{"paper_id":"61748c28-6022-45d2-9e11-d416efe354c5","body_text":"MRI markers of adenomyosis severity associated with worse\nIVF/ICSI outcomes\nCitation for published version (APA):\nRees, C. O., Kocyigit, S., Nederend, J., Mischi, M., van Vliet, H. A. A. M., & Schoot, B. C. (2023). MRI markers of\nadenomyosis severity associated with worse IVF/ICSI outcomes. Journal of Endometriosis and Pelvic Pain\nDisorders, 15(3-4), 134-144. https://doi.org/10.1177/22840265231195404\nDocument license:\nTAVERNE\nDOI:\n10.1177/22840265231195404\nDocument status and date:\nPublished: 01/12/2023\nDocument Version:\nPublisher’s PDF, also known as Version of Record (includes final page, issue and volume numbers)\nPlease check the document version of this publication:\n• A submitted manuscript is the version of the article upon submission and before peer-review. There can be\nimportant differences between the submitted version and the official published version of record. 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Jun. 2026\n\nhttps://doi.org/10.1177/22840265231195404\nJournal of Endometriosis and  \nPelvic Pain Disorders\n2023, Vol. 15(3-4) 134 –144\n© The Author(s) 2023\nArticle reuse guidelines: \nsagepub.com/journals-permissions\nDOI: 10.1177/22840265231195404\njournals.sagepub.com/home/pev\nJEPPD\nJournal of\nEndometriosis and \nPelvic Pain\nDisorders\nIntroduction\nAdenomyosis is a benign gynaecological condition char -\nacterised by the infiltration of endometrial tissue and \nstroma into the myometrium of the uterus, causing disrup-\ntion in the so-called junctional zone (JZ).\n1 The prevalence \nof adenomyosis is unclear due to lack of consensus in \ndiagnostic method and criteria, with reported prevalence \nvarying widely from 5 to 70%.\n2,3 Younger nulliparous \nwomen are being more frequently diagnosed with adeno-\nmyosis and it is increasingly being linked to poor obstetric \noutcomes and infertility.\n4–7 A recent meta-analysis showed \nMRI markers of adenomyosis severity \nassociated with worse IVF/ICSI outcomes\nConnie Odette Rees1,2,3 , Sehriban Kocyigit1 , Joost Nederend4, \nMassimo Mischi2, Hubertus A. A. M. van Vliet1,3  \nand Benedictus Christiaan Schoot1,2,3\nAbstract\nStudy objective: The aim of this study was to characterise the severity of adenomyosis on MRI in infertile women, and \nto assess if MRI characteristics of adenomyosis severity are associated with worse IVF/ICSI pregnancy outcomes versus \nmale infertility controls.\nMaterials and methods: This single-centre retrospective study was carried out at Catharina Hospital in Eindhoven, \nThe Netherlands. The MRIs of 124 infertile women undergoing their first, fresh embryo transfer during IVF/ICSI, \ndiagnosed with adenomyosis only (N = 31), or combined adenomyosis and endometriosis (N = 93) were assessed. \nMeasurements of MRI adenomyosis features were performed by two independent investigators. IVF/ICSI outcomes \n(biochemical pregnancy (BP), ongoing pregnancy (OP) and live birth (LB)) of adenomyosis patients were compared to \nthose of 889 male infertility controls.\nResults: Patients with adenomyosis had significantly worse IVF/ICSI outcomes compared to male infertility controls. \nWhen assessing individual MRI parameters, adenomyosis patients with a mean junctional zone (JZ) of > 12 mm, \na JZ/Myometrium ratio of > 40%, presence of myometrial cysts and presence of endometriosis (specifically deep \ninvasive endometriosis(DIE)) showed statistically significantly worse outcomes compared to patients with milder \ndisease.\nConclusion: The results of this retrospective study suggest that individual MRI markers for severe adenomyosis (mean \nJZ > 12 mm, myometrial cysts), especially when combined with (severe) endometriosis, may be associated with fewer \npregnancies during IVF/ICSI when compared to male infertility controls. Future prospective studies should investigate \nthe prognostic potential of these markers for prediction of IVF/ICSI success.\nKeywords\nAdenomyosis, infertility, assisted reproductive technologies, magnetic resonance imaging, pregnancy\nDate received: 13 January 2023; accepted: 29 July 2023\n1 Department of Gynaecology and Obstetrics, Catharina Hospital, \nEindhoven, North Brabant, the Netherlands\n2 Department of Electrical Engineering, Eindhoven University of \nTechnology, Eindhoven, North Brabant, the Netherlands\n3 Department of Reproductive Medicine, University Hospital Ghent, \nGhent, Belgium\n4 Department of Radiology, Catharina Hospital, Eindhoven, North \nBrabant, the Netherlands\nCorresponding author:\nConnie Odette Rees, Department of Gynaecology and Obstetrics, \nCatharina Hospital, Michelangelolaan 2, Eindhoven, North Brabant \n5623EJ, the Netherlands. \nEmail: connie.rees@catharinaziekenhuis.nl\n1195404PEV0010.1177/22840265231195404Journal of Endometriosis and Pelvic Pain DisordersRees et al.