Obstetrics & Gynecology:
Pharmacological Treatment of Women Awaiting Surgery for Stress Urinary Incontinence
Cardozo, Linda MD; Drutz, Harold P. MD; Baygani, Simin K. MS; Bump, Richard C. MD; Duloxetine Severe UI Study Group
From the *Kings College Hospital, London, United Kingdom; †Mt. Sinai Hospital, Toronto, Canada; and ‡Lilly Research Laboratories, Indianapolis, Indiana.
Received February 13, 2004. Received in revised form April 27, 2004. Accepted May 7, 2004.
This work was sponsored by Eli Lilly and Company and Boehringer Ingelheim.
*For other members of the Duloxetine Severe UI Study Group, see the Appendix.
Financial Disclosure Dr. Bump and Ms. Baygani are full-time employees of Eli Lilly and Company and hold stock and stock options in the company. Professors Cardozo and Drutz have served on advisory boards for and have consulting agreements with Eli Lilly and Company. They were investigators in the study, which was funded by Eli Lilly and Company and Boehringer Ingelheim.
Address reprint requests to: Richard C. Bump, MD, Eli Lilly and Company Corporate Center, Indianapolis, IN 46285; e-mail: firstname.lastname@example.org.
OBJECTIVE: Duloxetine, a serotonin/norepinephrine reuptake inhibitor, has been effective in the treatment of mild and moderate stress urinary incontinence. The aim of this trial was to assess its efficacy for women with severe stress urinary incontinence.
METHODS: One hundred nine women, aged 33–75 years, enrolled into this double-blind, randomized, placebo-controlled study. Subjects had to have a predominant symptom of stress urinary incontinence with an incontinence episode frequency 14 per week or more, pure urodynamic stress urinary incontinence, and continence surgery already scheduled. Women were randomized to placebo (n = 54) or duloxetine 80 mg/d (n = 55) for 4 weeks, escalated to 120 mg/d for 4 weeks. Assessment variables included incontinence episode frequency, continence pad use, the Incontinence Quality of Life (I-QOL) questionnaire, and the Willingness to Consider Surgery rating. A responder was defined as a subject with an incontinence episode frequency reduction of 50% or more.
RESULTS: There were significant improvements with duloxetine compared with placebo in incontinence episode frequency (−60% versus −27%, P < .001), I-QOL score (+10.6 versus +2.4, P = .003), and pad use (−34.5% versus −4.8%, P = .008). At the conclusion of the 8-week study, 10/49 (20%) duloxetine-treated women were no longer interested in surgery, compared with 0/45 placebo-treated women (P = .001). Duloxetine-treated subjects were significantly more likely to be classified as responders (relative risk 4.68, 95% confidence interval 2.27–9.66). The number of subjects-needed-to-treat to gain an additional incontinence episode frequency responder with duloxetine was 2.02. All duloxetine responses were observed within 2 weeks. Side effects and discontinuations because of side effects were significantly more common with duloxetine.
CONCLUSION: The data support duloxetine's efficacy in women with severe stress urinary incontinence and suggest that some women responding to duloxetine may reconsider their willingness to undergo surgery.
LEVEL OF EVIDENCE: I
Stress urinary incontinence, the involuntary leakage of urine on effort or exertion or on sneezing or coughing,1 is the most common kind of incontinence in women.2 Current treatment options for stress urinary incontinence are limited to pelvic floor muscle training, devices, behavioral interventions, and surgery. Surgery is often regarded as the final option for a woman with severe stress urinary incontinence. However, the majority of women with stress urinary incontinence in Europe and the United States manage their incontinence without surgery (Hunskaar S, Lose G, Viktrup L, Gohier J, Voss S. Prevalence of stress urinary incontinence in women in four European countries [abstract]. Proceedings of the International Continence Society 32nd Annual Meeting, Heidelberg, Germany, August 28–30, 2002).3 The decision to proceed with surgery seems to be reached by women who have exhausted other treatment options.
There is currently no widely approved pharmacological option for stress urinary incontinence. Recently, several clinical trials have reported significant improvements in stress incontinence with the balanced4 serotonin (5-HT)-norepinephrine reuptake inhibitor, duloxetine.5–8 Duloxetine's presumed mechanism of action, based on in vivo cat experiments, is stimulation of pudendal nerve motor nerve output resulting from increased levels of 5-HT and norepinephrine in the pudendal motor nucleus (Onuf's nucleus) in the sacral spinal cord.9,10 This is believed to improve urethral closure with increases in abdominal pressure.
