh ART cycle). For AMH serum \nlevel measurements, the assay used for each center will be \nrecorded to enhance comparability. Longer term re-assess-\nment (e.g. 1 year after start of ART) of ovarian reserve is \ncurrently not attempted due to a perceived higher risk of \nlosses to follow-up in that particular case.\nPelvic pain and QOL will be assessed at two time points: \nrandomization and the end of the study. If CPHB occurs \nduring the study period, this assessment will be done within \n6 weeks of confirmation of CPHB. Visual analog scales \n(V AS) will be used to assess pain, with different assess-\nments of dysmenorrhea (menstrual pain), dyspareunia (pain \nduring sexual intercourse), and non-menstrual pelvic pain \n(NMPP).\n57 The validated WERF EPHect Questionnaire—\nMinimum (EPQ-M)41 and the EHP-30 Oxford question-\nnaire42,43 will be filled in at randomization and at the end of \nthe study. For the EPQ-M, only relevant clinical parts \nregarding current situation will be filled in at the end of the \nstudy (questions C2–C11, C17–C24, C27–C35, D5–D7, \nE1–E2) to avoid duplication. Reporting of adverse events \nand complications will comply with the principles of Good \nClinical Practice and the local regulations and according to \nthe rules in the countries/centers where the study is con-\nducted. Study-specific recording of adverse events and \nother secondary outcomes are in the tables describing the \nART and surgical procedures.\nStatistical analysis\nData will be analyzed using a per-protocol approach (pri-\nmary outcome). Similarly, an intention-to-treat analysis \nwill be performed. Comparisons will be made using the \nchi-square tests for proportions and one-way analysis of \nvariance (ANOV A) for continuous variables (if conditions \nare not satisfied, Kruskal–Wallis will be used).\nFigure 1. Summary of participants flow in the WERF EndoART.\n\n170 Journal of Endometriosis and Pelvic Pain Disorders 10(3)\nSubgroup analysis per center will not be carried out as \nit is normal to have variability in success rates between \nand within centers just by chance in the number and pop-\nulation (e.g. age) of subjects studied in this trial. Subgroup \nanalysis per center can therefore lead to incorrect conclu-\nsions on surgical and/or ART performances of individual \ncenters. A subgroup analysis is proposed to account for \nthe possible effect of previous ovarian surgery for endo-\nmetriomas\n22 to compare women with and without previ-\nous ovarian surgery for endometrioma. Further subgroup \nanalysis will also be carried out according to the size and \nnumber of the ovarian endometrioma, the co-existence of \ndeep lesions, and (in the surgery group) for the surgical \ntechnique used (CO\n2-laser ablation, plasma energy abla-\ntion, micro-bipolar ablation, and combined CO 2-laser \ntechnique).53\nAn interim analysis will be performed for the primary \nendpoint only, to assess proven effectiveness or futility, by \na designated Data and Safety Monitoring Committee \n(DSMC) when half of the randomized patients have been \nassessed on the primary outcome (the presence or absence \nof CPHB within 6 months after initiation of the fresh \nTable 4. Pregnancy outcome variables.\nPregnancy diagnosis Date of HCG serum testing\n Positive/negative result\nIf positive: value of serum HCG in IU/L\nIf clinical pregnancy: date of first ultrasound confirmation\nIf fetal heartbeat: date of first ultrasound confirmation\nFirst trimester pregnancy evolution Maximal outcome at 12 weeks\n Biochemical pregnancy\n Clinical pregnancy (CP) but ectopic (N ectopic sacs)\n Clinical pregnancy, no fetal heartbeat, miscarriage\n Clinical pregnancy, fetal heartbeat\n  = PRIMARY OUTCOME: within 6 months of ART start\n Miscarriage\n Ongoing at 12 weeks\nIn case of clinical pregnancy\n Maximal N of intrauterine and/or ectopic sacs\n Maximal N of intrauterine fetal heartbeats\nIn case of multiple pregnancy\n N fetuses\n N chorion\n N amniotic sacs\n Vanishing multiple: yes/no (N vanished)\n Fetal reduction: yes/no (N of sacs removed)\nEnd of pregnancy Date\nInduced abortion: yes/no\nDelivery (>20 weeks): yes/no\n Mode of delivery: vaginal/caesarian section\n N of live born babies\n N of still born babies\n Birth weight and sex (of each baby)\n Admission to neonatal unit: yes/no (for each baby)\nSecondary outcomes studied CPHB rate at the end of the study period\nTime to CPHB: from moment of randomization, moment of surgery, and start of ovarian \nstimulation during the fresh ART cycle\nLive birth rate\nCP and CPHB rate\n Per initiated/aspirated/transferred fresh ART cycle\n Per frozen-thawed transferred cycle\n Per embryo transferred (fresh, frozen)\n Per completed cycle (fresh + frozen)\nMaternal/fetal pregnancy \ncomplications\nPregnancy-induced hypertension\nPre-eclampsia\nEclampsia\nAbnormal placentation (previa/accreta/percreta)\nGestational diabetes\nMajor congenital anomaly\n1\nHCG: human chorionic gonadotropin; CPHB: clinical pregnancy rate with fetal heart-beat; ART: assisted reproductive technologies.