Increased extracellular matrix stiffness regulates myofibroblast transformation through induction of autophagy-mediated Kindlin-2 cytoplasmic translocation.

The extracellular matrix (ECM) mechanical properties regulate biological processes, such as fibroblast-myofibroblast transformation (FMT), which is a crucial component in pelvic organ prolapse (POP) development. The 'Kindlin-2' protein, expressed by fibroblasts, plays an important role in the development of the mesoderm, which is responsible for connective tissue formation; however, the role of Kindlin-2 in FMT remains to be explored. In this study, we aimed to explore the role of Kindlin-2 in FMT as it relates to POP. We found that ECM stiffness induces autophagy to translocate Kindlin-2 to the cytoplasm of L929 cells, where it interacts with and degrades MOB1, thereby facilitating Yes-associated protein (YAP) entry into the nucleus and influencing FMT progression. Stiffness-induced autophagy was inhibited when using an autophagy inhibitor, which blocked the translocation of Kindlin-2 to the cytoplasm and partially reversed high-stiffness-induced FMT. In patients with POP, we observed an increase in cytoplasmic Kindlin-2 and nuclear YAP levels. Similar changes in vaginal wall-associated proteins were observed in a mouse model of acute vaginal injury. In conclusion, Kindlin-2 is a key gene affecting ECM stiffness, which regulates FMT by inducing autophagy and may influence the development of POP.

Silencing of cysteine and serine rich nuclear protein 1 inhibits apoptosis, senescence and collagen degradation in human-derived vaginal fibroblasts in response to oxidative stress or DNA damage.

Pelvic organ prolapse (POP) is a group of diseases caused by extracellular matrix (ECM) degradation in pelvic supportive tissues. Cysteine and serine rich nuclear protein 1 (CSRNP1) is involved in cell proliferation and survival regulation, and reportedly facilitates collagen breakdown in human chondrocytes. The present study aimed to probe the effect of CSRNP1 on collagen metabolism in human-derived vaginal fibroblasts. High expression of CSRNP1 was found in POP patient-derived vaginal fibroblasts in comparison to normal-derived vaginal fibroblasts. Following functional experiments revealed that CSRNP1 overexpression led to proliferation inhibition, apoptosis and collagen degradation in normal vaginal fibroblasts. In line with this, silencing of CSRNP1 inhibited hydrogen peroxide (H2O2)-triggered apoptosis, ROS generation and collagen loss in normal vaginal fibroblasts. Silencing of CSRNP1 also reduced the expression of cell senescence markers p21 and γ-H2Ax (the histone H2Ax phosphorylated at Ser139), as well as curbed collagen breakdown in normal vaginal fibroblasts caused by a DNA damage agent etoposide. Transcriptomic analysis of vaginal fibroblasts showed that differentially expressed genes affected by CSRNP1 overexpression were mainly enriched in the Wnt signaling pathway. Treatment with a Wnt pathway inhibitor DKK1 blocked CSRNP1 knockdown-caused collagen deposition. Mechanistically, CSRNP1 was identified to be a target of Snail family transcriptional repressor 2 (SNAI2). Forced expression of CSRNP1 reversed the anti-apoptotic, anti-senescent and anti-collagen loss effects of SNAI2 in normal vaginal fibroblasts exposed to H2O2 or etoposide. Our study indicates that the SNAI2/CSRNP1 axis may be a key driver in POP progression, which provides a potential therapeutic strategy for POP.

Early growth response 2, a novel target of pelvic organ prolapse, is highly expressed in anterior vaginal wall tissues with pelvic organ prolapse.

Pelvic organ prolapse (POP) is a common disorder among women that negatively affects women's quality of life. Early growth response 2 (EGR2) is a transcription factor that regulates cell growth. The present study aimed to explore the role of EGR2 in POP progression and provided a new target for the treatment and prevention of POP. Firstly, we extracted primary vaginal anterior wall fibroblasts from POP tissues and non-POP tissues and then constructed an EGR2-silencing lentivirus for further study. Immunoblotting, qPCR, TUNEL assay, CCK-8 assay, dual luciferase assay, and ELISA assay were carried out. EGR2 expression was much higher in POP tissues than in control tissues, and EGR2 expression positively correlated with cytokine signaling 3 (SOCS3) expression. Knockdown of EGR2 increased cell proliferation, upregulated PCNA expression, and reduced apoptosis in POP fibroblasts. Moreover, we found that the knockdown of EGR2 increased COL1A1, COL3A1, and Elastin expression and decreased MMP2 and MMP9 activities, and knockdown of EGR2 increased TGF-ß/Smad pathway activity in POP fibroblasts. Interestingly, the results of dual luciferase assay demonstrated that EGR2 was able to increase SOCS3 transcriptional activity. EGR2 knockdown alleviated the apoptosis of POP fibroblasts by reducing SOCS3 expression and improving the proliferation and collagen synthesis of POP fibroblasts. Overall, our study illustrated that EGR2 was highly expressed in POP tissues, and knockdown of EGR2 alleviated apoptosis and reduced matrix degradation in POP fibroblasts. This study might provide a new insight into the pathogenesis of POP.

Effectiveness and safety of a novel, collapsible pessary for management of pelvic organ prolapse.