The Willingness to Consider Surgery Rating and Responses Based upon your current symptoms of stress incontinence, would you consider a surgical intervention? □ Strongly interested □ Somewhat interested □ Unsure □ Somewhat NOT interested □ Strongly NOT interested
The earlier duloxetine trials included women with mildly, moderately, and severely abnormal control.5–8 The aim of our study was to evaluate the efficacy of duloxetine in women with predominantly severe stress urinary incontinence by enrolling subjects who were scheduled for and awaiting continence surgery.
MATERIALS AND METHODS
Women aged 18–75 years with severe stress urinary incontinence were eligible for this double-blind, placebo-controlled, randomized, forced dose-escalation clinical trial performed in 14 tertiary urogynecological or urological centers in Australia, Canada, the Netherlands, and the United Kingdom. The ethics review committee for each site approved the study, and written informed consent was obtained from every participant.
The case definition included both urodynamic and severity criteria. Pure urodynamic stress incontinence was defined as a predominant complaint of stress urinary incontinence and the finding of urodynamic stress incontinence without detrusor overactivity and with normal compliance on a urodynamic study within 6 months of enrollment. All urodynamic diagnoses conformed to the standards of the International Continence Society.1 Severity criteria included both 1) that the subject averaged at least 14 stress incontinence episodes per week and 2) that she had scheduled her continence surgery after having discussed all other reasonable treatment options for stress urinary incontinence with her physician
The urodynamic study was required to include a measure of urethral resistance, and all subjects had cotton-swab testing11 to measure the maximum straining urethral axis. Intrinsic sphincteric deficiency was defined as urodynamic stress incontinence with a maximum straining urethral axis less than 20°, maximum urethral closure pressure less than 20 cm H2O, or Valsalva leak-point pressure less than 60 cm H2O.11
Figure 1 summarizes the study design and the timing of data collection. After screening and a 2-week blinded placebo lead-in, subjects were randomized to receive, in a double-blind fashion, either duloxetine (40 mg twice daily for 4 weeks, escalating to 60 mg twice daily for another 4 weeks) or placebo for 8 weeks. Capsules appeared identical for placebo and duloxetine, and subjects took 3 capsules (either placebo or duloxetine 20 mg in various combinations) twice daily.
A stratified randomization (strata based on baseline incontinence severity: < 4 or ≥ 4 episodes per day) using a centralized computer voice-response system was performed to prevent imbalance in incontinence severity between treatment groups. Treatment assignments were also balanced at each investigative site. To preserve the blinding of the study, no investigator or sponsor personnel who were directly involved with the conduct of the study or the analysis of the data had access to the randomization table before validation of the database and the formal database lock after every subject had completed the double-blind portion of the study.
The primary efficacy measurement, incontinence episode frequency, was computed from subject-completed real-time paper diaries. An incontinence episode was defined as an easily noticeable leakage of urine that would wet a pad, containment garment, or article of clothing and that occurred at the time of activities such as coughing, sneezing, or exercising. The specific instruction written on the urinary diary was to record an episode “each time you accidentally lose urine. Even a small amount of accidental leakage should be marked each time it occurs.”
Other efficacy variables included the number of continence pads used, the validated Incontinence Quality of Life (I-QOL) questionnaire12,13 total and subscale scores, ratings from the validated Patient Global Impression of Severity and Improvement questions14 (PGI-S and PGI-I), and responses to the Willingness to Consider Surgery rating (an unvalidated scale developed for this study; see box). The PGI-I and PGI-S scales were adapted from scales described previously and used successfully in the psychopharmacological literature. They have been validated in previous clinical trials in subjects who received both duloxetine and placebo.14 For some prespecified analyses, a responder was defined as a woman who had at least a 50% decrease in incontinence episode frequency with treatment. A 50% improvement in quantitative measures of incontinence has been used previously as a threshold for substantial improvement in stress incontinence outcomes research for a number of different interventions, including bladder training and pelvic floor muscle training,15 devices,16 and surgery (Bodell DM, Leach GE. Update on the results of the cadaveric transvaginal sling (CATS) [abstract]. J Urol 2002;167S:78. Itano NB, Berman CJ, Rodriguez LV, Raz S. Polypropylene sling for the treatment of stress urinary incontinence: intermediate-term results [abstract]. J Urol 2003;169S:270. Rodriguez LV, Rosenblum N, Eilber K, Raz S. Prospective analysis of 263 women treated with the Prolene sling: surgical outcome and satisfaction determined by patient driven questionnaire [abstract]. J Urol 2002;167S:104–5). Safety was assessed by the evaluation of treatment-emergent adverse events, discontinuations because of adverse events, vital signs, clinical laboratory values, and electrocardiogram results.
