Ann-Sophie Page

INNOVATIVE THERAPIES IN PELVIC FLOOR DYSFUNCTION​ ANN-SOPHIE PAGE INNOVATIVE THERAPIES IN PELVIC FLOOR DYSFUNCTION

KU Leuven Biomedical Sciences Group Faculty of Medicine Department of Obstetrics and Gynaecology INNOVATIVE THERAPIES IN PELVIC FLOOR DYSFUNCTION Ann-Sophie PAGE Jury: Prof. dr. Dirk De Ridder Prof. dr. Wouter Froyman Prof. dr. Dudley Robinson Prof. dr. Jan-Paul Roovers Supervisor: Prof. dr. Jan Deprest Co-supervisors: Prof. dr. Frank Van der Aa Prof. dr. Johan Verhaeghe Chair examining committee: Prof. dr. Agnieszka Wozniak Chair public defense: Prof. dr. A. D’Hoore Dissertation presented in partial fulfilment of the requirements for the degree of Doctor in Biomedical Science 15/05/2025

ISBN: 978-94-6506-756-8 Cover by Marie Lebbe Printing by Ridderprint

“If I have seen further it is by standing on the shoulders of giants.” — Isaac Newton

TABLE OF CONTENTS Abbreviations 7 Chapter 1 Introduction 9 Chapter 2 Objectives 19 Chapter 3 Non-surgical treatment of prolapse and urinary incontinence 23 3.1 Vaginal laser therapy for pelvic organ prolapse: the VELPOP-study 25 3.2 Vaginal laser therapy for stress urinary incontinence: the VELSUI-study 37 Chapter 4 Surgical treatment of prolapse and urinary incontinence 49 4.1 Cervicosacropexy or vaginosacropexy for urinary incontinence and apical prolapse: 51 A systematic review 4.2 Evaluation and optimization of sacrocolpopexy as surgical treatment for apical prolapse 67 4.2.1 Long-term Data on Graft-Related Complications After Sacrocolpopexy With Lightweight 69 Compared With Heavier-Weight Mesh 4.2.2 Safety and medium-term outcome of redo laparoscopic sacrocolpopexy: a matched 83 case–control study 4.2.3 Cost of using glue rather than sutures for mesh fixation during sacrocolpopexy 97 4.2.4 An automated workflow analysis to evaluate novel modifications and learning curves 107 in sacrocolpopexy Chapter 5 Discussion 119 Chapter 6 Summary 127 Chapter 7 References 135 Chapter 8 Scientific Acknowledgement, Personal Contribution and Conflict of Interest 147 statements Chapter 9 Curriculum vitae 153 Acknowledgement - dankwoord 159

Abbreviations 7 ABBREVIATIONS AE Adverse Events BMI Body Mass Index CI Confidence Interval CESA Cervicosacropexy CMA Cost-Minimization Analysis DQN Deep Q-learning Network GRC Graft Related Complication HR Hazard Ratio ICS International Continence Society IUGA International Urogynecology Association IQR Inter Quartile Range LSCP Laparoscopic Sacrocolpopexy MUI Mixed Urinary Incontinence MUS Midurethral Sling NRS Non-Randomized Studies NTR Native Tissue Repair OR Odds Ratio PFE Pelvic Floor Exercises PFMT Pelvic Floor Muscle Training PGIC Patient Global Impression of Change POP Pelvic Organ Prolapse POP-Q Pelvic Organ Prolapse Quantification PVDF Polyvinylidene Fluoride RCT Randomized Controlled Trial ROB Risk Of Bias SAMPL Statistical Analyses and Methods in the Published Literature SCENIHR Scientific Committee on Emerging and Newly Identified Health Risks SCP Sacrocolpopexy STROBE Strengthening the Reporting of Observational Studies in Epidemiology SUI Stress Urinary Incontinence TOT Trans-Obturator Tape TRN Transition Retrieval Network UI Urinary Incontinence USL Uterosacral Ligaments UUI Urge Urinary Incontinence

9 CHAPTER 1 INTRODUCTION

Introduction 11 1.1 Pelvic floor disorders: epidemiology and pathophysiology Pelvic floor disorders include pelvic organ prolapse, urinary and fecal incontinence, defecatory disorders, pelvic pain and sexual dysfunction. More than a third of women will experience at least one pelvic floor dysfunction during their lifetime, and its prevalence is expected to increase due to aging of the population.1 This thesis focuses on prolapse and urinary incontinence. Although not lifethreatening conditions, its symptoms have a severe impact on the patients’ quality of life and wellbeing. The lifetime risk of undergoing surgery for prolapse or stress urinary incontinence (SUI) is estimated to be 20% by the age of 80 years.2 The pathophysiology of pelvic floor dysfunction is multifactorial. Delancey graphically summarized several causal factors in a ‘life-span model’ (Fig. 1). The life-span model plots a woman’s pelvic floor function in three main life phases. In Phase I, the woman develops her maximum pelvic floor functional capacity, which is dependent on her genetic background, nutrition and environment. In Phase II, the pelvic floor function may deteriorate due to the amount of injury and recovery of it, that occurs during pregnancy and after vaginal birth. Finally, in Phase III, the pelvic floor further deteriorates due to the aging process.3 Women will experience symptoms when their pelvic floor function depletes past a threshold. When, and if, this happens depends on several factors: the maximum functional capacity of the pelvic floor in Phase I, the rate of decline, stress their lifestyle places on the pelvic floor (e.g. chronic constipation, occupational lifting, obesity, chronic cough; Phase III), and in women having children, the events in Phase II (e.g. pregnancy, mode of delivery, obstetrical interventions). Aging may further enhance the deterioration of existing pelvic floor dysfunctions as the pelvic floor tissues weaken with age. As women live longer and lead more active lives, pelvic floor dysfunction is expected to become an increasingly important issue for both women and public health. Fig. 1. Integrated lifespan analysis of pelvic floor function (From Delancey JO et al. Graphic integration of causal factors of pelvic floor disorders: an integrated life span model. Am J Obstet Gynecol. 2008;199:6) Reproduced with permission of the publisher. The diagnosis of prolapse involves identifying the descent of one or more of the following: the anterior vaginal wall (cystocele) (Fig. 2A), the posterior vaginal wall (rectum and/or small bowel,

