Understanding diagnostic delay for endometriosis: a scoping review

20 We thank our employers for supporting this work. JF received support from Harrogate 21 Borough Council, AMJ received support from the University of York and AW received 22 support from York St John University. 23 24

25

26 Diagnostic delay for endometriosis is a well-established phenomenon. Despite this, little is 27 known about where in the health care system these delays occur or why they occur. Our 28 review is the first attempt to synthesise and analyse this evidence. 29

30 A systematic scoping review with a pre-specified protocol was used to incorporate the global 31 mixed methods literature on diagnostic delay for endometriosis. Four databases (PubMed, 32 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. 2 MEDLINE, EMBASE, PsychINFO) were searched from inception to September 2023 with a 33 search strategy designed specifically for each. 34

35 The search yielded 367 studies, 22 of which met the inclusion criteria. A third of studies has 36 been published since 2020 and 65% were from high income countries. Six were qualitative 37 and 16 were quantitative studies. The average age of onset of endometriosis was 14 years 38 for adolescents and 20 for adults. On average, the diagnostic delay reported for 39 endometriosis across the included studies was 6.6 years (range 1.5 to 11.3 years) but this 40 masked the very wide differences reported between countries such as a 0.5-year delay in 41 Brazil to a 27-year delay in the UK. 42

43 Health system barriers included access to private healthcare for those with limited finance, 44 physical access for those using public health systems and a general lack of knowledge 45 amongst patients and health care professionals. Women often reported feeling unheard by 46 health professionals. Considering the impact on individuals and the health system, 47 addressing diagnostic delay for endometriosis must remain a priority for researchers, health 48 care providers and policy makers. 49 50 What is already known on this topic 51 Endometriosis is currently difficult to diagnose. This results in delays in diagnosis which 52 negatively impacts those suffering and increases the severity of pain and extent of the 53 disease with increased costs to health systems. 54 What this study adds 55 The scoping review methodology included studies using a range of methods. The longest 56 average delay occurs in secondary care. Those seeking public health care experienced 57 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 3 longer average delay in diagnosis compared to those seeking private health care. Improved 58 clinical guidelines may reduce diagnostic delay. 59 How this study might affect research, practice or policy 60 This is the first known review to explore diagnostic delay for endometriosis and provides an 61 overview of the current literature. Clearer definitions of diagnostic delay for endometriosis 62 are needed to aid in comparisons across countries. Improving education, tracking outcomes 63 through medical records and developing non-invasive diagnostic tools will be crucial to 64 improve women’s health. 65 66 67 68 69 70 71 72 73 74 75 76 77 78 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 4

79 Endometriosis is an oestrogen dependent gynaecological condition characterised by the 80 presence of active endometrial tissue lying outside of the uterus, typically in the pelvic region 81 (1). It is a chronic, progressive inflammatory disease which affects more than 170 million 82 women worldwide (2). Endometriosis mainly affects women of reproductive age (15-49 83 years), with up to 1 in 10 believed to have t he condition, although it is estimated that as 84 many as 60% of endometriosis cases remain undiagnosed (2, 3). Prevalence estimates of 85 endometriosis are generally poor and highly varied, ranging from 4% to 50%; however the 86 most consistent estimates suggest prevalenc e ranging from 6-10% (4). Despite the 87 progressive nature of endometriosis, a correct diagnosis takes an average of 10 years and 88 at least 7 visits to a health prac titioner (5, 6). This lengthy del ay is reflected in the disease 89 burden in which gynaecological diseases are r eported as the leading cause of Disability 90 Adjusted Life Years (DALYs) and Years Lived with Disability (YLD) among the 15-49-year 91 age group (7). This is despite clear clinical diagnostic indicators including chronic pelvic pain 92 (CPP), dysmenorrhea (painful, heavy menstruation), dyspareunia (painful intercourse), that 93 are known for 82.9% of women (1, 8). Apart from the YLD the economic impact includes 94 increased costs to the individual, to health care providers, and to the wider economic 95 infrastructure (9). The current ‘gold st andard’ for diagnosis is a laparoscopy, although 96 surgeons may be hesitant to perform this due to the invasive nature of the procedure (8, 10). 97 There is also evidence that symptoms may be dismissed as ‘normal’ by health care 98 practitioners (1, 11). 99 100 The aim of this review was to explore the delay faced by those attempting to obtain a 101 diagnosis of endometriosis and appropriate treatment. 102 103