The statistical analysis plan was specified a priori. Because the normality assumption was not satisfied (Shapiro-Wilks < .01), van Elteren's test17 (a type of stratified Wilcoxon test) was used for analysis of percentage change in incontinence episode frequency, with baseline incontinence severity as the stratification variable. The primary analysis compared incontinence episode frequency data from all diaries from the baseline phase with data from all diaries from the treatment phase. By-visit analyses were also performed. The percentage change in the number of continence pads used was analyzed with van Elteren's test. Mean changes in I-QOL scores were analyzed using an analysis of covariance model because the hypothesis of normality was not rejected. The model included terms for baseline I-QOL scores, treatment, site, and baseline incontinence severity. Categorical variables were analyzed using the Pearson χ2, Fisher exact, or Cochran-Mantel-Haenszel tests. The number needed-to-treat to gain one additional responder with duloxetine relative to placebo was obtained using the ratio 1 ÷ (p2 – p1), where p1 and p2 are the proportions of subjects who had at least a 50% decrease in incontinence episode frequency from baseline to endpoint in each treatment group. A sample size of 100 subjects (50 in each treatment group) was determined to provide at least an 80% power to detect a treatment difference of 20% in the median percentage change in weekly incontinence episode frequency, with an overall Type I error of 0.05, with the assumption that at least 90% of subjects would provide postrandomization data for analysis. All primary analyses used the intent-to-treat principle, using data from all randomized subjects with at least one postrandomization measure, whether or not they were compliant with taking their medication. Subjects who discontinued the trial prematurely because of side effects may have experienced benefits that were linked to the side effect that led to their discontinuation. This could bias conclusions related to efficacy. Thus, efficacy was also evaluated for subjects who completed the trial. Prematurely discontinuing subjects had their last outcome measure carried forward only in the intent-to-treat analysis. Analyses were performed using SAS 8.1 (SAS Institute, Cary, NC). A two-sided P value of .05 was considered significant.
One hundred nine women, aged 33–75 years, were randomized between May 2001 and October 2002. Figure 2 summarizes the flow of subjects through the study. Ninety-eight women (placebo 52, duloxetine 46) completed postrandomization diaries and were included in the intent-to-treat analysis for incontinence episode frequency and pad use. More subjects completed the I-QOL questionnaire (52 in each treatment group) and the PGI-I rating (placebo 52, duloxetine 51) and are included in the intent-to-treat analyses of these variables.
Placebo-treated subjects took 91% and duloxetine-treated subjects took 80% of their doses (P = .05) during the first 4 weeks of the trial, a difference attributable to a lower compliance by duloxetine subjects who discontinued from the study early. There was no compliance difference after week 4 (93% for both groups).
Table 1 presents baseline demographic and incontinence severity data. Scheduled surgery was similar between groups and included tension-free vaginal tape (46.2%), retropubic urethropexy (38.7%), sling (13.2%), and other (1.9%) procedures.
The median percentage decrease in incontinence episode frequency was significantly greater in the duloxetine group than in the placebo group in both the intent-to-treat (59.8% versus 26.9%, P < .001) and completers'analyses (60.4% versus 24.2%, P = .01). In the intent-to-treat analysis, the duloxetine-treated group had a median decrease in the absolute number of incontinence episodes of 7.1 per week compared with 2.9 per week for the placebo-treated group (P < .001). Significant duloxetine decreases in incontinence episode frequency compared with placebo were seen both at 4 weeks (54.7% versus 26.3%, P = .002) and 8 weeks postrandomization (64.0% versus 28.6%, P < .001). Although not statistically significant, additional improvement in incontinence episode frequency was observed with the increase in duloxetine dosage (median 12.9% additional decrease from the 4-week visit to the 8-week visit). Duloxetine-treated subjects also had a significant median percentage reduction in continence pad use compared with placebo-treated subjects (duloxetine 34.5%, placebo 4.8%, P = .008). These differences were significant at both the 4-week and 8-week treatment visits.
