Long-term follow-up of sacrocolpopexy mesh implants at two time intervals at least 1 year apart using 4D transperineal ultrasound

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1 Ultrasound Obstet Gynecol 2017; 49: Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: /uog Long-term follow-up of sacrocolpopexy mesh implants at two time intervals at least 1 year apart using 4D transperineal ultrasound V. H. EISENBERG*, M. STEINBERG, Z. WEINER, E. SCHIFF* and L. LOWENSTEIN *Department of Obstetrics and Gynecology, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel; Department of Obstetrics and Gynecology, Rambam Health Care Campus, Haifa, Israel KEYWORDS: 4D transperineal ultrasound; cystocele; mesh erosion; mesh folding; mesh shrinkage; pelvic organ prolapse; sacrocolpopexy mesh ABSTRACT Objective To determine, using four-dimensional (4D) transperineal ultrasound, whether the appearance, position or dimensions of sacrocolpopexy mesh implants or the degree of tissue support change in the long term. Methods Women who had undergone minimally invasive abdominal sacrocolpopexy for pelvic organ prolapse were invited for follow-up assessment at two consecutive visits at least 1 year apart. All participants completed a Pelvic Floor Distress Inventory questionnaire (PFDI-20) and underwent a pelvic examination by one examiner and had 4D ultrasound volumes obtained by a different examiner. Volumes were analyzed offline for mesh position with the woman at rest and on maximal Valsalva maneuver, and for mesh dimensions and characteristics on three-dimensional orthogonal planes and rendered views, with the operator blinded to the clinical data. Findings were compared between the two examinations. Results Thirty women attended follow-up assessment at two time points, a median of 22 (range, 12 37) months apart. The median age at the latter visit was 60 (range, 46 72) years, median body mass index was 25.9 (range, ) kg/m 2, median parity was 3 (range, 1 7) and median time from surgery to first and second visit, respectively, was 11.2 (range, 6 26) months and 33.5 (range, 14 56) months. There were no significant differences between the two time points in symptom scores, reported satisfaction from surgery, pelvic examination findings or pelvic organ descent in any compartment according to ultrasound. While mesh dimensions of anterior and posterior arms did not change significantly over time, both arms descended less on Valsalva at the second follow-up compared with at the first (13.2 ± 6.7 mm vs 21.9 ± 10.0 mm and 9.1 ± 5.3 mm vs 16.1 ± 8.1 mm, respectively, both P < 0.001). There were no mesh erosions, but folding remained a consistent finding, occurring in 80% of women in each assessment. Conclusions Characteristics of tissue support and dimensions of sacrocolpopexy mesh implants remained constant over long-term follow-up, with no mesh shrinkage or erosion. Copyright 2016 ISUOG. Published by John Wiley & Sons Ltd. INTRODUCTION Abdominal sacrocolpopexy is considered the gold standard procedure for surgical management of apical prolapse 1. Due to the relatively high complication rate and Food and Drug Administration (FDA) warnings, many gynecologists are hesitant to use permanent vaginal mesh for pelvic organ prolapse and are more likely to offer abdominal, laparoscopic or robotic sacrocolpopexy for women with apical prolapse 2. Ultrasound is the method of choice for imaging mesh implants, due to their echogenicity on two- (2D), three- (3D) and four- (4D) dimensional ultrasound 3,4 ; implants are less visible on X-ray, computed tomography and magnetic resonance imaging. In our previous study 5, we demonstrated the effectiveness of 4D transperineal ultrasound in the evaluation of mesh implants following minimally invasive abdominal sacrocolpopexy procedures, finding mesh position and dimensions to be reproducible. Mesh folding following surgery was a very common finding, which may explain the decrease in mesh dimensions observed with time, while no clinical erosion was observed. The main limitation of our previous study was that mesh dimensions were measured only once following surgery at a median of 9 (range, 1 6) months. Long-term follow-up is important to allow correlation of postoperative sonographic findings with late clinical Correspondence to: Dr V. H. Eisenberg, Sheba Medical Center, Tel Hashomer, Ramat Gan, 52621, Israel ( veredeis@bezeqint.net) Accepted: 18 February 2016 Copyright 2016 ISUOG. Published by John Wiley & Sons Ltd. ORIGINAL PAPER

