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ABSTRACT: INTRODUCTION AND HYPOTHESIS: Pelvic organ prolapse (POP) in women is a common condition whose etiology is poorly understood. There is increasing evidence that POP is heritable. The aim of our study was to define and evaluate familial clustering of POP. METHODS: Using a population-based Utah genealogy linked to more than a decade of hospital data, we calculated relative risks (RR) of POP in female relatives of women with POP using age- and birth year-specific rates of POP. We compared the average pairwise relatedness of all POP cases to the population using a measure of genetic distance. RESULTS: We identified 1,292 women with diagnostic and procedure codes for POP. The RR of POP was significantly elevated in first- and third-degree female relatives (RR 4.15, p < 0.001; RR 1.24, p = 0.05). The average pairwise relatedness for all individuals with POP was significantly higher than expected (p < 0.001). CONCLUSIONS: These results strongly support a significant heritable contribution to POP.
International Urogynecology Journal 08/2012; · 1.83 Impact Factor
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Charles W Nager,
Linda Brubaker,
Heather J Litman,
Halina M Zyczynski,
R Edward Varner,
Cindy Amundsen,
Larry T Sirls, Peggy A Norton,
Amy M Arisco,
Toby C Chai, [......],
Elizabeth Mueller,
Gary Sutkin,
Tracey S Wilson,
Yvonne Hsu,
Thomas A Rozanski,
Leslie M Rickey,
David Rahn,
Sharon Tennstedt,
John W Kusek,
E Ann Gormley
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ABSTRACT: Urodynamic studies are commonly performed in women before surgery for stress urinary incontinence, but there is no good evidence that they improve outcomes.
We performed a multicenter, randomized, noninferiority trial involving women with uncomplicated, demonstrable stress urinary incontinence to compare outcomes after preoperative office evaluation and urodynamic tests or evaluation only. The primary outcome was treatment success at 12 months, defined as a reduction in the score on the Urogenital Distress Inventory of 70% or more and a response of "much better" or "very much better" on the Patient Global Impression of Improvement. The predetermined noninferiority margin was 11 percentage points.
A total of 630 women were randomly assigned to undergo office evaluation with urodynamic tests or evaluation only (315 per group); the proportion in whom treatment was successful was 76.9% in the urodynamic-testing group versus 77.2% in the evaluation-only group (difference, -0.3 percentage points; 95% confidence interval, -7.5 to 6.9), which was consistent with noninferiority. There were no significant between-group differences in secondary measures of incontinence severity, quality of life, patient satisfaction, rates of positive provocative stress tests, voiding dysfunction, or adverse events. Women who underwent urodynamic tests were significantly less likely to receive a diagnosis of overactive bladder and more likely to receive a diagnosis of voiding-phase dysfunction, but these changes did not lead to significant between-group differences in treatment selection or outcomes.
For women with uncomplicated, demonstrable stress urinary incontinence, preoperative office evaluation alone was not inferior to evaluation with urodynamic testing for outcomes at 1 year. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT00803959.).
New England Journal of Medicine 05/2012; 366(21):1987-97. · 53.30 Impact Factor
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ABSTRACT: There is evidence that both environmental and genetic factors contribute to pelvic organ prolapse. We conducted a genome-wide association study to investigate whether common genetic variants modify the risk of pelvic organ prolapse.
We recruited women who had been evaluated and treated for pelvic organ prolapse at the University of Utah from 1996 to 2008 and their affected female relatives. Those in the case group were genotyped on the Illumina 550K platform. We genetically matched 2,976 white control participants available from Illumina as the control group. Association tests were adjusted for related participants using two different software programs: EMMAX and Genie. Confirmation of findings was performed in a cohort of Dutch women (n=76) with recurrent pelvic organ prolapse and family history of pelvic organ prolapse.
The Utah study sample included 115 case group participants treated for pelvic organ prolapse, in most case group participants with surgery (n=78) or repeat surgery (n=35). Results from association analyses using EMMAX software identified five single-nucleotide polymorphisms (SNPs) significantly associated with pelvic organ prolapse (P<1×10). Independent association analysis with Genie software identified three of the same SNPs and one additional SNP. The six SNPs were located at 4q21 (rs1455311), 8q24 (rs1036819), 9q22 (rs430794), 15q11 (rs8027714), 20p13 (rs1810636), and 21q22 (rs2236479). Nominally significant findings (P<.05) or findings trending toward significance (P<.1) were observed for five of the six SNPs in the Dutch cohort.