Sixty-three percent of subjects in the duloxetine group were classified as responders, compared with 13.5% in the placebo group (P < .001). Duloxetine-treated subjects were significantly more likely to be classified as responders (relative risk 4.68, 95% confidence interval 2.27–9.66). The number of subjects-needed-to-treat to gain an additional incontinence episode frequency responder with duloxetine compared with placebo was 2.02. Three duloxetine-treated subjects who were not responders while taking 80 mg/d became responders after the dosage was increased to 120 mg/d. Intrinsic sphincteric deficiency status did not affect the response to duloxetine (Table 2). Although not statistically significant because of the small sample size, more subjects who had intrinsic sphincteric deficiency with a straining urethral axis less than 20° had at least a 50% reduction in their incontinence episode frequency with duloxetine (50%, 4 of 8) than with placebo (10%, 1 of 10; P = .12).
Figure 3 plots the cumulative distribution of time to response by using 3-day moving averages for the 61% (28 of 46) of duloxetine-treated subjects who were identified as responders during the first 4 weeks of treatment while taking duloxetine 40 mg twice daily. The figure demonstrates that 61% of responding subjects did so by days 1 to 3, 75% by days 3 to 5, and all by days 13 to 15.
Duloxetine-treated subjects demonstrated significant improvements in their I-QOL scores compared with placebo-treated subjects (Table 3), with similar significant improvements in all I-QOL subscales. PGI-I results also demonstrated significantly better improvement with duloxetine than with placebo (Table 4).
Based on their Willingness to Consider Surgery rating responses, 10 of 49 (20.4%) women who were unsure about, somewhat interested in, or strongly interested in surgery before taking duloxetine indicated that they were somewhat or strongly NOT interested in surgery while taking duloxetine, compared with none of 45 placebo-treated subjects (P = .001). Interestingly, although every subject had agreed to and was scheduled for surgery before being offered entry into the trial, 6 subjects randomized to placebo and 1 randomized to duloxetine said that they were somewhat or strongly not interested in surgery at baseline and were excluded from this analysis.
Treatment-emergent adverse events were experienced by more subjects in the duloxetine group than in the placebo group (92.7% versus 72.2%, P = .006). Table 5 lists all side effects that occurred in at least 10% of subjects. Most of these started within the first 4 weeks of treatment; the incidence of new side effects did not differ significantly between the duloxetine and placebo groups after the first 4 weeks. Nausea was the most common side effect with duloxetine; however, for 92% of these, the nausea was mild or moderate in severity, and most (23 of 25, 92%) subjects who developed nausea completed the study. Of these, 47.8% reported resolution of nausea within 1 week and 69.6% within 1 month.
Significantly more duloxetine-treated subjects discontinued the study because of adverse events compared with the placebo (18 of 55, 32.7% versus 3 of 54, 5.6%, P < .001); however, no single duloxetine-associated event caused more than 2 discontinuations. Nausea, headache, worsened hypertension, and vomiting each resulted in 2 discontinuations from the duloxetine group. None of the subjects taking duloxetine who experienced constipation or dry mouth discontinued treatment because of these effects. Serious adverse events, cardiovascular events, and laboratory abnormalities were rare and not significantly different with duloxetine compared with placebo.
Duloxetine is potentially the first drug specifically developed for the treatment of stress urinary incontinence. In this 8-week trial, the most severely affected women were studied, and yet we were still able to show significant short-term improvements, comparable with those observed in previous 12-week trials with less severely incontinent women.5–8 Importantly, 20% of the duloxetine-treated women awaiting surgery indicated a desire to revise their decision to proceed with surgery after 8 weeks, compared with none of the placebo-treated women.
Although most women with urodynamic stress incontinence have an element of both urethral hypermobility and intrinsic sphincteric deficiency, those with predominant intrinsic sphincteric deficiency represent the most difficult group to treat surgically because they often have failed continence surgery and may have a fixed, fibrosed, or scarred urethra. Thus, it is particularly relevant that duloxetine was equally effective in women with and those without intrinsic sphincteric deficiency.
Table 6 compares the pretreatment severity of previous duloxetine trials with the current trial and demonstrates that the current population was the most severely affected population yet enrolled in a duloxetine stress incontinence trial. The table also shows that duloxetine had similar 50–60% reductions in incontinence in all 5 studies. The 27% median reduction in incontinence episode frequency observed in the current placebo group is toward the lower end of the range of placebo responses observed in the prior trials (averaging 33%, range 27–40%). This is likely the result of a diminished, although appreciable, placebo response in women with more severe stress urinary incontinence and in those who have had prior treatments for stress urinary incontinence, issues we have considered in detail in another publication (Yalcin I, Bump RC. The effect of prior treatment experience and incontinence severity on the placebo response of stress urinary incontinence. Am J Obstet Gynecol, in press).
Most responses (75%) were observed within the first 5 days and all within 2 weeks. The current and previous phase 3 studies6–8 demonstrate that most duloxetine side effects, especially nausea, occur early and usually resolve within 1–4 weeks. Thus, in clinical practice, women could be reassured that within 2–4 weeks they will be able to assess both the efficacy and tolerability of duloxetine.
The improvements in incontinence were accompanied by significant improvements in condition-specific quality of life. Just as importantly, the improvements with duloxetine were clinically important because they exceeded the minimal clinically important difference levels established for the I-QOL total score (Patrick D, Yalcin I, Summers K, Kinchen K, Bump RC. The minimal clinically important difference in Incontinence Quality of Life Questionnaire score in studies examining the benefits of treatment in women with stress urinary incontinence [unpublished data]). The I-QOL minimal clinically important difference is 6.3 points within a treatment (compared with 10.6 for duloxetine and 2.4 for placebo in this study) and 2.5 points between treatments (compared with 8.2 for this study).
The maximally effective dose of duloxetine has not been established because no previous study used a dose greater than 40 mg twice daily. The dose escalation to 60 mg twice daily in this study was an effort to obtain data to examine enhanced efficacy or worsened tolerability of a higher dose. Previous 40-mg twice-daily fixed-dose trials demonstrated a plateauing of incontinence episode frequency reduction after 4 weeks of treatment, in contrast to the trend for an increased treatment effect at 8 weeks in the current study. The additional 12.9% improvement in incontinence episode frequency reduction and the appearance of 3 additional incontinence episode frequency responders at the higher dose, although not statistically significant, do suggest that a few women may realize additional improvement at duloxetine doses above 40 mg twice daily. Dose escalation did not result in an increase in side effects.
The majority of women who present with the symptom of stress urinary incontinence are first advised regarding lifestyle changes and then given information or instruction to perform pelvic floor muscle training. Before this, most have worn protective pads and suffered symptoms for many years before seeking treatment. The decision to proceed with surgery is made after these attempts at self-management and conservative management have proved inadequate. Duloxetine provides another treatment option for these women. In addition, there are relative contraindications to surgery, such as planned future childbearing or temporarily higher priority comorbidities. In these circumstances, duloxetine could allow deferral of surgery until conditions are optimal.
The side-effect profile for duloxetine was comparable qualitatively with that reported in previous duloxetine stress urinary incontinence trials, although side effects were somewhat more frequent in this study.5–8 For example, nausea occurred in 46% of duloxetine-treated women in the current study, compared with 23% of 958 subjects in previous trials. As was the case in those earlier trials, in this study nausea was usually mild or moderate, nonprogressive, and transient and did not commonly require discontinuation from the study. Discontinuation rates because of duloxetine-associated side effects were also higher in this trial (32.7%, 18 of 55 subjects) than in prior trials using the same dose of duloxetine (15.0%, 21 of 140;5 24.1%, 83 of 344;6 21.5%, 53 of 247;7 and 17.2%, 39 of 2278).
In summary, this is the first trial specifically to test duloxetine's ability to help women with the most severe stress urinary incontinence, those who have already decided to proceed with surgery. We have been able to demonstrate in this population that duloxetine is superior to placebo in reducing stress incontinence and improving condition-specific quality of life over 8 weeks. These short-term data also suggest that successful medical therapy of stress incontinence may cause some women to reconsider their willingness to proceed with surgery.
1. Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology of lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Neurourol Urodyn 2002;21:167–78.
2. Hampel C, Wienhold D, Benken N, Eggersmann C, Thüroff. Definition of overactive bladder and epidemiology of urinary incontinence. Urolology 1997;50 suppl:4–14.
3. Diokno AC, Burgio K, Fultz NH, Kinchen KS, Obenchain R, Bump RC. The prevalence and outcomes of continence surgery among community-dwelling women. J Urol 2003;170:507–11.
4. Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, Shaw JL, Thompson L, Nelson DL, et al. Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology 2001;25:871–80.