Chapter 1 12 referred to as rectocele or enterocele, respectively) (Fig. 2B), and the apical compartment (uterine or cervical descent if the uterus or cervix is still in place, or, after hysterectomy, vaginal vault prolapse) (Fig. 2C). Fig. 2. Classification of pelvic organ prolapse based on the descending organ. Images: UZ Leuven and VVOG, drawings made by DreamTeam. Prolapse can be present in one compartment, but more often, multiple compartments are affected simultaneously. The presence of any such sign may correlate with relevant prolapse symptoms. The feeling of heaviness or a lump in the genital area is the most common symptom, but urinary complaints, constipation, obstructed defecation, fecal incontinence, and other symptoms may coincide. Symptoms are generally worse after long periods of standing or exercise and improve when gravity no longer interferes, such as when lying supine. Prolapse may also be more prominent during abdominal straining, such as during defecation or when lifting heavy weights.4 In order to standardize quantification of the degree of prolapse, the Pelvic Organ Prolapse Quantification system (POP-Q) has been developed.5 POP-Q is the most frequently used staging system in both clinical (76%) and research (88%) settings.6,7 During vaginal examination, maximum prolapse is provoked by asking the patient to cough or to perform a Valsalva maneuver, while each vaginal wall is individually exposed when needed using a speculum. The degree of prolapse of the anterior vaginal wall (point Aa and Ba), the posterior vaginal wall (point Ap and Bp) and the cervix or vault (point C and D) are measured in centimeters either above/proximal to the hymen (negative number) or beyond/distal to the hymen (positive number) (Fig. 3). The plane of the hymen is defined as zero. Furthermore, the perineal body (pb), the genital hiatus (gh) and the total vaginal length (tvl) are measured. Based on these measurements, a stage (0-4) is determined for each compartment whereas stage 4 is classified as complete eversion. Studies correlating clinical findings with bladder or bowel symptoms have generally shown poor associations. However, the correlation between the sensation of a vaginal lump or bulge and clinical findings is somewhat better.8 Several authors have shown that women who complain of a vaginal bulge are more likely to be found to suffer from prolapse on clinical examination.9 A B C

Introduction 13 Fig. 3. POP-Q examination (From Bump RC et al. The standardization of terminology of female pelvic organ prolapse and pelvic floor dysfunction. Am J Obstet Gynecol 1996;175:10) Reproduced with permission of the publisher. Urinary incontinence (UI) is defined as the complaint of involuntary loss of urine, or the observations of involuntary loss of urine on examination. The three most common types of urinary incontinence are stress urinary incontinence (SUI), urge urinary incontinence (UUI) and mixed urinary incontinence (MUI). SUI is a condition of involuntary loss of urine on effort or physical exertion including sporting activities, or on sneezing or coughing. UUI is a condition where the involuntary loss of urine is associated with a feeling of urgency. Urgency is characterized by the sensation of a sudden, compelling desire to void which is difficult to defer. When both UUI and SUI are present, the term mixed urinary incontinence is used.4 A close association between prolapse and urinary incontinence has been reported.10 Prolapse repair may also result in the resolution of UI symptoms.11,12 The Integral Theory suggests that lax ligaments may lead to apical prolapse and urinary incontinence.13 Overall, treatment for prolapse and urinary incontinence is only indicated if the patient has symptoms for which she seeks therapy. In rare cases, advanced prolapse may compromise renal function due to ureteral obstruction, necessitating intervention to preserve renal function, or lead to vaginal bleeding due to erosive lesions. Apart from these cases, there are no absolute indications for intervention. Therefore, watchful waiting is a reasonable option for women with mild symptoms. Active treatment options include conservative and surgical approaches. An informed choice of treatment depends on the patient’s preferences.

Chapter 1 14 1.2 Non-surgical treatment Non-surgical treatment for both prolapse and urinary incontinence include life style interventions, pharmacotherapy for UUI, pelvic floor exercises (PFE; which officially should be referred to as Pelvic Floor Muscle Training (PFMT))14 and/or pessaries for prolapse and SUI. Each of these treatment modalities have their specific benefits and possible adverse events (AE). Lifestyle interventions include behavioral training (bladder training, fluid management), weight loss, reducing activities that strain the pelvic floor and treating constipation to avoid further exacerbation of pelvic floor dysfunctions by decreasing intra-abdominal pressure. There are no studies evaluating the long-term effectiveness of life style interventions in the treatment of pelvic floor dysfunction.15 Several studies have demonstrated efficacy of pelvic floor exercises in the treatment of pelvic floor dysfunctions. PFE may reduce the symptoms and severity of prolapse and stress urinary incontinence, and as a result improve quality of life on the short term, typically without any undesirable side effects. However, PFE requires a high level of commitment in order to achieve desired results and long-term follow-up studies are scarce and show inconsistent results.15,16 Pessaries are another non-surgical option for the treatment of both symptomatic prolapse or SUI. Pessaries can be categorized in two types: supporting type (e.g. ring pessaries) and spaceoccupying type (e.g. Gellhorn pessaries), shown in Fig. 4. In general, supporting pessaries are used in patients with mild prolapse (stage I or II), whereas space-occupying pessaries are typically used in advanced prolapse (stage III or IV) and when supporting pessaries fail.17 There is no difference in efficacy between pessary treatment and PFE in reducing pelvic floor symptoms, but specific prolapse-related symptoms seem to improve more with pessary treatment. For women suffering from SUI, vaginal pessaries may improve symptoms equally to little better compared to PFE.17 However, pessaries fit less good in 43% of women. Predictors of unsuccessful pessary fitting are higher BMI, older patients, shorter transvaginal length, previous hysterectomy and underactive pelvic floor muscles.18 Furthermore, pessary use is associated with local side effects (e.g. increased vaginal discharge, bleeding, extrusion) in more than half of women, leading to discontinuation rates up to 24-86% after 5 or more years.19 Fig. 4. Pessary fitting (A) and available pessary types (B). (Drawing by DreamTeam) A B