2 Sacrocolpopexy mesh 399 findings, such as prolapse recurrence and mesh erosion, and to ascertain whether mesh shortening results from folding or shrinkage. Previous studies on mesh changes following placement investigated vaginal mesh procedures 6 9. In Svabik et al. s 6,7 study of vaginal repair of pelvic organ prolapse, they found mesh folding and physiological wound healing, rather than contraction, to be the dominant factors affecting changes in mesh appearance in the period immediately following surgery. These findings were supported by Dietz et al. 8, but not by Feiner et al. 9. The primary aims of the current study were to determine, using 4D transperineal ultrasound, whether the characteristics of sacrocolpopexy mesh implants change in the long term, with follow-up at two time points, at least 1 year apart, and to determine whether the degree of tissue support changes with time. Our secondary aims were to assess prolapse recurrence, as well as mesh shrinkage and folding, after surgery throughout a long follow-up period. SUBJECTS AND METHODS We invited to participate in this study all women who participated in our previous study 5 and women who were assessed subsequently. All women had undergone minimally invasive abdominal sacrocolpopexy for pelvic organ prolapse at our tertiary-care referral center between June 2009 and March All were examined at least 6 months following surgery. For the current study, we invited them for a second examination, at least 1 year following their initial examination. The Research Ethics Institutional Review Committee of Rambam Health Care Campus approved the study protocol. Signed informed consent was obtained from all participants at each assessment. All sacrocolpopexy procedures were performed by a single experienced endoscopic urogynecology-trained surgeon (L.L.). Robotic sacrocolpopexy was performed using the da Vinci Surgical System (Intuitive Surgical Inc., Sunnyvale, CA, USA), with laparoscopic procedures being performed using a similar technique. In women with uterovaginal prolapse, a supracervical hysterectomy was performed, with or without bilateral salpingo-oophorectomy, as indicated. The surgical technique is detailed in our previous publication 5. Each of the two follow-up assessments was performed using the same protocol, as described previously 5. All participants completed a validated Pelvic Floor Distress Inventory questionnaire (PFDI-20) 10, underwent a pelvic examination with Pelvic Organ Prolapse Quantification System (POP-Q) assessment 11 by a single examiner (L.L.), and had 4D ultrasound volumes obtained by a different examiner (V.H.E.), who was not involved in the surgical procedure. Clinical, demographic and surgical data, including concomitant procedures, were retrieved from patients electronic records. Patients also graded their satisfaction with the surgery on a scale from 1 to 10. Subjective prolapse recurrence was defined when the patient reported bulging in the vagina. Response to the Urinary Distress Inventory (UDI-6), the Colorectal Anal Distress Inventory (CRADI-8) and the Pelvic Organ Prolapse Distress Inventory (POPDI-6) subscales of the PFDI-20 were scored from 0 to 100 according to standard scoring, with higher scores indicating more severe symptoms 10. Clinical objective prolapse recurrence was defined as cystocele, rectocele or cervical/apical prolapse Stage 2 or above, based on the POP-Q classification 11. Pelvic floor imaging was performed with 2D/3D/4D transperineal ultrasound, using a Voluson 730 ultrasound system (GE Medical Systems, Zipf, Austria) equipped with a 4 8-MHz RAB curved-array volume transducer (acquisition angle, 85 ). Volume acquisition was performed with the patient at rest and on maximal Valsalva maneuver, as described previously by Dietz et al. 12. Care was taken to minimize probe pressure, so as not to reduce maximal descent. The ultrasound examiner (V.H.E.) was blinded to the clinical data at each of the visits. Post-processing analysis of ultrasound volume datasets was performed offline later using proprietary software 4DView (GE Medical Systems), to determine mesh parameters, measurements and