The Pelvic Floor Disorders Network is a multicenter group of Female Pelvic Medicine and Reconstructive Surgery researchers that is sponsored by the National Institute of Child Health and Human Development. Since it was established in 2001, there have been 148 papers published. Over the past few years, the Pelvic Floor Disorders Network has completed and published on 2 notable randomized controlled trials (RCTs) with level 1 evidence that have the ability to change clinical practice: 1) the ESTEEM study, which compared mid-urethral sling (MUS) combined with behavioral/pelvic floor therapy to MUS alone in women with moderate or severe mixed urinary incontinence (MUI), and 2) the SUPeR study, which compared vaginal hysterectomy (VH) with uterosacral ligament suspension (ULS) to sacrospinous vaginal mesh hysteropexy (VMH) in women undergoing vaginal treatment of symptomatic uterovaginal prolapse.

ESTEEM

ESTEEM was an RCT that compared MUS, either retropubic or obturator, combined with behavioral/pelvic floor therapy (1 preoperative and 5 postoperative sessions through 6 months) to MUS alone for women with MUI.¹ Each subject was ≥21 years of age and had moderate or severe stress and urgency urinary incontinence (UUI). Exclusion criteria consisted of vaginal prolapse at or beyond the hymen, planned concomitant surgery for vaginal prolapse, prior sling or current overactive bladder medication use. The primary outcome was the change in Urogenital Distress Inventory (UDI) total score (range 0–300 points, with higher scores indicating greater severity) between baseline and 12 months, with the minimal clinically important difference (MCID) set at 35 points. Secondary outcomes included changes in the 3-day bladder diary, Incontinence Impact Questionnaire and the need for additional treatment of lower urinary tract symptoms.

Of the 480 women randomized, 402 (198 in the combined group and 204 in the MUS alone group) had outcome data and were included in the primary analysis. The UDI total score in the combined group decreased from 178.0 points at baseline to 30.7 points at 12 months, and the UDI total score in the MUS alone group decreased from 176.8 points at baseline to 34.5 points at 12 months (p=0.04 between groups). Although the combined group had greater improvements in the UDI total score, the model-estimated between-group difference of 13.4 points did not meet the MCID threshold of 35 points. As for secondary outcomes, bladder diary outcomes were more favorable for the combined group, including greater mean reductions in total incontinence episodes per day (−2.4 combined vs −1.4 MUS alone, p=0.009), UUI episodes/day (−1.1 combined vs −0.4 MUS alone, p=0.02) and normalization of voids per day (74% combined vs 46% MUS alone, p <0.001). Also, the combined group had significantly greater improvements in Incontinence Impact Questionnaire scores (−132 combined vs −102 MUS alone, p=0.009). Finally, the combined group at 12 months was less likely to receive additional treatment for lower urinary tract symptoms than the MUS alone group (8.5% combined vs 15.7%, p=0.01). The time to additional treatment was greater in the combined group as shown in the Kaplan-Meier curve in figure 1 (log-rank test, p=0.008).

Figure 1. Kaplan-Meier probability curve for additional treatment in the ESTEEM study.¹

In conclusion, in women with moderate or severe MUI treatment with behavioral/pelvic floor therapy and MUS resulted in a small statistically significant difference in urinary incontinence symptoms at 12 months; however, that difference did not meet the prespecified MCID. Yet, adding behavioral/pelvic floor therapy to MUS did result in greater improvements in total and UUI episodes, urinary frequency and quality of life. Furthermore, adding behavioral/pelvic floor therapy decreased the need for additional treatment for urinary symptoms.

ESTEEM-HMS was a planned secondary analysis of ESTEEM that aimed to describe whether preoperative urinary and vaginal microbiomes were associated with surgical treatment responses at 12 months after MUS.² The authors hypothesized that the relative abundance of Lactobacillus among preoperative urinary or vaginal microbiota would be associated with surgical treatment responses. Twelve-month objective response was defined as a ≥70% reduction from baseline urinary incontinence episodes in a 3-day diary. Compared with responders (72), objective nonresponders (28) were older (58.5 vs 51.6 years) and more likely to be postmenopausal without hormone use. Although urinary microbiota were not associated with MUS outcomes, a greater abundance of baseline vaginal Lactobacillus was associated with an objective response from MUS surgery (p=0.04); however, controlling for age diminished this association. Nonresponders after an MUS had greater vaginal Prevotella (p=0.01), and this relationship remained significant after adjusting for age (p=0.01). Thus, vaginal microbiota at the time of the surgery were associated with objective treatment responses 1 year later.