104 The study protocol was registered on the Open Science Framework OSF: 105 10.31219/osf.io/yzuvb 106 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 5 Patient and public involvement 107 Women who have experienced diagnostic delay for endometriosis were involved in 108 designing the research. The research question was informed by their priorities, experiences 109 and preferences. Dissemination of this research will be facilitated through charities focussed 110 on endometriosis. 111 Data sources and search strategy 112 Development of the search strategy was guided by the SPIDER framework to ensure key 113 concepts were captured in searches. Four databases were searched between from inception 114 to September 2023. They included PubMed, MEDLINE, EMBASE and PsycINFO. No date 115 limits were set on the searches. Search terms included key terms derived from search 116 strings relating to ‘endometriosis’ and ‘diagnostic delay’ and were adapted for each 117 database; For example, the search strategy for MEDLINE was: ‘Endometriosis.mp. or (exp 118 Pelvic Pain/ or exp Chronic Pain/)) and exp Delayed Diagnosis/’. 119 Eligibility criteria 120 Included studies were primary research in English involving the pelvic region or reproductive 121 organs only, that mentioned pelvic pain with a suspicion of endometriosis, and diagnostic 122 delay (in the context of endometriosis). 123 Screening and data extraction 124 All studies were screened by one reviewer (JF) with a 10 percent sample checked by a 125 second reviewer (MS) and any disagreements resolved by a third reviewer (AW/AMJ). 126 Data were extracted on a predeveloped and piloted data extraction form and included study 127 characteristics, methods and design, and demographic characteristics of the population. 128 Additionally, the most frequently reported symptoms, length of and reason for delay were 129 recorded. 130 Analysis 131 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 6 Studies were grouped by themes that emerged from the individual included studies (12) and 132 contextualised to form a public policy perspective using the socio-ecological model (13). 133