dimensions, and prolapse recurrence and folding, with the examiner (V.H.E.) blinded to the clinical data and findings on pelvic examination. Volume acquisition and manipulation were performed as described previously by Eisenberg et al. 5. The lowest anterior and posterior mesh positions, relative to the symphysis pubis (SP), were determined in the midsagittal plane with the patient at rest and on maximal Valsalva maneuver. Mesh mobility was measured on Valsalva, relative to the measurement at rest, taking into account the lowest mesh position on Valsalva. Significant prolapse recurrence on ultrasound was defined as bladder descent of 10 mm below the SP on maximal Valsalva for significant cystocele, rectal descent of 15 mm below the SP for significant rectocele, and descent to the level of the SP for significant apical prolapse 12. Folding was defined as doubling over of mesh, creating two layers of mesh in one location. This is particularly seen in the extremities of the mesh where it is not anchored to native tissue. Statistical analysis was performed with SPSS for Windows version 21 (SPSS Inc., Chicago, IL, USA). Continuous parameters were checked for normality by the Kolmogorov Smirnov test. Repeatability was tested in our previous study. Paired Student s t-test and McNemar s test were used to compare between continuous and categorical values, respectively. Pearson s correlation was used to test for the effect of time from surgery and mesh dimensions. Multivariable linear regression analysis was used to define the independent factors affecting the length of the mesh arms. The relationship between time elapsed from surgery and mesh dimensions was evaluated using bivariate analysis with backward logistic regression analysis for factors affecting mesh dimensions. All tests were considered significant if P < 0.05 and were two-sided. RESULTS At the time of the second follow-up assessment, 30 women had an interval of at least 1 year after the first examination

3 400 Eisenberg et al. Table 1 Symptoms and clinical findings in 30 women assessed at two time intervals at least 1 year apart following sacrocolpopexy mesh implant for pelvic organ prolapse Parameter First assessment Second assessment P* Symptoms POPDI (0 75) 14.1 ( ) CRADI ( ) 18.2 (0 71.8) UDI (0 83.3) 21.4 (0 58.3) Satisfaction with surgery 10 (1 10) 9 (5 10) Pelvic examination POP-Q points Aa 3 ( 3 to 1) 3 ( 3 to 1) Ba 3 ( 3 to3) 2.5 ( 3 to 1) C 9.5 ( 11 to 6) 10 ( 11 to 6) D 10 ( 11 to 1) 10 ( 12 to 5) Ap 3 ( 3 to 1) 3 ( 3 to 1) Bp 3 ( 3 to 1) 3 ( 3 to 1) TVL 11 (1 to 12) 11 (8 to 12) GH 2(2to3) 2.25(1to3) PB 1 (1 to 2) 1 (1 to 2) POP-Q stage 0.5 (0 2) 1 (0 2) Clinical prolapse recurrence 2 (6.7) 4 (13.3) Anterior prolapse 2 (6.7) 4 (13.3) Posterior prolapse 1 (3.3) 3 (10.0) Data are presented as mean/median (range) or n (%). *Paired Student s t-test and McNemar s test for comparison between continuous and categorical values, respectively (all bivariate, with two-tailed significance). Scale of CRADI-8, Colorectal Anal Distress Inventory; POPDI-6, Pelvic Organ Prolapse Distress Inventory; POP-Q, Pelvic Organ Prolapse Quantification System; UDI-6, Urinary Distress Inventory. and agreed to participate in this study. All 4D volumes obtained were appropriate for evaluation such that none was excluded from analysis. The median age of participants at the last assessment was 60 (range, 46 72) years, their median body mass index was 25.9 (range, ) kg/m 2 and their median parity was 3 (range, 1 7). Three women had delivered only by Cesarean section. Previous surgery included a hysterectomy in eight women, placement of transobturator tape in one and placement of tension-free vaginal tape in one. The index surgery was laparoscopic and robotic sacrocolpopexy in 17 and 13 women, respectively. Fifteen women had additional concurrent procedures: 22 laparoscopic hysterectomies, seven tension-free vaginal tape-obturator (TVTO) (Gynecare, Johnson & Johnson) procedures, two anterior colporrhaphies and five posterior colporrhaphies. The duration of the sacrocolpopexy procedure was 175 ± 48 (range, ) min. There were no complications during or after surgery and no bleeding episodes that required transfusion. The median time from surgery to the first and second follow-up assessments was 11.2 (range, 6 26) and 33.5 (range, 14 56) months, respectively. The