BACKGROUND: Pessaries are an effective treatment for pelvic organ prolapse, yet currently available pessaries can cause discomfort during removal and insertion. An early feasibility trial of an investigational, collapsible pessary previously demonstrated mechanical feasibility during a brief 15-minute office trial. Longer-term, patient-centered safety and efficacy data are needed. OBJECTIVE: This study aimed to assess the effectiveness and safety of the investigational vaginal pessary for pelvic organ prolapse at 3 months. STUDY DESIGN: This was a prospective, 7-center, open-label equivalence study with participants serving as their own controls. Subjects were current users of a Gellhorn or ring pessary with ≥stage 2 prolapse. Subjective and objective data were collected at baseline for 1 month while subjects used their current pessary. Data were then collected throughout a 3-month treatment phase with the study pessary. The primary outcome was change in Pelvic Floor Distress Inventory-20 score. Secondary outcome measures included objective assessment of prolapse support, changes in the Pelvic Floor Impact Questionnaire-7, and pain with insertion and removal, measured using a visual analog scale. Data from subjects fitted with the study pessary were analyzed using an intention-to-treat approach, and those who dropped out were assigned scores at the upper limit of the predefined equivalence limits. Secondary per protocol analyses included subjects who completed treatment. The study was powered to 80% with a minimal important change equivalence limit of 18.3 points on the Pelvic Floor Distress Inventory-20 scale. Square root transformations were used for nonparametric data, and P values were adjusted for multiple comparisons. RESULTS: A total of 78 subjects were enrolled, however, 16 withdrew before study pessary placement. The study pessary was fitted in 62 subjects (50 ring and 12 Gellhorn pessary users), and 48 (62%) completed the 3-month intervention. The change in Pelvic Floor Distress Inventory-20 scores at 3 months demonstrated equivalence when compared with the subjects' baseline scores (mean difference, -3.96 [improvement]; 90% confidence interval, -11.99 to 4.08; P=.002). Among those completing study, the Pelvic Floor Distress Inventory-20 scores, equivalence was not demonstrated and scores favored the study pessary (mean difference, -10.45; 90% confidence interval, -20.35 to 0.54; P=.095). Secondary outcomes included objective measures of support, which were similar (mean difference: Ba, 0.54 cm; Bp, 0.04 cm, favoring study pessary; improvement in mean Pelvic Floor Impact Questionnaire-7 scores for those who completed the trial: before, 32.23; after, 16.86; P=.019), and pain with insertion and removal, which was lower with the study pessary than with the subject's own pessary (mean difference visual analog scale score insertion, 9.91 mm; P=.019; removal, 11.23 mm; P=.019). No serious adverse events related to the pessary were reported. CONCLUSION: Equivalence was demonstrated in the primary outcome of the study pessary when compared with current, noncollapsible pessaries in terms of change in severity and bother of pelvic floor symptoms. Among participants who completed the trial, the Pelvic Floor Impact Questionnaire-7 improved with study pessary use and change in Pelvic Floor Distress Inventory-20 scores were nonequivalent, favoring the study pessary. Subjects reported significantly lower pain scores with both pessary insertion and removal with the novel collapsible pessary when compared with their standard pessary.

Preoperative prolapse phenotype is predictive of surgical outcome with minimally invasive sacrocolpopexy.

BACKGROUND: The gold-standard treatment for advanced pelvic organ prolapse is sacrocolpopexy. However, the preoperative features of prolapse that predict optimal outcomes are unknown. OBJECTIVE: This study aimed to develop a clinical prediction model that uses preoperative scores on the Pelvic Organ Prolapse Quantification examination to predict outcomes after minimally invasive sacrocolpopexy for stages 2, 3, and 4 uterovaginal prolapse and vaginal vault prolapse. STUDY DESIGN: A 2-institution database of pre- and postoperative variables from 881 cases of minimally invasive sacrocolpopexy was analyzed. Data from patients were analyzed in the following 4 groups: stage 2 uterovaginal prolapse, stage 3 to 4 uterovaginal prolapse, stage 2 vaginal vault prolapse, and stage 3 to 4 vaginal vault prolapse. Unsupervised machine learning was used to identify clusters and investigate associations between clusters and outcome. The k-means clustering analysis was performed with preoperative Pelvic Organ Prolapse Quantification points and stratified by previous hysterectomy status. The "optimal" surgical outcome was defined as postoperative Pelvic Organ Prolapse Quantification stage <2. Demographic variables were compared by cluster with Student t and chi-square tests. Odds ratios were calculated to determine whether clusters could predict the outcome. Age at surgery, body mass index, and previous prolapse surgery were used for adjusted odds ratios. RESULTS: Five statistically distinct prolapse clusters (phenotypes C, A, A>P, P, and P>A) were found. These phenotypes reflected the predominant region of prolapse (apical, anterior, or posterior) and whether support was preserved in the nonpredominant region. Phenotype A (anterior compartment prolapse predominant, posterior support preserved) was found in all 4 groups of patients and was considered the reference in the analysis. In 111 patients with stage 2 uterovaginal prolapse, phenotypes A and A>P (greater anterior prolapse than posterior prolapse) were found, and patients with phenotype A were more likely than those with phenotype A>P to have an optimal surgical outcome. In 401 patients with stage 3 to 4 uterovaginal prolapse, phenotypes C (apical compartment predominant, prolapse in all compartments), A, and A>P were found, and patients with phenotype A>P were more likely than those with phenotype A to have ideal surgical outcome. In 72 patients with stage 2 vaginal vault prolapse, phenotypes A, A>P, and P (posterior compartment predominant, anterior support preserved) were found, and those with phenotype A>P were less likely to have an ideal outcome than patients with phenotype A. In 297 patients with stage 3 to 4 vaginal vault prolapse, phenotypes C, A, and P>A (prolapse greater in posterior than in anterior compartment) were found, but there were no significant differences in rate of ideal outcome between phenotypes. CONCLUSION: Five anatomic phenotypes based on preoperative Pelvic Organ Prolapse Quantification scores were present in patients with stages 2 and 3 to 4 uterovaginal prolapse and vaginal vault prolapse. These phenotypes are predictive of surgical outcome after minimally invasive sacrocolpopexy. Further work needs to confirm the presence and predictive nature of these phenotypes. In addition, whether the phenotypes represent a progression of prolapse or discrete prolapse presentations resulting from different anatomic and life course risk profiles is unknown. These phenotypes may be useful in surgical counseling and planning.