134 Selection of studies 135 The searches yielded 367 studies following deduplication. Title and abstract screening, and 136 full-text screening resulted in 23 studies that met the inclusion criteria (see figure 1). 137 [Figure 1] 138 139 No formal quality appraisal was undertaken in line with methodological guidance for scoping 140 reviews (14). 141 142 Study characteristics 143 Table 1 provides an overview of the included studies and highlights the diversity of methods 144 used. Six were qualitative and 16 were quantitative studies. Almost a third of studies (8/22) 145 were published relatively recently (since 2020) from a range of countries. Fifteen were 146 conducted in high income countries including the UK (15, 16), US (17-21), Netherlands (22, 147 23), Norway (24, 25), Canada (26), Australia (27), New Zealand (28), and Italy (29). Three 148 were conducted in middle income countries; Brazil (30, 31) and Iran (32) and four were 149 conducted in multiple countries (33-36). The average age of participants across the studies 150 was 32.7 but the age range of participants was between 12 and 74 years old. 151 Age of onset of endometriosis 152 The mean age at onset of endometriosis symptoms was 14.1 years old for adolescents 153 (range 13-15.3 years), and 20.4 years old for adults (range 20-23.2 years). The average age 154 at diagnosis was 16 for adolescents and 28.8 for adults (range 22-32). Average age of first 155 GP visit was 14 for adolescents and 25.8 years for adults (range 20-32.6). 156 [Table 1] 157 158 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 7 Diagnostic delay 159 The definition of diagnostic delay was consistent across studies and was defined as the time 160 between symptom onset and diagnosis. The average diagnostic delay was 6.6 years with an 161 average of 1.5 years in Australia (27) and 11.3 years in the US (18). However, there was a 162 wide range between the shortest and longest delay reported. The shortest delay was 0.5 163 years in Brazil (30), and the longest delay was 27 years in the UK (15). Though the range 164 was wider than previously reported by other studies i.e. 3.3 - 11.7 years, the average 165 diagnostic delay was consistent with their finding of 6.7 years (35). Some studies reported 166 specific points at which delays occurred, these were from symptom onset to primary care 167 consultation (15, 17-19, 21-23, 25, 26, 28, 33), referral for gynaecology consultation (15, 16, 168 22, 23, 33), and gynaecology referral to diagnosis (15, 16, 22, 23, 33). Mean delays through 169 this pathway reported across the studies were 2.0 years, 2.5 years, and 2.8 years 170 respectively. Time from primary care presentation to diagnosis was reported by some 171 studies without mention of transition to secondary care (16, 19, 21, 25, 26). The average 172 diagnostic delay between primary care presentation and diagnosis was 2.9 years (see figure 173 2). 174 [Figure 2] 175 176 Reasons for delay 177 Most studies focussed on the patients’ perspective, two studies focussed on the health care 178 provider (HCP) perspective, and one included both perspectives. There were 6 main themes 179 that emerged. A summary of these can be seen in table 2. 180 [Table 2] 181 182 Access to care differed depending on the specific health system in place. While financial 183 barriers were more prominent for those seeking private healthcare, physical access to care 184 was more frequently noted for those seeking public healthcare services. Only one study 185 compared wait times between those seeking public healthcare and insurance or self-funded 186 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 8 healthcare (35). They found that wait times for endometriosis care were significantly longer 187 for those seeking public rather than private healthcare (8.3 years vs. 5.5 years). 188 Both HCPs and patients shared similar views on the reasons for diagnostic delay although 189 they expressed the delays differently. Where HCP thought frequently presenting patients 190 were somatising, patients stated they presented frequently because they felt unheard by 191 HCPs. This was reflected by the number of doctors seen, which averaged 2.0 for 192 adolescents (19) and 4.1 for adults (range 2.5-7) (19, 26, 28, 33, 35) and the number of 193 times symptoms were discussed before diagnosis, with more than a quarter of women 194 saying they discussed symptoms more than 20 times (34). Interestingly, none of the studies 195 evaluated the number of consultations prior to referral, nor the effect of diagnostic delay 196 qualitatively or quantitatively based on the type (doctor, nurse, etc.) or gender of the HCP. 197 The emerging themes identified increased diagnostic delay at each point along the 198 diagnostic pathway, from symptom onset to diagnosis. This resulted in prolonging diagnosis 199 which led to increases in both the severity of pain and the extent of disease (20, 21) (see 200 figure 3). Both patients and HCPs appeared to demonstrate an overall lack of understanding 201 and education about endometriosis. 202 [Figure 3] 203 204 Diagnostic delay: evidence of delays being addressed 205 Overall, four studies reported interventions implemented to tackle diagnostic delay. Of these, 206 two studies reported reduced time to diagnosis following the introduction of clinical 207 guidelines (27, 28) and one study that found diagnostic delays were reduced by the 208

of specialist endometriosis centres in the US, but not in the UK (16). Only one 209 study quantified the reduction in delay (8.4 years), while the others reported a ‘downward 210 trend’ in diagnostic delays (16, 27, 28). Becoming a member of an endometriosis society had 211 no effect on diagnostic delay (35). 212 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 9 The discrepancy in effectiveness of the introducti on of specialist endometriosis centres may 213 be due to differences in health care systems including access to care, service use, service 214 cost, referral pathways and diagnostic guidelines. 215 216 A range of interventions to reduce diagnostic delay for endometriosis were suggested 217 including education and awareness campaigns, collaboration, and multidisciplinary working 218 between HCPs, promoting health-seeking behaviour for patients, the use of screening tools, 219 increased research into endometriosis, improving access to medical records, clinical 220 guidelines written in the native language, the use of reliable diagnostic indicators and early 221 intervention. 222 [Figure 4] 223 The interventions suggested span the entirety of the socio-ecological framework (see figure 224 5). This multi-level approach to intervention allows for the introduction of all encompassing, 225 yet targeted and effective interventions tailored according to individual factors and 226 behaviours (13) and the wider health care system. Using this framework for diagnostic delay 227 in endometriosis is useful to visualise the complexity involved whilst providing a range of 228 options for intervention. 229 [Figure 5] 230 The breadth of interventions identified was aide d by the diversity of participants included in 231 the studies and was enhanced by the inclusion of views from a range of HCPs (17, 24, 32). 232 233