\nresearch-article2023\nOriginal Research Article\n\n\nRees et al. 135\ndetrimental effects of adenomyosis on in vitro fertilisation \n(IVF) outcomes, with significantly reduced implantation, \nclinical pregnancy, ongoing pregnancy and live birth in \nadenomyosis patients.\n8\nDiagnosis of adenomyosis\nConventionally, the diagnosis of adenomyosis was obtained \nhistologically from hysterectomy specimens, and this \nremains the gold standard.\n9 With the advent of improved \nimaging techniques, the diagnosis can also be made via \ntrans-vaginal ultrasound (TVUS, sensitivity 78%, specific-\nity 78%, positive likelihood ratio of 3.5 and a negative like-\nlihood ratio of 0.28) and magnetic resonance imaging \n(MRI, sensitivity of 78%, specificity of 88%, a positive \nlikelihood ratio of 6.8 (4.5–10%), and a negative likelihood \nratio of 0.25).\n10,11 TVUS is arguably less reliable for diag-\nnosing adenomyosis as it is relatively operator dependent.10 \nFurthermore, distinguishing adenomyosis from other uter-\nine disorders such as leiomyomas or carcinomas can be dif-\nficult on TVUS. MRI is therefore often the preferred \ndiagnostic method, specifically in atypical or mild cases of \nadenomyosis.\n9,12 Unfortunately, in contrast to TVUS, which \nhas clear diagnostic criteria (the MUSA criteria13), there are \nno accepted diagnostic criteria for adenomyosis for MRI. \nThe most widely reported MRI criteria are based on the \nappearance of the JZ, by looking at the following three fea-\ntures: (i) a JZ thickness ⩾12 mm; (ii) a ratio of greater than \n40% of JZ to myometrium and (iii) a difference greater than \n5 mm between the maximum and minimum JZ diameter. \nThere are further reported indirect and direct criteria for \nadenomyosis (with presence of myometrial cysts seeming \nmost promising) on MRI but their diagnostic and clinical \npotential remains unclear.\n14,15\nJunctional zone and infertility\nAlterations in the JZ have been linked to fertility, as the JZ \nis influenced by cyclical hormonal changes in accordance \nwith the endometrium.\n16,17 The JZ is believed to play an \nimportant in role in uterine contractions which are crucial \nfor spermatozoa transport and embryo implantation.\n18 A \nhandful studies have specifically investigated whether \nchanges in the JZ could be linked with fertility outcomes.\n19,20 \nLimited studies have investigated the direct link of the type \nand the severity of adenomyosis to fertility outcomes how-\never, with those that have showing conflicting results. A \nstudy by Tamura et al.\n21 showed that women with diffuse \nadenomyosis had worse fertility outcomes. Conversely, a \nstudy by Exacoustos et al.\n22 showed that focal adenomyosis \nwas more often associated with infertility. By extensively \ncharacterising adenomyosis on MRI, the burden of disease \ncould perhaps be definitively correlated with fertility out-\ncomes and thereby inform clinical decision making.\nTherefore, the aim of this study was to retrospectively \nquantify and characterise the extent of adenomyosis on \nMRI in infertile women undergoing IVF/ICSI, and to eval-\nuate if certain MRI characteristics of adenomyosis severity \nshow worse IVF/ICSI outcomes compared to controls.\nMaterials and methods\nStudy design and setting\nThis single-centre retrospective case-control study was \nconducted at the Catharina Hospital in Eindhoven, the \nNetherlands, a regional referral centre for fertility and \nendometriosis treatment. Patients were included between \nthe years of 2007 and 2020. This study was ethically \napproved by the local institutional review board and the \nregional Medical Ethical Committee with study number \nnWMO-2020.005/W20.045, in March 2020.\nEligibility criteria\nIVF/ICSI patients between the ages of 18 and 42 years, \nundergoing their first, fresh embryo transfer in our centre \nbetween 2008 and 2020 were eligible.