second assessment was performed a median of 22 (range, 12 37) months after the first. A summary of symptoms, ratings of satisfaction with surgery and clinical findings, as evaluated at each of the two follow-up assessments, is presented in Table 1. We did not find any significant differences between the two assessments with respect to symptom scores, reported satisfaction with surgery or findings from pelvic examinations. Satisfaction with surgery was high overall, with a median score of 9 on a scale of Recurrent prolapse symptoms were reported by four (13.3%) women. Clinical prolapse recurrence (POP-Q Stage 2) was observed in two (6.7%) and four (13.3%) women in the first and second assessments, respectively (Table 1), a difference that was not statistically significant. There were no apical recurrences, and none of the patients required reoperation. Mesh visualization on ultrasound was similar for both follow-up assessments for the anterior and posterior mesh arms (Figure 1). In one patient, neither mesh arm could be seen at the second assessment due to a huge echogenic rectocele. However, visualization of the sacral arm tackers was more difficult at the second assessment; these were not visualized in five and 15 women at first and second examinations, respectively, (P = 0.023), presumably because of bulky rectoceles. Mesh dimensions on ultrasound of the anterior, posterior and sacral arms are presented in Table 2. None of these dimensions changed significantly between the two assessments. Furthermore, in the second examination, shorter mesh dimensions were no longer found to correlate with greater time elapsed from surgery. There were no mesh erosions, but folding remained a consistent finding, occurring in 80% of women in each assessment, usually in the distal parts of the mesh arms. Sonographic data regarding mesh and compartment descent on Valsalva are presented in Table 3. There were no statistically significant differences between the two assessments in the descent of any compartment. There was no enterocele identified in the first assessment, while two were diagnosed in the second. The organs, as well as the mesh, tended to be higher, i.e. more caudal, in the second follow-up examination for most of the parameters; however, these differences did not

4 Sacrocolpopexy mesh 401 Figure 1 4D transperineal sonographic multiplanar view showing sacrocolpopexy mesh location (arrows) on maximal Valsalva maneuver in the same patient at two assessments 12 months apart: time point 1 (a) and time point 2 (b). Adequate mesh position can be seen. Midsagittal (A-plane), coronal (B-plane) and axial (C-plane) views are shown. Note, in this patient there is more anterior descent at the second assessment, a rare finding in this study. A, anterior; B, bladder; P, posterior; R, rectum; U, urethra. reach statistical significance. Since descent was determined by subtracting the distance during Valsalva maneuver from that with the woman at rest, this difference was greater and did reach significance: both anterior and posterior mesh arms descended significantly less Copyright 2016 ISUOG. Published by John Wiley & Sons Ltd. on Valsalva at the second examination (Table 3 and Figure 2), with a mean descent distance for the anterior arm of 21.9 ± 10.0 vs 13.2 ± 6.7 mm, and for the posterior arm of 16.1 ± 8.1 vs 9.1 ± 5.3 mm, at first and second assessments, respectively. Ultrasound Obstet Gynecol 2017; 49:

5 402 Eisenberg et al. Table 2 Mesh dimensions on three/four-dimensional ultrasound volume rendering in 30 women assessed at two time intervals at least 1 year apart following sacrocolpopexy for pelvic organ prolapse Mesh dimension First assessment Second assessment P* Anterior arm Length (cm) 3.38 ± 0.89 ( ) 3.71 ± 0.75 ( ) Maximum width (cm) 3.36 ± 0.5 ( ) 3.41 ± 0.55 ( ) Minimum width (cm) 2.24 ± 0.7 ( ) 2.51 ± 0.6 ( ) Posterior arm Length (cm) 4.3 ± 1.1 ( ) 4.29 ± 0.9 ( ) Maximum width (cm) 3.27 ± 0.5 ( ) 3.31 ± 0.6 ( ) Minimum width (cm) 2.18 ± 0.67 ( ) 2.41 ± 0.7 ( ) Sacral arm Width (cm) 1.56 ± 0.44 ( ) 1.49 ± 0.3 ( ) Data are given as mean ± SD (range). *Paired Student s t-test (bivariate, with two-tailed significance). Table 3 Mesh position and descent and compartment descent on maximal Valsalva maneuver, as seen on two-dimensional transperineal ultrasound in 30 women