234 Diagnostic delay associated with endometriosis is a well-established phenomenon. Prior to 235 our review it was not clear where in the health care system these delays occurred or why 236 they occurred. Our review is the first attempt to synthesise and analyse this evidence. On 237 average, the diagnostic delay for endometriosis was 6.6 years across the studies and 238 ranged from 1.5 years to 11.3 years. Delays were identified at all stages from symptom 239 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 10 onset to receiving a diagnosis. The longest average delay was the time from gynaecology 240 referral to diagnosis (2.8 years), followed by primary care presentation to diagnosis (2.5 241 years), and finally, from symptom onset to primary care presentation (2.0 years). Only 2 242 studies used a CPP comparator group, while 2 used healthy controls, no other studies used 243 a comparator or control, and none provided information on women with negative findings at 244 laparoscopy. 245 246 We acknowledge the limitation of the scoping review methodology. The exclusion criteria 247 meant that some papers were not included, such as those focussing on specific biomarkers. 248 All included studies relied on patients recalli ng the start of their symptoms rather than 249 tracking patients throughout their diagnostic journey or using medical records for verification 250 which could reduce recall bias. The strength of our study was a clear focus following a pre-251 published protocol, including a wide range of papers from all over the world and locating the 252 problem within the socio-ecological framework. 253 254 An area in critical need of further research is closer tracking of patients throughout their 255 diagnostic journey. This should include the time from presentation to diagnosis, including 256 cases where patients have met all criteria to be considered for surgery but do not have 257 endometriosis, what their differential diagnoses are and what the differences are between 258 women with a positive and negative laparoscopy. This may be improved by using reporting 259 endometriosis as a differential diagnosis earlier along the diagnostic journey, and by 260 ensuring primary and secondary care are better connected so the diagnostic journey can be 261 properly followed. Additionally, it may be useful to have the details of the HCP available and 262 their role e.g. primary care practitioner, gynaecologist, and their gender, age, and length of 263 service, all of which may affect diagnostic delay. 264 265 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 11 The definition and calculation of diagnostic delay is also an area that requires urgent 266 attention. Rather than studies describing the time from symptom onset to diagnosis, the 267 current definition of diagnostic delay used across studies, it would be more beneficial to 268 determine excess delay. This could provide regional and national estimates of the true 269 diagnostic delay or excess delay based on regional and national average wait times for 270 primary care appointments, referral to gynaecology, and for surgery. This measure could 271 allow direct comparisons of care and delays between public and private provision of services 272 for endometriosis care. 273 274 Secondly, the length of delay matters in terms of cost and severity for women and the wider 275 health system. Accurate calculation of diagnostic delay for endometriosis may be the first 276 step to improving guidelines, diagnostic measures, and diagnosis more broadly. Additionally, 277 it is important to establish and address barriers to diagnosis. More investigation is needed on 278 the effect of diagnostic delay to determine the cost-benefit of reducing diagnostic delay (37). 279 Though there remains much to be done, the results of this study can provide a platform for 280 further future research to prevent the unnecessary and extended suffering resulting from 281 diagnostic delays of endometriosis. The socio-ecological framework can be used to assess 282 where improved policies may be effective, how widespread the effects might be and to 283 provide a benchmark for their perceived benefit (financial and otherwise). Further research 284 studies would benefit from utilising medical records to track the number of consultations, 285 range of HCPs, and time elapsed from initial referral to a final diagnosis and treatment. Our 286 review provides a starting point for others to improve our understanding of where changes 287 need to be made to reduce the delay in diagnosis of endometriosis. 288

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Journal of Endometriosis and Pelvic Pain 375 Disorders. 2020;12(1):16-25. 376 35. Nnoaham KE, Hummelshoj L, Webster P, d'Hooghe T, de Cicco Nardone F, de Cicco 377 Nardone C, et al. Impact of endometriosis on quality of life and work productivity: a 378 multicenter study across ten countries. Fertil Steril. 2011;96(2):366-73.e8. 379 36. Van Niekerk L, Johnstone L, Matthewson M. Predictors of self-compassion in 380 endometriosis: the role of psychological health and endometriosis symptom burden. Hum 381 Reprod. 2022;37(2):264-73. 382 37. Cromeens MG, Carey ET, Robinson WR, Knafl K, Thoyre S. Timing, delays and 383 pathways to diagnosis of endometriosis: a scoping review protocol. BMJ Open. 384 2021;11(6):e049390. 385 386 387 Fig ur e 1 PRISMA flow diagr am 388 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 16 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 17 Table 1: Table of included studies 406 First author, year, country Study design Participants and

Main finding(s) Quantitative Andres, 2014, Brazil Retrospective study 21 patients (aged 13-20) with histologically confirmed endometriosis after undergoing surgery. Need for increased awareness of adolescent onset of endometriosis. Current imaging techniques are inadequate. Gynaecologists fail to recognise symptoms. Armour, 2020, Australia Cross- sectional study 409 participants (aged 18-45), 340 with endometriosis, 69 without. Recruited via survey link. ESHRE guidelines reduced diagnostic delay from 9.9 years before 2005 to 1.5 years as of 2013 onwards. Year medical attention is sought, number of doctors seen and delayed health seeking all increase diagnostic delay. DiVasta, 2018, United States Cross- sectional longitudinal cohort study 670 participants (aged 12-49), 402 with self- reported endometriosis, Need to understand changing symptom patterns and symptom base more – particularly how this may differ between an adult and All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 18 268 controls. Recruited from 2 tertiary centres. adolescent population. Acyclic pain appears to increase with age – potentially due to increased severity of endometriosis at surgery. Dmowski, 1997, United States Retrospective study 693 patients (aged 15-40), 377 with CPP symptoms, 336 infertility +/- pain. Evaluated at the Institute for the Study and Treatment of Endometriosis. Diagnostic delays were found to be longer in women who were symptomatic earlier in life. Longer delays led to more advanced disease at laparoscopy. These findings were only significant in the pain group. Diagnostic delay steadily decreased between 1979 and 1995. Delays were longer in the pelvic pain group than the infertility group. Ghai, 2020, United Kingdom Retrospective cross- sectional study 101 women with surgically confirmed endometriosis recruited via written postal questionnaire. Women often have their pain normalised and do not feel their pain is taken seriously. Misdiagnosis, menstrual cramps during adolescence, earlier symptom onset and delays between presenting with symptoms and onward referral all increased diagnostic delays. Shorter All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 19 delays were found when women changed to a more understanding gynaecologist. Hudelist, 2012 Austria and Germany Cross- sectional study 171 patients (aged >18) with histologically confirmed endometriosis recruited from tertiary referral centres for diagnosis and treatment of endometriosis. Increasing number of misdiagnoses, patient impression of not been taken seriously, normalisation of symptoms, women with cramps during adolescence, and whose mothers viewed menstruation as a negative event all experienced increased diagnostic delays. Medication use, extent of disease and main symptomatic complaint were all non-significant factors. Husby, 2003, Norway Cross- sectional study 261 patients with pain and endometriosis, 223 members of the Norwegian Endometriosis Association, 38 non-members. There were no statistically significant differences in the mean diagnostic delay between 1978-2001. Delays did not differ between those with pain only and pain and infertility, additionally, there was no difference in diagnostic delay between members and non-members. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 20 Most of the delays were from seeing a GP to diagnosis. Lamvu, 2020, United States, Australia, Canada, Ireland, New Zealand, South Africa, and the United Kingdom Cross- sectional study 451 respondents (aged 19-60) with or without endometriosis. Recruited through ‘My Endometriosis Team’. Respondents described discussing their symptoms more than 20 times and were commonly misdiagnosed with both mental and physical conditions. About half of respondents waited over 6 years for a diagnosis while almost a quarter waited 11 or more years. Longer delay was associated with more pelvic symptoms. Many women felt doctors did not listen and that their recommendations were inconsistent with what they wanted. Lukic, 2015, Italy Cohort study 67 patients with deep dyspareunia diagnosed with pelvic endometriosis attending an endometriosis unit. Women often suffer from pathology for a long time before presenting to health services. Both signs and symptoms of endometriosis need to be better recognised or women need to be clearer in describing signs and symptoms to allow diagnosis. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 21 Roughly two-thirds of women don’t consult their GP for sexual dysfunction. Nnoaham, 2011 (Belgium, Brazil, China, Ireland, Italy, Nigeria, United Kingdom, United States and Spain) Multicentre cross- sectional study with prospective recruitment 1,418 premenopausal women (aged 18-45) without previous surgical diagnosis of endometriosis. 745 with endometriosis, 587 symptomatic, 86 sterilised. Recruited in hospital before surgery. Delays were increased when state funded care was sought when compared to self- funded care or through insurance. Patients with longer delays had more pelvic symptoms and a higher Body Mass Index (BMI), even when adjusting for potential confounders. Most of the delay was due to length of time between referral from primary care to a gynaecologist. Women with endometriosis had a longer delay than symptomatic controls without endometriosis at surgery. Diagnostic delays ranged from 3.3 years to 10.7 years. Santos, 2012, Brazil Retrospective analytical study 262 women (aged 17-49) with surgically confirmed Diagnostic delay differed between different age categories; however, the difference was found to be All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 22 endometriosis. Recruited through an outpatient clinic for endometriosis and CPP. non-significant. Women with dysmenorrhea and deep dyspareunia had a longer delay, which those with dyspareunia (not deep) and acyclic pain had a shorter delay. Women experiencing infertility experienced a longer delay than their fertile counterparts. Site and severity of disease were not significant factors. Singh, 2020, Canada Cross- sectional survey 2004 women (aged 18-49) were recruited via email using 3 independent survey sampling panels. Delays in health seeking were longer than physician-related delays. On average women saw 3 different physicians before receiving a diagnosis. The odds of receiving a diagnosis of endometriosis were highest when women experienced infertility, cyclic pelvic pain or cramping, and pelvic pressure. Soliman, 2017, United States Cross- sectional study 683 respondents (aged 18-29) recruited from 3 Younger age at symptom onset and white ethnicity were associated with a longer diagnostic delay. Patients with All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 23 market research panels. constipation, bloating or diarrhoea were diagnosed sooner than those with pain during sex. Delays were also shorter among women having a diagnostic procedure, women seen by a gynaecologist and women diagnosed via non-surgical methods. Staal, 2016, Netherlands Retrospective cross- sectional study 47 patients (aged 14-29) diagnosed with endometriosis by surgery or MRI. Diagnostic delay was shorter for patients who consulted their GP due to subfertility rather than pain. A longer delay from presenting to a GP to referral was experienced by patients who were a young age when they developed symptoms, misdiagnosed or their symptoms were normalised – the same delays were not experienced between referral to a gynaecologist and diagnosis. Tewhaiti-Smith 2022, New Zealand Cross- sectional study 800 respondents (aged 18-74), Diagnostic delay was longer in patients with endometriosis than those experiencing CPP. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 24 620 with endometriosis, 180 with CPP. Recruited using social media, flyers, and through targeted dissemination. On average women saw 4.8 doctors before they were diagnosed with endometriosis. Year of first doctors visit was negatively correlated with the number of doctors consulted suggesting health-seeking delays are reducing over time. Overall diagnostic delay was reduced by 6.5 years by the

of guidelines. Van Niekerk, 2022, Australia, Oceania, United Kingdom and North America Cross- sectional study 318 women (23 of whom with symptoms of perimenopause, 35 in medical menopause and 7 in surgical menopause). Recruited via online advertising on social media. Longer diagnostic delays, number of endometriosis- related symptoms, depression, anxiety, pain after sexual intercourse and during urination were all negative predictors of self-compassion. Women with longer diagnostic delays were found to have higher levels of endometriosis-related distress are likely to report lower levels of self-compassion and would benefit from early engagement in psychological All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 25 interventions. Qualitative As-Sanie, 2019, United States Qualitative study – interactive

Interdisciplinary group of expert researchers, clinicians, and patients put together the The Society for Women’s Health Research. Identified themes impacting diagnostic delay through guided interactive discussion. These included diagnostics, barriers to diagnosis, the future of diagnostics, treatment, barriers to treatment and the future of treatment – with several subthemes including stigma and understanding. Ballard, 2006, United Kingdom Qualitative, interview- based study 32 women (aged 16-47) attending a pelvic pain clinic. 28 diagnosed with endometriosis. Delays occur at every stage of the diagnostic pathway. Delays occur at both the patient-level and medical- level, with normalisation being a common factor. Others include stigma, non-specific testing, and improper use of treatments. DiBenedetti, 2018, United States Qualitative cross- sectional study with an interview 16 women (aged 24-48), 11 with endometriosis and 5 healthy A painful periods screening tool was developed to aid in the recognition of pathological symptoms of endometriosis. The tool was found have face All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 26 element controls. Recruited via 2 qualitative research facilities. validity and content validity, clearly and concisely able to assess core symptoms and distinguish between normal and pathological symptoms. Fernandes 2020, Norway Qualitative interview- based study 13 doctors- 8 gynaecologists and 5 General Practitioners (GP’s) identified via google search. Patients attending clinic often feel embarrassed and disbelieved regarding symptoms. Doctors do not like to take responsibility for diagnosis due to not being specialised in women’s health issues. Diagnosis is often delayed due to multiple misdiagnoses. Riazi, 2014, Iran Qualitative interview- based study 12 endometriosis patients (aged 22-37) and 6 gynaecologists Dyspareunia was noted as one of the most important symptoms of the disease. Women’s recognition of this symptom is often delayed due to delayed marriage (and so delayed intercourse). Beliefs around dysmenorrhoea being normal and common during virginity also delay diagnosis. From a medical viewpoint, unreliability of diagnostic All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 27 markers, misdiagnosis and mismanagement all increase diagnostic delay. Van der Zanden, 2022, Netherlands Qualitative focus group- based study 23 women (aged 29-45) placed in 6 focus groups. Recruited by social media, through a patient interest group and through a centre of expertise in endometriosis Health-seeking behaviour is often influenced by peers, normalisation leads to delays. Non-discriminatory tests, being referred to the wrong specialist and given pain medication without proper indication for use were all attributed to diagnostic delays. Referral was faster in women with menstruation specific complaints. Not all doctors have equal knowledge and some women received incomplete examination. 407 408 409 410 411 412 413 414 415 416 417 418 419 Fig ur e 2: Sc hematic r ep r esentation of gl obal ave r a ge diag nos tic delay 420 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 28 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 Table 2: The main themes and sub-themes relating to diagnostic delay 456 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 29 Main theme Contributing factors (sub-themes) 1 Access to healthcare Physical access to care, financial barriers, stigma, embarrassment, not being aware of endometriosis, religious beliefs, and normalisation of symptoms. 2 Knowledge limitations Poor recognition of symptoms (patients and HCP), HCP thinking endometriosis is a ‘rare’ disease, inability to define between normal and pathological symptoms (patients and HCP), lack of awareness and lack of training and evidence available to HCP. 3 Misdiagnosis Differential presentation of symptoms between women, atypical symptoms, comorbidities, communication challenges between different HCP, lack of specificity of testing, lack of definitive diagnostic testing, and use of non-definitive tests. 4 Stigmatisation Stigma, normalisation, dismissal, patient unable to properly verbalise pain and/or symptoms causing communication challenges between patient and HCP, and lack of patient assertiveness. 5 Method of diagnosis Hesitation to refer for more invasive, definitive tests, age, HCP uncomfortable with requirement to perform physical exam (particularly adolescents), and perceived need for surgical over clinical diagnosis in some health systems. 6 Lack of guidelines No screening tools available, inconsistency in available PROMs and guidelines, poor interdisciplinary handling of patients, and need for involvement of multiple HCP. 457 458 Figure 3: Pathways to diagnostic delay 459 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 30 460 461 462 463 464 465 466 467 468 469 470 471 472 473 Figure 4: Thematic map of interactions between themes and subthemes 474 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 31 475 476 477 478 479 480 481 482 483 484 Figure 4: The socio-ecological model of endometriosis 485 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint 32 486 487 488 489 490 491 492 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted January 9, 2024. ; https://doi.org/10.1101/2024.01.08.24300988doi: medRxiv preprint