Six SNPs have been identified that are significantly associated with pelvic organ prolapse in high-risk familial case group participants and that provide evidence for a genetic contribution to pelvic organ prolapse.
II.
Obstetrics and Gynecology 12/2011; 118(6):1345-53. · 4.73 Impact Factor
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Linda Brubaker, Peggy A Norton,
Michael E Albo,
Toby C Chai,
Kimberly J Dandreo,
Keith L Lloyd,
Jerry L Lowder,
Larry T Sirls,
Gary E Lemack,
Amy M Arisco,
Yan Xu,
John W Kusek
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ABSTRACT: To describe surgical complications in 597 women over a 24-month period after randomization to retropubic or transobturator midurethral slings.
During the Trial of Midurethral Slings study, the Data Safety Monitoring Board regularly reviewed summary reports of all adverse events using the Dindo Surgical Complication Scale. Logistic regression models were created to explore associations between clinicodemographic factors and surgical complications.
A total of 383 adverse events were observed among 253 of the 597 women (42%). Seventy-five adverse events (20%) were classified as serious (serious adverse events); occurring in 70 women. Intraoperative bladder perforation (15 events) occurred exclusively in the retropubic group. Neurologic adverse events were more common in the transobturator group than in retropubic (32 events vs 20 events, respectively). Twenty-three (4%) women experienced mesh complications, including delayed presentations, in both groups.
Adverse events vary by procedure, but are common after midurethral sling. Most events resolve without significant sequelae.
American journal of obstetrics and gynecology 07/2011; 205(5):498.e1-6. · 3.28 Impact Factor
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Holly E Richter,
Michael E Albo,
Halina M Zyczynski,
Kimberly Kenton, Peggy A Norton,
Larry T Sirls,
Stephen R Kraus,
Toby C Chai,
Gary E Lemack,
Kimberly J Dandreo, [......],
Robert L Holley,
Charles W Nager,
Pamela Moalli,
Elizabeth Mueller,
Amy M Arisco,
Marlene Corton,
Sharon Tennstedt,
T Debuene Chang,
E Ann Gormley,
Heather J Litman
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ABSTRACT: Midurethral slings are increasingly used for the treatment of stress incontinence, but there are limited data comparing types of slings and associated complications.
We performed a multicenter, randomized equivalence trial comparing outcomes with retropubic and transobturator midurethral slings in women with stress incontinence. The primary outcome was treatment success at 12 months according to both objective criteria (a negative stress test, a negative pad test, and no retreatment) and subjective criteria (self-reported absence of symptoms, no leakage episodes recorded, and no retreatment). The predetermined equivalence margin was +/-12 percentage points.
A total of 597 women were randomly assigned to a study group; 565 (94.6%) completed the 12-month assessment. The rates of objectively assessed treatment success were 80.8% in the retropubic-sling group and 77.7% in the transobturator-sling group (3.0 percentage-point difference; 95% confidence interval [CI], -3.6 to 9.6). The rates of subjectively assessed success were 62.2% and 55.8%, respectively (6.4 percentage-point difference; 95% CI, -1.6 to 14.3). The rates of voiding dysfunction requiring surgery were 2.7% in those who received retropubic slings and 0% in those who received transobturator slings (P=0.004), and the respective rates of neurologic symptoms were 4.0% and 9.4% (P=0.01). There were no significant differences between groups in postoperative urge incontinence, satisfaction with the results of the procedure, or quality of life.
The 12-month rates of objectively assessed success of treatment for stress incontinence with the retropubic and transobturator approaches met the prespecified criteria for equivalence; the rates of subjectively assessed success were similar between groups but did not meet the criteria for equivalence. Differences in the complications associated with the two procedures should be discussed with patients who are considering surgical treatment for incontinence. (ClinicalTrials.gov number, NCT00325039.)