\nStudy population\nIVF/ICSI patients that received an MRI at our hospital \n(according to local MRI protocol, see Supplemental \nAppendix 1) on suspicion of adenomyosis and/or endome-\ntriosis were chosen as our study group. In order to confirm \nthe initial diagnosis of adenomyosis and/or endometriosis \nof the MRI’s that were conducted, a reassessment was \nmade of these MRI’s by pelvic radiologists and a study \ninvestigator (CR). The diagnosis of adenomyosis on MRI \nwas made based on one of three criteria: (I) JZ thickness \n⩾12 mm on T2 either focally or diffusely, (II) the presence \nof high signal intensity foci (HSI) in the myometrium on \nT1 and/or T2 concordant with an adenomyotic cyst, (III) \nJZ/myometrium ratio of >40% on T2. The diagnosis for \nendometriosis was based on the presence of one of the fol-\nlowing criteria; (I) hyperintense (multiple) ovarian cysts \non T1 and hypointense intensity on T2, (II) endometriosis \nplaques and (III) deep infiltrating endometriosis. Patient \nmedical files were then assessed in order to identify which \nof these patients had undergone IVF/ICSI treatment and \nreceived their first fresh embryo transfer (ET) in our fertil-\nity department. Patients were included regardless of the \ntiming of the MRI in relation to IVF/ICSI treatment.\nControl population\nThe control group included women undergoing IVF/ICSI \ntreatment due to a male factor only, with normal uteri on \nTVUS, or MRI where available. We chose only to include \ncontrols on the basis of normal uterus on imaging and only \na male factor to minimise the chance of including undiag-\nnosed adenomyosis patients into the control group.\n\n136 Journal of Endometriosis and Pelvic Pain Disorders 15(3-4)\nExclusion criteria\nPatients who did not undergo ET, or only underwent fro-\nzen ET were excluded. Patients who explicitly objected to \nthe usage of their medical data for research purposes were \nalso excluded.\nIVF/ICSI treatment protocol\nIncluded patients had to meet the local eligibility require-\nments of IVF/ICSI treatment protocol (see Supplemental \nAppendix 2). Patients first received pituitary downregulation \nwith a recombinant GnRH agonist (Decapeptyl®, Ferring \nGmbh, Germany), followed by ovarian stimulation. For \novarian stimulation either recombinant follicle stimulating \nhormone (Gonal-F®, Merck B.V . the Netherlands) or human \nmenopausal gonadotrophin (Menopur®, Ferring B.V . the \nNetherlands, Fostimon®, Goodlife Fertility B.V . the \nNetherlands) was used. Fertilisation of the oocytes occurred \nthe same day as oocyte retrieval, either by IVF or ICSI \ndepending on the patients’ medical indication. Three days \nafter oocyte retrieval, ET (single or double) was carried out \nafter administration of a human gonadotrophin (HCG, \nPregnyl®, Merck Sharp & Dohme, Canada) boost. According \nto the local and alpha scoring criteria (see Supplemental \nAppendix 3) selection of the best quality embryos for trans-\nfer was carried out. Luteal support was maintained with \nintravaginal progesterone (Uterogestan®, Besins Healthcare, \nthe Netherlands) and was initiated after ET.\nPelvic magnetic resonance imaging\nThe standard MRI protocol for pelvic examinations at this \nhospital included the following sequences; T2-weighted \nturbo spin echo (T2-TSE) sequences in the sagittal, axial \nand coronal planes, as well as T1-weighted turbo spin echo \n(T1-TSE) sequences in the axial plane. All scans were car-\nried out with either a 1.5T or 3T MRI system (Phillips, \nIngenia, the Netherlands). In order to minimise the effects \nof bowel motions/spasms and uterine peristalsis on image \ninterpretation, all patients were administered an antispas-\nmodic agent (1 mL of 20 mg/mL Buscopan®, Sanofi, Paris, \nFrance) intravenously or intramuscularly. The slice thick-\nness used was generally 3 mm, with slight variations rang-\ning from 3 to 5 mm. Minor changes existed in the protocol \nthroughout the years, but had no significant impact on the \ndiagnostic quality of the MRIs. In case of patients receiv-\ning multiple MRI’s, the MRI performed closest to IVF/\nICSI treatment was chosen for measurements. Full details \ncan be found in Supplemental Appendix 1.\nMRI measurements\nThe MRI features assessed with a brief definition, unit, \ncalculation and stratification can be found in Table 1, and \nan illustration of measurements taken shown in Figure 1. \nMeasurements were performed independently by two \nstudy investigators (COR and SK) using Sectra IDS7 ver -\nsion 21.1 (Linköping, Sweden). The investigators’ meas-\nurements were subsequently compared and measurements \nwere considered equal when there was a difference ⩽1 mm. \nA pelvic radiologist was consulted when doubts presented \nabout the performed measurements. For all measurements, \nthe junctional zone was defined as a low signal intensity \nregion between the high signal intensity region of the \nendometrium and the intermediate signal intensity region \nof the outer myometrium on T2. In case of an ill-defined \njunctional zone which inhibited accurate measurement, the \nMRI was labelled as having ‘poor JZ definition’. Focal \nadenomyosis was defined as focal widening of the JZ, or \nan ill-defined low signal intensity region of the uterine \nwall. In order to avoid mistaking uterine contractions for \nfocal lesions, the precise location of the low signal inten-\nsity region was assessed in three directions (using a locali-\nsation cursor). When this low intensity region was not seen \nin other directions, it was categorised as a uterine contrac-\ntion. Diffuse adenomyosis was defined in case of a diffuse \nthickening of the JZ of ⩾12 mm showing a low T2 signal \nintensity with indistinct margins (Figure 1(c)).