Introduction 15 Antimuscarinic (anticholinergic) drugs and beta-3 agonists (e.g., mirabegron) are the most frequently used drugs for UUI. For anticholinergics, dry mouth is the most common side effect (reported in nearly one-third of patients), though constipation, blurred vision, fatigue, and, particularly in the elderly, cognitive dysfunction may occur. Although modern anticholinergics have more selective and longer-lasting binding to muscarinic receptors compared to older anticholinergics, side effects remain common.20 Mirabegron, on the other hand, may increase blood pressure and is therefore contraindicated in patients with severe uncontrolled hypertension.21 Antimuscarinics and mirabegron 50mg have similar efficacy and are significantly better than placebo, however overall efficacy is rather low (56%, depending on the outcome measure used).21 Combination treatment of solifenacin 5 mg plus mirabegron 25 or 50 mg has been shown to be more efficacious than monotherapy and may therefore be an effective treatment option in patients who respond inadequately to first-line pharmacological treatment, potentially reducing the number of patients moving on to more invasive treatment options.21 This creates a clinical need for non-surgical alternatives for treating prolapse and (S)UI. The use of vaginal laser therapy to treat urogynaecological conditions seems appealing, as if proven effective, this could be an alternative minimally invasive treatment to add to the current portfolio of non-surgical treatments. Lasers have been widely used in areas other than gynecology, mainly in the field of medical aesthetics and dermatology. The two main types of laser used for tissue remodeling, are categorized depending on the medium used to generate the laser energy: CO2 laser and Erbium Yag laser. Current evidence suggests that lasers can cause shrinkage of collagen with subsequent remodeling of the connective tissue of the dermis. As a result, clinicians and companies started to explore whether the tissue remodeling properties seen with laser therapy to the dermis may also be adopted as non-surgical treatment to the vaginal epithelium and subepithelial fascia for gynaecological conditions caused by damaged connective tissues, including genitourinary syndrome of menopause (GSM), urinary incontinence and prolapse.22 However, the current lack of robust data on its efficacy and safety and the typically high cost of laser therapy have hindered its implementation in clinical practice. Fig 5. Vaginal laser therapy. Drawings made by Myrthe Boymans.

Chapter 1 16 1.3 Surgical treatment Another, yet invasive alternative is surgical repair. The main goals of pelvic floor reconstructive surgery are to restore normal pelvic anatomy, while also eliminating POP symptoms and normalizing bowel, bladder and sexual function. Surgery for prolapse can be performed by either the vaginal or abdominal route, and with insertion of implants or without, i.e. using the patient’s own tissue and sutures (referred to as native tissue repair). The same goes for surgical management of SUI where suspension of the bladder neck or mid-urethra can be done via abdominal route by sutures (e.g. Burch colposuspension) or by vaginal route using synthetic mesh (midurethral sling; MUS) or an autologous sling (fascia lata or rectus sheet). Based on current evidence, both autologous pubovaginal slings and Burch colposuspension have cure rates comparable to those of MUS, but are obviously more morbid with a less beneficial safety profile and more common adverse events such as storage lower urinary tract symptoms following autologous slings, and more mid- or posterior vaginal wall prolapse following Burch.23,24 Surgical treatment options for UUI include neuromodulation and botulinum toxin instillation, however improvement rates do not exceed 70%, and adverse events, including infection and obstructive voiding, are not uncommon.25 Clearly defined guidelines on the surgical treatment of both prolapse and urinary incontinence are lacking. The choice of surgery depends on several factors, including the general health status of the patient, the expertise of the surgeon, the preferences of both patient and surgeon, and, in the case of prolapse, the site and severity of the prolapse. Whereas most patients with symptomatic prolapse can be adequately managed via the vaginal route, correction of apical descent or multi-compartment prolapse, including a so-called level I defect, is, based on current evidence, better treated via the abdominal approach.26 In sacrocolpopexy the vaginal vault and/or cervix is fixed by means of a graft to the anterior longitudinal ligament over the sacrum, as shown in Fig. 6. The technique can be empirically divided in five steps, each of them requiring specific skills to overcome specific challenges. Following the dissection of the promontory, the right paracolic gutter and vaginal vault are dissected. Next the mesh is fixed to the vaginal vault by resorbable sutures and to the promontory, by either sutures or tackers. As a last step the peritoneum is closed, although the necessity of this step is questioned.27 There are numerous reports on the successful outcome of laparoscopic sacrocolpopexy (LSCP), including data from our own group. We first implemented LSCP in our unit in the late 1990s, and earlier reported on short and medium-term outcomes.28,29 Laparoscopic sacrocolpopexy yields excellent objective (97% anatomical cure) and subjective (83% improvement) outcomes, yet at the expense of longer operating times and a steep learning curve (between 30 and 60 cases, depending on what outcome measures are considered).30,31 One potential way to reduce operating time might be decreasing the number of sutures. Some surgeons use fewer sutures without apparent impact on outcomes. The development of alternative, faster mesh fixation methods, including surgical glue, could also help.32 As different approaches to

