High rate of dyspareunia and probable vulvodynia in Ehlers–Danlos syndromes and hypermobility spectrum disorders: An online survey

Abstract Vulvodynia is debilitating vulvar pain accompanied by dyspareunia (pain with sexual intercourse). Ehlers–Danlos syndromes (EDS) and hypermobility spectrum disorders (HSD) may represent a predisposing factor for vulvodynia given a high rate of dyspareunia in these conditions. We conducted an online survey of women with EDS or HSD to assess rates of dyspareunia and estimate rates of vulvodynia, report rates of comorbid conditions common to EDS or HSD and vulvodynia, and examine rates of conditions contributing to dyspareunia in women with EDS or HSD. Women with EDS or HSD (N = 1,146) recruited via social media were 38.2 ± 11.5 years old, primarily White (94.4%), and resided in the United States (78.5%). 63.7% of participants reported dyspareunia and 50% screened positive for vulvodynia. The rate of comorbid conditions common to EDS or HSD and vulvodynia were: irritable bowel syndrome, 6.5%; fibromyalgia, 40.0%; temporomandibular joint dysfunction, 56.4%; migraine, 6.7%; interstitial cystitis, 1.7%; and mast cell activation syndrome, 10.2%. Participants reporting dyspareunia also reported ovarian cysts, fibroids, or abdominal or pelvic scars, 47.5%; endometriosis, 26.5%; and genital lacerations, 19.3%. Women with EDS or HSD may have a higher rate of vulvodynia (50.0%) than women in the U.S. population at large (8%) and should be assessed for dyspareunia and vulvodynia.


| INTRODUCTION
Pain is nearly universal in hypermobility spectrum disorders (HDS) Demes, McNair, & Taylor, 2020), is a diagnostic criterion of hypermobile Ehlers-Danlos syndrome (hEDS) (Malfait This article is an extension of either a plenary guest speaker lecture or an abstract presented at the EDS ECHO Conference on the Ehlers-Danlos syndromes held October 2-3, 2020. The Editors-in-Chief of this journal affirm that this article was evaluated editorially and rigorously edited by the expert Guest Editors for this issue, Dr. Hakim, Dr. Francomano, and Dr. Tinkle, and was not anonymously peer reviewed. et al., 2017), and is common in adults with rarer types of EDS (Schubart, Schaefer, Hakim, Francomano, & Bascom, 2019;Voermans, Knoop, Bleijenberg, & van Engelen, 2010). Co-morbidities of EDS are equally common in HSD and hEDS (Copetti et al., 2019). Given the evolving use of the terms hEDS , HSD , and joint hypermobility syndrome (Grahame, Bird, & Child, 2000) an "old" term incorporated in HSD (Grahame et al., 2000), in this paper, we used the acronym "hEDS/HSD" to identify the community of phenotypes belonging to these three, partially overlapping groups. In hEDS and presumably HSD, as an individual ages recurrent injuries accumulate resulting in chronic pain, with hypothesized central and/or peripheral nervous system sensitization (Castori, 2016;Sacheti et al., 1997).
Pain is estimated to affect 90% (Voermans et al., 2010) of individuals with hEDS/HSD and has such a profound effect that even with pain management 87% (Voermans et al., 2010) report difficulties performing activities of daily living (Castori, 2016). Phenotypic dimensions of pain in EDS are heterogeneous and still incompletely understood.
Due to the rare nature of EDS and the lack of healthcare specialists familiar with EDS and HSD, patients have used Facebook™ (Meta Platform Inc, Menlo Park, CA) to form support groups where tips and resources are shared. In these groups, we observed women complaining of dyspareunia. Pain from dyspareunia can decimate a person's life, rendering them incapable of having sexual intercourse, shattering an intimate relationship . A review of the literature found five studies that reported the rate of dyspareunia in EDS and HSD but no studies examined the conditions that may contribute to dyspareunia in EDS and HSD (Castori et al., 2012;Chopra et al., 2017;Hugon-Rodin et al., 2016;Hurst et al., 2014;McIntosh et al., 1995) Seehusen et al., 2014;Sorensen, Bautista, Lamvu, & Feranec, 2018). Separately, it is known that EDS, HSD, and vulvodynia are both associated with comorbid conditions such as irritable bowel syndrome (Maeland, Assmus, & Berglund, 2011;Reed, Harlow, Sen, Legocki, et al., 2012;Vieira-Baptista, Lima-Silva, Cavaco-Gomes, & Beires, 2014), fibromyalgia Vieira-Baptista et al., 2014), temporomandibular joint dysfunction (Murray, Yashar, Uhlmann, Clauw, & Petty, 2013;Vieira-Baptista et al., 2014), interstitial cystitis Vieira-Baptista et al., 2014), mast cell disorders (McDonald & Rapkin, 2012;Regauer, Eberz, & Beham-Schmid, 2015;Seneviratne, Maitland, & Afrin, 2017), and migraine (Hakim & Grahame, 2004;Puledda et al., 2015;Vieira-Baptista et al., 2014). The intersections of these comorbid conditions have never been reported in the EDS, HSD, or vulvodynia literature. The primary aim of this study was to determine the rate of dyspareunia and vulvodynia in women with EDS or HSD. The secondary aim was to report the rate of comorbid conditions that are common in both EDS, HSD, and vulvodynia. The third aim was to examine the rate of conditions known to contribute to dyspareunia in women with EDS or HSD.

| METHODS AND MATERIALS
The study was a cross-sectional online self-reported survey that was completed from June to July of 2019. This study was approved by the University of Illinois Chicago Institutional Review Board.
F I G U R E 1 Participation flow chart A convenience sample of participants was recruited through social media and met the inclusion criteria of: (1) a self-reported diagnosis of EDS or HSD previously confirmed by a healthcare provider; (2) assigned to the female sex at birth and not had genital gender reassignment surgery; (3) 18 years of age or older; and (4) able to read English. Figure 1 illustrates participation in the study. A total sample of 1,146 participants were used for all calculations. Fourteen participants skipped occasional questions regarding conditions associated with dyspareunia but were kept in the final count due to the small percentage of missing data.
The survey was conducted using Qualtrics (Qualtrics ® , Provo, UT) and was accessed via a link posted in EDS Facebook support groups and on Twitter (Twitter Inc, San Francisco, CA). Of the 171 EDS support groups approached on Facebook, 55 gave permission to post our survey link once. The survey was posted with the title Ehlers-Danlos Syndrome and Women's Health Issues to prevent participants from ascertaining that the survey was focused on dyspareunia and vulvodynia which could skew participation. Furthermore, the survey description encouraged women with and without women's health issues to participate to accurately reflect the presence of women's health issues in women with EDS or HSD. The same study description and link was also posted on Twitter with the hashtag #EDS. Individuals that were interested in this survey selected the link via either Facebook or Twitter and were brought to Qualtrics where electronic consent was obtained. Qualtrics prevented participants from completing the survey more than once by limiting participation to one per Internet Protocol address. Qualtrics deidentified data available to researchers by removing the IP addresses.
This survey was developed based on a previously validated online survey used to evaluate dyspareunia and vulvodynia . For this study, dyspareunia was defined as painful vaginal ing Criteria developed for this study was used in a previous vulvodynia study  and was adapted from surveys by Reed et al. (2006) and Harlow et al. (2009) the survey compared to an in-office visit. Reed et al.'s (2006) survey also had 94.1% accuracy in determining subjects without vulvodynia.
Our survey ranged from 29 to 56 questions using branch logic (depending on reported symptomatology) and took an average of 10-20 min to complete, with only deidentified data collected.
Data were exported from Qualtrics into Microsoft Excel for cleaning and coding prior to analysis using Stata Software for Statistics 15 (StataCorp LLC, College Station, TX). Missing data were minimal (<3%) in the analysis sample, suggesting minimal bias to our results. Listwise deletion was used in cases with missing responses.
Descriptive statistics were used to summarize and describe data results. Correlation tables were used to assess for multicollinearity.
Logistic regression was used to describe the effect of demographics and EDS type on a participant's odds of having dyspareunia and vulvodynia. Logistic regression was also used to describe the effect of comorbid conditions in common between EDS (or HSD) and vulvodynia on a participant's odds of having vulvodynia ( Table 2). The α level was set at <0.05. "I'm not sure" follow-up questions were assessed by a vulvodynia expert (J.S.) and were left as "I'm not sure" or changed to "Yes" or "No" based on the response.  (Table 1). Eighty-eight percent of participants resided in either the United States or England, and 12% in 1 of 27 other countries. Characteristics of the sample are summarized in Table 1. The rate of dyspareunia was determined by the response to the question "Do you have, or have you had pain with sexual intercourse?".

| RESULTS
Next, 63.7% (n = 730) of all participants reported pain with intercourse and 3.6% (n = 42) of all participants reported they were virgins or not sexually active and were unable to determine if they had dyspareunia.
Of the 42 (3.6%) participants who reported they were virgins or not sexually active, 15 reported pain with tampon insertion. The rate of vulvodynia was determined using the Vulvodynia Screening Criteria ( Figure 2) with 573 (50%) participants screening positive. The rate of each vulvodynia symptom is shown in Figure 3. Figure 4 shows the rate of each condition associated with dyspareunia. Vulvodynia, ovarian cysts, fibroids, abdominal and pelvic scars, and endometriosis were the most common conditions associated with dyspareunia in our sample.
Participants' demographics were significantly associated with the odds of whether or not they had dyspareunia or screened positive for vulvodynia ( Table 2). The odds of having dyspareunia varied significantly based on age and whether or not a participant was White (p = .006). Age had a nonlinear relationship with the odds of women having dyspareunia. Younger women and older women had higher odds of having dyspareunia than middle age women; with women in their mid-40s having the lowest odds ( Figure 6) be as high as 77% (Castori et al., 2012;Hugon-Rodin et al., 2016;Hurst et al., 2014). However, this study also examined the rate of other conditions associated with dyspareunia in women with EDS (Castori et al., 2012;Hugon-Rodin et al., 2016;Hurst et al., 2014;Tinkle et al., 2017). Our finding that 50% of women with EDS or HSD may also have vulvodynia, over six times the rate of the general population, is important because this group has a high chronic pain burden Tinkle et al., 2017;Voermans et al., 2010). Women with EDS have fragile lax tissues (Ehlers-Danlos Syndrome: National Library of Science (Vulvodynia Screening Criteria) (Harlow et al., 2009;Reed et al., 2006) were instrumental in enabling us to perform this survey in a large sample of women from around the world. Identifying that dyspareunia  (Bornstein et al., 2016;Castori, Morlino, et al., 2013;. Clinical presentation is typically complex, with multiple comorbidities, rendering it unlikely that an individual or cohort would respond to one single treatment option. Our study's large sample size is noteworthy and would have not been possible in a prospective design. A limitation of this study was that all diagnoses were self-reported or diagnosed through a reliable and validated screening tool and were not verified by a healthcare provider (Harlow et al., 2009;Reed et al., 2006). Using self-report and a screening tool to examine the rate of conditions could increase the rate of false positives. However, the burden of performing pelvic exams would have made the large sample size difficult, if not impossible to obtain. In addition, our findings are roughly in line with the "real world" experience in clinics and daily living of affected individuals, which documents a wide array of chronic pain manifestations in people with EDS and HSD.
Conducting EDS research is difficult as most types are classified as a rare disease (National Insititutes of Health, 2017; Steinmann, Royce, & Superti-Furga, 2002) which hampers case finding. Using social media enabled us to examine gynecological conditions in women with EDS or HSD in a large population from around the globe, thus suggesting the utility and benefit of using an online survey format. Our sample was a convenience sample of only women who had access to providers that diagnosed EDS or HSD, used social media, and could read English. Participants in this study were predominantly from the United States, White, had internet access, and used social media; and the study was conducted in English. The Vulvodynia Screening Criteria enabled us to identify women who may have vulvodynia in a large sample who also have a rare disease.

| CONCLUSION
The findings of our study suggest important information for clinicians caring for women with EDS or HSD. EDS, HSD, and vulvodynia have shared comorbid conditions that include fibromyalgia, interstitial