Perioperative Vaginal Estrogen as Adjunct to Native Tissue Vaginal Apical Prolapse Repair: A Randomized Clinical Trial

Abstract

Importance: Surgical repairs of apical/uterovaginal prolapse are commonly performed using native tissue pelvic ligaments as the point of attachment for the vaginal cuff after a hysterectomy. Clinicians may recommend vaginal estrogen in an effort to reduce prolapse recurrence, but the effects of intravaginal estrogen on surgical prolapse management are uncertain.

Objective: To compare the efficacy of perioperative vaginal estrogen vs placebo cream on prolapse recurrence following native tissue surgical prolapse repair.

Design, setting, and participants: This randomized superiority clinical trial was conducted at 3 tertiary US clinical sites (Texas, Alabama, Rhode Island). Postmenopausal women (N = 206) with bothersome anterior and apical vaginal prolapse interested in surgical repair were enrolled in urogynecology clinics between December 2016 and February 2020.

Interventions: The intervention was 1 g of conjugated estrogen cream (0.625 mg/g) or placebo, inserted vaginally nightly for 2 weeks and then twice weekly to complete at least 5 weeks of application preoperatively; this continued twice weekly for 12 months postoperatively. Participants underwent a vaginal hysterectomy (if uterus present) and standardized apical fixation (either uterosacral or sacrospinous ligament fixation).

Main outcomes and measures: The primary outcome was time to failure of prolapse repair by 12 months after surgery defined by at least 1 of the following 3 outcomes: anatomical/objective prolapse of the anterior or posterior walls beyond the hymen or the apex descending more than one-third of the vaginal length, subjective vaginal bulge symptoms, or repeated prolapse treatment. Secondary outcomes included measures of urinary and sexual function, symptoms and signs of urogenital atrophy, and adverse events.

Results: Of 206 postmenopausal women, 199 were randomized and 186 underwent surgery. The mean (SD) age of participants was 65 (6.7) years. The primary outcome was not significantly different for women receiving vaginal estrogen vs placebo through 12 months: 12-month failure incidence of 19% (n = 20) for vaginal estrogen vs 9% (n = 10) for placebo (adjusted hazard ratio, 1.97 [95% CI, 0.92-4.22]), with the anatomic recurrence component being most common, rather than vaginal bulge symptoms or prolapse repeated treatment. Masked surgeon assessment of vaginal tissue quality and estrogenization was significantly better in the vaginal estrogen group at the time of the operation. In the subset of participants with at least moderately bothersome vaginal atrophy symptoms at baseline (n = 109), the vaginal atrophy score for most bothersome symptom was significantly better at 12 months with vaginal estrogen.

Conclusions and relevance: Adjunctive perioperative vaginal estrogen application did not improve surgical success rates after native tissue transvaginal prolapse repair.

Trial registration: ClinicalTrials.gov Identifier: NCT02431897.

Figure 1.. Pelvic Organ Prolapse Quantification System Measures

Figure 2.. Flow of Participants in a Randomized Clinical Trial of Perioperative Vaginal Estrogen as Adjunct to Native Tissue Vaginal Apical Prolapse Repair

^aOther reasons for patient exclusion: planned for nonnative tissue transvaginal surgery, enrolled in an alternative research study, surgery planned in less than 5 weeks, patient inability to speak/read/write in English or Spanish, ulcerated or excoriated tissues, or requiring a coordinated procedure with other surgical teams.

Figure 3.. Failure Probability for the Composite Primary Outcome Comparing Adjunctive Use of Vaginal Estrogen With Placebo Cream After Standardized Vaginal Vault Suspension Surgery

Failure probability from survival analysis was estimated using an interval-censored proportional hazard model, controlled for clinical site and treatment assignment. Hazard ratio estimates the relative risk of failure using conjugated vaginal estrogen as compared to placebo cream. Available follow-up data were included for all participants through 12 months. At the time of analysis, 140 participants were censored prior to 12 months (67 with vaginal estrogen and 73 with placebo). The table indicates the number of patients who have not been censored or experienced a failure and who are still at risk for failure at the specified time point. The latest 12-month visit was recorded at 16.9 months after surgery; patients who had not experienced a failure prior to that time were censored for this analysis.