\nOutcomes\nThe primary outcomes of this study included: (I) biochem-\nical pregnancy (BP, a positive HCG test on day 16 post- \nET), (II) ongoing pregnancy (OP, presence of a foetal \ncardiac activity on ultrasound 11 weeks after ET), (III) live \nbirth (LB, delivery of a viable foetus >24 weeks of gesta-\ntional age). Secondary outcomes included the MRI charac-\nteristics of adenomyosis as shown in Table 1.\nData sources and management\nPatient characteristics, radiology reports and MRI data \nwere retrieved from the electronic hospital patient records \nprogramme HIX (Chipsoft 6.1, Amsterdam, The \nNetherlands). Data concerning the IVF and ICSI cycles \nwas retrieved from the Dutch national fertility database \n(Landelijk Specialistisch Fertiliteits Dossier, LFSD, \nStichting Automatisering Fertiliteit (SAF), Utrecht, the \nNetherlands)). All patient data and MRI measurements \nwere recorded in a secure electronic database (Research \nManager version 5.53 (Cloud9 software, Deventer, the \nNetherlands)) and were later exported to IBM SPSS statis-\ntics (version 27) for data analysis.\nStatistical analysis\nThe Shapiro-Wilk test was applied to assess normal distri-\nbution of data. Normally distributed data were presented \n\nRees et al. 137\nas mean ± standard deviation (SD) and in case of non-\nnormally distributed data as median (interquartile range). \nBetween-group differences were assessed using the inde-\npendent T-test or Mann-Whitney U test for the continuous \nvariables, and for categorical variables a Chi-squared test \nor Fisher’s exact test was performed (with Bonferroni cor-\nrection). Subsequently, a multivariate logistic regression \nanalysis for IVF/ICSI outcomes was carried out correct-\ning for age at IVF, IVF or ICSI treatment, number of \ntransferred embryos and embryo quality, leading to \nadjusted odds ratios (aOR). with 95% confidence interval \n(95% CI). Overall, a p -value of < 0.05 was considered \nsignificant.\nResults\nPatient inclusion and characteristics\nOne hundred twenty-four women with MRI-diagnosed \nadenomyosis were included (see Figure 2). Thirty-one \nwomen had only adenomyosis and 93 women had both \nadenomyosis and endometriosis. Eight hundred eighty-\nnine patients undergoing IVF/ICSI treatment due to male \nfactor only were included in the control group. Table 2 \nshows demographic and IVF/ICSI treatment characteris-\ntics of both groups.\nControls more often underwent ICSI treatment (80.1 vs \n25.0%, p < 0.001) and also had more viable oocytes (8.0 \nvs 7.0, p = 0.015) and embryos (5.0 vs 4.0, p < 0.001) ver-\nsus adenomyosis patients. Embryo quality was similar \nbetween groups (p = 0.112), but did differ (p < 0.001) \nwhen looking only at the second transferred embryo where \napplicable.\nMRI characteristics\nA summary of all MRI characteristics can be seen in \nTable 3. Figure 3 shows several illustrative examples of \nadenomyosis. Thirty-six women received an MRI in \nadvance of their first IVF/ICSI cycle,  of which twelve \nwomen achieved pregnancy, and 24 did not. Seventy-\neight women underwent MRI after fertility treatment, of \nTable 1. MRI characteristics of adenomyosis: objective adenomyosis MRI features, based on Rees et al. 14\nMRI feature Definition Unit Stratification\nAverage Junctional Zone \nthickness (AJZ)\nMean of JZ measurement at 6 points of the uterus: \nFundus, Mid-corpus, Isthmus, measuring the anterior \nand posterior wall at each point in the mid-sagittal \nplane.\nmm >7 mm, >10 mm, >12 mm\nMaximal Junctional Zone \nThickness (JZMax)\nMaximal diameter of JZ from those measured at the \n6 points as described above, with location\nmm >7 mm, >10 mm, >12 mm\nMinimal Junctional Zone \nThickness (JZMin)\nMinimal diameter of JZ from those measured at the \n6 points as described above\nmm  \nJunctional Zone Differential \n(JZDiff)\nAs a measure of JZ irregularity\nDifference between maximal and minimal JZ\nmm >5 mm\nJunctional Zone Asymmetry \n(JZAsymm)\nDifference between anterior and posterior JZ (based \non measurement at 6 points previously described)\nmm  \nJunctional Zone to Myometrium \nRatio (JZ/Myo Ratio)\nRatio of Junctional zone to full myometrium thickness \n(measured at 6 points previously described)\n% >40%\nUterine volume Uterine length × width × height × 0.523.