Awareness of post-surgical adhesions among gynecological surgeons: focus on the surgical management of endometriosis

Postoperative adhesions, bands of connective tissue that join two normally separate anatomical structures, have become one of the commonest sequelae of 75% to 93% of gynecological surgeries, leading to chronic pain, infertility or bowel obstruction, [1- 3]. Secondary adhesions due to endometriosis could affect fertility and pregnancy rates through anatomical distorsion or internal reproductive organs [4]. or could produce small bowel obstruction. [3]. Since 40% to 60% of surgeons were not aware of the consequences of adhesion for their clinical practice and women’s life, [5] a first consensus position was published in 2007 by the European Society of Gynecological Endoscopy (ESGE) with the aim to provide evidence-based recommendations to reduce postsurgical adhesions in gynecological surgery. Awareness of Post-Surgical Adhesions among Gynecological Surgeons: Focus on the Surgical Management of Endometriosis Rudy Leon De Wilde1, Julio Alvarez2, Hans Brölmann3, Ying Cheong4, Pierre Collinet5, Attilio Di Spiezio Sardo6, Philippe Koninckx7, Per Lundorff8, Leszek Pawelczyk9, Luz Angela Torres-de la Roche1, Markus Wallwiener10 1Clinic of Gynecology, Obstetrics and Gynecological Oncology, University Hospital for Gynecology, Pius-Hospital Oldenburg, Medical Campus University of Oldenburg, Germany, 2Hospital Universitario Infanta Sofía, San Sebastián de Los Reyes, Madrid, Spain, 3Department of Obstetrics and Gynecology, VU University Medical Centre, Amsterdam, The Netherlands, 4Human Development and Health, Faculty of Medicine, University of Southampton and Complete Fertility Centre, Southampton, United Kingdom, 5Centre Hospitalier Régional Universitaire de Lille, France, 6Department of Public Health, University “Federico II” of Naples, Italy, 7University Hospital Gasthuisberg, Katholieke Universiteit, Leuven, Belgium, 8Clinic of Gynecology, Private Hospital Mølholm, Vejle, Denmark, 9Division of Infertility and Reproductive Endocrinology, Poznan University of Medical Sciences, Poznan, Poland, 10Department of Obstetrics and Gynecology, University Clinic Heidelberg, Germany

Objective: Postoperative adhesions occur in 80% of cases of gynecological surgery. Therefore evidence-based recommendations have been made to improve surgeons´ knowledge of postoperative adhesion formation and preventive strategies. The objective of this survey was to assess the perceptions and practice of international gynecological surgeons on adhesions following endometriosis surgery. Materials and Methods: Data capture was conducted via online survey. The questionnaire was accessible worldwide during 2 weeks through the Society of Endometriosis and Uterine Disorders (SEUD) website. The qualitative variables were described as number and percent of the different response modalities, comparing European participants (n= 35) within the whole sample of surgeons (n= 65) vs non-European participants (n= 30). Results: 97% of Europeans and 63% of non-European surgeons recognize adhesion prevention as useful to reduce chronic postoperative pain and to avoid complications related to adhesions. To minimize adhesions, good surgical technique was considered relevant to almost all responders, also the use of anti-adhesive barriers or solutions (77% Europeans vs 57% non-European). 20% of all responders do not provide their patients with information about the risks of adhesion formation, related long-term complications or preventive treatment options. Conclusion: Despite a substantial awareness, disparities in daily practice of gynecological surgeons around the world facing the problem of adhesion formation in surgical endometriosis management exist. In order to improve adherence to anti-adhesion strategies in endometriosis surgery, more scientific evidence is needed. National and international scientific societies can play an important role to initiate research; also it might be helpful to call for more communication in this field.

Surgery-induced adhesions; Gynecological surgery; Awareness; Prevention; Endometriosis Corresponding author: Rudy Leon De Wilde, Clinic of Gynecology, Obstetrics and Gynecological Oncology, University Hospital for Gynecology, Pius- Hospital, Medical Campus University of Oldenburg, Georgstrasse 12, 26121 Oldenburg, Germany, Tel: +4904412291524 - 2291506; E-mail: rudy-leon.dewilde@pius- hospital.de [3] which allowed an improvement in the European surgeons’ knowledge and antiadhesion strategies, as demonstrated in a subsequent survey performed in 2014. [6]. In that survey 70% of respondents thought that endometriosis surgery, myomectomy, adhesiolysis, and adnexal surgery are the most likely to be associated with adhesions, but only 60% reported to know the surgical techniques recommended for adhesion prevention; 14Annals of Medical and Health Sciences Research | October 2017 | Vol 7 | Special Issue 2 | De Wilde RL, et al.: Post-endometriosis surgery Adhesions and few (38.4%) used antiadhesion agents regularly, because they did not consider these agents as an important measure in adhesion prevention. [6]. Based on this findings, the Society of Endometriosis and Uterine Disorders (SEUD), an international scientific network of experts in women’s and reproductive health, performed the present survey with the aim to assess the perceptions and practice of international gynecological surgeons on adhesions following endometriosis surgery.

This was an international online survey conducted among gynecological surgeons, who were recruited through the SEUD website (http://seud.org/about-the-society-of-endometriosis- and-uterine-disorders/). This web-site is a platform of information to promote medical education about disease awareness, pathogenesis, risk factors, diagnosis and treatments of diseases that negatively affect women’s health and fertility. The survey was accessible during 2 weeks, from 5 th to 22 nd April 2014, to surgeons who voluntarily filled up a 12-items questionnaire (Appendix 1). Questions were related to the impact of adhesions on endometriosis and its management, factors associated with adhesion prevention in endometriosis surgery, information of patients and patients consent, prevention of adhesions during surgical management of endometriosis, and the role of the anti-adhesion agents during laparoscopic surgery of endometriosis. It was an anonymous survey; surgeons all around the world, both members and non-members of the SEUD were allowed to access it, and there was no financial incentive for participants. Questionnaires were provided with a qualitative 4-point-scale to answer each question: strongly applicable, undetermined, and slightly or not applicable. Every participant was allowed to answer the questionnaire only once. Data were analyzed using SAS software version 9.4. The qualitative variables were described as number and percent of the different response modalities, comparing European surgeons (ES) within the whole sample of surgeons (WSS) vs. Non-European Surgeons (NES). The numbers of missing data were also included.