New England Journal of Medicine 06/2010; 362(22):2066-76. · 53.30 Impact Factor
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ABSTRACT: Predisposition factors for pelvic floor disorders (PFDs), including pelvic organ prolapse (POP), stress urinary incontinence (SUI), urge urinary incontinence (UUI), and hernias, are not well understood. We assessed linkage evidence for PFDs in mostly sister pairs who received treatment for moderate-to-severe POP. We genotyped 70 affected women of European descent from 32 eligible families with at least two affected cases by using the Illumina 1 million single-nucleotide polymorphism (SNP) marker set. Parametric linkage analysis with general dominant and recessive models was performed by the Markov chain Monte Carlo linkage analysis method, MCLINK, and a set of SNPs was formed, from which those in high linkage disequilibrium were eliminated. Significant genome-wide evidence for linkage was identified on chromosome 9q21 with a HLOD score of 3.41 under a recessive model. Seventeen pedigrees (53%) had at least nominal evidence for linkage on a by-pedigree basis at this region. These results provide evidence for a predisposition gene for PFDs on chromosome 9q.
The American Journal of Human Genetics 05/2009; 84(5):678-82. · 10.60 Impact Factor
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ABSTRACT: We determined the clinicodemographic factors associated with complications of continence procedures, the impact of concomitant surgery on the complication rate and the relationship between the incidence of cystitis and the method of postoperative bladder drainage.
We reviewed serious adverse events and adverse events in the Stress Incontinence Surgical Efficacy Trial, a randomized trial comparing Burch colposuspension to the autologous rectus fascial sling. Clinicodemographic variables were analyzed to determine those associated with adverse events using logistic regression analysis. Complications were stratified based on the presence or absence of concomitant surgery. Differences in complication rates (controlling for concomitant surgery) and cystitis rates (controlling for the bladder emptying method) were compared using Fisher's exact test.
Blood loss (p = 0.0002) and operative time (p <0.0001) were significantly associated with an adverse event. Patients who underwent concomitant surgery had a significantly higher serious adverse event rate (14.2% vs 7.3%, p = 0.01) and adverse event rate (60.5% vs 48%, p <0.01) than patients who underwent continence surgery alone. Cystitis rates were higher in the sling vs the Burch group up to 6 weeks postoperatively regardless of concomitant surgery status (p <0.01). Intermittent self-catheterization increased the cystitis rate by 17% and 23% in the Burch and sling groups, respectively.
Concomitant surgery at continence surgery increased the risk of complications. Sling surgery was associated with a higher risk of cystitis within the first 6 weeks postoperatively. Intermittent self-catheterization increased the risk of cystitis in each group. Complications were associated with surgical factors and not with patient related factors.
The Journal of urology 03/2009; 181(5):2192-7. · 4.02 Impact Factor
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ABSTRACT: The purpose of this study was to identify risks for mesh/suture erosions following abdominal sacral colpopexy (ASC).
We analyzed demographic, perioperative variables, and erosion status in 322 participants in the Colpopexy and Urinary Reduction Efforts study 2 years after sacral colpopexy.
The predominant graft used was synthetic mesh: woven polyester (Mersilene; Ethicon, Inc, Somerville, NJ) (42%) or polypropylene (48%). Twenty subjects (6%) experienced mesh/suture erosion. Unadjusted risk factors for mesh/suture erosion were expanded polytrafluroethylene (ePTFE) mesh (ePTFE 4/21 [19%] vs non-ePTFE 16/301 [5%]; odds ratio [OR], 4.2), concurrent hysterectomy (OR, 4.9), and current smoking (OR, 5.2). Of those with mesh erosion, most affected women (13/17) underwent at least 1 surgery for partial or total mesh removal. Two were completely resolved, 6 had persistent problems, and 5 were lost to follow-up. No resolution was documented in the 4 women who elected observation.
Expanded PTFE mesh should not be used for sacral colpopexy. Concurrent hysterectomy and smoking are modifiable risks for mesh/suture erosion.
American journal of obstetrics and gynecology 11/2008; 199(6):688.e1-5. · 3.28 Impact Factor
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ABSTRACT: To estimate whether perioperative and postoperative outcomes after Burch colposuspension or pubovaginal sling for stress urinary incontinence (SUI) differed with age.
This study was a prospective secondary analysis of the Stress Incontinence Surgical Treatment Efficacy Trial. Baseline characteristics, adverse events, and 2-year outcomes of women at least 65 years old were compared with those younger than 65 years using chi(2) and t tests. Multivariable analyses were performed, including age and outcomes that differed between age groups on univariable analysis, adjusting for variables that differed by age group at baseline and by surgical treatment group.