Another secondary analysis of ESTEEM assessed cost-effectiveness between the 2 treatment arms.³ Effectiveness was measured in quality-adjusted life-years and reductions in urinary incontinence episodes per day. Incremental cost-effectiveness ratios of combined treatment vs MUS alone were calculated. The authors found no difference between combined treatment and MUS alone in quality-adjusted life-years (0.87 vs 0.87, p=0.90) or mean reduction in urinary incontinence episodes per day (−4.76 vs −4.50, p=0.13). Yet for women with baseline UDI irritative scores ≥50th percentile, combined treatment was cost-effective compared with MUS alone. Thus, for that subset of women with MUI who have baseline severe UUI symptoms, combined treatment was a good value compared to MUS alone.

SUPeR

The SUPeR study was an RCT of surgical treatments for uterovaginal prolapse that compared VH with ULS to VMH using Uphold LITE.⁴ Eligible participants included women ≥21 years of age requesting vaginal surgery for symptomatic uterovaginal prolapse beyond the hymen. Participants were amenorrheic for at least 1 year to allow masking, had completed childbearing and had uterine descent into the lower half of the vagina. The primary outcome was treatment failure assessed at 3 years as a composite measure in which failure could be any of the following events: 1) any retreatment for prolapse (pessary or surgery), 2) any prolapse beyond the hymen and 3) positive response to the question, “Do you usually have a bulge or something falling out that you can see or feel in your vaginal area?” This outcome was evaluated with survival models. Secondary outcomes included operative outcomes, adverse events and patient-reported outcomes (PROs), and these were evaluated with longitudinal models or contingency tables as appropriate. Specifically, the secondary outcomes included group differences in POP-Q (Pelvic Organ Prolapse Quantification system) points, the Patient Global Impression of Improvement (PGI-I) and the Prolapse Incontinence Sexual Function Questionnaire (PISQ-IR). Participants consented to remaining masked to treatment assignment for the study duration unless a medical indication for unmasking was identified. In-person POP-Q examinations by nonsurgeons and PRO assessments administered by study coordinators masked to study group were performed every 6 months.

Figure 2. Failure probability for composite primary outcome comparing VMH to VH with ULS in the SUPeR study.⁵

A total of 183 women were randomized either to VH with ULS (90) or to VMH (93), of whom 169 (97%) completed the 3-year followup. With respect to the composite primary outcome, no statistically significant difference in failure risk was demonstrated between the 2 groups at 3 years (p=0.06). Yet the model-estimated failure at 3 years was 24% for the VMH group and 36% for the VH with ULS group. Also, the mean total vaginal length was 8.5 cm in the VMH group and 7.7 cm in the VH with ULS group (p <0.001). There was no difference in the PGI-I between the 2 groups at 36 months (p=0.93). Of the 40% of women (70) who were sexually active before surgery, sexual function as measured by the PISQ-IR improved by a mean of 0.4 points after VMH vs 0.3 points after VH with ULS (p=0.69). Also, de novo dyspareunia was very low and was noted in 2 women after VMH and in 3 women after VH with ULS.

Adverse events included mesh exposure (8% after VMH vs 0% after VH with ULS), granulation tissue after 12 weeks (1% after VMH vs 11% after VH with ULS) and suture exposure after 12 weeks (3% after VMH vs 21% after VH with ULS). In the same year as the publication of this study and with the absence of data at 36 months supporting superior outcomes that were statistically significant with transvaginal mesh compared to native tissue repair, the U.S. Food and Drug Administration ordered manufacturers of transvaginal mesh for prolapse to stop selling and distributing their products.

In the 5-year SUPeR study, a total of 156 women (89%) completed the 5-year followup, of whom 81 underwent VMH and 75 underwent VH with ULS.⁵ With respect to the primary outcome at 5 years, there was now a statistically significant difference in failure risk between the 2 groups, as shown in figure 2, with fewer failures after VMH compared to VH with ULS (p=0.03). The failure rates at 5 years were 37% for VMH and 54% for VH with ULS, a difference of 18%. There were no new differences in PROs (PGI-I and PISQ-IR) at 5 years. New or worsening dyspareunia was seen in 9% of women (8 of 87) after VMH and 2% (2 of 86) after VH with ULS (p=0.10). Thus, among women with symptomatic uterovaginal prolapse undergoing vaginal surgery, VMH resulted in a lower failure rate compared to VH with ULS after 5 years. The authors concluded that, based on their results, the vaginal mesh hysteropexy procedure used in this study should be made available to patients.