Clifford Y. Wai

Etiology of pelvic organ prolapse

Introduction Pelvic organ prolapse is a global health concern affecting adult women of all ages. The exact prevalence of prolapse is unknown. The lifetime risk of a woman undergoing surgery for prolapse or incontinence in the United States is estimated to be 11%. A study by Swift et al of 1004 women, aged 18 to 83, presenting for routine annual gynecologic examination, revealed the distribution of pelvic organ support by Pelvic Organ Prolapse Quantification (POPQ) staging to be: stage 0 = 24%, stage 1 = 38%, stage 2 = 35%, and stage 3 = 3%. These data are similar to those found in 27,342 women who participated in the Women’s Health Initiative Hormone Replacement Therapy Clinical Trial (WHI), in which approximately 40% were found to have some form of prolapse. The discrepancy between the percentage of women undergoing surgery for prolapse and those found to have it on a routine examination may be the result of the fact that this condition is often asymptomatic. However, if increased emphasis is placed on careful evaluation of symptoms and directed prolapse examination, the practitioner is likely to identify many symptomatic women who would benefit from nonsurgical or surgical therapy. In this chapter, we discuss the etiology of pelvic organ prolapse with emphasis on risk factors and mechanisms of prolapse.

5-Year Longitudinal Followup after Retropubic and Transobturator Mid Urethral Slings

PURPOSE Few studies have characterized longer-term outcomes after retropubic and transobturator mid urethral slings. MATERIALS AND METHODS Women completing 2-year participation in a randomized equivalence trial who had not undergone surgical re-treatment for stress urinary incontinence were invited to participate in a 5-year observational cohort. The primary outcome, treatment success, was defined as no re-treatment or self-reported stress incontinence symptoms. Secondary outcomes included urinary symptoms and quality of life, satisfaction, sexual function and adverse events. RESULTS Of 597 women 404 (68%) from the original trial enrolled in the study. Five years after surgical treatment success was 7.9% greater in women assigned to the retropubic sling compared to the transobturator sling (51.3% vs 43.4%, 95% CI -1.4, 17.2), not meeting prespecified criteria for equivalence. Satisfaction decreased during 5 years but remained high and similar between arms (retropubic sling 79% vs transobturator sling 85%, p=0.15). Urinary symptoms and quality of life worsened with time (p <0.001), and women with a retropubic sling reported greater urinary urgency (p=0.001), more negative impact on quality of life (p=0.02) and worse sexual function (p=0.001). There was no difference in the proportion of women experiencing at least 1 adverse event (p=0.17). Seven new mesh erosions were noted (retropubic sling 3, transobturator sling 4). CONCLUSIONS Treatment success decreased during 5 years for retropubic and transobturator slings, and did not meet the prespecified criteria for equivalence with retropubic demonstrating a slight benefit. However, satisfaction remained high in both arms. Women undergoing a transobturator sling procedure reported more sustained improvement in urinary symptoms and sexual function. New mesh erosions occurred in both arms over time, although at a similarly low rate.

Further validation of the short form versions of the Pelvic Floor Distress Inventory (PFDI) and Pelvic Floor Impact Questionnaire (PFIQ).

To evaluate validity and responsiveness of PFDI and PFIQ short forms across four multi‐center studies and develop conversion formulas between short and long versions.

Reproducibility of Dynamic MR Imaging Pelvic Measurements : A Multi-institutional Study

PURPOSE To assess the reproducibility of bone and soft-tissue pelvimetry measurements obtained from dynamic magnetic resonance (MR) imaging studies in primiparous women across multiple centers. MATERIALS AND METHODS All subjects prospectively gave consent for participation in this institutional review board-approved, HIPAA-compliant study. At six clinical sites, standardized dynamic pelvic 1.5-T multiplanar T2-weighted MR imaging was performed in three groups of primiparous women at 6-12 months after birth: Group 1, vaginal delivery with anal sphincter tear (n = 93); group 2, vaginal delivery without anal sphincter tear (n = 79); and group 3, cesarean delivery without labor (n = 26). After standardized central training, blinded readers at separate clinical sites and a blinded expert central reader measured nine bone and 10 soft-tissue pelvimetry parameters. Subsequently, three readers underwent additional standardized training, and reread 20 MR imaging studies. Measurement variability was assessed by using intraclass correlation for agreement between the clinical site and central readers. Acceptable agreement was defined as an intraclass correlation coefficient (ICC) of at least 0.7. RESULTS There was acceptable agreement (ICC range, 0.71-0.93) for eight of 19 MR imaging parameters at initial readings of 198 subjects. The remaining parameters had an ICC range of 0.13-0.66. Additional training reduced measurement variability: Twelve of 19 parameters had acceptable agreement (ICC range, 0.70-0.92). Correlations were greater for bone (ICC, >or=0.70 in five [initial readings] and eight of nine [rereadings] variables) than for soft-tissue measurements (ICC, >or=0.70 in three [initial readings] of 10 and four [rereadings] of 10 readings, respectively). CONCLUSION Despite standardized central training, there is high variability of pelvic MR imaging measurements among readers, particularly for soft-tissue structures. Although slightly improved with additional training, measurement variability adversely affects the utility of many MR imaging measurements for multicenter pelvic floor disorder research.

Recovery of the injured external anal sphincter after injection of local or intravenous mesenchymal stem cells

OBJECTIVES: To understand the endogenous process of wound healing after anal sphincter injury and to determine possible mechanisms by which mesenchymal stem cells (MSCs) exert their regenerative potential. METHODS: Virginal female rats (n=204) underwent anal sphincter laceration and repair. Thereafter, animals were randomly assigned to control injection, injection with intravenous MSCs, or direct injection of MSCs into the injured sphincter. Twenty uninjured animals served as baseline controls. Sphincters were analyzed for contractile function and parameters of wound healing 24 hours, 48 hours, 7 days, and 21 days after injury. RESULTS: Direct injection of MSCs into the injured anal sphincter resulted in improved contractile function 21 days after injury compared with controls. Although expression of both proinflammatory (cyclooxygenase-2 and interleukin-6) and anti-inflammatory (interleukin-10 and tumor necrosis factor-&agr;–stimulated gene-6) genes were increased dramatically and transiently after injury, MSCs did not alter this response. In contrast, transforming growth factor (TFG)-&bgr;1 (an important mediator of matrix deposition by mesenchymal cells) and lysyl oxidase (an enzyme important for synthesis of collagen and elastin) expression increased dramatically at earlier time points in the direct MSC injection group compared with controls. Increased expression of TFG-&bgr;1 and lysyl oxidase in directly injected sphincters was associated with increased collagen deposition and engraftment of MSCs in the sphincter. CONCLUSION: In this preclinical animal model, direct, but not intravenous, injection of MSCs into the injured anal sphincter at the time of repair resulted in improved contractile function of the sphincter after injury, increased matrix deposition in the external anal sphincter, and increased expression of TFG-&bgr;1 and lysyl oxidase in the acute phase after injury.

Outcomes following vaginal prolapse repair and mid urethral sling (OPUS) trial - Design and methods

Background The primary aims of this trial are to determine whether the use of a concomitant prophylactic anti-incontinence procedure may prevent stress urinary incontinence symptom development in women undergoing vaginal prolapse surgery and to evaluate the cost-effectiveness of this prophylactic approach. Purpose To present the rationale and design of a randomized controlled surgical trial (RCT), the Outcomes following vaginal Prolapse repair and mid Urethral Sling (OPUS) Trial highlighting the challenges in the design and implementation. Methods The challenges of implementing this surgical trial combined with a cost-effectiveness study and patient preference group are discussed including the study design, ethical issues regarding use of sham incision, maintaining the masking of study staff, and pragmatic difficulties encountered in the collection of cost data. The trial is conducted by the NICHD-funded Pelvic Floor Disorders Network. Results The ongoing OPUS trial started enrollment in May 2007 with a planned accrual of 350. The use of sham incision was generally well accepted but the collection of cost data using conventional billing forms was found to potentially unmask key study personnel. This necessitated changes in the study forms and planned timing for collection of cost data. To date, the enrollment to the patient preference group has been lower than the limit established by the protocol suggesting a willingness on the part of women to participate in the randomization. Limitations Given the invasive nature of surgical intervention trials, potential participants may be reluctant to accept random assignment, potentially impacting generalizability. Conclusion Findings from the OPUS trial will provide important information that will help surgeons to better counsel women on the benefits and risks of concomitant prophylactic anti-incontinence procedure at the time of vaginal surgery for prolapse. The implementation of the OPUS trial has necessitated that investigators consider ethical issues up front, remain flexible with regards to data collection and be constantly aware of unanticipated opportunities for unmasking. Future surgical trials should be aware of potential challenges in maintaining masking and collection of cost-related information. Clinical Trials 2009; 6: 162—171. http://ctj.sagepub.com

Effect of myogenic stem cells on contractile properties of the repaired and unrepaired transected external anal sphincter in an animal model

OBJECTIVE: To estimate the effect of myogenic stem cells on contractile function of the external anal sphincter after transection with or without repair in an animal model. METHODS: One hundred twenty virginal female rats were randomly assinged to repair (n=60) or no repair (n=60) after anal sphincter transection. Animals were further divided into two groups: 40-microliter injection at the transection site with either phosphate-buffered solution (control) or myogenic stem cells (3.2×106 cells). Animals were killed at 7, 21, or 90 days, and the anal sphincter complex dissected and analyzed for contractile function. RESULTS: Contractile function of the external anal sphincter was severely impaired 7 days after sphincter transection with or without repair. Twitch tension, maximal tetanic contraction, and maximal contractile force in response to electrical field stimulation improved significantly with time after sphincter repair. Injection of myogenic stem cells in the anal sphincter at the time of repair resulted in superior contractile function at both 7 days and 90 days compared with controls. Interestingly, contractile function of the nonrepaired external anal sphincter did not improve with time with or without myogenic stem cells. Indicators of denervation (fatigue and twitch or tetany ratios) did not change among groups. CONCLUSION: In this animal model, injection of myogenic stem cells at the time of external anal sphincter repair resulted in enhanced contractile function at 90 days compared with repair alone. Without repair, function of the external anal sphincter was not improved by stem cell therapy at any time point. These results suggest that addition of myogenic stem cells improves both acute and long-term function of the external anal sphincter after mechanical injury.

Patient Satisfaction with Stress Incontinence Surgery

To identify predictors and correlates of patient satisfaction 24 months after Burch colpopexy or autologous fascial sling for treatment of stress urinary incontinence (SUI).

Urodynamics, the supine empty bladder stress test, and incontinence severity

Determine whether urodynamic measures of urethral function [(valsalva leak point pressure (VLPP), maximum urethral closure pressure (MUCP), functional urethral length (FUL)] and the results of the supine empty bladder stress test (SEBST) correlate with each other and with subjective and objective measures of urinary incontinence (UI).

Urethral erosion of tension-free vaginal tape presenting as recurrent stress urinary incontinence

The suburethral sling with tension-free vaginal tape (TVT) has become a popular treatment for stress urinary incontinence. Erosion of the mesh into the urethra is rare, usually presenting with hematuria, pain, voiding dysfunction or urge incontinence. A patient with stress incontinence was treated with a TVT suburethral sling. One month later, symptoms of recurrent stress incontinence developed. Cystourethroscopy revealed urethral mesh erosion. Surgical removal involved cystourethroscopic-assisted transurethral resection of the mesh, followed by vaginal dissection and periurethral withdrawal. Urethral mesh erosion should be considered in a patient who presents with atypical symptoms after being treated with a suburethral sling. It is important to obtain a detailed history and have a high clinical index of suspicion for erosion. Careful and comprehensive urethroscopy, in addition to cystoscopy, should be a mandatory part of the TVT procedure. Further study is needed to determine the optimal technique for mesh removal.