\n\nTomassetti et al. 171\ncycle). The results of this analysis will not be disclosed to \nthe investigators, unless it is necessary to stop the trial (e.g. \nproven effect). The study will only be stopped if signifi-\ncance for the primary outcome variable is reached before \nthe anticipated number of patients have been recruited. \nFurthermore, the DSMC can terminate the study if in their \nopinion, for whatever reason, a significant number of \nadverse events have occurred as a result of performing the \nstudy, although unexpected severe adverse events are not \nanticipated since this trial compares three existing and \naccepted treatment strategies.\nConclusion\nClinical management of endometriomas prior to starting \ntreatment with Assisted Reproductive Technology (ART) \nhas long been a matter of debate, but so far no large (rand-\nomized) trials have been performed to settle firmly the dis-\ncussion on the ideal patient management strategy. Whereas \ncystectomy prior to ART has been advocated in the past, \nrecently more evidence is emerging on the potential nega-\ntive effect of surgery on ovarian reserve. Next to this, pro-\nlonged downregulation with GnRH-a prior to starting ART \nhas been described to improve ART pregnancy rates in \nwomen with endometriosis. The WERF EndoART trial is \nessential to answer one of the most frequently asked ques-\ntions by both patients and physicians regarding endome-\ntriosis and ART: what to do with an endometrioma in the \ncontext of ART? Therefore, this study is designed to assess \nwhether ovarian surgery (but not complete cystectomy \nnear the hilum) or prolonged GnRH-a downregulation \nresult in higher pregnancy rates after ART compared to no \nintervention in women with endometrioma(s), by means of \na parallel randomized multi-center trial. The history of this \ntrial protocol is long: back in 2007 the study question of \nthis trial was recognized by WERF as one of the most \nimportant knowledge gaps in endometriosis and infertility \ntreatment and selected as a top priority project eligible for \nfunding. Between 2008 and 2015, this protocol has been \nrewritten and re-edited by the authors many times, with the \naim to appeal to a large group of international endometrio-\nsis and ART specialists and to comply with the ever evolv-\ning scientific literature. Unfortunately, this study did not \ncommence due to various reasons.\nFirst (and most important), a lack of funding and finan-\ncial support, despite efforts made by WERF and the \nauthors of this article to attract industry partners. Second, \nto reach the sufficient power to answer the study question, \nthere is a need for a large international consortium with \nextensive logistic support to organize this trial, at present \nnot possible with funding by academic resources only. The \npublication of this protocol is important for future investi-\ngators and sponsors, as it has been thoroughly developed \naccording to the state of the art in trial design by a large \ngroup of international experts.\nAuthors’ note\nDr. Adamson is no longer associated with Palo Alto Medical \nFoundation Fertility Physicians of Northern California, East Palo \nAlto, CA, USA. He is Clinical Professor, ACF at Stanford \nUniversity and Associate Clinical Professor at University of \nCalifornia San Francisco, San Francisco, CA, USA. Ben-Willem \nMol is now affiliated to Monash University, Melbourne, VIC, \nAustralia.\nDeclaration of conflicting interests\nThe author(s) declared the following potential conflicts of interest \nwith respect to the research, authorship, and/or publication of this \narticle: Dr D’Hooghe reports grants from Merck Serono and \nFerring; personal consultancy fees paid to him via Leuven Research \nand Development for consultancy work for WHO, Actavis, \nAstellas, Cartagenia, Bayer, Roche, and Proteomika; and clinical \ntrial financial support from Actavis, Roche, and Proteomika, In \nOctober 2015, Dr D’Hooghe became Vice-President and Head of \nGlobal Medical Affairs Infertility for Merck Serono. He continues \non a part-time basis his academic appointment as Professor of \nReproductive Medicine at the University of Leuven (KU Leuven) \nin Belgium and as Adjunct Professor at the Department of Obstetrics \nand Gynecology at Yale University, New Haven, CT, USA. 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