assessed at two time intervals at least 1 year apart following sacrocolpopexy for pelvic organ prolapse Mesh descent* First assessment Second assessment P Bladder neck on Valsalva (mm) 11.7 ± 8.8 ( 28 to 4.9) 11.4 ± 7.3 ( 28.6 to 2.7) NS Bladder neck descent (mm) 13.4 ± 9.0 (0.4 to 37.7) 12.5 ± 7.4 (0 to 26.9) NS Cystocele on Valsalva (mm) 9.9 ± 9.6 ( 23.4 to 8.6) 10.5 ± 7.1 ( 28.6 to 2.7) NS Cystocele descent (mm) 15.1 ± 10.5 (1.9 to 41.4) 13.4 ± 7.7 (0 to 26.9) NS Central/apical on Valsalva (mm) 34.5 ± 10 ( 66.3 to 20.7) 37.5 ± 10.7 ( 54.4 to 14.6) NS Central/apical descent (mm) 12.6 ± 8.2 (1 to 37) 10.1± 7.1 (0 to 24) NS Rectocele on Valsalva (mm) ( 15 to 15.5) 2.4 ± 6.6 ( 13.3 to 12.8) NS Rectocele descent (mm) 18.6 ± 10.6 (2 to 50.8) 17.4 ± 7.1 (6.7 to 31.1) NS Anterior mesh on Valsalva (mm) 3.1 ± 11.1 ( 26.1 to 15) 5.3 ± 8.4 ( 25.7 to 14.5) NS Anterior mesh descent (mm) 21.9 ± 10.0 (3.5 to 47.7) 13.2 ± 6.7 (2.6 to 31.8) <0.001 Posterior mesh on Valsalva (mm) 5.6 ± 5.9 ( 6 to 20) 2.3 ± 6.3 ( 8.7 to 13.7) Posterior mesh descent (mm) 16.1 ± 8.1 (1 to 31.9) 9.1 ± 5.3 (0.6 to 21) <0.001 Sonographic cystocele recurrence 2 (6.7) 0 (0) NS Sonographic apical recurrence 0 (0) 0 (0) NS Sonographic rectocele recurrence 1 (3.3) 1 (3.3) NS Data are given as mean ± SD (range) or n (%). *Valsalva is position on Valsalva relative to symphysis pubis (SP); descent is difference between position on Valsalva relative to SP and position at rest relative to SP; a negative sign indicates position cranial to/above point of reference. Paired Student s t-test and McNemar s test for comparison between continuous and categorical values, respectively (all bivariate, with two-tailed significance). NS, not significant. DISCUSSION In this study we carried out long-term follow-up of sacrocolpopexy mesh implants at two time points at least 1 year apart, using 4D transperineal ultrasound. We found that mesh dimensions, appearance and characteristics did not change significantly during the interval evaluated, indicating that there was no additional mesh shortening or shrinkage, though folding was a consistent finding during this follow-up period. These findings contrast with those of our previous study 5, in which the mesh dimensions were shorter at the first follow-up assessment compared with the original dimensions before placement, presumably due to folding in the immediate postoperative period. An interesting finding was the observation that both anterior and posterior mesh arms descended significantly less on Valsalva at the second assessment. The reason for this is unknown, but it is possible that fibrosis formation around both mesh arms over time may result in less descent of the vaginal wall, as fibrosis occurs at a relatively late stage in tissue repair. In our previous study 5, we demonstrated the effectiveness of transperineal ultrasound in mesh evaluation following minimally invasive abdominal sacrocolpopexy procedures. We showed that ultrasound enables reproducible measurement of mesh position and dimensions, and can be used to compare, in a prospective manner, changes in mesh dimensions over time following surgery. We believe that our current study further elucidates the process of mesh shrinkage and folding following surgery. This is the first study to assess sacrocolpopexy mesh at two separate times, at least 1 year apart. Previous studies on imaging of mesh implants involved mesh inserted vaginally; no ultrasound studies on sacrocolpopexy have been published. Dietz et al. 8 reported that mesh is apparently either folded or contracted following surgery, with dimensions being smaller than before surgery. However, unlike Feiner et al. 9,theydid not observe shrinkage. This finding may also be due to wound contraction as a component of physiological healing during the immediate period following surgery, as was described by Svabik et al. 6,7. Mesh folding seems to