Six-hundred fifty-five women were included in analyses of perioperative events and 520 for 2-year outcomes. Mean age (+/-standard deviation) was 69.7 (+/-3.7) years in the older group and 49.4 (+/-8.2) in the younger group. Older women had slightly longer time to normal activities (50 days compared with 42 days, P=.05), but there was no difference in time to normal voiding (14 days compared with 11 days, P=.42). Older women were more likely to have a positive stress test at follow-up (odds ratio [OR] 3.7, 95% confidence interval [CI] 1.70-7.97, P=.001), less subjective improvement in stress (8 point lesser decrease, 95% CI 1.5-14.1, P=.02), and urge incontinence (7 point lesser decrease, 95% CI 1.5-12.2, P=.01) by the Medical and Epidemiologic Social Aspects of Aging questionnaire, and were more likely to undergo surgical retreatment for SUI (OR 3.9, 95% CI 1.30-11.48). Perioperative adverse events and length of stay did not differ between groups.
Older women undergoing surgery for stress incontinence can expect to do as well as younger women with respect to perioperative outcomes, but experience 2-year outcomes that are worse.
Obstetrics and Gynecology 10/2008; 112(3):621-9. · 4.73 Impact Factor
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ABSTRACT: Our purpose was to determine the long-term results after abdominal sacrocolpopexy.
Computer-coded procedure logs identified women who had an abdominal sacrocolpopexy performed from 1985 to 1992. Subjects answered a validated, condition-specific symptom questionnaire, a sexual function questionnaire, and a demographic survey. Failures were defined by reoperation or symptoms. The data were analyzed with use of the Student t test and the Fisher exact test.
At the time of surgery the subjects (n=38) had a mean age of 59.2 years (range 40-77 years), parity 4.03 (1-9), BMI 26.5 (18.6-40.2), and stage of prolapse 2.56 (0-4). The mean follow-up interval was 13.7 years (10-17 years). The total number of failures was 10 (26.3%), 4 (10.5%) because of reoperation and 6 (16%) because of symptoms. Symptom distress scores were low and similar between failures and successes. Twelve subjects were available for examination and most defects were noted in the anterior wall.
This long-term outcome analysis of abdominal sacrocolpopexy found the procedure to be durable with a 74% success rate at a mean follow-up of 13.7 years.
American Journal of Obstetrics and Gynecology 01/2004; 189(6):1606-10; discussion 1610-1. · 3.47 Impact Factor
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ABSTRACT: Duloxetine, a selective serotonin and norepinephrine reuptake inhibitor, increases rhabdosphincter contractility via the stimulation of pudendal motor neuron alpha-1 adrenergic and 5-hydroxytryptamine-2 receptors. In this first phase 3 study we assessed the efficacy and safety of duloxetine in women with stress urinary incontinence (SUI).
A total of 683 North American women 22 to 84 years old were enrolled in this double-blind, placebo controlled study. The case definition included a predominant symptom of SUI with a weekly incontinence episode frequency (IEF) of 7 or greater, the absence of predominant symptoms of urge incontinence, normal diurnal and nocturnal frequency, a bladder capacity of 400 ml or greater, and a positive cough stress test and stress pad test. After a 2-week placebo lead-in period subjects were randomly assigned to receive placebo (339) or 80 mg duloxetine daily (344) as 40 mg twice daily for 12 weeks. Primary outcome variables included IEF and an incontinence quality of life questionnaire. Van Elteren's test was used to analyze percent changes in IEF with a stratification variable of weekly baseline IEF (less than 14 and 14 or greater). ANCOVA was used to analyze incontinence quality of life scores.
Mean baseline IEF was 18 weekly and 436 subjects (64%) had a baseline IEF of 14 or greater. There was a significant decrease in IEF with duloxetine compared with placebo (50% vs 27%, p <0.001) with comparably significant improvements in quality of life (11.0 vs 6.8, p <0.001). Of subjects on duloxetine 51% had a 50% to 100% decrease in IEF compared with 34% of those on placebo (p <0.001). These improvements with duloxetine were associated with a significant increases in the voiding interval compared with placebo (20 vs 2 minutes, p <0.001) and they were observed across the spectrum of incontinence severity. The discontinuation rate for adverse events was 4% for placebo and 24% for duloxetine (p <0.001) with nausea the most common reason for discontinuation (6.4%). Nausea, which was also the most common side effect, tended to be mild to moderate and transient, usually resolving after 1 week to 1 month. Of the 78 women who experienced treatment emergent nausea while taking duloxetine 58 (74%) completed the trial.
These phase 3 data are consistent with phase 2 data and they provide further evidence for the safety and efficacy of duloxetine as a pharmacological agent for the treatment of women with SUI.
The Journal of Urology 10/2003; 170(4 Pt 1):1259-63. · 3.75 Impact Factor
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ABSTRACT: To investigate the relationship between the symptom of mixed urinary incontinence and incontinence severity, urodynamic findings, and treatment response.
This is a secondary analysis of data from 553 women randomized into a double-blind, placebo-controlled study evaluating duloxetine (serotonin-norepinephrine reuptake inhibitor) for the treatment of predominant stress urinary incontinence. Assessment variables included incontinent episode frequency, the Incontinence Quality of Life Questionnaire (I-QOL), and the Patient Global Impression of Severity Scale (PGI-S). Urge symptoms were identified with three urge I-QOL questions not included in corrected I-QOL calculations.
At baseline, 171 women (31%) had mixed urinary incontinence. They had more severe baseline urinary incontinence than did those with stress urinary incontinence (mean incontinent episode frequency 14.3 versus 10.5; PGI-S normal or mild 26.5% versus 70.4%; mean corrected I-QOL 59.1 versus 79.9; all Ps <.001). Baseline urodynamics were performed on a subset of 86 women. Subjects with both urodynamic stress incontinence and detrusor overactivity had less severe incontinence compared with subjects with only urodynamic stress incontinence. Both mixed urinary incontinence and stress urinary incontinence groups had significant decreases in median incontinent episode frequency at a 40 mg per day (62% and 58%, respectively) and 80 mg per day (63% and 65%) duloxetine dose compared with placebo (33% and 44%; all Ps <.05). Response was not dependent on the type of symptoms (interaction P =.47).
For women presenting with predominant stress urinary incontinence symptoms, the major determinant of concurrent urge symptoms was incontinence severity and not the pathophysiologic condition(s) causing the incontinence; duloxetine demonstrated equal efficacy for women with mixed urinary incontinence and pure stress urinary incontinence.
Obstetrics and Gynecology 08/2003; 102(1):76-83. · 4.73 Impact Factor
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ABSTRACT: The purpose of this study was to assess the efficacy and safety of duloxetine, a selective inhibitor of serotonin and norepinephrine reuptake, in the treatment of stress urinary incontinence.
A double-blind, randomized, placebo-controlled study was conducted in 553 women aged 18 to 65 years with a predominant symptom of stress urinary incontinence. Subjects were randomized to placebo (n = 138 women) or duloxetine at one of three doses (20 mg/d, n = 138 women; 40 mg/d, n = 137 women; or 80 mg/d, n = 140 women). Outcome variables that were assessed after 12 weeks of treatment included incontinence episode frequency recorded in a real-time diary and answers provided to the Patient Global Impression of Improvement scale and the Incontinence Quality of Life questionnaire.
Duloxetine was associated with significant and dose-dependent decreases in incontinence episode frequency that paralleled improvements that were observed in the Patient Global Impression of Improvement scale and the Incontinence Quality of Life questionnaire. The median incontinence episode frequency decrease with the use of the pooled diary analysis with placebo was 41% compared with 54% for duloxetine 20 mg per day (P =.06), 59% for duloxetine 40 mg per day (P =.002), and 64% for duloxetine 80 mg per day (P <.001). One half of the subjects at the 80 mg per day dose had a > or = 64% reduction in incontinence episode frequency (P <.001 vs placebo); 67% had > or = 50% reduction (P =.001 vs placebo). These improvements were observed despite significant concurrent dose-dependent increases in the average voiding interval in the duloxetine groups compared with the placebo group. Similar statistically significant improvements were demonstrated in a subgroup of 163 subjects who had more severe stress urinary incontinence (> or = 14 incontinence episode frequency per week; 49%-64% reduction in incontinence episode frequency in the duloxetine groups compared with 30% in the placebo group). Discontinuation rates for adverse events were 5% for placebo and 9%, 12%, and 15% for duloxetine 20, 40, and 80 mg per day, respectively (P =.04). Nausea was the most common symptom that led to discontinuation. None of the adverse events that were reported were considered to be clinically severe.
This trial provides evidence for the efficacy and safety of duloxetine as a pharmacologic agent for the treatment of stress urinary incontinence.
American Journal of Obstetrics and Gynecology 07/2002; 187(1):40-8. · 3.47 Impact Factor