Three-year outcomes of a randomized clinical trial of perioperative vaginal estrogen as adjunct to native tissue vaginal apical prolapse repair.

BACKGROUND: As the muscular and connective tissue components of the vagina are estrogen responsive, clinicians may recommend vaginal estrogen to optimize tissues preoperatively and as a possible means to reduce prolapse recurrence, but long-term effects of perioperative intravaginal estrogen on surgical prolapse management are uncertain. OBJECTIVE: This study aimed to compare the efficacy of perioperative vaginal estrogen vs placebo cream in reducing composite surgical treatment failure 36 months after native tissue transvaginal prolapse repair. STUDY DESIGN: This was an extended follow-up of a randomized superiority trial conducted at 3 tertiary US sites. Postmenopausal patients with bothersome anterior or apical vaginal prolapse were randomized 1:1 to 1-g conjugated estrogen cream (0.625 mg/g) or placebo, inserted vaginally twice weekly for ≥5 weeks preoperatively and continued twice weekly for 12 months postoperatively. All participants underwent vaginal hysterectomy (if the uterus was present) and standardized uterosacral or sacrospinous ligament suspension at the surgeon's discretion. The primary report's outcome was time to failure by 12 months postoperatively, defined by a composite outcome of objective prolapse of the anterior or posterior walls beyond the hymen or the vaginal apex descending below one-third the total vaginal length, subjective bulge symptoms, and/or retreatment. After 12 months, participants could choose to use-or not use-vaginal estrogen for atrophy symptom bother. The secondary outcomes included Pelvic Organ Prolapse Quantification points, subjective prolapse symptom severity using the Patient Global Impression of Severity and the Patient Global Impression of Improvement, and prolapse-specific subscales of the 20-Item Pelvic Floor Distress Inventory and the Pelvic Floor Impact Questionnaire-Short Form 7. Data were analyzed as intent to treat and "per protocol" (ie, ≥50% of expected cream use per medication diary). RESULTS: Of 206 postmenopausal patients, 199 were randomized, and 186 underwent surgery. Moreover, 164 postmenopausal patients (88.2%) provided 36-month data. The mean age was 65.0 years (standard deviation, 6.7). The characteristics were similar at baseline between the groups. Composite surgical failure rates were not significantly different between the estrogen group and the placebo group through 36 months, with model-estimated failure rates of 32.6% (95% confidence interval, 21.6%-42.0%) and 26.8% (95% confidence interval, 15.8%-36.3%), respectively (adjusted hazard ratio, 1.55; 95% confidence interval, 0.90-2.66; P=.11). The results were similar for the per-protocol analysis. Objective failures were more common than subjective failures, combined objective and subjective failures, or retreatment. Using the Patient Global Impression of Improvement, 75 of 80 estrogen participants (94%) and 72 of 76 placebo participants (95%) providing 36-month data reported that they were much or very much better 36 months after surgery (P>.99). These data included reports from 51 of 55 "surgical failures." Pelvic Organ Prolapse Quantification measurements, Patient Global Impression of Severity scores, and prolapse subscale scores of the 20-Item Pelvic Floor Distress Inventory and Pelvic Floor Impact Questionnaire-Short Form 7 all significantly improved for both the estrogen and placebo groups from baseline to 36 months postoperatively without differences between the groups. Of the 160 participants providing data on vaginal estrogen usage at 36 months postoperatively, 40 of 82 participants (49%) originally assigned to the estrogen group were using prescribed vaginal estrogen, and 47 of 78 participants (60%) assigned to the placebo group were using vaginal estrogen (P=.15). CONCLUSION: Adjunctive perioperative vaginal estrogen applied ≥5 weeks preoperatively and 12 months postoperatively did not improve surgical success rates 36 months after uterosacral or sacrospinous ligament suspension prolapse repair. Patient perception of improvement remained very high at 36 months.

Patient perspectives in adverse event reporting after vaginal apical prolapse surgery.