5. Norton PA, Zinner NR, Yalcin I, Bump RC. Duloxetine versus placebo in the treatment of stress urinary incontinence. Am J Obstet Gynecol 2002;187:40–8.
6. Dmochowski RR, Miklos JR, Norton PA, Zinner NR, Yalcin I, Bump RC; Duloxetine UI Study Group. Duloxetine versus placebo in the treatment of North American women with stress urinary incontinence. J Urol 2003;170:1259–63.
7. van Kerrebroeck P, Abrams P, Lange R, Slack M, Wyndaele J-J, Yalcin I, et al.; Duloxetine UI Study Group. Duloxetine versus placebo in the treatment of European and Canadian women with stress urinary incontinence. BJOG 2004;111:249–57.
8. Millard RJ, Moore K, Rencken R, Yalcin I, Bump RC; the Duloxetine UI Study Group. Duloxetine versus placebo in the treatment of stress urinary incontinence: a four-continent randomized clinical trial. BJU Int 2004;93:311–8.
9. Thor KB, Katofiasc MA. Effects of duloxetine, a combined serotonin and norepinephrine reuptake inhibitor, on central neural control of lower urinary tract function in the chloralose-anesthetized female cat. J Pharmacol Exp Ther 1995;274:1014–24.
10. Katofiasc MA, Nissen J, Audia JE, Thor KB. Comparison of the effects of serotonin selective, norepinephrine selective, and dual serotonin and norepinephrine reuptake inhibitors on lower urinary tract function in cats. Life Sci 2002;71:1227–36.
11. Bump RC, Coates KW, Cundiff GW, Harris RL, Weidner AC. Diagnosing intrinsic sphincteric deficiency: comparing urethral closure pressure, urethral axis, and Valsalva leak point pressures. Am J Obstet Gynecol 1997;177:303–10.
12. Wagner TH, Patrick DL, Bavendam TG, Martin ML, Buesching DP. Quality of life of persons with urinary incontinence: development of a new measure. Urology 1996;47:67–71.
13. Patrick DL, Martin ML, Bushnell DM, Yalcin I, Wagner TH, Buesching DP. Quality of life of women with urinary incontinence: further development of the Incontinence Quality of Life Instrument (I-QOL) [published erratum appears in Urology 1999;53:1072]. Urology 1999;53:71–6.
14. Yalcin I, Bump RC. Validation of two global impression questionnaires for incontinence. Am J Obstet Gynecol 2003;189:98–101.
15. Wyman JF, Fantl JA, McClish DK, Bump RC. Comparative efficacy of behavioral interventions in the management of female urinary incontinence. Am J Obstet Gynecol 1998;179:999–1007.
16. Kondo A, Yokoyama E, Koshiba K, Fukui J, Gotoh M, Yoshikawa Y, et al. Bladder neck support prosthesis: a nonoperative treatment for stress or mixed urinary incontinence. J Urol 1997;157:824–7.
17. van Elteren PH. On the combination of independent two-sample tests of Wilcoxon. Bull Int Stat Inst 1960;37:1–13.
The Duloxetine Severe UI Study Group included the following principal investigators and their staff:
Linda Cardozo, md, Kings College Hospital, London, United Kingdom; Jacques Corcos, md, McGill Urology Associate, Montreal, Quebec, Canada; Harold Drutz, md, Mount Sinai Hospital–Canada, Toronto, Ontario, Canada; P. W. H. Houben, md, Gemini Hospital, Den Helder, Netherlands; Simon Jackson, md, John Radcliffe Hospital, Oxford, United Kingdom; Andrew Korda, md, Royal Prince Alfred Medical Centre, Newtown, Australia; Thomas Mainprize, md, Foothills Hospital, Calgary, Alberta, Canada; Tom McNicholas, md, Lister Hospital, Stevenage Herts, United Kingdom; Peter Pommerville, md, Can-Med Clinical Research Inc, Victoria, British Columbia, Canada; Edward Shaxted, md, Northampton General Hospital, Northampton, United Kingdom; Gary Steinhoff, md, G. Steinhoff Clinical Research, Victoria, British Columbia, Canada; C. H. van der Vaart, md, University Hospital Utrecht, Utrecht, Netherlands; Jean Guy Vezina, md, Centre de Recherche Clinique en Urologie, Quebec City, Quebec, Canada; and Chui Kin Yuen, md, Manitoba Clinic, Winnipeg, Manitoba, Canada. Cited Here...
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© 2004 The American College of Obstetricians and Gynecologists