Introduction 17 sacrocolpopexy are introduced, studies become necessary to understand how they affect surgical learning rates at the level of each phase. This can be done quicker and more objectively by using Artificial Intelligence (AI) techniques. Indeed, going through large volumes of lengthy surgical videos to annotate the duration of each phase, is time-consuming, and subjective and requires clinically trained staff. Automating this task, by surgical workflow segmentation, would thereby greatly assist in the investigation of surgical skills and the impact of procedural changes in sacrocolpopexy. Fig. 6. Sacrocolpopexy. Drawing by Myrthe Boymans. Any pelvic floor surgery may cause adverse events, including pain, dyspareunia, infection, voiding dysfunction, and other functional bladder and bowel symptoms. There are also adverse events uniquely associated with mesh use, such as mesh exposure and extrusion. The increasing number of reports of adverse events following the vaginal insertion of implants has led to the withdrawal or restricted use of vaginal prolapse mesh and, in some countries, of MUS as well. This has caused women and practitioners to become hesitant about pelvic floor surgery. Although we have argued for their effectiveness and limited invasiveness, their use is increasingly being questioned. Moreover, a study on patient preferences has shown that participants are willing to accept a slightly lower probability of cure to avoid substantial postoperative pain and possible complications by receiving a less invasive treatment..36 The rising reluctance to have mesh inserted over the past decade underscores the need for continuous monitoring of our surgical practices. Surgical modifications in sacrocolpopexy, including the use of new meshes that may be more biocompatible, might lower long-term mesh-related morbidity. At the same time, the potential benefits of “mesh-less” or mesh-free surgical alternatives, such as cervicosacropexy or vaginosacropexy (CESA/VASA), should be explored. These procedures involve the replacement of the USL with synthetic tapes and could cure both urinary incontinence and prolapse simultaneously.37,38

19 CHAPTER 2 OBJECTIVES

Objectives 21 The overarching aim of this project is to explore the potential benefit of three novel therapies and to optimize current surgical management options, for prolapse and/or urinary incontinence. Non-surgical treatment of prolapse and urinary incontinence Vaginal laser therapy for pelvic organ prolapse: the VELPOP-study To evaluate the efficacy and safety of vaginal Er:YAG laser application for symptomatic grade 2-3 anterior and/or posterior vaginal wall prolapse, as compared to PFE over a one year follow-up period. Vaginal laser therapy for stress urinary incontinence: the VELSUI-study To evaluate the efficacy and safety of vaginal Er:YAG laser application for mild to moderate SUI, as compared to PFE over a one year follow-up period. Surgical treatment of prolapse and urinary incontinence Cervicosacropexy or vaginosacropexy for urinary incontinence and apical prolapse: A systematic review To systematically review and summarize the evidence on the efficacy and safety of cervicosacropexy and vaginosacropexy as alternative surgical treatment options for urge and/or mixed urinary incontinence and apical prolapse, in view of potential addition to our portfolio. Evaluation and optimization of sacrocolpopexy as surgical treatment for apical prolapse • Long-term Data on Graft-Related Complications After Sacrocolpopexy With Lightweight Compared With Heavier-Weight Mesh To estimate the long-term incidence and characteristics of GRC, rate of reinterventions for GRC and prolapse, subjective and anatomical outcomes after laparoscopic sacrocolpopexy with heavier-weight (over 44 g/m²) compared to lightweight (28 g/m²) polypropylene mesh, the latter with a resorbable poliglecaprone component. • Safety and medium-term outcome of redo laparoscopic sacrocolpopexy: a matched case–control study To document the functional and anatomical outcomes of redo laparoscopic sacrocolpopexy procedures on the medium-term, when compared to primary procedures. • Cost of using glue rather than sutures for mesh fixation during sacrocolpopexy To perform a cost minimization study when replacing (part of the) sutures by a synthetic glue for mesh fixation. • An automated workflow analysis to evaluate novel modifications and learning curves in sacrocolpopexy Surgical workflow analysis is an important component to standardize the timeline of a procedure and for later training purposes. Automating this task would greatly assist in the

Chapter 2 22 investigation of surgical skills and the impact of procedural changes, and this can be accomplished with surgical workflow segmentation. Herein we aim to develop this for sacrocolpopexy, and thereafter implement it on a consecutive series.

23 CHAPTER 3 NON-SURGICAL TREATMENT OF PROLAPSE AND URINARY INCONTINENCE

25 3.1 Vaginal laser therapy for pelvic organ prolapse: the VELPOP-study Ann-Sophie Page, Eline Borowski, Emma Bauters, Susanne Housmans, Frank Van der Aa, Jan Deprest Published in Eur J Obstet Gynecol Reprod Biol, 2024, 303:165-170.

VELPOP 27 ABSTRACT Objectives: To compare the efficacy of Er:YAG laser for mild to moderate pelvic organ prolapse (POP) to that of pelvic floor exercises (PFE). Design: Single center randomised controlled trial. Setting: Tertiary center, Belgium. Participants: Forty-six women with mild to moderate prolapse were enrolled (23 in each group). There were no missing data for the primary outcome; three patients were lost to follow-up at 24months. Interventions: Comparison of vaginal laser treatment (3–6 applications) to PFE (9–18 sessions). Main outcome measures: Subjective change in prolapse symptoms at four months from baseline measured by the Pelvic Organ Prolapse Distress Inventory-6 (POPDI-6) (primary), adverse events, other subjective outcomes and independent anatomical assessment up to 24 months. Results: The mean difference in POPDI-6 scores at 4 months was 1.09 (95 %CI = −6.02;8.12), showing non-inferiority of laser to PFE (p = 0.004). Within groups, the difference in mean POPDI-6 four months following the start of therapy tended to be lower for laser-treatment (65.2 % (15/23) of laser-participants were ‘better’ or ‘much better’) than for PFE (60.9 % (14/23) in the PFE group), yet without difference between groups (OR = 1.21; 95 %CI = 0.39–3.23). There were no obvious between group differences in any other subjective nor objective outcomes. At 24 months, 50 % (11/22) of laser-patients and 43 % (9/21) of PFE-patients requested additional, yet alternative treatment. There were no serious adverse events at any time-point. Conclusions: Vaginal laser application and PFE improve symptoms of mild and moderate prolapse to a similar extent. Both treatments had a measurable yet not durable effect. There were no adverse events in either arm. Trial registration: ClinicalTrials.gov(NCT04523298). Funding: The laser device was provided by Fotona, Slovenia for the duration of this trial.