BACKGROUND: Many clinical trials use systematic methodology to monitor adverse events and determine grade (severity), expectedness, and relatedness to treatments as determined by clinicians. However, patient perspectives are often not included in this process. OBJECTIVE: This study aimed to compare clinician vs patient grading of adverse event severity in a urogynecologic surgical trial. Secondary objectives were to estimate the association of patient grading of adverse events with decision-making and quality of life outcomes and to determine if patient perspective changes over time. STUDY DESIGN: This was a planned supplementary study (Patient Perspectives in Adverse Event Reporting [PPAR]) to a randomized trial comparing 3 surgical approaches to vaginal apical prolapse. In the parent trial, adverse events experienced by patients were collected per a standardized protocol every 6 months during which clinicians graded adverse event severity (mild, moderate, severe/life-threatening). In this substudy, we obtained additional longitudinal patient perspectives for 19 predetermined "PPAR adverse events." Patients provided their own severity grading (mild, moderate, severe/very severe/life-threatening) at initial assessment and at 12 and 36 months postoperatively. Clinicians and patients were masked to each other's reporting. The primary outcome was the interrater agreement (kappa statistic) for adverse event severity between the initial clinician and patient assessment, combining patient grades of mild and moderate. The association between adverse event severity and the Decision Regret Scale, Satisfaction with Decision Scale, the 12-Item Short-Form Health Survey, and Patient Global Impression of Improvement scores was assessed using the Spearman correlation coefficient (ρ) for continuous scales, the Mantel-Haenszel chi-square test for Patient Global Impression of Improvement, and t tests or chi-square tests comparing the assessments of patients who rated their adverse events or symptoms as severe with those who gave other ratings. To describe patient perspective changes over time, the intraobserver agreement was estimated for adverse event severity grade over time using weighted kappa coefficients. RESULTS: Of the 360 randomly assigned patients, 219 (61%) experienced a total of 527 PPAR adverse events (91% moderate and 9% severe/life-threatening by clinician grading). Mean patient age was 67 years; 87% were White and 12% Hispanic. Among the patients reporting any PPAR event, the most common were urinary tract infection (61%), de novo urgency urinary incontinence (35%), stress urinary incontinence (22%), and fecal incontinence (13%). Overall agreement between clinician and participant grading of severity was poor (kappa=0.24 [95% confidence interval, 0.14-0.34]). Of the 414 adverse events that clinicians graded as moderate, patients graded 120 (29%) as mild and 80 (19%) as severe. Of the 39 adverse events graded as severe by clinicians, patients graded 15 (38%) as mild or moderate. Initial patient grading of the most severe reported adverse event was mildly correlated with worse Decision Regret Scale (ρ=0.2; P=.01), 12-Item Short-Form Health Survey (ρ=-0.24; P<.01), and Patient Global Impression of Improvement (P<.01) scores. There was no association between adverse event severity and Satisfaction with Decision Scale score. Patients with an initial grading of "severe" had more regret, lower quality of life, and poorer global impressions of health than those whose worst severity grade was mild (P<.05). Agreement between the patients' initial severity ratings and their ratings at 12 months (kappa=0.48 [95% confidence interval, 0.39-0.58]) and 36 months (kappa=0.45 [95% confidence interval, 0.37-0.53]) was fair. CONCLUSION: Clinician and patient perceptions of adverse event severity are discordant. Worse severity from the patient perspective was associated with patient-centered outcomes. Including the patient perspective provides additional information for evaluating surgical procedures.

Pelvic floor injury during vaginal birth is life-altering and preventable: what can we do about it?

Pelvic floor disorders after childbirth have distressing lifelong consequences for women, requiring more than 300,000 women to have surgery annually. This represents approximately 10% of the 3 million women who give birth vaginally each year. Vaginal birth is the largest modifiable risk factor for prolapse, the pelvic floor disorder most strongly associated with birth, and is an important contributor to stress incontinence. These disorders require 10 times as many operations as anal sphincter injuries. Imaging shows that injuries of the levator ani muscle, perineal body, and membrane occur in up to 19% of primiparous women. During birth, the levator muscle and birth canal tissues must stretch to more than 3 times their original length; it is this overstretching that is responsible for the muscle tear visible on imaging rather than compression or neuropathy. The injury is present in 55% of women with prolapse later in life, with an odds ratio of 7.3, compared with women with normal support. In addition, levator damage can affect other aspects of hiatal closure, such as the perineal body and membrane. These injuries are associated with an enlarged urogenital hiatus, now known as antedate prolapse, and with prolapse surgery failure. Risk factors for levator injury are multifactorial and include forceps delivery, occiput posterior birth, older maternal age, long second stage of labor, and birthweight of >4000 g. Delivery with a vacuum device is associated with reduced levator damage. Other steps that might logically reduce injuries include manual rotation from occiput posterior to occiput anterior, slow gradual delivery, perineal massage or compresses, and early induction of labor, but these require study to document protection. In addition, teaching women to avoid pushing against a contracted levator muscle would likely decrease injury risk by decreasing tension on the vulnerable muscle origin. Providing care for women who have experienced difficult deliveries can be enhanced with early recognition, physical therapy, and attention to recovery. It is only right that women be made aware of these risks during pregnancy. Educating women on the long-term pelvic floor sequelae of childbirth should be performed antenatally so that they can be empowered to make informed decisions about management decisions during labor.

Associated factors of vaginal laxity and female sexual function: a cross-sectional study.

BACKGROUND: Female sexual dysfunction (FSD), including vaginal laxity (VL), can lead to a decrease in quality of life and affect partner relationships. AIM: We aimed to investigate the associated factors of VL and FSD and their relationship with other pelvic floor disorders in a female population. METHODS: This cross-sectional study was conducted at Chelsea and Westminster Hospital from July to December 2022. All women referred to clinical care at the urogynecology clinic were included. Participants were assessed according to sociodemographic and clinical aspects, the Pelvic Organ Prolapse Quantification system, sexual function, VL, sexual attitudes, sexual distress, sexual quality of life, vaginal symptoms, and pelvic floor disorders. Unadjusted and adjusted associated factors of VL and FSD were analyzed. OUTCOMES: The primary outcome was the identification of the associated factors of VL and FSD in a female population, and secondary outcomes included the association between VL and pelvic organ prolapse (POP) with the questionnaire scores. RESULTS: Among participants (N = 300), vaginal delivery, multiparity, perineal laceration, menopause, and gel hormone were significantly more frequent in those reporting VL (all P < .05). When compared with nulliparity, primiparity and multiparity increased the odds of VL by approximately 4 and 12 times, respectively (unadjusted odds ratio [OR], 4.26 [95% CI, 2.05-8.85]; OR, 12.77 [95% CI, 6.53-24.96]). Menopause and perineal laceration increased the odds of VL by 4 and 6 times (unadjusted OR, 4.65 [95% CI, 2.73-7.93]; OR, 6.13 [95% CI, 3.58-10.49]). In multivariate analysis, menopause, primiparity, multiparity, and POP remained associated with VL. CLINICAL IMPLICATIONS: Parity, as an obstetric factor, and menopause and staging of POP, as clinical factors, were associated with VL. STRENGTHS AND LIMITATIONS: The investigation of associated factors for VL will contribute to the understanding of its pathophysiology. The study design makes it impossible to carry out causal inference. CONCLUSION: Menopause, primiparity, multiparity, and POP were highly associated with VL complaints in multivariate analysis.

Accelerometer-measured physical activity, sedentary behavior, and risk of incident pelvic organ prolapse: a prospective cohort study in the UK Biobank.

BACKGROUND: Previous studies on physical activity (PA) and pelvic organ prolapse (POP) were largely limited to self-reported PA in athletes, soldiers, and women in postpartum. We aimed to investigate the association of accelerometer-measured PA and sedentary behavior with the risk of POP in middle-aged and elderly women. METHODS: In this prospective cohort derived from the UK Biobank, the intensity and duration of PA and sedentary behavior were measured with wrist-worn accelerometers over a 7-day period in 2013-2015 for 47,674 participants (aged 42.8-77.9 years) without pre-existing POP. Participants were followed up until the end of 2022, during which incident POP was ascertained mainly by the electronic health records. Multivariable-adjusted Cox proportional hazards models and restricted cubic splines were used to assess the associations of interest. Isotemporal substitution models were applied to test the effects of substituting a type of activity with equivalent duration of others. RESULTS: During a median follow-up of 8.0 years, 779 cases of POP were recorded. The duration of light-intensity PA (LPA) was positively whereas sedentary time was negatively associated with the risk of POP. Every additional 1 h/day of LPA elevated the risk of POP by 18% (95% confidence interval [CI], 10%-26%). In contrast, the risk decreased by 5% (95% CI, 0-8%) per 1 h/day increment in sedentary behavior. No associations were found between moderate-intensity PA (MPA) or vigorous-intensity PA (VPA) and POP, except that women who had a history of hysterectomy were more likely to develop POP when performing more VPA (53% higher risk for every additional 15 min/day). Substituting 1 h/day of LPA with equivalent sedentary time was associated with a 18% (95% CI, 11%-24%) lower risk of POP. The risk can also be reduced by 17% (95% CI, 7%-25%) through substituting 30 min/day of LPA with MPA. CONCLUSIONS: More time spent in LPA or less sedentary time was linked to an elevated risk of POP in middle-aged and elderly women, while MPA or VPA was not. Substituting LPA with equivalent duration of sedentary behavior or MPA may lower the risk of POP.

Cost-Effectiveness of 2 Models of Pessary Care for Pelvic Organ Prolapse: Findings From the TOPSY Randomized Controlled Trial.

OBJECTIVES: Pelvic organ prolapse is the descent of one or more reproductive organs from their normal position, causing associated negative symptoms. One conservative treatment option is pessary management. This study aimed to to investigate the cost-effectiveness of pessary self-management (SM) when compared with clinic-based care (CBC). A decision analytic model was developed to extend the economic evaluation. METHODS: A randomized controlled trial with health economic evaluation. The SM group received a 30-minute SM teaching session, information leaflet, 2-week follow-up call, and a local helpline number. The CBC group received routine outpatient pessary appointments, determined by usual practice. The primary outcome for the cost-effectiveness analysis was incremental cost per quality-adjusted life year (QALY), 18 months post-randomization. Uncertainty was handled using nonparametric bootstrap analysis. In addition, a simple decision analytic model was developed using the trial data to extend the analysis over a 5-year period. RESULTS: There was no significant difference in the mean number of QALYs gained between SM and CBC (1.241 vs 1.221), but mean cost was lower for SM (£578 vs £728). The incremental net benefit estimated at a willingness to pay of £20 000 per QALY gained was £564, with an 80.8% probability of cost-effectiveness. The modeling results were consistent with the trial analysis: the incremental net benefit was estimated as £4221, and the probability of SM being cost-effective at 5 years was 69.7%. CONCLUSIONS: Results suggest that pessary SM is likely to be cost-effective. The decision analytic model suggests that this result is likely to persist over longer durations.

Urinary incontinence, faecal incontinence and pelvic organ prolapse symptoms 20-26 years after childbirth: A longitudinal cohort study.

OBJECTIVE: To investigate pelvic floor dysfunction (PFD; urinary incontinence (UI), faecal incontinence (FI) and prolapse) ≥20 years after childbirth and their association with delivery mode history and demographic characteristics. DESIGN: Cohort study with long-term follow-up. SETTING: Maternity units in Aberdeen and Birmingham (UK) and Dunedin (NZ). POPULATION: Women giving birth in 1993/1994. METHODS: Postal questionnaires at 20 (New Zealand) or 26 (United Kingdom) years after index birth (n = 6195). Regression analyses investigated associations between risk factors and UI, FI and prolapse symptoms. MAIN OUTCOME MEASURES: Prevalence of self-reported UI, FI, 'something coming down' from or in the vagina (SCD), and the Pelvic Organ Prolapse-Symptom Score, and relationships with delivery method. RESULTS: Thirty-seven per cent (n = 2270) responded at 20/26 years, of whom 61% reported UI (59% of whom reported more severe UI), 22% FI and 17% prolapse symptoms. Having only caesarean section (CS) was associated with a significantly lower risk of UI (OR 0.63, 95% CI 0.46-0.85), FI (OR 0.63, 95% CI 0.42-0.96) and SCD (OR 0.44, 95% CI 0.27-0.74) compared to only spontaneous vaginal deliveries (SVDs). Having any forceps delivery was associated with reporting FI compared to only SVDs (OR 1.29, 95% CI 1.00-1.66), but there was no association for UI (OR 0.95, 95% CI 0.76-1.19) or SCD (OR 1.05, 95% CI 0.80-1.38). Higher current BMI was associated with all PFD outcomes. CONCLUSIONS: Prevalence of PFD continues to increase up to 26 years following index birth, and differences were observed according to delivery mode history. Exclusive CS was associated with less risk of UI, FI and any prolapse symptoms.

The difference in extracellular matrix metabolism in women with and without pelvic organ prolapse: A systematic review and meta-analysis.

BACKGROUND: Studies on the changes of extracellular matrix (ECM) in pelvic organ prolapse (POP) are still controversial. OBJECTIVE: To identify the changes in the ECM in POP patients. SEARCH STRATEGY: Comprehensive searching in Embase, PubMed, Web of Science and the Cochrane Library was carried out until 23 February 2023. SELECTION CRITERIA: Studies comparing the protein levels of ECM-related components between women with and without POP. DATA COLLECTION AND ANALYSIS: Quality and risk of bias were assessed using the Agency for Healthcare Research and Quality assessment. Indicators were pooled with random or fixed effect meta-analysis based on heterogeneity and sub-grouped analysed by the biopsy site. MAIN RESULTS: Thirty cross-sectional studies were included, comprising 840 POP cases and 755 controls. Overall results showed that the expression of type III collagen (COLIII) and several matrix metalloproteinases (MMP-1, -2 and -9) were increased, whereas those of type I collagen (COLI), and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) were decreased in patients with POP. Subgroup analysis showed that the expression of COLIII in the anterior vaginal wall (AVW) and COLIII, MMP-2 and -9 in the uterosacral ligament (USL) were consistent with the overall results. However, the expression of COLI and MMP-1 in the AVW showed no difference and the expression of COLI and MMP-1 in the USL is still controversial based on current studies. CONCLUSIONS: Patients with POP have lower expression of COLI and TIMP-1 and higher expression of COLIII and MMPs compared with non-POP cases, but further studies are required to investigate in specified anatomical sites.

Vaginal hysteropexy compared with vaginal hysterectomy with apical suspension for the treatment of pelvic organ prolapse: A 5-year cost-effectiveness Markov model.

OBJECTIVE: Our objective was to perform a 5-year cost-effectiveness analysis of transvaginal hysteropexy (HP) via sacrospinous ligament fixation (SS) or uterosacral ligament suspension (US) versus vaginal hysterectomy (VH) with apical suspension via sacrospinous ligament fixation (SS) or uterosacral ligament suspension (US) for the treatment of uterine prolapse. DESIGN: A decision analytic model assessed the cost-effectiveness of the surgical intervention over a 5-year horizon. SETTING: This model was constructed using TreeAge® software. POPULATION OR SAMPLE: Healthy women undergoing surgery for uterine prolapse were modeled. METHODS: A Markov model was constructed to simulate the possible recurrence of prolapse. Recurrence rates, repeat surgery for surgical failures and complication rates were modeled. Base case, sensitivity analyses and probabilistic modeling were performed. MAIN OUTCOME MEASURES: The primary outcome was the incremental cost-effectiveness ratio (ICER) of <$100 000 per quality-adjusted life year (QALY). RESULTS: Using the available prolapse recurrence rates and repeat surgery rates in the literature, both HP-SS and HP-US are cost-effective at a willingness-to-pay (WTP) threshold of <$100 000 per QALY. The incremental cost-effectiveness ratio (ICER) for HP-US compared to HP-SS is $90 738.14, while VH-US and VH-SS are both dominated strategies. HP-US is the optimal cost-effective strategy but decays exponentially with increasing probability of prolapse recurrence and need for repeat surgery after failed hysteropexy. The cost-effectiveness acceptability curve (CEAC) favors sacrospinous hysteropexy until reaching a WTP threshold between $90 000 and $100 000. CONCLUSION: Hysteropexy surgical strategies are cost-effective transvaginal surgical approaches for uterine prolapse. Vaginal hysterectomy with apical suspension becomes more cost-effective with increasing probability of prolapse recurrence and need for repeat surgery after failed hysteropexy. Given the variability of prolapse recurrence rates in the literature, more comparative studies are needed to understand the cost-effectiveness relationship between these different surgical approaches.

Vaginal morphology and position associated with prolapse recurrence after vaginal surgery: A secondary analysis of the DEMAND study.

OBJECTIVE: To identify vaginal morphology and position factors associated with prolapse recurrence following vaginal surgery. DESIGN: Secondary analysis of magnetic resonance images (MRI) of the Defining Mechanisms of Anterior Vaginal Wall Descent cross-sectional study. SETTING: Eight clinical sites in the US Pelvic Floor Disorders Network. POPULATION OR SAMPLE: Women who underwent vaginal mesh hysteropexy (hysteropexy) with sacrospinous fixation or vaginal hysterectomy with uterosacral ligament suspension (hysterectomy) for uterovaginal prolapse between April 2013 and February 2015. METHODS: The MRI (rest, strain) obtained 30-42 months after surgery, or earlier for participants with recurrence who desired reoperation before 30 months, were analysed. MRI-based prolapse recurrence was defined as prolapse beyond the hymen at strain on MRI. Vaginal segmentations (at rest) were used to create three-dimensional models placed in a morphometry algorithm to quantify and compare vaginal morphology (angulation, dimensions) and position. MAIN OUTCOME MEASURES: Vaginal angulation (upper, lower and upper-lower vaginal angles in the sagittal and coronal plane), dimensions (length, maximum transverse width, surface area, volume) and position (apex, mid-vagina) at rest. RESULTS: Of the 82 women analysed, 12/41 (29%) in the hysteropexy group and 22/41 (54%) in the hysterectomy group had prolapse recurrence. After hysteropexy, women with recurrence had a more laterally deviated upper vagina (p = 0.02) at rest than women with successful surgery. After hysterectomy, women with recurrence had a more inferiorly (lower) positioned vaginal apex (p = 0.01) and mid-vagina (p = 0.01) at rest than women with successful surgery. CONCLUSIONS: Vaginal angulation and position were associated with prolapse recurrence and suggestive of vaginal support mechanisms related to surgical technique and potential unaddressed anatomical defects. Future prospective studies in women before and after prolapse surgery may distinguish these two factors.

The long-term impact of vaginal surgical mesh devices on pain clinic and psychological service referrals, anti-inflammatory testing and pelvic scans in UK primary care: A cohort study with the Clinical Practice Research Datalink.

OBJECTIVE: To examine long-term complications in women with stress urinary incontinence (SUI) and pelvic organ prolapse (POP), with and without surgical mesh implants. DESIGN: Longitudinal open cohort study from 1 April 2006 (or 1 April 2012) to 30 November 2018. SETTING: The Clinical Practice Research Datalink (CPRD) Gold database, which is linked to Hospital Episodes Statistics (HES) inpatient data, the HES Diagnostic Imaging Dataset (DID), Office for National Statistics mortality data and Index of Multiple Deprivation socio-economic status data. SAMPLE: Women aged ≥18 years with a diagnostic SUI/POP Read code. METHODS: Rates are estimated using negative binomial regression. MAIN OUTCOME MEASURES: Rates of referrals for: psychological and pain services; urinalysis, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) testing; and pelvic ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI) scans. RESULTS: A cohort of 220 544 women were eligible for inclusion; 74% (n = 162 687) had SUI, 37% (n = 82 123) had POP and 11% (n = 24 266) had both. Rates of psychological referrals and CT scans were lower in women with SUI mesh surgery, but this was offset by higher rates of CRP testing in women with SUI or POP mesh, MRI scans in women with SUI mesh, and urinalysis testing and referrals to pain clinics for women with POP mesh. CONCLUSIONS: Our results suggest a higher burden of morbidity in women with SUI/POP mesh surgery, and that these women may require ongoing follow-up in the primary care setting.

Pelvic floor dysfunction after intervention, compared with expectant management, in prolonged second stage of labour: A population-based questionnaire and cohort study.

OBJECTIVE: To investigate the effect of vacuum extraction (VE) or caesarean section (CS), compared with expectant management, on pelvic floor dysfunction (PFD) 1-2 years postpartum in primiparous women with a prolonged second stage of labour. DESIGN: A population-based questionnaire and cohort study. SETTING: Stockholm, Sweden. POPULATION: A cohort of 1302 primiparous women with a second stage duration of ≥3 h, delivering from December 2017 to November 2018. METHODS: The 1-year follow-up questionnaire from the Swedish National Perineal Laceration Register was distributed 12-24 months postpartum. Exposure was VE or CS at 3-4 h or 4-5 h, compared with expectant management. MAIN OUTCOME MEASURES: Pelvic floor dysfunction was defined as at least weekly symptoms of urinary incontinence, pelvic organ prolapse or a Wexner score of ≥4. The risk of PFD was calculated using Poisson regression with robust variance estimation, presented as crude and adjusted relative risks (RRs and aRRs) with 95% confidence intervals (95% CIs). The implication of obstetric anal sphincter injury (OASI) on pelvic floor disorders was investigated through mediation analysis. RESULTS: In total, 35.1% of women reported PFD. Compared with expectant management, the risk of PFD was increased after VE at 3-4 h (aRR 1.33, 95% CI 1.06-1.65) and 4-5 h (aRR 1.34, 95% CI 1.05-1.70), but remained unchanged after CS. The increased risk after VE was not mediated by OASI. CONCLUSIONS: Pelvic floor dysfunction was common in primiparous women after a prolonged second stage, and the risk of PFD increased after VE but was unaffected by CS, compared with expectant management. If a spontaneous vaginal delivery eventually occurred, allowing an extended duration of labour did not increase the risk of PFD.

Harvest of large fascia lata autograft: Outcomes in 108 patients.

PURPOSE: Due to the reclassification of transvaginal mesh as a high-risk device, there has been renewed interest in the use of fascia lata in pelvic floor reconstruction. Here we report our experience in 108 patients who underwent large fascia lata harvest for pelvic organ prolapse (POP) repair. Our primary objective was to highlight the postoperative morbidity of the large fascia lata harvest in patients who underwent POP repair using fascia lata autograft. METHODS: Surgery involved harvesting a fascia lata graft through a small lateral upper thigh incision and was used for either autologous transvaginal POP repair or autologous sacrocolpopexy. To prevent seroma, a temporary Jackson-Pratt drain was intraoperatively placed and a mild compression wrap was applied to the area for 4-6 weeks postoperatively. Patient demographics were obtained preoperatively, while physical exam findings and postoperative outcomes related to the fascia lata harvest were collected at sequential follow up visits. RESULTS: One-hundred eight patients underwent 111 large fascia lata harvests for either transvaginal or abdominal/robotic POP repair from July 2016 to January 2022. Mean follow-up was 19.6 months (range: 1-65) with 38 patients having 24 months or more of follow-up. Mean Visual Analog Pain (VAP) score was 1 (range: 0-10). Sixteen patients developed asymptomatic thigh bulges, 16 patients developed harvest site seromas (of which 14 resolved), and 59 patients experienced mild, non-bothersome paresthesia near the incision. CONCLUSION: Large fascia lata harvest offers a robust autograft for transvaginal or transabdominal POP repair with minimal morbidity. Harvest site complications are minor and typically resolve with expectant management. This technique can be safely utilized in patients who desire graft-augmented repair of POP without the use of synthetic mesh, allograft, or xenograft.

The effect of the COVID-19 lockdown on women presenting with pelvic organ prolapse.

PURPOSE: To determine whether there is a difference in pelvic organ prolapse (POP) stage at time of presentation after lifting coronavirus disease (COVID-19) lockdown restrictions, as compared to before the lockdown. Enhancing our understanding of how healthcare utilization for pelvic floor disorders may be affected by limited accessibility, such as the COVID-19 pandemic, could prove invaluable for similar future circumstances. METHODS: This is a retrospective study of women with POP at their initial visit. Patients were grouped into two cohorts based on their initial presentation time: pre-COVID-19 lockdown (before March 2020) and post-COVID-19 lockdown (after December 2020). The cohorts were compared using demographic, clinical, and surgical variables. A logistic regression controlling for confounders was used to evaluate the influence of the COVID-19 lockdown on prolapse stage. RESULTS: There were 656 (50.3%) patients in the pre-COVID-19 lockdown cohort and 648 (49.7%) in the post-COVID-19 lockdown cohort. All baseline characteristics were similar between both cohorts except for race (p = 0.015). Treatment choices differed with the post-COVID-19 lockdown cohort having a lower proportion (26.5%) opting for surgery and a higher proportion (50.5%) of patients opting for nonsurgical interventions compared to the pre-COVID-19 lockdown cohort (p = 0.0005). A higher proportion of women presented with stages I and II prolapse in the post-COVID-19 lockdown (70.4%) cohort as compared to the pre-COVID-19 lockdown (62.5%) cohort (p = 0.002). CONCLUSIONS: Women in the post-COVID-19 lockdown cohort presented with early stage prolapse with preference for more conservative treatment options.

SIRT1 as a potential therapeutic target in pelvic organ prolapse due to protective effects against oxidative stress and cellular senescence in human uterosacral ligament fibroblasts.

INTRODUCTION: The pathogenesis of pelvic organ prolapse (POP), an age-related disease, has not been fully elucidated. Therapeutic targets of POP are limited. Silencing information regulator 2 related enzyme 1 (SIRT1), a gene considered capable of regulating oxidative stress and cellular senescence, has been widely demonstrated involved in aging and age-related diseases. The present study aimed to explore the role of SIRT1 in POP in vivo and in vitro. METHODS: Expression levels of SIRT1 in uterosacral ligament (USL) tissues from patients with or without POP were measured using immunohistochemical assays. SRT1720, a SIRT1 agonist, was used to upregulate SIRT1, and hydrogen peroxide (H2O2) was used to establish an oxidative stress model in human uterosacral ligament fibroblasts (hUSLFs). The effects of SIRT1 on cell viability, apoptosis, senescence, and reactive oxygen species (ROS) levels were detected, respectively. Western blot assays were used to examine expression levels of apoptosis- and senescence-associated biomarkers. Unpaired Student's t test, Mann-Whitney U test, χ2 test, and one-way ANOVA were performed for determining statistically significant differences. RESULTS: Compared to the control group, expression levels of SIRT1 were downregulated in USL tissues and hUSLFs from patients with POP, and associated with stage (p < 0.05). hUSLFs of patients with POP had lower growth rates (p < 0.0001) than those of the control group, which were improved by upregulating SIRT1 (p < 0.05). The senescent proportion was higher in the POP group than the control group (43.63 ± 10.62% vs. 4.84 ± 5.32%, p < 0.0001), which could be reduced by upregulating SIRT1 (p < 0.0001). High ROS levels in the POP group were also alleviated by SRT1720. H2O2 exposure increased ROS levels, inhibited proliferation, and triggered apoptosis and senescence in hUSLFs of patients without POP in a concentration-dependent manner. Further, these damages were alleviated by pretreatment with SRT1720. CONCLUSIONS: SIRT1 is downregulated in patients with POP, and the development of SIRT1 activators or agonists may have applications in the treatment and prevention of POP through antioxidative stress and antisenescence effects.