Sixty-five gynecological surgeons participated [Table 1], most of them Europeans (35/65); mainly working in university hospitals (63%), with a median of 42 beds in their departments. The main countries represented were France (16.9%), Spain (13.8%), Brazil (7.7%), Russia (6.2%) and South Korea (4.6%). During the 6 months prior to the survey, comparable numbers of laparoscopies and laparotomies were performed by each surgeon. The mean numbers of interventions for endometriosis reported during the previous 5 years were 307 for WSS (mean 61/year), mostly by ES, indicting participants had an appropriate level of expertise in the endometriosis field. Regarding the impact of adhesions on endometriosis and its management [Table 2], few NES (20%) think that adhesions can trigger ovarian endometrioma, but 57% of them recognize adhesions as a risk factor for endometrioma recurrence, while 43% of ES agree with both statements. About the negative consequences of endometriosis on fertility, most of participants recognize this effect, but only 63% of NES recognize adhesion prevention as useful to reduce chronic pain and to avoid complications related to adhesions. This medium-low level of knowledge in the pathogenesis of long-term complications related to endometriosis and peritoneal adhesion could affect the surgeon´s pre and intra-operative decision-making process regarding adhesion prevention when facing patients with endometrioma. Table 1: Survey respondents by country of residency. Country Total Country Total n % n % Europe Asia Belgium 2 3.1 Japan 1 1.5 South Korea 3 4.6 France 11 16.9 Other Countries Algeria 1 1.5 Germany 2 3.1 Israel 1 1.5 Kenya 1 1.5 Greece 1 1.5 Lebanon 1 1.5 Russia 4 6.2 Italy 3 4.6 South Africa 2 3.1 Turkey 1 1.5 Portugal 3 4.6 Ukraine 1 1.5 United Arab Emirates 1 1.5 Spain 9 13.8 Uzbekistan 1 1.5 USA 4 6.2 Sweden 1 1.5 Central and South America Argentina 1 1.5 Netherlands 1 1.5 Brazil 5 7.7 Chile 1 1.5 United Kingdom 2 3.1 Mexico 1 1.5 Total 35 0.538 Total 30 0.461 When asked about their experience with endometriosis patients, and patient counselling [Table 3], it was found that patients with endometriosis and adhesions are an important part of their daily work, both medically (87% NES vs 74% ES), and surgically (90% NES vs. 74% ES). During the patient counselling process, most surgeons provide information regarding adhesion formation, but the majority did not discuss long-term complications of adhesions (73% NES vs. 74% ES), or provide information about prevention options to patients with endometriosis undergoing pelvic surgery (67% NES vs 74% ES). As mentioned before, the lack of up-dated information about the consequences of adhesions between surgeons could also impact the quality of information and care that patients receive by their physicians. When asked about the factors associated with adhesion prevention during surgical management of endometriosis [Table 4], the large majority of respondents have well defined surgical strategies to prevent adhesions, and also consider adhesiolysis as an important preliminary step in the surgical procedures for endometriosis. To minimize adhesions, good surgical technique was considered as relevant for both groups, more than the use of anti-adhesive barriers or solutions (57% NES vs. 77% ES). Here, 60% of NE and 57% of ES reported to use these agents regularly as an adhesion prevention strategy. These results suggest that surgeons relay adhesion prevention on surgical technique more than in anti-adhesion substances, reflecting what ESGE and other international guidelines emphasize, but 15Annals of Medical and Health Sciences Research | October 2017 | Vol 7 | Special Issue 2 | De Wilde RL, et al.: Post-endometriosis surgery Adhesions also could be related with a low availability of the substances in some settings. Specifically, anti-adhesion agents during laparoscopic surgery [Figure 1] are used on a regular basis by most of all responders in case of diagnosis of adhesions during endometriosis surgery. Different agents were mentioned to be used, or to be considered to use, such as oxidized regenerated cellulose (Interceed®) hyaluronic acid (Hyalobarrier gel®) and 4% icodextrin (Adept®); and 20% of surgeons use Ringer´s lactate as an adhesion prophylactic agent. In addition, environmental peritoneal conditioning technique, which includes the use of humidified CO 2 and physiologic temperature during laparoscopy, was considered useful in adhesion reduction and prevention by one third of AS. Here, participants reflect the wide option of antiadhesion agents available and used; but in accordance to the medium-frequency of use yet discussed, participants prefer to use them as a secondary prevention measure after adhesiolysis of preexisting adhesions. Table 2: Impact of adhesions on the endometriosis and its management. Variables Strongly applicable Undetermined Slightly or not applicable WSS N=65 NES N=30 ES N=35 WSS N=65 NES N=30 ES N=35 WSS N=65 NES N=30 ES N=35 Adhesions can trigger ovarian endometrioma 21(32%) 6 (20%) 15 (43%) 8 (12%) 0 8 (23%) 29 (45%) 17 (45%) 12 (34%) Presence of adhesions is a risk factor for endometrioma recurrence 32 (49%) 17 (57%) 15 (43%) 9 (14%) 3 (10%) 6 (17%) 24 (36%) 10 (33%) 14 (40%) Endometriosis may affect fertility by various mechanisms, including disturbance of pelvic anatomy by adhesions 64 (98%) 29 (97%) 35 (100%) 0 0 0 1 (2%) 1 (3%) 0 Adhesion prevention is very important in reducing pain, avoiding complications such as bowel obstruction, and preserving fertility 53 (81%) 19 (63%) 34 (97%) 2 (3%) 1 (3%) 1 (3%) 0 0 0 WSS: Whole Sample of Surgeons; NES: Non‑European surgeons; ES: European Surgeons Table 3: Information of patients and patients’ consent. Variables Strongly applicable Undetermined Slightly or not applicable WSS N=65 NES N=30 ES N=35 WSS N=65 NES N=30 ES N=35 WSS N=65 NES N=30 ES N=35 Patients with endometriosis and adhesions are an important part of my daily medical work besides surgery 52 (80%) 26 (87%) 26 (74%) 7 (11%) 3 (10%) 4 (11%) 6 (9%) 1 (3%) 5 (14%) Patients with endometriosis and adhesions are important part of my daily surgical work 53 (82%) 27 (90%) 26 (74%) 6 (9%) 3 (10%) 3 (9%) 6 (9%) 0 6 (17%) I provide information on treatment options for adhesions for all patients with endometriosis undergoing pelvic surgery 46 (71%) 20 (67%) 26 (74%) 8 (12%) 8 (12%) 3 (9%) 11 (17%) 5 (17%) 6 (17%) I provide information on long‑term complications of adhesions 48 (74%) 22 (73%) 26 (74%) 8 (12%) 4 (13%) 4 (11%) 9 (14%) 4 (11%) 5 (14%) I provide information about adhesion formation during the consent process 52 (80%) 22 (73%) 30 (86%) 4 (6%) 4 (13%) 0 9 (14%) 4 (11%) 5 (14%) WSS: Whole Sample of Surgeons; NES: Non‑European Surgeons; ES: European Surgeons Table 4: Prevention of adhesions during surgical management of endometriosis. Variables Strongly -applicable Undetermined Slightly or not applicable WSS N=65 NES N=30 ES N=35 WSS N=65 NES N=30 ES N=35 WSS N=65 NES N=30 ES N=35 Adhesion prevention is one of the goals of laparoscopic surgery for endometriosis 58 (89%) 29 (97%) 29 (83%) 5 (8%) 1 (3%) 4 (11%) 2 (3%) 0 2 (6%) Adhesiolysis is considered an important preliminary step in the surgical procedures for endometriosis 64 (99%) 30 (100%) 34 (97%) 1 (1%) 0 1 (3%) 0 0 0 Good surgical technique is important to minimizing adhesions 64 (99%) 30 (100%) 34 (97%) 1 (1%) 0 1 (3%) 0 0 0 Anti‑adhesive barriers or solutions are important in adhesion reduction and prevention 44 (68%) 17 (57%) 27 (77%) 13 (20%) 10 (33%) 3 (9%) 8 (12%) 3 (10%) 5 (14%) I regularly (at least two times in the last month) use agents for adhesion reduction and prevention intra‑operatively 38 (59%) 18 (60%) 20 (57%) 10 (15%) 0 10 (33%) 17 (26%) 12 (40%) 5 (14%) WSS: Whole Sample of Surgeons; NES: Non‑European Surgeons; ES: European Surgeons 16Annals of Medical and Health Sciences Research | October 2017 | Vol 7 | Special Issue 2 | De Wilde RL, et al.: Post-endometriosis surgery Adhesions Figure 1: Anti‑adhesion agents used during laparoscopic surgery of endometriosis, as reported by all respondents (n=65).