\n23 The length \nof measured in the sagittal plane from the outer ostium \nof the cervix until the fundus. Width was measured in \nthe axial plane, and height in the transverse plane at \nthe mid-corpus.\nmm\n3  \nAverage Uterine Wall Thickness Uterine wall thickness measured from endometrium to \nmyometrium, at 6 points previously described\nmm  \nAdenomyotic foci volume Volume of adenomyotic foci in 3 orientations\nCalculated using the formula of a sphere: \n4\n3\n.π.r3\nmm3 <40 mm3, 40–60 mm3, >60 mm3\n(Number of) HSI adenomyotic \nfoci (Myometrial Cysts)\nVisible high signal intensity (HSI) myometrial foci \n(compared to normal myometrium) on T1 or T2-\nweighted imaging\na\n>5\nAdenomyosis Signal intensity \nratio (SIR)\nSignal intensity ratio of adenomyotic tissue compared \nto that of the rectus muscle on T2 imaging (as \nmeasured using Region of Interest (ROI) circles).\n \naOn the total MRI scan, not per image slice. Duplicate counting foci in various slices was avoided by tracking lesions across slices using the localisa-\ntion cursor.\n\n138 Journal of Endometriosis and Pelvic Pain Disorders 15(3-4)\nFigure 1. Measurements on MRI of Adenomyosis characteristics. All MRI images shown were performed on a T2-TSE. Figure a, b \nand c are shown in a sagittal plane, d in the transverse plane. (a) The JZ thickness (yellow line) and the myometrium thickness (red \nline) measured at the level of fundus (F), mid-corpus (M) and isthmus (I) in the anterior (A) and posterior (P) wall of the uterus. (b) \nThe measurements of JZ thickness and myometrium thickness. (c) A uterus with diffuse adenomyosis with a JZ ⩾ 12 mm. (d) Uterus \nvolume determination using the width in the transverse plane (78.8 mm). JZ is showing high signal intensity foci’s determined with \ndashed yellow circles. Volume of focal adenomyosis shown in the red circle.\n\nRees et al. 139\nwhich nineteen women became pregnant and 59 did not. \nThere was no significant difference in terms of pregnancy \nobserved between the group with MRI prior to fertility \ntreatment and the group that had it afterwards (p  = 0.83, \nSupplemental Table S4). Most women (83/124) had an \nMRI within 5 years of fertility treatment. No significant \ndifference in terms of pregnancy rate was found when \ncomparing these women to those received an MRI out-\nside this time-frame (p  = 0.91, Supplemental Table S4).\nIVF/ICSI Outcomes\nA complete overview of IVF/ICSI outcomes for the adeno-\nmyosis versus controls is seen in Supplemental Table S6. \nOverall, patients with MRI-diagnosed adenomyosis \nshowed significantly fewer biochemical and ongoing preg-\nnancies and live births versus controls in crude analysis \n(25 vs 36.3%, p = 0.013, 15.6 vs 29.4%, p = 0.001, and 14.0 \nvs 26.8%, p = 0.009, respectively). A sub-analysis of \nTable 2. Patient characteristics of IVF/ICSI patients with MRI-diagnosed adenomyosis versus male infertility controls.\nAdenomyosis (N = 124) Control Group (N = 889) p-Value\nBMI in kg/m2 (Median, IQR) 23.95 (21.30–28.33) 23.60 (21.44–27.04) 0.48\nInfertility time in months (Median, IQR) 35.00 (23.50–53.50) 27.00 (20.00–41.00) 0.11\nAge during 1st IVF cycle (years, Median, IQR) 33.00 (30.00–35.50) 31.00 (28.00–35.00) 0.042\nYear of IVF Treatment (Median, (IQR)) 2011 (2008–2016) 2011 (2009–2014) 0.54\nCycle length (days, Median, IQR) 28.00 (28.00–30.00) 28.00 (28.00–30.00) 0.43\nPrimary subfertility 79 (63.7%) 616 (69.4%) 0.92\nSecondary subfertility 36 (29.0%) 272 (30.6%)\nIndication for fertility treatment\n Male factor 20 (16.3%) 889 (100%) <0.001\n Female factor§ 13 (10.6%)\n Combined 26 (21.1%)\n Endometriosis 37 (30.1%)\n Idiopathic 27 (22.0%)\nType of treatment (N (%))\n IVF 93 (75.0) 177 (19.9) <0.001\n ICSI 31 (25.0) 712 (80.1)\nNumber of viable oocytes (Median, IQR) 7.0 (4.0–10.0) 8.0 (5.0–12.0) 0.015\nNumber of viable embryos (Median, IQR) 4.0 (2.0–6.0) 5.0 (3.0–8.0) <0.001\nFertilisation rate (%, Median, IQR) 60.0 (45.0–75.0) 57.1 (40.0–72.0) 0.21\nNumber of embryos transferred (N (%))\n Single 83 (68.0) 570 (64.2) 0.42\n Double 39 (32.0) 318 (35.8)\nEmbryo quality of first transferred embryo (N (%))\na\n Super 28 (23.5) 298 (33.7) 0.11\n Good 19 (16.0) 138 (15.6)\n Fair 48 (40.3)* 314 (50.6)\n Moderate 22 (18.5) 133 (14.9)\n Poor 2 (1.7) 33 (3.7)\nEmbryo quality of second transferred embryo (N (%))a\n Super 2 (5.7)* 0 (0.0) <0.001\n Good 8 (22.9) 63 (20.1)\n Fair 19 (54.3) 217 (69.1)\n Moderate 5 (14.3)* 0 (0.0)\n Poor 1 (2.9)* 34 (10.8)\n*An asterisk denotes statistically significant difference versus control.\naSee Supplemental Appendix 3, Table S3 for details on embryo quality criteria.\n§Female factor infertility included indications such as: ovulation disorders, tubal factor and cervical issues as IVF/ICSI indications.\nFigure 2. Flowchart of patient selection and inclusion.\n\n140 Journal of Endometriosis and Pelvic Pain Disorders 15(3-4)\npatients with only fair-to-super quality embryos was also \ncarried out (see Supplementary File, Table S5), with com-\nparable results (p = 0.010, p = 0.002 and p = 0.014, respec-\ntively in crude analysis).\nSubsequently, IVF/ICSI outcomes for patients with \nmarkers for adenomyosis or endometriosis severity were \ncompared to controls (see Supplemental Table S6 for full \nresults).\nTable 4 presents a sub-analysis of adenomyosis MRI \nmarkers and reports the live birth rate (LBR) and adjusted \nodds ratio’s for LB versus male infertility controls cor -\nrected for age at IVF, embryo quality, number of trans-\nferred embryos, and year of treatment. Results for BP and \nOP are shown in Supplemental Table S7. Adenomyosis \npatients overall showed statistically significantly fewer LB \ncompared to controls (aOR 0.560 (95% CI 0.318–0.988, \np = 0.045). The sub-analysis for patients with only fair-to-\nsuper quality embryos showed comparable results (aOR \n0.457 (95% CI 0.239–0.877, p = 0.018) Furthermore, the \nMRI markers of myometrial cysts, JZ-Diff >5 mm, JZ/\nMyometrium ratio >40% and added presence of endome-\ntriosis remained statistically significantly associated with \nfewer LB versus controls.\nDiscussion\nPrevious studies have suggested that adenomyosis nega-\ntively affects reproductive outcomes, however, a lack of \nconsensus in diagnostic criteria on MRI makes the relation-\nship between disease severity and IVF/ICSI outcomes \nunclear. Hence, we investigated known MRI markers of \nadenomyosis severity in relation to IVF/ICSI outcomes. Our \nstudy showed a wide range of adenomyosis characteristics \nin infertile women, reflecting the varied nature of the dis-\nease, and highlighting the challenges in its diagnosis and \nclinical presentation. Results showed that within adenomy-\nosis (and endometriosis) patients, patients with certain MRI \nmarkers (namely concomitant endometriosis, myometrial \ncysts, JZ Diff >5 mm and/or a JZ/Myometrium ratio >40%) \nexhibited significantly worse IVF/ICSI versus male infertil-\nity controls (p < 0.05). These findings were confirmed when \ncorrecting for confounders in multivariate analysis.\nDespite the fact that there are limited comparable stud-\nies, it can be said that our results are consistent with the \ncurrent literature. In a study by Meylaerts et al.,\n19 a thick-\nened AJZ and JZmax on MRI were associated with infer -\ntility. A similar study by Maubon et al. 20 examined the \ninfluence of JZ thickness in infertile women on implanta-\ntion rates during IVF, and showed that a thickened JZ was \na negative predictor for embryo implantation. This study \nalso investigated JZ cut-offs and showed a implantation \nfailure rate of 95.8% for patients with an AJZ> 7 mm and \na JZmax >10 mm compared to patients with a smaller JZ \n(p < 0.0001). In our study on the other hand, a higher JZ \ncut-off of 12 mm was significantly associated with worse \nIVF/ICSI outcomes. The majority of women in our popu-\nlation already had a relatively thickened junctional zone \ndue to the presence of adenomyosis, so the threshold prof-\nfered in the aforementioned study may well not be applica-\nble to our population.\nTable 3. MRI characteristics of IVF/ICSI patients with MRI-\ndiagnosed adenomyosis.\nAdenomyosis \npatients (n = 124)\nAge at MRI (years, mean, SD) 34.96 (5.46)\nMRI conducted prior to IVF/ICSI \ntreatment (N (%))\n46 (37.1)\nMRI within 5 years of fertility treatment \n(N (%))\n83 (66.9)\nAdenomyosis type\n Focal 58 (47.9)\n Diffuse 31 (25.6)\n Cystic 5 (4.1)\n Focal and cystic 17 (14.0)\n Diffuse and cystic 10 (8.3)\n Missing 3 (2.4%)\nAverage JZ (mm, mean, SD)\n 8.68 mm (3.57)\n >7 mm 89 (71.8)\n >10 mm 41 (33.1)\n >12 mm 20 (16.1)\n >15 mm 9 (7.3)\nMaximal JZ (mm, mean, SD)\n 17.05 mm (8.70)\n >7 mm 115 (92.7)\n >10 mm 104 (83.4)\n >12 mm 94 (77.4)\n >15 mm 68 (54.8)\nJZ differential (mm, mean, SD)\n 13.36 mm (8.68)\n >5 mm 110 (88.7)\nAverage JZ/myometrium ratio (mean, SD)\n 0.46 (0.14)\n >40% 92 (74.2)\nJZ asymmetry (mm, mean, SD)\n 0.07 mm (0.81)\n >2 mm 22 (17.7)\nPresence of high signal intensity foci (myometrial cysts)\n 60 (48.8)\n >5 HSI foci 24 (19.4)\n T1-high signal HSI Foci 24 (19.4)\n Uterine length, in sagittal direction \n(mm, median, IQR)\n78.90 (18.50)\n Maximal focal lesion (mm, median, \nIQR)\n23.30 (13.0)\nPresence of endometriosis (N (%))\n 93 (75.0)\n Presence of plaques 86 (69.4)\n Endometriomas 62 (50.0)\n Deep invasive endometriosis (DIE) 26 (21.0)\nPresence of fibroids (N (%))\n Yes 5 (4.2)\n\nRees et al. 141\nA handful of recent studies have investigated individ-\nual adenomyosis MRI characteristics and IVF/ICSI out-\ncomes.24–26 A study by Iwasawa et al.25 found that patients \nwith the extrinsic adenomyosis subtype had better fertility \noutcomes compared to other adenomyosis subtypes. Our \nstudy did not find a clear difference in IVF/ICSI outcomes \nbetween adenomyosis subtypes however. A possible \nexplanation for this lies in the diverse categorisations of \nadenomyosis that exist, making consensus of certain MRI \nmarkers difficult.\n9 Our finding that the added presence of \n(deep invasive) endometriosis affects IVF/ICSI preg-\nnancy outcomes has been described before.\n22,27,28 One \nrecent study also found that women with combined aden-\nomyosis (irrespective of subtype) and endometriosis on \nMRI had fewer live births compared to endometriosis \nalone.\n26 Bourdon et al. 26 additionally reported a signifi-\ncantly lower live birth rate in women with adenomyosis \nand endometriosis exhibiting myometrial cysts. Our study \nshowed a similar relationship between live birth rate in \nrelation to myometrial cysts (aOR 0.420, p  = 0.049). \nOverall therefore, our results support that adenomyosis in \ncombination with (extensive) endometriosis could be seen \nas a more severe form of disease, and that these patients \nmay form a specific subgroup potentially needing specific \ntreatment protocols.\nStrength and limitations\nOur study has several strengths. First, the fact that the \nmeasurements were performed by two independent study \ninvestigators, reduces information bias. We also re-\nassessed all included MRIs during the study instead of \nrelying on radiology report, accounting for differences in \nadenomyosis diagnosis over time and thereby increasing \nthe internal consistency of our data. Correcting our results \nfor relevant IVF/ICSI confounders also increases the reli-\nability of our findings.\nThis study admittedly has limitations. First, despite our \nsample size being comparable to previous studies, the \nnumber of absolute pregnancies achieved in our study \ngroup is low (only 14% live births in patients with adeno-\nmyosis), reducing the power of the results. This is also \nreflected in the larger confidence intervals in the multivari-\nate logistic regression analysis. It is possible that our study \npopulation represents a group of women with more severe \ndisease (due to their infertility and indication for MRI in \nFigure 3. Examples of adenomyotic uteri in the study population: (a) uterus with focal adenomyosis in the posterior wall, (b) \nuterus with cystic adenomyosis in the anterior wall and a diffusely widened JZ, (c) enlarged uterus with a myoma in the anterior \nwall and diffuse adenomyosis with hyperintense foci in the JZ, and an ovarian endometrioma, and (d) uterus with various myomas as \nwell as a diffusely enlarged JZ with scattered hyperintense foci (myometrial cysts).\n\n142 Journal of Endometriosis and Pelvic Pain Disorders 15(3-4)\nthe first place), introducing an element of selection bias, \nand adding to the low pregnancy rate. Additionally, most \nMRI diagnoses of adenomyosis were made after IVF/ICSI \ntreatment (78/124 patients). One could question whether \nthe adenomyosis was present to a similar extent at the time \nof fertility treatment. We do not believe this to be a rele-\nvant issue however, as a sub-analysis based on the timing \nof the MRI in relation to IVF/ICSI treatment did not affect \nthe results. Moreover, adenomyosis is known to be a disor-\nder that develops over a lifetime, and can be assumed to be \npresent throughout the reproductive life-phase.\n29 Another \nelement of our study to consider when interpreting our \nfindings is the choice of control group. The majority of our \ncontrol group did not undergo MRI, which means that the \npresence of adenomyosis in this group cannot be com-\npletely excluded, despite normal TVUS findings and lack \nof clinical adenomyosis symptoms. It is possible therefore \nthat there are some undiagnosed adenomyosis patients in \nthe control group, which may affect the final analysis. \nFurthermore, patients in our study cohort could have had \nother indications for infertility treatment in addition to \nendometriosis/adenomyosis, whereas our control group in \ntheory only had male infertility. This inevitably introduces \na further element of bias into our case group.\nClinical and future implications\nOur results support that specific MRI markers of adeno-\nmyosis and endometriosis severity may be associated with \nworse IVF/ICSI outcomes compared to male infertility \ncontrols. In this context, there is arguably value in thor -\noughly assessing severity and extent of adenomyosis pre-\nconceptionally, especially when in combination with \nendometriosis. Detailed mapping of adenomyosis on MRI \nmay improve clinical counselling and management of \nadenomyosis and/or endometriosis patients considering \nIVF/ICSI. Our data shows that the lower IVF/ICSI preg-\nnancy rates are mainly seen in patients with combined \nadenomyosis and endometriosis, with adenomyosis alone \nseemingly not enough to cause convincingly worse fertil-\nity outcomes in our study population. If adenomyosis and \nendometriosis are seen as a spectrum of the same disease, \nthe combined diseases constitute more severe disease, and \nthus have a greater impact on reproductive ability. We did \nnot include patients with only endometriosis so could not \nassess its potentially confounding effect here. However, \nprevious work by our group has shown that endometriosis \nalone has less effect on IVF/ICSI outcomes than combined \ndisease.\n27 Larger future studies with a prospective design \nshould confirm these results, and aid in creating more per-\nTable 4. Live birth rate for adenomyosis severity MRI markers versus controls.\nAnalysed subgroup (N) LBR adenomyosis \ncases (%)\nLBR control group \n(N = 889, %)\naOR (95% CI)* p-Value**\nAdenomyosis patients with myometrial cysts \n(n = 60)\n7 (12.1) 233 (26.8) 0.420 (0.177−0.997) 0.049\nAdenomyosis patients without myometrial cysts \n(n = 63)\n10 (16.1) 0.556 (0.255−1.214) 0.14\nAdenomyosis patients with mean JZ < 12 mm \n(N = 103)\n15 (15.) 0.510 (0.264−0.985) 0.045\nAdenomyosis patients with mean JZ > 12 mm \n(N = 20)\n2 (10.5) 0.374 (0.082−1.700) 0.20\nAdenomyosis patients with JZ-diff < 5 mm \n(N = 13)\n1 (7.7) 0.255 (0.032−2.041) 0.20\nAdenomyosis patients with JZ-diff >5 mm \n(N = 110)\n16 (15.0) 0.519 (0.273−0.990) 0.046\nAdenomyosis patients with JZ-\nmyometrium < 40% (N = 31)\n5 (16.7) 0.598 (0.212−1.683) 0.33\nAdenomyosis patients with JZ-myometrium \nratio > 40% (N = 92)\n12 (13.3) 0.453 (0.222−0.921) 0.029\nDiffuse adenomyosis (N = 31) 5 (16.7) 0.583 (0.209−1.201) 0.30\nFocal adenomyosis (N = 58) 9 (15.5) 0.525 (0.230−1.626) 0.13\nAdenomyosis alone (n = 31) 5 (17.2) 0.652 (0.225−1.889) 0.43\nAdenomyosis and endometriosis (n = 93) 12 (14.1)\n§ 0.440 (0.219−0.886) 0.021\nAdenomyosis without DIE (n = 98) 15 (15.8) 0.542 (0.280−1.050) 0.070\nAdenomyosis with DIE (n = 26) 2 (7.7)§ 0.272 (0.061−1.212) 0.088\nLBR: live birth rate; aOR: adjusted Odds Ratio; DIE: deep invasive endometriosis.\n*Multivariate logistic regression adjusted for: age at time of IVF, IVF or ICSI treatment, embryo quality, year of IVF treatment and number of trans-\nferred embryos.\n**p-Value for logistic regression analysis.\n§Denotes p < 0.05 versus controls in crude analysis.\n\nRees et al. 143\nsonalised management and treatments for (infertile) aden-\nomyosis patients.\nConclusion\nThis study assessed a number of MRI parameters (added \npresence of endometriosis (DIE), mean JZ >12 mm, mean \nJZ/Myometrium ratio of >40% and presence of myome-\ntrial cysts) that could function as markers for IVF/ICSI \noutcomes and aid in counselling patients prior to starting \ntreatment. We believe further (prospective) research \nshould be encouraged. Mapping out the severity and the \nextent of adenomyosis and endometriosis in correlation to \nfurther clinical (fertility) outcomes could aid in clinical \nmanagement of (infertile) women with the disease.\nDeclaration of conflicting interests\nThe authors declared no potential conflicts of interest with \nrespect to the research, authorship, and/or publication of this \narticle.\nFunding\nThe authors received no financial support for the research, \nauthorship, and/or publication of this article.\nORCID iDs\nConnie Odette Rees  https://orcid.org/0000-0001-7742-3050\nSehriban Kocyigit  https://orcid.org/0000-0002-8318-1163\nSupplemental material\nSupplemental material for this article is available online.\nReferences\n 1. Campo S, Campo V and Benagiano G. Adenomyosis and \ninfertility. Reprod Biomed Online 2012; 24(1): 35–46.\n 2. Graziano A, Lo Monte G, Piva I, et al. 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