6 Sacrocolpopexy mesh 403 (a) Mesh descent (mm): second examination (b) Mesh descent (mm): second examination Mesh descent (mm): first examination rather than a drawback, as it mitigates the bias that arises from the performance of different operating techniques, it precludes reaching broader conclusions. In addition, our patient population was demographically Caucasian, with no ethnic variation, so our results may not be applicable to other populations. Recurrence of clinical prolapse was observed infrequently, even at the second assessment. It is difficult to determine whether this is a result of the limited study period, selection bias of our participants or the surgical technique used. To investigate a possible correlation between clinical symptoms and ultrasound findings, a larger group of patients with prolapse recurrence is needed. We did not observe mesh erosion in any of our participants, suggesting that it may occur rarely, if at all, with this type of procedure. To determine whether erosion is a consequence of mesh folding, mesh contraction or both, a larger case series of patients with mesh erosion is needed. In conclusion, this study supports the use of 4D transperineal ultrasound in the follow-up of women after prolapse repair with minimally invasive abdominal sacrocolpopexy mesh implants. A relatively long-term follow-up at two time intervals at least 1 year apart, with the first at least 6 months after surgery, did not demonstrate further changes in mesh dimensions or mesh topography after the first assessment. Our findings showed consistency in degree of tissue support and dimensions of the sacrocolpopexy mesh over long-term follow-up, without the occurrence of mesh shrinkage or erosion. The observation of less descent of the mesh over time suggests adequate tissue repair. These new data may aid the surgeon in tailoring patient-specific treatment and surgery Mesh descent (mm): first examination Figure 2 Scatterplots comparing mesh descent on maximal Valsalva maneuver at first and second of two assessments at least 1 year apart, showing less descent at second assessment for both anterior (a) and posterior (b) sacrocolpopexy mesh arms. be a significant feature of the immediate and later postoperative period 5. While previous researchers associated vaginal mesh folding with an increased risk of mesh erosion, we did not observe any clinical erosion, in either our previous 5 or our current study. There are both drawbacks and strengths of this study. We were able to reassess only about half of our original patient population. The main reason for this relatively low compliance was technical; the study was performed on a single date, so not all patients were able to attend. Furthermore, all the procedures were performed by a single surgeon, so the outcome may be operator-dependent. While this may in fact be a strength REFERENCES 1. Nygaard IE, McCreery R, Brubaker L, Connolly A, Cundiff G, Weber AM, Zyczynski H; Pelvic Floor Disorders Network. Abdominal sacrocolpopexy: a comprehensive review. Obstet Gynecol 2004; 104: Wang LC, Al Hussein Al Awamlh B, Hu VC, Laudano MA, Davison WL, Schulster ML, Zhao F, Chughtai B, Lee RK. Trends in mesh use for pelvic organ prolapse repair from the medicare database. Urology 2015; 86: Dietz HP. Pelvic floor ultrasound in prolapse: What s in it for the surgeon? Int Urogynecol J 2011; 22: Dietz HP. Mesh in prolapse surgery: an imaging perspective. Ultrasound Obstet Gynecol 2012; 40: Eisenberg VH, Steinberg M, Weiner Z, Alcalay M, Itskovitz-Eldor J, Schiff E, Lowenstein L. Three-dimensional transperineal ultrasound for imaging of mesh implants following sacrocolpopexy. Ultrasound Obstet Gynecol 2014; 43: Svabik K, Martan A, Masata J, Elhaddad R. Vaginal mesh shrinking ultrasound assessment and quantification. Int Urogynecol J 2009; 20: S Svabík K, Martan A, Masata J, El-Haddad R, Hubka P, Pavlikova M. Ultrasound appearances after mesh implantation--evidence of mesh contraction or folding? Int Urogynecol J 2011; 22: Dietz HP, Erdmann M, Shek KL. Mesh contraction: myth or reality? Am J Obstet Gynecol 2011; 204: 173.e Feiner B, Maher C. Vaginal mesh contraction: definition, clinical presentation, and management. Obstet Gynecol 2010; 115: Barber MD, Walters MD, Bump RC. Short forms of two condition-specific quality-of-life questionnaires for women with pelvic floor disorders (PFDI-20 and PFIQ-7). Am J Obstet Gynecol 2005; 193: Bump RC, Mattiasson A, Bø K, Brubaker LP, DeLancey JO, Klarskov P, Shull BL, Smith AR. The standardization of terminology of female pelvic organ prolapse and pelvic floor dysfunction. Am J Obstet Gynecol 1996; 175: Dietz HP, Haylen BT, Broome J. Ultrasound in the quantification of female pelvic organ prolapse. Ultrasound Obstet Gynecol 2001; 18: