Abstract
Background
Women with refractory urgency urinary incontinence can be treated with onabotulinumtoxinA or sacral neuromodulation. Little data exists on the comparative effects of treatment of refractory UUI on other pelvic floor complaints, such as bowel and sexual function.
Objective
The objective of this study was to compare the impact of these treatments on fecal incontinence and sexual symptoms.
Methods
This was a planned supplemental analysis of a randomized trial in women with refractory UUI treated with onabotulinumtoxinA (n=190) or sacral neuromodulation (n=174). Fecal Incontinence and sexual symptoms were assessed at baseline, 6, 12, and 24 months. Fecal incontinence symptoms were measured using the St Mark’s (Vaizey) Fecal Incontinence severity scale. Sexual symptoms were measured using the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire-12 (PISQ-12) and the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR). The PISQ-IR allows measurement of sexual symptoms in both sexually active and non-sexually active adults. Primary outcomes were change in Vaizey and PISQ-12 scores between baseline and 6 months. Secondary outcomes were change in PISQ-IR total and subscores between baseline and 6 months and change in Vaizey, PISQ-12 and PISQ-IR scores between baseline and 12 and 24 months. Intent to treat analysis was performed using repeated measures mixed model to estimate change in all parameters from baseline while adjusting for the baseline score. A subgroup analysis of women with clinically significant bowel symptoms was conducted based on baseline Vaizey score of ≥12.
Results
At baseline, mean Vaizey scores were indicative of mild fecal incontinence symptoms and were not different between onabotulinumtoxinA and sacral neuromodulation groups (7.6±5.3 v 6.6±4.9, p=0.07). The proportion of sexually active women (56% v 63%, p=0.25), mean PISQ-12 score (33.4±7.5 v 32.7±6.7, p=0.55), or PISQ-IR subscores were also not different between the BTX and SNM groups at baseline. There was no difference between women treated with BTX and SNM at 6 months in improvement in fecal incontinence symptom score (Vaizey: −1.9, 95% CI −2.6 to −1.2 v −0.9, 95% CI −1.7 to −0.2, p=0.07) or sexual symptoms score (PISQ-12: 2.2, 95% CI 0.7 to 3.7 v 2.2, 95% CI 0.7 to 3.7, p=0.99). There was no difference in improvement between groups in the sexual symptom subscores in sexually active and non-sexually active women at 6 months. Similar findings were noted at 12 and 24 months. In a subgroup (onabotulinumtoxinA =33 and sacral neuromodulation =22) with clinically significant fecal incontinence at baseline (Vaizey score ≥12), there was a clinically meaningful improvement in symptoms in both groups from baseline to 6 months with no difference in improvement between the onabotulinumtoxinA and sacral neuromodulation groups (−5.1, 95% CI −7.3 to −2.8 v −5.6, 95% CI −8.5 to −2.6, p=0.8).
Conclusions
There were no differences in improvement of fecal incontinence and sexual symptoms in women with urgency urinary incontinence treated with onabotulinumtoxinA or sacral neuromodulation. Women with significant fecal incontinence symptoms at baseline had clinically important improvement in symptoms with no difference between the treatments. Our findings can help clinicians counseling women considering treatment for refractory urgency urinary incontinence.
Condensation
In women with refractory urgency urinary incontinence, treatment with onabotulinumtoxinA and sacral neuromodulation result in similar improvements in fecal incontinence and sexual symptoms.
Introduction
Pelvic floor disorders, which include urinary incontinence and fecal incontinence, are common with 25% of women in the United States reporting at least one disorder. [1] Women with pelvic floor disorders report worse sexual function especially when associated with urinary incontinence. [2] A growing body of literature suggests that treatment for one pelvic floor disorder may positively impact other pelvic floor complaints, including sexual dysfunction. Recent work demonstrated that sacral neuromodulation (SNM) for the treatment of fecal incontinence may improve other pelvic floor complaints including urinary and sexual issues. [3] Additionally, the use of OnabotulinumtoxinA (BTX) for the treatment of overactive bladder also demonstrated improvement in sexual function in a small study. [4] Given the common coexistence of pelvic floor disorders, studies that investigate the impact of treatment of one condition on other pelvic floor symptoms are needed.
Little data exists on the comparative effects of treatment of refractory urgency urinary incontinence(UUI) on other pelvic floor complaints, such as bowel and sexual function. The ROSETTA trial, a randomized trial comparing BTX versus SNM for treatment of refractory UUI in women [5], was an ideal group to comparatively assess the impact of treatment of refractory UUI on global pelvic floor function. The primary objective of this planned supplemental analysis was to compare the impact of these treatments for refractory UUI on fecal incontinence and sexual symptoms.
Materials and Methods
The ROSETTA trial was an open-label, randomized trial conducted at 9 sites participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development sponsored Pelvic Floor Disorders Network. The study design and methods have been previously published. [5] Women with refractory UUI who experienced ≥ 6 UUI episodes on a 3 day diary and failed behavioral interventions, physical therapy, and two medications were invited to participate. Women with neurologic disease, post-void residual >150ml, previous treatment with either study intervention, or ≥ Stage 3 prolapse were excluded. All sites received IRB approval, and all participants gave written informed consent (Clinicaltrials.gov ).
Participants were randomized 1:1 to undergo sacral neuromodulation (InterStim, Medtronic) or to receive 200 U of onabotulinumtoxin A (Botox A, Allergan) and were stratified by clinical site and age group (<65 versus ≥65 yrs). SNM participants who demonstrated ≥50% reduction in UUI episodes on a bladder diary following Stage I lead placement and proceeded to undergo Stage II pulse generator placement were considered SNM clinical responders. BTX participants with ≥50% reduction in UUI episodes on a bladder diary 1 month following injection were considered BTX clinical responders. Nonresponders to SNM were allowed medication and could receive BTX therapy after 6 months. Nonresponders to BTX were allowed medication and could receive SNM therapy after 6 months. Between 6 and 24 months, responders to BTX could receive two additional injections performed a minimum of 4 months apart.
For this planned supplementary analysis, fecal incontinence and sexual symptoms were measured at baseline, 6, 12, and 24 months. Data was collected, via telephone, by research staff masked to the subjects’ randomized group assignment. Fecal incontinence symptoms were measured using the St Mark’s (Vaizey) Fecal Incontinence severity scale. The Vaizey scale has 7 items and assesses for frequency of incontinence of solid stool, liquid stool and gas as well as alterations in lifestyle secondary to fecal incontinence, need to wear a pad or plug, use of constipating medication and an assessment of fecal urgency. Total scores range from 0 (perfect continence) to 24 (totally incontinent). [6, 7] The St. Mark’s score was chosen to assess FI based on NIH and Cochrane instrument recommendations and availability of robust data that correlates change in Vaizey score with change in FI episodes and data that the score is responsive to change. [8–10] The Vaizey score has been used extensively in the literature including ongoing FI treatment studies by our group [11] which will allow for comparison of treatment effects across studies. Sexual symptoms were measured using the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire Short Form (PISQ-12) and the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR). [12,13] The PISQ-12 total score ranges from 0 to 48, with higher scores indicating better sexual function. The PISQ-12 was only administered if the participant indicated sexual activity in the past 6 months. The PISQ-IR measures sexual function for both sexually active and non-sexually active women. It allows calculation of a total score and subscores for sexually active women in six areas: Arousal, Orgasm (SA-AO); Partner Related (SA-PR); Condition Specific (SA-CS); Global Quality Rating (SA-GQR); Condition Impact (SA-CI); Desire (SA-D). Subscores for women not sexually active (NSA) are calculated in four areas: Partner Related (NSA-PR); Condition Specific (NSA-CS); Global Quality Rating (NSA-GQR), and Condition Impact (NSA-CI). Each individual subscore ranges from 1 to 5 with higher score indicating better sexual function. The minimum important difference (MID) is the smallest change in score on patient reported questionnaire that patients would perceive as clinically meaningful improvement. The MID for the Vaizey scale is 5.0. [7] The MID for the PISQ-12 and PISQ-IR scales have not been published. In the absence of a published MID, a distribution based determination of the MID designates a change of 0.20 standard deviation as a “small” effect and 0.5 SD as a “medium” effect size for patient-reported questionnaires. [14]
The primary outcomes for this supplementary analysis were change in Vaizey and PISQ-12 scores between baseline and 6 months. Secondary outcomes included change in PISQ-IR total and subscores between baseline and 6 months and change in Vaizey, PISQ-12 and PISQ-IR total and subscores between baseline and 12 and 24 months.
Intent-to-treat(ITT) analysis was performed using repeated measures mixed model to estimate change in all parameters from baseline while adjusting for the baseline score. A subgroup analysis of women with more severe bowel symptoms, defined as baseline Vaizey score ≥ 12 was performed.
The modified ITT population, used for the primary analysis, consisted of all randomized participants who initiated treatment and provided at least 1 post-baseline bladder diary assessment, as reported previously. [15, 16] A planned secondary analysis was based on Clinical Responders, defined as participants with a 50% or more initial reduction in mean episodes of UUI in both treatment groups, and full device implantation in the SNM group.
Treatment groups were compared for mean change from baseline scores using a linear mixed model to account for missing data due to missed visits and early discontinuations with month (6, 12 and 24) as the unit of analysis and monthly change from baseline as the outcome. The model had terms for baseline value, treatment group, month category, treatment by month interaction, age group (<65 v. ≥65 years), and site consistent with randomization strata. Participant was treated as a random effect to account for within-person correlation. The model generated adjusted estimates of change from baseline by treatment group at the three time periods; F-test p values at each time assessed the hypothesis that the mean change from baseline differed between treatment groups. T-test p-values assessed whether the adjusted mean change in score from baseline differed from zero. The primary ITT comparisons for Vaizey and PISQ-12 score change at months 6 relative to baseline were each evaluated for statistical significance relative to p<0.05. There was no adjustment for multiple primary outcomes because the bowel and sexual symptoms were considered separate domains. All other analyses are considered descriptive in nature, with no adjustment for multiple testing, and p-values should be interpreted accordingly. A pre-planned subgroup analysis of the Vaizey score was based on Vaizey baseline score ≥12 and < 12. The interaction between baseline Vaizey score and treatment group at 6 months was assessed within the linear mixed model. All p-values are based on 2-sided tests. Analyses were performed using SAS Version 9.4 (SAS Institute, Inc.)
Results
As has previously been reported, 386 women were randomized to BTX (n=194) or SNM (n=192). Women with baseline and at least one post-baseline incontinence diary data were included in the ITT analysis (BTX= 190 and SNM= 174). Eighty-nine percent of women completed the 24-month follow-up (166 in BTX and 162 in SNM). Women with at least 50% reduction in UUI episodes were included in the Clinical Responder population (BTX=159 and SNM=139). [16] Baseline demographics and clinical characteristics were not different between the two groups (Table 1; see online supplement for Clinical Responder results). The average age was 63.0±11.6, 85% were post-menopausal and the majority were white. Participants had an average of 5.3 UUI episodes per day at baseline.(Table 1)
Table 1:
Demographic and Baseline Characteristics for Intention-to-treat Population
| Treatment Group | ||||
|---|---|---|---|---|
| Characteristic | Statistic/ Category | BTX (N=190) | SNM (N=174) | Total (N=364) |
| Race | White | 154 (81%) | 149 (86%) | 303 (83%) |
| Black/African American | 22 (12%) | 16 (9%) | 38 (10%) | |
| American Indian/Alaskan Native | 4 (2%) | 1 (1%) | 5 (1%) | |
| Asian | 1 (1%) | 1 (1%) | 2 (1%) | |
| Other | 6 (3%) | 4 (2%) | 10 (3%) | |
| More than one race | 1 (1%) | 2 (1%) | 3 (1%) | |
| Unknown/Not Reported | 2 (1%) | 1 (1%) | 3 (1%) | |
| Ethnicity | Hispanic/Latina | 18 (9%) | 10 (6%) | 28 (8%) |
| Not Hispanic/Latina | 167 (88%) | 160 (92%) | 327 (90%) | |
| Unknown/Not Reported | 5 (3%) | 4 (2%) | 9 (2%) | |
| Age at Baseline (years) | Mean (SD) | 62.9 (11.5) | 63.1 (11.8) | 63.0 (11.6) |
| BMI (kg/m^2) | Mean (SD) [N] | 32.6 (8.7) [189] | 31.7 (7.5) | 32.2 (8.2) |
| Functional Comorbidity Index | Mean (SD) | 3.8 (2.3) | 3.6 (2.3) | 3.7 (2.3) |
| Current Smoker | No | 168 (88%) | 156 (90%) | 324 (89%) |
| Yes | 22 (12%) | 18 (10%) | 40 (11%) | |
| Menopausal Status | Post-menopausal | 162 (85%) | 149 (86%) | 311 (85%) |
| Pre-menopausal | 20 (11%) | 18 (10%) | 38 (10%) | |
| Not sure | 8 (4%) | 7 (4%) | 15 (4%) | |
| Mean Urge Urinary Incontinence Episodes (UUIE) per day | Mean (SD) | 5.4 (2.7) | 5.2 (2.7) | 5.3 (2.7) |
| Mean Urinary Incontinence Episodes (UIE) per day | Mean (SD) | 6.0 (3.0) | 5.8 (3.0) | 5.9 (3.0) |
| Vaizey Score | N | 164 | 153 | 317 |
| Mean (SD) | 7.6 (5.3) | 6.6 (4.9) | 7.1 (5.2) | |
| Not Reported (N) | 26 | 21 | 47 | |
| PISQ-12 Sexually Active in past 6 months | No | 59 (44%) | 47 (37%) | 106 (41%) |
| Yes | 74 (56%) | 79 (63%) | 153 (59%) | |
| Not Reported(N) | 57 | 48 | 105 | |
| PISQ-12 Score (Sexually Active in past 6 months) | N | 73 | 76 | 149 |
| Mean (SD) | 33.4 (7.5) | 32.7 (6.7) | 33.0 (7.1) | |
| PISQ-IR Total Score (Sexually Active Women) | N1 | 59 | 62 | 121 |
| Mean (SD) | 2.9 (0.6) | 3.0 (0.5) | 3.0 (0.5) | |
| PISQ-IR Arousal Orgasm (Sexually Active Women) | Mean (SD) | 3.3 (0.9) | 3.4 (0.8) | 3.4 (0.8) |
| PISQ-IR Partner Related (Sexually Active Women) | Mean (SD) | 3.4 (0.6) | 3.4 (0.6) | 3.4 (0.6) |
| PISQ-IR Condition Specific (Sexually Active Women) | Mean (SD) | 4.3 (0.9) | 4.3 (0.7) | 4.3 (0.8) |
| PISQ-IR Global Quality Rating (Sexually Active Women) | Mean (SD) | 3.2 (1.2) | 3.3 (1.1) | 3.3 (1.2) |
| PISQ-IR Condition Impact (Sexually Active Women) | Mean (SD) | 2.9 (1.0) | 2.9 (1.0) | 2.9 (1.0) |
| PISQ-IR Desire (Sexually Active Women) | Mean (SD) | 2.9 (1.0) | 3.1 (0.9) | 3.0 (1.0) |
| PISQ-IR Partner Related (Not Sexually Active Women) | N1 | 87 | 66 | 153 |
| Mean (SD) | 2.2 (1.1) | 2.2 (1.0) | 2.2 (1.0) | |
| PISQ-IR Condition Specific (Not Sexually Active Women) | Mean (SD) | 2.9 (1.0) | 3.0 (1.0) | 3.0 (1.0) |
| PISQ-IR Global Quality Rating (Not Sexually Active Women) | Mean (SD) | 2.6 (1.3) | 2.8 (1.3) | 2.7 (1.3) |
| PISQ-IR Condition Impact (Not Sexually Active Women) | Mean (SD) | 2.9 (1.1) | 3.0 (1.2) | 2.9 (1.2) |
Sample sizes vary slightly across subscales of the PISQ-IR due to sporadic missed items.
Fecal Incontinence Symptoms
Mean baseline Vaizey scores were indicative of mild fecal incontinence symptoms and were not different between women randomized to BTX versus SNM (7.6 ± 5.3 v 6.6 ± 4.9, p=0.07). (Table 1) Only 10 of the 364 women had a Vaizey score of 0 at baseline. At 6 months, there was statistically significant improvement from baseline in the Vaizey score in both the BTX and SNM groups which was not significantly different between groups (−1.9, 95% CI −2.6 to −1.2 v −0.9, 95% CI −1.7 to −0.2, p=0.07) but was less than the MID of 5.0. [7] The results were similar at 12 and 24 months with the exception that at 24 months, the improvement in Vaizey scores was attenuated (−0.6,95% CI −1.3 to 0.1) in the SNM group (Table 2). Similar results were noted in the Clinical Responder analysis. (online supplement)
Table 2:
Adjusted Mean (95% CI) Fecal Incontinence and Sexual Symptoms changes from Baseline to 6, 12, and 24 Months for the Intention-To-Treat Population
| Treatment Group | Difference | |||||
|---|---|---|---|---|---|---|
| Outcome N, adjusted mean (95%CI) | BTX (N=190) | p-value1 | SNM (N=174) | p-value1 | SNM-BTX | P-value2 |
| Vaizey Score Change from Baseline | 151 | 138 | ||||
| Month 6 | −1.9 (−2.6, −1.2) | <0.001 | −0.9 (−1.7, −0.2) | 0.017 | 1.0 (−0.1, 2.0) | 0.069 |
| Month 12 | −1.4 (−2.1, −0.7) | <0.001 | −1.1 (−1.8, −0.3) | 0.005 | 0.4 (−0.6, 1.3) | 0.48 |
| Month 24 | −1.4 (−2.1, −0.7) | <0.001 | −0.6 (−1.3, 0.1) | 0.11 | 0.8 (−0.2, 1.8) | 0.12 |
| PISQ-12 Score Change from Baseline | 59 | 66 | ||||
| Month 6 | 2.2 (0.7, 3.7) | 0.005 | 2.2 (0.7, 3.7) | 0.004 | 0.0 (−1.8, 1.9) | 0.99 |
| Month 12 | 1.6 (0.0, 3.1) | 0.044 | 1.5 (−0.0, 3.0) | 0.054 | −0.1 (−1.9, 1.8) | 0.95 |
| Month 24 | 1.6 (0.0, 3.2) | 0.044 | 1.3 (−0.3, 2.8) | 0.11 | −0.4 (−2.3, 1.5) | 0.69 |
| PISQ-IR (Sexually Active Women) Overall Score Change from Baseline | 46 | 54 | ||||
| Month 6 | 0.0 (−0.1, 0.2) | 0.47 | 0.2 (0.0, 0.3) | 0.010 | 0.1 (−0.0, 0.3) | 0.16 |
| Month 12 | 0.1 (−0.0, 0.2) | 0.18 | 0.1 (−0.1, 0.2) | 0.34 | −0.0 (−0.2, 0.1) | 0.72 |
| Month 24 | 0.1 (−0.1, 0.2) | 0.24 | 0.1 (−0.0, 0.2) | 0.065 | 0.0 (−0.1, 0.2) | 0.65 |
| PISQ-IR (Sexually Active Women) Arousal, Orgasm Score Change from Baseline | 46 | 55 | ||||
| Month 6 | 0.1 (−0.1, 0.3) | 0.44 | 0.1 (−0.1, 0.3) | 0.19 | 0.0 (−0.2, 0.3) | 0.73 |
| Month 12 | 0.1 (−0.1, 0.3) | 0.35 | 0.1 (−0.1, 0.4) | 0.16 | 0.0 (−0.2, 0.3) | 0.76 |
| Month 24 | 0.2 (−0.0, 0.4) | 0.13 | 0.2 (−0.0, 0.4) | 0.069 | 0.0 (−0.3, 0.3) | 0.91 |
| PISQ-IR (Sexually Active Women) Partner Related Score Change from Baseline | 43 | 51 | ||||
| Month 6 | −0.0 (−0.2, 0.2) | 0.66 | 0.0 (−0.1, 0.2) | 0.71 | 0.1 (−0.1, 0.3) | 0.50 |
| Month 12 | −0.0 (−0.2, 0.2) | 0.78 | −0.0 (−0.2, 0.2) | 0.96 | 0.0 (−0.2, 0.2) | 0.84 |
| Month 24 | −0.1 (−0.3, 0.1) | 0.40 | 0.0 (−0.2, 0.2) | 0.99 | 0.1 (−0.1, 0.3) | 0.45 |
| PISQ-IR (Sexually Active Women) Condition Specific Score Change from Baseline | 46 | 55 | ||||
| Month 6 | 0.4 (0.2, 0.6) | <0.001 | 0.2 (0.0, 0.4) | 0.039 | −0.2 (−0.4, 0.1) | 0.13 |
| Month 12 | 0.3 (0.1, 0.5) | 0.007 | 0.3 (0.1, 0.5) | 0.002 | 0.0 (−0.2, 0.3) | 0.87 |
| Month 24 | 0.4 (0.2, 0.6) | <0.001 | 0.3 (0.1, 0.5) | 0.002 | −0.1 (−0.3, 0.2) | 0.50 |
| PISQ-IR (Sexually Active Women) Global Quality Rating Score Change from Baseline | 45 | 54 | ||||
| Month 6 | 0.1 (−0.3, 0.4) | 0.75 | 0.3 (−0.0, 0.6) | 0.10 | 0.2 (−0.2, 0.6) | 0.32 |
| Month 12 | 0.1 (−0.2, 0.5) | 0.48 | −0.0 (−0.4, 0.3) | 0.80 | −0.2 (−0.6, 0.2) | 0.43 |
| Month 24 | 0.3 (−0.1, 0.6) | 0.10 | 0.2 (−0.1, 0.5) | 0.24 | −0.1 (−0.5, 0.3) | 0.63 |
| PISQ-IR (Sexually Active Women) Condition Impact Score Change from Baseline | 46 | 54 | ||||
| Month 6 | 0.4 (0.2, 0.7) | <0.001 | 0.5 (0.2, 0.7) | <0.001 | 0.0 (−0.3, 0.3) | 0.92 |
| Month 12 | 0.3 (0.1, 0.5) | 0.018 | 0.4 (0.2, 0.6) | <0.001 | 0.1 (−0.2, 0.4) | 0.50 |
| Month 24 | 0.3 (0.0, 0.5) | 0.021 | 0.4 (0.2, 0.6) | <0.001 | 0.1 (−0.2, 0.4) | 0.41 |
| PISQ-IR (Sexually Active Women) Desire Score Change from Baseline | 46 | 53 | ||||
| Month 6 | −0.0 (−0.2, 0.2) | 0.84 | 0.0 (−0.2, 0.2) | 0.94 | 0.0 (−0.2, 0.3) | 0.82 |
| Month 12 | 0.1 (−0.1, 0.4) | 0.22 | −0.0 (−0.2, 0.2) | 0.77 | −0.2 (−0.4, 0.1) | 0.22 |
| Month 24 | −0.1 (−0.3, 0.1) | 0.48 | −0.0 (−0.2, 0.2) | 0.68 | 0.0 (−0.2, 0.3) | 0.78 |
| PISQ-IR (Not Sexually Active Women) Partner Related Score Change from Baseline | 75 | 57 | ||||
| Month 6 | −0.1 (−0.3, 0.1) | 0.48 | −0.2 (−0.4, 0.1) | 0.18 | −0.1 (−0.4, 0.2) | 0.58 |
| Month 12 | −0.1 (−0.3, 0.1) | 0.48 | −0.3 (−0.5, −0.0) | 0.028 | −0.2 (−0.5, 0.1) | 0.22 |
| Month 24 | −0.1 (−0.3, 0.1) | 0.48 | −0.2 (−0.5, 0.0) | 0.065 | −0.2 (−0.5, 0.2) | 0.34 |
| PISQ-IR (Not Sexually Active Women) Condition Specific Score Change from Baseline | 71 | 56 | ||||
| Month 6 | 0.3 (0.1, 0.5) | 0.005 | 0.2 (−0.0, 0.5) | 0.058 | −0.1 (−0.4, 0.2) | 0.63 |
| Month 12 | 0.2 (0.0, 0.4) | 0.025 | 0.2 (−0.1, 0.4) | 0.18 | −0.1 (−0.4, 0.2) | 0.65 |
| Month 24 | 0.3 (0.1, 0.5) | 0.003 | 0.1 (−0.1, 0.4) | 0.26 | −0.2 (−0.5, 0.1) | 0.24 |
| PISQ-IR (Not Sexually Active Women) Global Quality Rating Score Change from Baseline | 70 | 57 | ||||
| Month 6 | 0.4 (0.1, 0.6) | 0.003 | 0.3 (0.1, 0.6) | 0.018 | −0.0 (−0.4, 0.3) | 0.80 |
| Month 12 | 0.4 (0.2, 0.6) | <0.001 | 0.2 (−0.1, 0.5) | 0.13 | −0.2 (−0.6, 0.1) | 0.17 |
| Month 24 | 0.5 (0.2, 0.7) | <0.001 | 0.2 (−0.0, 0.5) | 0.075 | −0.2 (−0.6, 0.1) | 0.17 |
| PISQ-IR (Not Sexually Active Women) Condition Impact Score Change from Baseline | 71 | 58 | ||||
| Month 6 | 0.4 (0.1, 0.6) | 0.001 | 0.5 (0.3, 0.7) | <0.001 | 0.1 (−0.2, 0.4) | 0.41 |
| Month 12 | 0.5 (0.3, 0.7) | <0.001 | 0.4 (0.2, 0.6) | <0.001 | −0.0 (−0.3, 0.3) | 0.77 |
| Month 24 | 0.5 (0.3, 0.7) | <0.001 | 0.4 (0.2, 0.6) | <0.001 | −0.1 (−0.4, 0.2) | 0.56 |
Adjusted means and 95%CI are from a mixed linear repeated measures model with month as a categorical effect and adjustment for site, age group strata, and baseline value. N is the number of participants with baseline and at least one post-baseline score.
P-value from within-group test of adjusted mean change from baseline = 0
P-value from treatment group comparison of adjusted mean change from baseline
The subgroup of women (N=55) with baseline Vaizey scores ≥12 had clinically and statistically significant improvement from baseline at 6 months in both the BTX and SNM groups (−5.1, 95% CI −7.3 to −2.8 and −5.6,95% CI −8.5 to −2.6), with no difference between groups (p= 0.8). The change in Vaizey score remained different from baseline in both groups at 12 and 24 months. (Table 3, figure 1)
Table 3:
Adjusted Mean (95% CI) Vaizey Score change from Baseline to 6, 12, and 24 Months by Baseline Vaizey Score for the Intention-To-Treat Population
| Treatment Group | Difference | |||||
|---|---|---|---|---|---|---|
| Outcome N, adjusted mean (95%CI) | BTX (N=190) | p-value1 | SNM (N=174) | p-value1 | SNM-BTX | P-value2 |
| Baseline Vaizey Score ≥12 | ||||||
| Vaizey Score Change from Baseline | 33 | 22 | ||||
| Month 6 | −5.1 (−7.3, −2.8) | <0.001 | −5.6 (−8.5, −2.6) | <0.001 | −0.5 (−4.2, 3.2) | 0.78 |
| Month 12 | −4.5 (−6.6, −2.4) | <0.001 | −4.5 (−7.4, −1.7) | 0.002 | 0.0 (−3.4, 3.5) | 0.99 |
| Month 24 | −5.8 (−8.0, −3.7) | <0.001 | −3.9 (−6.9, −1.0) | 0.009 | 1.9 (−1.7, 5.5) | 0.29 |
| Baseline Vaizey Score <12 | ||||||
| Vaizey Score Change from Baseline | 118 | 116 | ||||
| Month 6 | −1.0 (−1.8, −0.3) | 0.007 | 0.2 (−0.5, 1.0) | 0.51 | 1.3 (0.3, 2.3) | 0.013 |
| Month 12 | −0.6 (−1.3, 0.1) | 0.11 | −0.1 (−0.8, 0.7) | 0.86 | 0.5 (−0.5, 1.5) | 0.29 |
| Month 24 | −0.1 (−0.9, 0.6) | 0.71 | 0.4 (−0.3, 1.1) | 0.27 | 0.5 (−0.4, 1.5) | 0.28 |
Adjusted means and 95% CI are from a mixed linear repeated measures model for each subgroup with month as a categorical effect and with adjustment for site, age group, and baseline value. N is the number of participants with baseline and at least one post-baseline score.
P-value for within-group test of adjusted mean change from baseline = 0
P-value for treatment group comparison of adjusted mean change from baseline
P-values for interaction of Baseline Vaizey Score and each time point when added to the main model: 6 months 0.42; 12 months 0.64; 24 months 0.62
Figure 1:
Observed Change in Vaizey Score from Baseline by Month for the Intention-To-Treat Population
In the subgroup (N=234) with Vaizey scores <12, women in the BTX group had greater improvement in Vaizey score from baseline to 6 months compared to the SNM group (−1.0, 95% CI −1.8 to −0.3 v 0.2, 95% CI −0.5 to 1.0, p=0.01); however, the clinical significance of this small difference is not clear, and this difference was no longer present at 12 and 24 months. (Table 3, figure 1)
Sexual Symptoms
At baseline, 56% and 63% of women who completed the PISQ-12 reported being sexually active in the past 6 months in the BTX and SNM groups, respectively (p=0.25). Mean baseline PISQ-12 scores were reflective of the presence of poor sexual function [8] and did not differ between groups (33.4 ± 7.5 v 32.7 ± 6.7, p= 0.55). Of those who reported sexual activity at baseline, one patient in the BTX group and 3 patients in the SNM group reported becoming non-sexually active at 6 months. Of those who reported being non-sexually active at baseline, one in each group reported sexual activity at 6 months. There was a statistically significant improvement in PISQ-12 score in both the BTX and SNM groups (2.2, 95% CI 0.7 to 3.7 and 2.2, 95% CI 0.7 to 3.7) corresponding to a “small” improvement in effect size. There was no difference between groups (p=0.99). The effects waned but a similar trend was noted at 12 and 24 months, which was only statistically significant in the BTX group. (Table 2)
There were no differences between groups in the total PISQ-IR score or any of the PISQ-IR subscores in both sexually active and non-sexually active women. In sexually active women, both groups demonstrated an improvement from baseline in the PISQ-IR Condition Specific Score and Condition Impact Score at 6, 12 and 24 months, with mean improvement ranging from 0.2 to 0.5 points. In non-sexually active women, there was improvement from baseline in the PISQ-IR Condition Specific Score and Global Quality Rating Score in the BTX group only and in the PISQ-IR Condition Impact Score in both the BTX and SNM groups, also with mean improvement ranging from 0.2 to 0.5 points. These improvements in subscores all correspond to “small” improvement in effect size.
Comments
In women with refractory UUI treated with SNM or BTX, we found small improvements from baseline in fecal incontinence and sexual symptom scores, which were similar in both groups; however, although statistically significant, the improvements did not uniformly meet a clinically meaningful difference. Only in the subgroup of women with clinically significant fecal incontinence symptoms at baseline was the symptom improvement in bowel symptoms clinically meaningful. Furthermore, this improvement was similar following treatment with SNM compared with BTX. These findings may help clinicians when counseling women considering treatment for refractory UUI.
In our study, fecal incontinence symptoms improved following treatment for refractory UUI for women with clinically significant symptoms at baseline. This finding is consistent with others that have reported improvement in fecal incontinence symptoms following SNM for UUI although the retrospective nature of those studies and lack of use of validated questionnaires make it challenging to directly compare the results. [17, 18] In a small retrospective cohort of women with symptomatic UUI and fecal incontinence at baseline, Kim et al reported statistically significant and clinically meaningful improvement in Cleveland Clinic Fecal Incontinence Score with median follow-up of 14 months following SNM placement; however, baseline fecal incontinence was poorly defined and characterized.[19] Importantly, we identified that in women with refractory UUI, a clinically meaningful improvement in bowel symptoms can be expected in women with Vaizey score ≥12 at baseline.
Our study design allowed for direct comparison between SNM and BTX; surprisingly we found that improvement in fecal incontinence symptoms were similar following treatment with BTX compared to SNM. SNM is an FDA approved treatment for fecal incontinence and is believed to result in neuromodulation of bowel activity via stimulation of the pudendal afferent somatic fibers. [20] Thus, we had expected that it would have a more substantial impact on fecal incontinence symptoms compared to BTX. The lack of difference in improvement in fecal incontinence symptoms between SNM and BTX may indicate that rather than specific impact on bowel mechanisms, the improvement in fecal incontinence symptoms seen with SNM and BTX treatment reflects the impact of UUI treatment on improvement in global quality of life including perception of bowel symptoms. Alternatively, our findings may provide clinical evidence of pelvic organ cross-sensitization, a phenomenon in which disease, and by extension therapeutic intervention, in one pelvic organ impacts another pelvic organ. Neural “cross-talk” in the pelvis exists under normal conditions and is necessary for the normal regulation of sexual, bladder and bowel function. [21] Animal studies have demonstrated an association between dysfunction in the lower urinary tract and the gastrointestinal tract such that, for example, acute cystitis may result in lower colorectal sensory thresholds and an acute colitis may result in irritative voiding symptoms. [22] Thus, intradetrusor BTX could have an impact on bowel function by a mechanism of pelvic organ cross-sensitization resulting in similar effects on fecal incontinence symptoms as SNM. Further mechanistic research is required to confirm cross sensitization and future therapies may be designed to target the “key organ”, that is the one that confers the most global benefit. Nonetheless, our findings may reassure women undergoing treatment for refractory UUI, especially in those with significant fecal incontinence at baseline, that they can expect improvements in their symptoms if they elect to pursue treatment with BTX instead of SNM.
We found that sexually active women had statistically significant improvements in sexual function following SNM and BTX although these only represented “small” improvement in effect size from baseline on the PISQ-12 questionnaire. Parnell et al, in a cohort of women treated with SNM for UUI, found significant improvement of “moderate” effect size in sexual symptom scores also using the PISQ-12 instrument. [23] Following BTX for UUI, Balzarro et al also reported statistically significant improvement in overall sexual function although these authors used a different instrument to measure sexual function. [4] Taken together with our findings, this suggests that in sexually active women undergoing treatment for refractory UUI, at least small improvements in sexual function can be expected with similar improvement with either SNM or BTX.
Sexual dysfunction in women is complex and can be related to general issues unrelated to the pelvic floor such as desire, arousal and the ability to obtain an orgasm. The mechanism by which treatment for UUI with SNM or BTX may improve sexual function is uncertain. In our study, we found small improvements from baseline in the condition-specific and condition-impact subscales but not in the other subscales such as Arousal/Orgasm, Partner Related, and Desire of the PISQ-IR questionnaire in sexually active women. This suggest that the improvement in sexual function was a result of improvement in urinary symptoms and not other aspects of sexual function. Using a different instrument to examine domains of sexual function, Parnell et al reported significant improvements following SNM in the desire domain of sexual function but not the arousal, orgasm, or lubrication domains.[23] In contrast, Blazarro reported significant improvements in arousal, lubrication, orgasm and satisfaction domains after BTX injection.[4] Given these conflicting results, the impact of treatments for refractory UUI on sexual function beyond their effect on improving urinary symptoms requires further investigation. Nevertheless, the positive impact of SNM and BTX on both urinary symptoms and sexual function further underscores the importance of providing effective treatments for women with refractory UUI.
The strengths of our study include the use of condition-specific validated measures of sexual function and fecal incontinence, prospective data collected by research staff masked to the subjects’ randomized group assignment and the geographical diversity of the participating study sites. There is limited evidence in terms of the effect of neuromodulation, especially BTX, on bowel and sexual function therefore our paper substantially adds to the literature to help guide clinicians. Study limitations include mild baseline fecal incontinence symptoms in our study population, which inherently limits the degree of improvement possible and generalizability of our findings to women with concurrent severe FI. We sought to mitigate this issue by performing a sub-analysis of women with more significant baseline fecal incontinence symptoms, (ie higher Vaizey scores) and noted similarly that there was no difference in improvement in symptoms between the two interventions. Importantly, the improvement seen in this group did meet the clinically meaningful difference highlighting the likely positive impact of these treatments on fecal incontinence symptoms. Nonetheless, it is important to note that the subgroup of women with Vaizey score ≥ 12 only included 14% of the study population. Second, a quarter of our study population did not complete the sexual symptom questionnaires at baseline and fewer than 60% of our population were sexually active at baseline; thus, the data needs to be interpreted cautiously. The importance of the small improvements we noted in sexual function would be better explored in a larger trial with the a more affected target population. Finally, given the complex nature of female sexual function, although we used well-validated instruments to assess change in sexual function, there are likely other social and emotional aspects of sexual function that our study could not assess.
Our results suggest that women with refractory UUI treated with both SNM and BTX can expect some improvement in bowel and sexual function with no difference between the two interventions. Women with significant fecal incontinence symptoms at baseline will have clinically meaningful improvement with no difference between the treatments.
Supplementary Material
AJOG at a Glance
A. Why was this study conducted?
This study compares bowel and sexual function outcomes in women seeking treatment for refractory urgency urinary incontinence and who were randomized to either onabotulinumtoxinA or sacral neuromodulation.
B. What are the key findings?
There were no differences in improvement of fecal incontinence and sexual symptoms between the two treatments. Women with clinically significant fecal incontinence symptoms (Vaizey score ≥12) at baseline had clinically meaningful improvement in fecal incontinence symptoms after either treatment.
C. What does this study add to what is already known?
Our findings add to the limited evidence on how treatment for refractory urgency urinary incontinence affects other pelvic floor disorders such as bowel and sexual function. Further, our findings can help clinicians when counseling women considering either onabotulinumtoxinA or sacral neuromodulation for refractory UUI and highlights that women with concomitant bothersome fecal incontinence symptoms can expect improvement when undergoing either treatment for refractory urgency urinary incontinence.
Acknowledgements
We thank the coordinators and all those who made this work possible, including the following:
Coordinators included the following: University of Alabama, Velria B. Willis, RN, BSN, CCRC, Nancy B. Saxon, RN, BSN, Kathy S. Carter, RN, BSN; Brown University, Alexandra Lynch, Allegra Parrillo; University of California, San Diego/Kaiser San Diego/Kaiser Downey, JoAnn Columbo, Gisselle Zazueta-Damian, Linda M. Mackinnon, MPH; Cleveland Clinic, Andrea Aaby, BS, Ly Pung, RN; Duke University, Akira Hayes, MS, Shantae McLean, MPH, CCRC; Oregon Health Sciences University, Amanda Holland, MPH; University of New Mexico, Karen Taylor, BA, Julia Middendorf, RN; University of Pennsylvania, Michelle Kinglee; and University of Pittsburgh, Judy Gruss, RN, Karen Mislanovich, RN. Collaborators included the following: University of Alabama, R. Edward Varner, MD, Tracey S. Wilson, MD, L. Keith Lloyd, MD, Holly Richter, MD, PhD, Robert L. Holley, MD, Alicia C. Ballard, MD, David R. Ellington, MD, Patricia S Goode, MD; Brown University, Vivian W. Sung, MD, MPH, Charles R. Rardin, MD, B. Star Hampton, MD, Vivian Sung, MD, Kyle J. Wohlrab, MD, Cassandra L. Carberry, MD, MS; University of California, San Diego/Kaiser San Diego/Kaiser Downey, Emily Lukacz, MD, Charles Nager, MD, Shawn A. Menefee, MD, Jasmine Tan-Kim, MD, Karl M. Luber, MD, Gouri B. Diwadkar, MD, Michael Albo, MD, John N. Nguyen, MD, Sharon Jakus-Walman, MD; Cleveland Clinic, Bradley Gill, MD, Matthew Barber, MD, MHS, Marie F. R. Paraiso, MD, Mark Walters, MD, Cecile Unger, MD, MPH, Beri Ridgeway, MD; and Duke University, Amie Kawasaki, MD, Nazema Y. Siddiqui, MD, Anthony G. Visco, MD, Alison C. Weidner, MD; Oregon Health Sciences University, S. Renee Edwards, MD, Mary Anna Denman, MD; Kamran Sajadi, MD; University of New Mexico, Rebecca Rogers, MD, Yuko Komesu, MD, Peter Jeppson, MD, Sara Cichowski, MD; University of Pennsylvania, Lily A. Arya, MD, Ariana L. Smith, MD, Heidi Harvie, MD; University of Pittsburgh, Michael Bonidie, MD, Christopher Chermansky, MD, Pamela Moalli, PhD, MD, Jonathan Shepherd, MD, Gary Sutkin, MD, Halina Zyczynski, MD; and RTI International: Marie Gantz, PhD.
Disclosures
Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institutes of Health Office of Research on Women’s Health. ClinicalTrials.gov Identifier:
Authors’ Potential Conflict of Interest
Uduak U. Andy: PI Grant R03-AG-053277-01, National Institute on Aging, NIH; PI Industry Grant, Pelvalon Inc.
Cindy L. Amundsen: No Conflicts of Interest
Emily Honeycutt: No Conflicts of Interest
Alayne D. Markland: No Conflicts of Interest
Gena Dunivan: PI Industry Grant, Pelvalon Inc.
Keisha Y. Dyer: PI Industry Grant, Pelvalon Inc.
Nicole B. Korbly: No Conflicts of Interest
Megan Bradley: No Conflicts of Interest
Sandip Vasavada: Consulting, Medtronic. Consulting, Allergan. Consulting, BlueWind.
Consulting, Amphora.
Donna Mazloomdoost: No Conflicts of Interest
Sonia Thomas: No Conflicts of Interest
Footnotes
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