Chapter 3.1 28 INTRODUCTION Pelvic organ prolapse (POP) affects 1-65% of women and its symptoms have a severe impact on their quality of life and wellbeing.39 Treatment options typically include watchful waiting, vaginal pessary use, pelvic floor exercises (PFE) and surgery. Both PFE and pessaries are cheap and safe options, but their use is limited by moderate improvement in symptoms or, in case of pessary use, high discontinuation rates due to side effects.40-42 Surgery has overall good to very good long-term anatomical and subjective cure rates, but comes with an increased risk for complications.43-45 Surgical management of POP also faced increased scrutiny due to concerns over the use of mesh, leading women to be hesitant about undergoing surgery. This has created a renewed interest for non-surgical alternatives for treating POP. Vaginal laser application seems appealing, as, if proven effective, this is a minimally invasive treatment with minimal morbidity. However, the safety and efficacy of laser treatment for the management of numerous indications, including genitourinary syndrome of menopause (GSM), stress urinary incontinence (SUI) and prolapse has not yet been confirmed, as highlighted by the US Food and Drug Administration and other authorities46-48. This includes the European Board and College of Obstetrics and Gynaecology (EBCOG) who called for good quality research with appropriate patient reported outcome measures and long-term follow-up in its 2024-position statement.49 Both for GSM and SUI, the use of laser remains controversial, due to contradictory findings in available randomised trials.49,50 Conversely, for prolapse, there is less robust data. A recent systematic review suggested short-term beneficial effects of laser yet the quality of included studies was judged to be subpar in terms of study design and short follow-up.51 Therefore, the purpose of this study was to evaluate the efficacy and safety of vaginal application of Erbium:Yttrium Aluminium Gadolinium (Er:YAG) laser application for symptomatic stage 2-3 anterior and/or posterior vaginal wall prolapse, as compared to PFE over a two-year follow-up period. MATERIALS AND METHODS Study design and participants This is a single-center, randomised controlled trial on the efficacy of vaginal Er:YAG laser application in reducing prolapse symptoms as compared to PFE. The study took place at a tertiary center in Belgium and the target group were women with bothersome POP symptoms with midvaginal (level II defects, i.e. either anterior and/or posterior wall prolapse) moderate (stage 2 and 3) prolapse according to the Pelvic Organ Prolapse Quantification System (POP-Q).52,53 Exclusion criteria included symptoms or anatomical evidence of intussusception or rectal prolapse or descent of the uterus, cervix or vault (C>Ba/Bp), stage 4 prolapse, any previous PFE or vaginal laser therapy 12 months prior to inclusion, previous POP surgery, pregnancy or within 12 months after delivery,

VELPOP 29 vaginal bleeding, injuries or infection in the treated area, or conditions that could affect study compliance. Following assessment of eligibility criteria and written informed consent, participants were randomised (1:1) by the study coordinator, who was not further involved in the treatment nor clinical assessment of study participants via a secure website using a single block computergenerated list (https://www.sealedenvelope.com/simple-randomiser/v1/trials/velpop-2). Procedures Laser was applied using a 2940 nm vaginal erbium laser (SP Spectro, Fotona, Ljubljana, Slovenia) with SMOOTH mode setting, allowing for non-ablative, thermal-only operation.54 The parameters were the standard settings defined by the manufacturer, based on preclinical and clinical studies.55-57 We used the erbium laser rather than the CO2-laser to enable comparison with other trials on prolapse, which all reported on the erbium laser.57-59 Participants in the laser group received three applications at monthly intervals with the option to request additional treatment courses, up to a maximum of six applications. Laser treatment was performed by an independent physician experienced with vaginal laser application. An application consisted of a full vaginal canal irradiation (using a 360° circular adapter), followed by additional irradiation of the prolapsed vaginal wall (using a 90° angular adaptor) and concluded with irradiation of the vestibule area (using a straight handpiece). In Belgium, the standard conservative management consists of a course of nine PFE sessions supervised one-to-one by a pelvic floor physiotherapist, chosen by the women at their discretion (http://www.bicap.be). Again, patients could request nine additional PFE courses if they felt the need for this. Crossover was permitted four months after the first treatment. Patients were clinically assessed at baseline, treatment and followup visits, by an independent and experienced urogynecologist. Study participants self-reported outcomes at baseline and prior to each treatment visit. Follow-up visits were scheduled at 1, 6, 12 and 24 months after the last therapeutic session. Outcomes Primary outcome was subjective improvement of POP symptoms, measured through the Pelvic Organ Prolapse Distress Inventory-6 (POPDI-6) as suggested by the International Consultation on Incontinence (ICI) guideline, comparing scores at baseline to those four months after first treatment.60,61 Participants answered to six questions on POP-symptoms with a response scale from 0 to 4 (not present (=0), not at all (=1), somewhat (=2), moderately (=3), quite a bit (=4)). The total score (range:0-100) was obtained by multiplying the mean value of all items by 25 with Higher scores indicate more distress. A mean difference of 11 points in the POPDI-6 has been reported as a clinically relevant difference between groups.62 Secondary, subjective success defined as a reduction of at least 25% compared to baseline was measured.63

Chapter 3.1 30 Other secondary outcomes were patient reported and objective measures that assess the short and long-term (24 months) effect of treatment, its adverse events, the degree of discomfort of the treatment procedure by the patient and the operator reported degree of difficulty, if any, encountered during laser application. Patients were clinically assessed at baseline, treatment and follow-up visits, by an independent and experienced urogynecologist, blinded for the allocated treatment. Anatomical success was assessed by means of the POP-Q System and defined as POP-Q = stage 0 (no prolapse) or stage 1 (leading edge <-1cm).5,52 Patient satisfaction was measured by means of the Patient Global Impression of Improvement (PGI), using a 5-point Likert scale (1=much worse, 2=worse, 3=same, 4=better, 5=much better).64 Sexual function was assessed by means of the Pelvic Organ prolapse/Urinary Incontinence Sexual Questionnaire IUGA revised (PISQ-IR)65 and urinary symptoms by means of the Urogenital Distress Inventory (UDI-6).66 Longevity of the effect was measured by the need for, and the timing for repeating the same, or initiating an alternative therapy. Patient reported discomfort of the treatment was measured by means of a continuous VAS-score (0100mm) and the degree of difficulty encountered by the operator by means of a 5-point Likert scale (1=very difficult, 2=difficult, 3=neutral, 4=easy, 5=very easy). Statistics and ethics The primary objective of this study was to show the absence of a clinically relevant different POPDI-6 score in patients treated with laser compared to patients treated with PFE as standard treatment. A non-inferiority analysis was performed for the primary endpoint, adopting an 11-point non-inferiority margin.62 A pooled variance t-test was used for the analysis. Sample size to demonstrate with 80% of power that laser is not inferior to PFE with respect to the 4-month POPDI-6 score resulted in 23 patients per arm. The calculation was performed using sealed envelope, assuming a 11-point non-inferiority margin, equal mean POPDI-6 scores in both treatment arms, and an SD of 13.2.67,68 Superiority analyses were applied for testing differences between treatment arms on secondary outcomes. Changes versus baseline were calculated for POP-Q scores, the PISQ-IR score and UDI6 score. and compared using a linear model. The analysis of PGI was performed using a logistic regression model for ordinal data, or, proportional odds model, its results presented as odds ratio (OR). The score test was then used for testing the proportional odds assumption. Linear mixed models for repeated measurements were used for estimating time evolutions. A random intercept was modelled to deal with data clustering. Normality of model residuals was checked graphically. Continuous variables are reported as mean (Standard deviation (SD)) or median (interquartile ranges (IQR)) for ordinal or skewly distributed variables. Categorical variables are reported as frequencies with percentages. This article follows the CONSORT (Consolidated Standards of Reporting Trials) guidelines for reporting parallel group randomised trials.69 This study was executed at the University Hospitals Leuven, Belgium, its protocol was approved by its Ethics Committee on Clinical Research (S64093), and registered at ClinicalTrials.gov (NCT04523298).

VELPOP 31 RESULTS Forty-six women were randomised between November 20, 2020 and February 22, 2022 (Figure 1). All participants completed all treatment sessions. In the laser group, 30.4%(7/23) had the three planned applications either due to being subjectively cured (n=3) or experiencing no improvement at all (n=4). Remaining participants requested four (26.1%(6/23)), five (13%(3/23)) or six (7/23(30.4%)) applications. In the PFE group, two participants (8.7%) requested nine additional supervised PFE sessions. There were no missing data for the primary endpoint. By 24 months, three patients were lost to follow-up (1 in the laser, 2 in the PFE group). Figure 1: CONSORT flow diagram. There were no missing data points for any outcomes at the 4 months follow-up visit. At 24-months follow-up 3 participants were lost to follow-up. Despite several attempts we were unable to contact these participants. Baseline characteristics of participants were comparable between groups and are presented in Table 1. The mean difference in POPDI-6 scores between laser and PFE at 4 months was 1.09 (95% CI: (-6.02;8.20)) indicating non-inferiority of laser compared to PFE (p=0.004). The mean POPDI-6 scores compared to baseline tended to be lower in both groups: for laser, POPDI-6 scores decreased from 23.91±14.61 to 19.20±12.55 (-19.6%) and in PFE participants from 26.09±13.66 to 18.12±11.35 (-30.5%). Success, defined as a at least 25% reduction in score was reached in 11/23 participants (47.8%) in both groups.

Chapter 3.1 32 In the laser group, 65.2%(15/23) of participants rated the PGI at 4 months as ‘better or much better’ compared to 60.9%(14/23) in the PFE group. A proportional odds model did not show any trend towards increased PGI scores in one group over the other (OR=1.12; 95% CI=0.39-3.23; p=0.833). There were no obvious differences in changes in other subjective outcome measurements (Table 2), nor was there any apparent inter-group difference in the objective outcome (Table 3). Six months after the last treatment, 43.5%(10/23) of participants in the laser group and 39.1%(9/23) in the PFE group sought additional yet alternative treatment: in the laser group 7/23(30.4%) participants opted for a pessary, 1/23(4.3%) began PFE and 2/23(8.7%) underwent surgery, whereas in the PFE group 8/23(34.8%) chose a pessary, 1/23(4.3%) underwent surgery and 2/23(8.7%) received repeated PFE treatment. Twenty-four months after the last treatment, 50% (11/22) of participants in the laser group and 57%(12/21) in the PFE group did not seek additional treatment. Of those, 63.6%(7/11) of the laser, and 75%(9/12) of the PFE-group reported feeling better or much better (PGI >3). No serious adverse events were observed at any time point. Minor complications were confined to the laser group (7/23) and included vaginal bleeding, spotting or discharge, that were mild and self-limiting. The participant‐reported degree of discomfort during laser manipulation was 21.72±17.58mm. There were no apparent differences between subsequent applications. Overall, the operator rated the degree of difficulty of treatment as ‘easy’ (median level=4). Table 1: Demographic characteristics of the study participants at baseline according to treatment group. Laser group (n=23) PFE group (n=23) All participants (n=46) Age (years) 62.00 ± 9.11 60.00 ± 12.04 61.00 ± 10.61 BMIa 23.65 ± 3.97 24.53 ± 3.24 24.09 ± 3.61 Parity 2.65 ± 1.15 2.26 ± 0.96 2.46 ± 1.07 Menopause 21/23 (91.3%) 16/23 (69.6%) 37/46 (80.4%) Smoking 3/23 (13%) 0/23 (0%) 3/46 (6.5%) Previous hysterectomy 3/23 (13%) 0/23 (0%) 3/46 (6.5%) aBMI: Body Mass Index. Data are mean ± SD or n/N (%) as appropriate.

VELPOP 33 Table 2: Subjective outcomes at baseline and after 4 months Laser PFE Mean difference between groups p-value POPDI-6 score N=23 N=23 Baseline 23.91 ± 14.61 26.09 ± 13.66 4 months 19.20 ± 12.55 18.12 ± 11.35 Mean difference versus baseline -4.710 (-11.04;1.616) -7.971 (-14.30;1.644) 3.261 (-5.686;12.208) 0.466 UDI-6 score N=23 N=23 Baseline 23.91 ± 14.55 27.36 ± 20.37 4 months 19.93 ± 15.59 22.46 ± 15.93 Mean difference versus baseline -3.986 (-13.28;5.31) -4.891 (-14.19;4.41) 0.91 (-12.24;14.05) 0.890 PISQ-IR score (sexually active patients) N=13 N=18 Baseline 3.35 ± 0.60 3.44 ± 0.41 4 months 3.63 ± 0.41 3.47 ± 0.43 Mean difference versus baseline 0.22 (0.01;0.44) -0.01 (-0.19;0.17) 0.23 (-0.05;0.52) 0.102 A statistical comparison between both treatment groups was performed on the change scores using a linear model. Results are presented by mean differences with 95% confidence intervals. Table 3: POP-stages at baseline and after 4 months. Laser (n=23) PFE (n=23) Baseline 4 months Baseline 4 months Mean difference (95% CI) p-value Anterior wall prolapse Stage 0 1/23 (4.3%) 2/23 (8.7%) 2/23 (8.7%) 1/22 (4.5%) Stage 1 1/23 (4.3%) 0/23 (0%) 1/23 (4.3%) 0/23 (0%) Stage 2 12/23 (52.2%) 13/23 (56%) 15/23 (65%) 17/22 (77.3%) Stage 3 9/23 (39.1%) 8/23 (34.8%) 5/23 (21.7%) 4/22 (18.2%) Mean change versus baseline (95% CI) -0.087 (-0.277;0.103) 0.045 (-0.149;0.240) -0.132 (-0.404;0.139) 0.331 Cervix / Vault prolapse Stage 0 5/23 (21.7%) 6/23 (26.1%) 5/23 (21.7%) 8/22 (36.4%) Stage 1 14/23 (60.9%) 13/23 (56%) 16/23 (69%) 11/22 (50%) Stage 2 4/23 (17.4%) 4/23 (17.4%) 2/23 (8.7%) 3/22 (13.6%) Stage 3 0/23 (0%) 0/23 (0%) 0/23 (0%) 0/23 (0%) Mean change versus baseline (95% CI) -0.043 (-0.321;0.234) -0.091 (-0.375;0.193) 0.047 (-0.350;0.445) 0.811 Posterior wall prolapse Stage 0 12/23 (52.2%) 12/23 (52%) 6/23 (26.1%) 7/22 (31.8%) Stage 1 8/23 (34.8%) 7/23 (30.4%) 9/23 (39.1%) 9/22 (40.9%) Stage 2 3/23 (13.1%) 4/23 (17.4%) 8/23 (34.8%) 6/22 (27.3%) Stage 3 0/23 (0%) 0/23 (0%) 0/23 (0%) 0/23 (0%) Mean change versus baseline (95% CI) 0.043 (-0.140;0.227) -0.182 (-0.370;0.006) 0.225 (-0.038;0.488) 0.091 A statistical comparison between both treatment groups was performed on the change scores using a linear model. Results are presented by mean differences with 95% confidence intervals.

Chapter 3.1 34 DISCUSSION In women with symptomatic stage 2 and 3 anterior and/or posterior wall prolapse, the treatment response four months from baseline to vaginal laser was comparable to that to PFE. Although initially the majority of women were at least satisfied, 24 months after the last treatment, more than half of patients sought additional, yet alternative, treatments. This study has several strengths, including its design. It was an assessor-blinded RCT with concealed allocation of participants and pre-determined sample size, and used relevant patientreported outcomes. To our knowledge, this is the first RCT logically comparing laser therapy to another standard conservative therapy that patients can choose. It has a meaningful longer term follow-up period to evaluate the durability and safety of both treatments. Secondly, validated methods of outcomes assessment according to the International Continence Society (ICS)/ International Urogynecological Association (IUGA) guidelines were used. We also recorded all outcomes at each treatment and follow-up visit, minimizing the risk of recall bias. Thirdly, inclusion and exclusion criteria were clearly defined. For instance, previous studies57-59 did not state whether previous vaginal surgery patients were excluded: the role of laser in scarred or fibrosed tissue compared to intact tissue may impact its efficacy. Finally, there were no missing data for the primary outcome, and results were interpreted on an intention-to-treat basis. We acknowledge some weaknesses. Laser was not compared to sham application, so we cannot rule out placebo effects of laser, which have been reported.70-72 We opted to compare to PFE, as this is the standard of conservative care in our setting. PFE were not standardized but offered within the clinical “real life” setting, consisting of pelvic floor muscle training supervised by an experienced physiotherapist.14 One could also argue the non-inferiority design given the typically higher costs of laser therapy compared to PFE. However, based on the available evidence, we did not expect superiority of laser.58 The clinical aim of our study was therefore to evaluate whether laser could be a worthy alternative non-surgical treatment for women with bothersome POP symptoms. Another limitation is the we only treated Caucasian women, who constitute the vast majority in our clinic. Finally, although adequately powered, the number of patients remains small, which may underestimate the occurrence of uncommon adverse events. At first glance, these results contrast with those of Athanasiou et al, who randomised women with symptomatic stage 2 or 3 prolapse between Er:YAG laser and watchful waiting. They did not report any objective nor subjective improvement over a four month period in either group.58 They concluded therefore that laser was not a treatment option in symptomatic POP-patients. In that study however, only menopausal women, who failed earlier conservative therapy, and were already scheduled for surgery, were included. Conversely, our study population were patients with bothersome POP seeking conservative treatment. Moreover, we excluded patients who had undergone PFE or vaginal laser therapy 12 months before enrollment. It is plausible that the patient profile and their expectations played a role in the perceived efficacy of conservative therapy.73,74 Another difference

VELPOP 35 is that we powered for subjective improvement rather than physician measured anatomical cure (POP-Q). Clearly, the former is much stricter, but in our view, for a condition like POP, certainly when treated conservatively, of less importance.75 At closer look, part of Athanasiou’s study population reported subjective improvement (PGI > 3) after laser (53% (8/15)) yet not when they were assigned to watchful waiting (0% (0/15)). Additional data on laser treatment for POP is limited to two observational studies that suggest treatment benefit of laser.57,59 However, next to the limitations of the study design, both trials report on completely different study populations, and report on anatomical rather than subjective outcomes. Ogrinc et al. prospectively studied patients with GSM who also had concomitant mild POP. Mikic et al. retrospectively studied patients who had a combination of stress urinary incontinence and also presented with an anterior wall prolapse . Overall, we believe that the aforementioned observational studies contribute little to the current body of evidence. Patient safety is always the first priority. In that respect, there is an abundance of studies in a variety of patient populations, that show that vaginal laser therapy is generally well-tolerated, safe, and the incidence of adverse events is low.76 Conversely, in terms of treatment effect for the management of bothersome POP, data is limited and the findings are contradictory. Therefore, this study is an important addition. Although not-inferior, the limited treatment effect of laser therapy questions its widespread use as it comes at a higher cost and requires appropriate training of operators to minimize side effects and to ensure the safety of this intervention. Further trials may focus on the place of laser alongside and in combination with other conservative therapies, including the use of a pessary and lifestyle changes. If such studies confirm our findings, identifying specific subgroups of women who might benefit more from any conservative therapy would be of interest, yet then still health-technology assessment studies would need to follow.

37 3.2 Vaginal laser therapy for stress urinary incontinence: the VELSUI-study Ann-Sophie Page, Eline Borowski, Emma Bauters, Susanne Housmans, Frank Van der Aa, Jan Deprest Published in Int Urogynecol J, 2025.

VELSUI 39 ABSTRACT Introduction and Hypothesis: Current studies on vaginal laser therapy for the management of stress urinary incontinence (SUI) are inconclusive, and many lack comparison to another conservative treatment. Therefore, we compared the efficacy of Er:YAG laser for SUI to that of pelvic floor muscle training (PFMT). Methods: Single centre, randomised controlled trial comparing laser treatment (3-6 applications) to PFMT (9-18 sessions) in women with mild to moderate SUI. Main outcome measures included subjective change in urinary incontinence symptoms by change from baseline to four months after randomisation by Urogenital Distress Inventory-6 (UDI-6) (primary), adverse events, other subjective and objective outcomes up to 24 months. A priori sample size calculation for a non-inferiority study resulted in 28 patients per arm. Because of a higher than expected dropout early in the study, we increased our sample size from 56 to 60, without unblinding of the data. Results: Sixty women were enrolled. Two participants discontinued their allocated treatment (one in each group). At four months, mean difference in change of UDI-6 scores was -6.99(95% CI=- 22.34;8.37) demonstrating non-inferiority of laser to PFMT (p=0.023). Within groups, most patients improved, yet subjective cure was reached in only a minority (laser:11%(3/28); PFMT:8%(2/26)). The mean number of treatment visits was 4.25 (SD 1.17) in the laser group and 10.04 (SD 6.36) in the PFMT group. There were no subjective or objective inter-group differences. At 24 months, the majority of patients requested additional, yet alternative treatment. There were no serious adverse events at any time-point. Conclusions: Treatment effect of vaginal laser and PFMT in patients with mild and moderate SUI were comparable, limited and short lasting. No adverse events were reported.

Chapter 3.2 40 INTRODUCTION The prevalence of stress urinary incontinence (SUI) ranges between 10 and 39% in the general population.77 Although SUI is not a life-threatening condition, its symptoms have a severe impact on the patients’ quality of life and wellbeing. Conservative treatments for women who actively seek help typically include pelvic floor muscle training (PFMT) and pessaries, both requiring a high level of commitment in order to achieve optimal results. Pessaries are less successful on the longer term, mainly due to high discontinuation rates.78 PFMT improves SUI symptoms both on the short (74%) and longer (41-85%) term and is therefore considered to be the first line conservative treatment.79,80 Though surgery by mid-urethral slings is the most effective treatment 81, their use is increasingly being questioned and even banned in some countries, due to graft related complications. Moreover, a study on patient preference has shown that participants are willing to accept a slightly lower probability of cure to avoid substantial postoperative pain and possible complications by receiving a less invasive treatment.36 This has created a clinical need for non-surgical alternatives for treating SUI. Vaginal laser application is appealing as, if proven effective, this is a minimally invasive treatment with minimal morbidity. However, the safety and efficacy of laser treatment has not yet been confirmed, as highlighted by the US Food and Drug Administration, the European board and College of Obstetrics and Gynaecology (EBCOG) and other authorities.46,47,49 In its recent 2024-position statement, EBCOG again urgently called for good quality research with appropriate patient reported outcome measures and long-term follow-up data for vaginal laser therapy.49 Indeed, although multiple studies investigated the use of Erbium : Yttrium Aluminium Gadolinium (Er:YAG) laser for the management of SUI, they report conflicting results, and many studies lack comparison to another conservative treatment.82-88 Therefore, the purpose of this study was to evaluate the efficacy and safety of vaginal Er:YAG laser application for mild to moderate SUI, as compared to PFMT, and this over a two year followup period. MATERIALS AND METHODS Study design and participants This is a single centre, randomised controlled clinical trial on the efficacy of Er:YAG laser application in reducing SUI. The comparator was PFMT and the target group comprised women with mild to moderate SUI expressing a desire for treatment. Diagnostic criteria to identify SUI in participants were according to established guidelines and included history and clinical examination.89

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