Endometriosis and its associated adhesions adversely impact on women’s reproductive health and quality of life, and is a significant health care burden for patients, clinicians and health care providers. The adverse impact of endometriosis on fertility and the optimal surgical options in their treatment are recently highlighted as two of the top ten concerns in endometriosis by health care practitioners and the public. [7]. In addition, there is inconclusive evidence about the long-term effectiveness of prevention agents. [8]. Many scientific communities involved with women’s health are also concerned and they performed surveys to assess the awareness of gynecological surgeons regarding postsurgical adhesions after surgical management of endometriosis. A previous survey, conducted by ESGE among 253 gynecological surgeons from European countries [5], reported that the knowledge of recommended surgical techniques and preventive measures to reduce adhesions were not widely spread; although the responders showed a good knowledge of the risk factors. In the present survey, conducted with the assistance of SEUD, it was demonstrated that even in gynecological surgeons with expertise in the field of endometriosis surgery, discrepancies in the respondent’s opinion regarding the impact of adhesions on endometriosis and its management exist. Regarding the impact of adhesions and endometriosis, the associated impairment of fertility is well recognized by all participants. In contrast, the role of adhesions in ovarian endometrioma occurrence and recurrence is not recognized by more than half of WSS, especially by NES. Different studies have reported that ovarian endometrioma reoccurs in 9.6 to 80% of cases after complete laparoscopic resection. [9,10]. Presence of adhesions, previous pelvic surgery, fulguration, and higher Ca 125 levels, seem to be risk factors for endometrioma recurrence. [10,11]. Interestingly, small endometrioma (< 3 cm) could be associated with a higher degree of pelvic adhesions. [10]. In contrast to the 40% of ESGE respondents, we found that most of WSS recognize the importance of adhesion prevention to reduce long term complications related to abdominal and gynecological surgery. As well, WSS reported to follow the international recommendations for surgical management of endometriosis [12,13] that is using laparoscopic approach, adhesiolysis and good surgical technique. Thus, patients with endometriosis are a high risk for pre and postsurgical adhesions, being laparotomy more adhesiogenic than laparoscopy (1.23 ± 0.22, p<0.000; 95% IC 1.02-1.99), [14]. and that laparoscopic surgery is associated with higher pregnancy rates (RR 1.44, 95% CI: 1.24-1.68, p<0.01), and live birth rates (RR 1.52, 95% CI: 1.26-1.84, p<0.01). [15]. This awareness improvement could be the

of new evidence and educational activities that promotes the application of good surgical technique and complementary measurements for patients at high risk of adhesions. Therefore more patients will benefit from practices that reduce their own risk of peritoneal adhesions after endometriosis surgery. Based on the safety and reported efficacy compared to no- treatment to reduce surgical adhesions, [16]. anti-adhesive barriers and the use of peritoneal conditioning have been proposed in the recommendations as complementary measures. Antiadhesion agents were reported to be important, or to be used in daily practice by our responders in similar way to what was reported by ESGE participants (59% SEUD vs. 60.5% ESGE). [5]. However, we found a decrease in the frequency of use of peritoneal conditioning compared to ESGE survey (34% SEUD vs. 55.3% ESGE). [6]. This limited use of complementary and effective measures to prevent postsurgical adhesions could be explained by the non-availability of these technologies in low income settings or by their high cost, when available. Meanwhile, in some settings the woman reproductive health or the burden of postsurgical adhesions will not be improved, what is contrary to the objectives of the clinical guidelines? Despite the interest of gynecological surgeons in post-surgical adhesions and their preventive measures facing one of the major medical problems in gynecology, The majority of surgeons yet does not provide their patients with information about the risks of adhesion formation, long-term complications related with or preventive treatment options (73% NES vs. 80% ES). This frequency is higher than was former reported by surgeons in the Netherlands (10% to 41%), and the United Kingdom (23% to 48%). [1]. Incorporating adhesion prevention as a routine in the pre-operative counselling procedure could thus help to prevent medical malpractice lawsuits when complications occur. [1]. We recognize that the scope of the present survey was limited by the low number of respondents, especially NES. In consequence, the composition of our groups did not constitute completely representative sample of gynecologists that take care of women with endometriosis. But, all together these results reflect again that the knowledge, perceptions and practices of surgeons regarding adhesions should be improved in order to increase the benefits of adhesion prevention after endometriosis surgical management, especially on women´s reproductive health.

The results of this survey highlight the disparity in the opinion of gynecological surgeons around the world, on the management of adhesions in the context of endometriosis. It is prudent that surgeons remain up to date with evidence in order to provide women with adequate information on the impact of endometriosis and adhesions on their reproductive health. National and international, scientific and funding bodies should 17Annals of Medical and Health Sciences Research | October 2017 | Vol 7 | Special Issue 2 | De Wilde RL, et al.: Post-endometriosis surgery Adhesions prioritize research in the area of endometriosis, particularly around its detrimental impact on women’s reproductive health and ways to optimize surgical management with a focus on adhesion formation, reformation and prevention.

The authors thank all responders of the survey for their important opinions, and Laurence Saya, MD, Altius Pharma CS, Paris, France, for the help in medical writing. Author Disclosure Statement All members of the ANGEL group received travel reimbursement fees to attend the author´s meeting to analyze and discuss the survey´s results. Funding Nordic Pharma sponsored the survey´s platform and the transcription of the author’s meeting for the preparation of this manuscript. Authorship All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the final version to be published.

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