Systematic review of the efficacy and safety of using mesh or grafts in surgery for uterine or vaginal vault prolapse

Transcription

1 Systematic review of the efficacy and safety of using mesh or grafts in surgery for uterine or vaginal vault prolapse Xueli Jia, Cathryn Glazener, Graham Mowatt, David Jenkinson, Cynthia Fraser, Jennifer Burr June 2008

2 INTERVENTIONAL PROCEDURES PROGRAMME NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE REVIEW BODY REPORT Title Produced by Systematic review of the efficacy and safety of using mesh or grafts in surgery for uterine or vaginal vault prolapse Health Services Research Unit University of Aberdeen 3 rd Floor, Health Sciences Building Foresterhill Aberdeen AB25 2ZD Authors Xueli Jia, Cathryn Glazener, Graham Mowatt, David Jenkinson, Cynthia Fraser, Jennifer Burr Correspondence to Xueli Jia Research Fellow Health Services Research Unit University of Aberdeen 3 rd Floor, Health Sciences Building Foresterhill AB25 2ZD Tel: (01224) Fax: (01224) x.jia@abdn.ac.uk Date completed June 2008 i

3 Home unit details The Health Services Research Unit (HSRU) is a multidisciplinary research group of about 50 people based in the University of Aberdeen. The Unit is core-funded by the Chief Scientist Office of the Scottish Government Health Directorates, and has responsibility for the following general remit: 1. To study or evaluate clinical activities with a view to improving effectiveness and efficiency in health care; 2. To work for the implementation of proven changes in clinical activities; 3. To encourage and support similar work throughout Scotland; 4. To train NHS staff in Scotland, and others, in the principles and practice of health services research in general, and health care evaluation in particular. The Unit has an established portfolio of health services research focusing on two main programmes health care assessment and delivery of care. The Unit is one of the two research groups that make up the Review Body for the National Institute for Health and Clinical Excellence Interventional Procedures Programme. The other is based at Health Services Research, University of Sheffield. Contributions of authors Xueli Jia screened the search results, contacted manufacturers, assessed studies for inclusion, undertook data abstraction and quality assessment, conducted data analysis, and drafted the review. Cathryn Glazener drafted the scope, determined outcome categories, drafted the background and methods sections of the review, and commented on drafts of the review. Graham Mowatt commented on the scope of the review, drafted letters for contacting mesh/graft manufacturers for additional information, supervised the conduct of the review, and commented on drafts of the review. David Jenkinson provided advice on statistical analysis, checked the analysis results, and commented on drafts of the review. Cynthia Fraser developed and ran the literature search strategies, obtained papers, formatted the references, and drafted sections concerning search strategies and search results. Jennifer Burr supervised the conduct of the review, and commented on drafts of the review. ii

4 Conflict of interest There is no conflict of interest. Acknowledgements We thank Chris Bain (Consultant Obstetrician and Gynaecologist, Aberdeen Royal Infirmary) for providing specialist advice and commenting on the draft of the report. The Health Services Research Unit receives a core grant from the Chief Scientist Office of the Scottish Government Health Directorates. The views expressed are those of the authors and not necessarily those of the funding bodies. Special thanks also go to James Browning (Mpathy Medical Devices Ltd.), Christine Clarke (Bard Ltd.), Hazel Edwards (American Medical Systems (UK), Ltd.), Adrian Griffin (Johnson & Johnson Medical Ltd.), William Hynes (WL Gore & Associates (UK) Ltd.), Nathalie Verin (Boston Scientific Ltd.), and Coloplast Ltd. for providing details of properties of mesh produced by their respective companies and of published studies reporting mesh efficacy and safety. iii

5 TABLE OF CONTENTS Executive summary List of abbreviations x xxiii 1 OBJECTIVE OF THE REVIEW 1 2 BACKGROUND Description of the underlying health problem Epidemiology Burden of disease Aetiology, pathology and prognosis Current management and alternative procedures The interventional procedure under review Description of the technology (mesh) Description of the interventional procedure Suitable candidates and relevant subgroups Proposed clinical indications/contraindications and putative impact of the procedure 8 3 METHODS FOR REVIEWING SAFETY AND EFFICACY Search strategy Inclusion and exclusion criteria Types of studies Types of participants Types of interventions Types of outcomes Quality assessment Data extraction Data analysis 13 4 RESULTS Number and type of included studies Included studies Ongoing studies Number and type of excluded studies; reason for exclusion Quality of available evidence Sacrocolpopexy (mesh) 24 iv

6 4.4.1 Sacrocolpopexy for uterine prolapse repair (mesh) Efficacy Safety Operation time and hospital stay Sacrocolpopexy for vault prolapse repair (mesh) Efficacy Safety Operation time and hospital stay Sacrocolpopexy for uterine and/or prolapse repair (not reported separately) 47 (mesh) Efficacy Safety Operation time and hospital stay Summary of the evidence for and against sacrocolpopexy Infracoccygeal sacropexy (mesh) Infracoccygeal sacropexy for uterine prolapse repair (mesh) Efficacy Safety Operation time and hospital stay Infracoccygeal sacropexy for vault prolapse repair (mesh) Efficacy Safety Operation time and hospital stay Infracoccygeal sacropexy for uterine and/or vault prolapse repair (not reported 72 separately) (mesh) Efficacy Safety Operation time and hospital stay Summary of the evidence for and against infracoccygeal sacropexy Uterine suspension sling (mesh) Uterine suspension sling for uterine prolapse repair (mesh) Efficacy Safety Operation time and hospital stay Summary of the evidence for and against uterine suspension sling Other mesh techniques or a mixture of mesh techniques Uterine and/or vault repair (not reported separately) (mesh) 91 v

7 Efficacy Safety Operation time and hospital stay Summary of the evidence for and against other mesh techniques or a mixture of techniques that use mesh 93 5 DISCUSSION Summary of main findings Sacrocolpopexy Infracoccygeal sacropexy Uterine suspension sling Other mesh techniques or a mixture of mesh techniques Assumptions, limitations, and uncertainties 96 6 CONCLUSIONS Implications for the NHS Implications for future research 99 7 REFERENCE LIST 101 vi

8 LIST OF TABLES Table 1 Classification of uterine or vault prolapse stages 3 Table 2 The different mesh types in pelvic organ prolapse repair 5 Table 3 Search results 16 Table 4 Papers selected for full assessment 17 Table 5 Number of studies and reports included 18 Table 6 Characteristics of women included and treatment details 19 Table 7 Characteristics of ongoing studies 21 Table 8 Sacrocolpopexy: summary of patient characteristics and surgical procedures 25 Table 9 Sacrocolpopexy, efficacy: summary of median (range) event rates 31 Table 10 Sacrocolpopexy, safety: summary of median (range) event rates 33 Table 11 Infracoccygeal sacropexy: summary of patient characteristics and surgical 62 procedures Table 12 Infracoccygeal sacropexy, efficacy: summary of median (range) event rates 64 Table 13 Infracoccygeal sacropexy, safety: summary of median (range) event rates 66 Table 14 Uterine suspension sling: summary of patient characteristics and surgical 79 procedures Table 15 Uterine suspension sling, efficacy: summary of median (range) event rates 80 Table 16 Uterine suspension sling, safety: summary of median rates (range) 81 Table 17 Other mesh techniques or a mixture of mesh techniques (not reported 88 separately): summary of patient characteristics and surgical procedures Table 18 Other mesh techniques or a mixture of mesh techniques (not reported 89 separately), efficacy: summary of median (range) event rates Table 19 Other mesh techniques or a mixture of mesh techniques, safety: summary of median rates (range) 90 vii

9 LIST OF FIGURES Figure 1 Summary of quality assessment of the RCTs (full text, n=5) 22 Figure 2 Summary of quality assessment of the non-randomised comparative studies 23 (n=17) Figure 3 Summary of quality assessment of the case series (n=29) 23 Figure 4 Sacrocolpopexy, vault prolapse repair, efficacy, subjective failure 39 Figure 5 Sacrocolpopexy, vault prolapse repair, safety, blood loss requiring transfusion 41 Figure 6 Sacrocolpopexy, vault prolapse repair, safety, damage to surrounding organs 42 Figure 7 Sacrocolpopexy, vault prolapse repair, safety, infection 44 Figure 8 Sacrocolpopexy, uterine or vault prolapse repair, efficacy, subjective failure 47 Figure 9 Sacrocolpopexy, uterine or vault prolapse repair, efficacy, objective failure 48 Figure 10 Sacrocolpopexy, uterine or vault prolapse repair, safety, number of women 50 requiring blood transfusion Figure 11 Sacrocolpopexy, uterine or vault prolapse repair, safety, damage to 51 surrounding organs Figure 12 Sacrocolpopexy, uterine or vault prolapse repair, safety, de novo urinary 53 symptoms Figure 13 Sacrocolpopexy, uterine or vault prolapse repair, safety, infection 54 Figure 14 Sacrocolpopexy, uterine or vault prolapse repair, safety, other serious adverse 55 effects not otherwise specified Figure 15 Sacrocolpopexy, uterine or vault prolapse repair, safety, other adverse effects 56 not otherwise specified Figure 16 Ranges of event rates across studies: sacrocolpopexy, efficacy 58 Figure 17 Ranges of event rates across studies: sacrocolpopexy, safety 59 Figure 18 Ranges of event rates across studies: infracoccygeal sacropexy, efficacy 76 Figure 19 Ranges of event rates across studies: infracoccygeal sacropexy, safety 76 Figure 20 Ranges of event rates across studies: uterine suspension sling, efficacy 86 Figure 21 Ranges of event rates across studies: uterine suspension sling, safety 86 Figure 22 Ranges of event rates across studies: other mesh techniques or a mixture of 94 mesh techniques, efficacy, efficacy Figure 23 Ranges of event rates across studies: other mesh techniques or a mixture of mesh techniques, efficacy, safety 94 viii

10 LIST OF APPENDICES Appendix 1 Search strategies 108 Appendix 2 Checklist of quality assessment of randomised controlled trials 112 Appendix 3 Checklist of quality assessment of non-randomised studies 113 Appendix 4 Included studies 114 Appendix 5 Characteristics of the included studies by mesh techniques 119 Appendix 6 Excluded studies; reasons for exclusion 160 Appendix 7 Detailed quality assessment results for included studies: randomised 169 controlled trials (full-text), n=5 Appendix 8 Detailed quality assessment results for non-randomised comparative studies, 170 n=17 Appendix 9 Detailed quality assessment results for case series, n= Appendix 10 Summary of outcomes: sacrocolpopexy, efficacy 173 Appendix 11 Summary of outcomes: sacrocolpopexy, safety 177 Appendix 12 Summary of outcomes: sacrocolpopexy, operation time and hospital stay 191 Appendix 13 Summary of outcomes: infracoccygeal sacropexy, efficacy 193 Appendix 14 Summary of outcomes: infracoccygeal sacropexy, safety 195 Appendix 15 Summary of outcomes: infracoccygeal sacropexy, operation time and 199 hospital stay Appendix 16 Summary of outcomes: uterine suspension sling, efficacy 200 Appendix 17 Summary of outcomes: uterine suspension sling, safety 201 Appendix 18 Summary of outcomes: uterine suspension sling, operation time and hospital 203 stay Appendix 19 Summary of outcomes: other mesh techniques or a mixture of mesh 204 techniques, efficacy Appendix 20 Summary of outcomes: other mesh techniques or a mixture of mesh 205 techniques, safety Appendix 21 Summary of outcomes: other mesh techniques or a mixture of mesh techniques, operation time and hospital stay 207 ix

11 EXECUTIVE SUMMARY Background Pelvic organ prolapse (POP) is a protrusion of one or more pelvic organs (bladder, rectum, uterus, vaginal vault, bowel) through vaginal fascia into the vagina and the downward displacement ( prolapse ) of the associated vaginal wall from its normal location to or outside the vaginal opening. POP affects a woman s quality of life by its local physical effects (pressure, bulging, heaviness or discomfort) or its effect on urinary, bowel or sexual function. POP can be classified according to the compartment affected as: anterior vaginal wall prolapse (urethrocele, cystocele); posterior vaginal wall prolapse (rectocele, enterocele); prolapse of the uterus; and prolapse of the vaginal vault (which can only occur after prior hysterectomy). A woman can present with prolapse of one or more of these sites. The present review focuses on uterine and vaginal vault pelvic organ prolapse. Current treatment options for upper vaginal prolapse include pelvic floor muscle training (PFMT), use of pessaries (mechanical devices such as rings or shelves), and surgery. Surgical repairs which necessarily involve the use of mesh include: Sacrocolpopexy; Infracoccygeal sacropexy (also known as Posterior IntraVaginal Slingplasty, IVS); Uterine suspension sling (including sacrohysteropexy); and Other mesh techniques such as sacrocolpoperineopexy. Surgeries which do not involve mesh include: Hysterectomy; Cervical amputation (often called Manchester repair); and Uterine/vault suspension (without sling). There are numerous types of mesh materials available, which vary according to type of material, structure, and physical properties such as absorbability. There are no existing classification systems for mesh. For the purposes of this review we have defined four classes of mesh: absorbable synthetic mesh, biological graft, combination of absorbable and non-absorbable mesh (termed combined hereafter), and non-absorbable synthetic mesh. Objective To systematically review the evidence for the efficacy and safety of mesh in surgery for uterine or vaginal vault pelvic organ prolapse. The specific objectives were to: x

12 (a) (b) (c) (d) Report efficacy and safety of procedures using mesh (each type); Compare efficacy and safety between procedures using mesh and no mesh; Compare efficacy and safety of different procedures that use mesh; and Compare efficacy and safety of different types of mesh for the same procedure. Methods We searched electronic databases, conference proceedings and relevant websites, contacted experts in the field and scanned bibliographies of retrieved papers. Extensive highly sensitive electronic searches were conducted to identify reports (both full-text papers and conference abstracts) of published and ongoing studies on the safety and efficacy of mesh used in the repair of pelvic organ prolapse. Searches were restricted to publications from 1980 onwards and to those published in the English language. Conference proceedings from five major urogynaecological organisations were searched from 2005 onwards for additional reports of randomised controlled trials (RCTs). Reference lists of all included studies were scanned to identify additional potentially relevant studies. Eleven manufacturers were identified and contacted for information on properties of mesh produced and for any studies related to mesh. We considered the following types of studies: RCTs (full-text publication) RCTs (conference abstracts from 2005 onwards) Non-randomised comparative studies (full-text publication) Case series (full-text publication). As the volume of literature for sacrocolpopexy was substantial, only case series with a sample size of at least 100 women were included. There was no sample size restriction placed on case series that reported uterine suspension sling or infracoccygeal sacropexy as the volume of literature for these techniques was very limited. Population-based registry reports that prospectively collected audit data on the use of mesh for uterine or vault prolapse. We did not search for studies that only reported procedures without mesh. One reviewer screened titles/abstracts and undertook data extraction. The same reviewer assessed the quality of the included studies using one of two separate checklists according to study design. Both checklists were developed through the Review Body for Interventional Procedures. xi

13 For each mesh technique, data analysis was conducted for three subgroups of women according to the type of prolapse being repaired: Uterine prolapse; Vault prolapse; and Uterine or vault prolapse (not reported separately). Meta-analyses of full-text RCTs, RCTs available as conference abstracts, and nonrandomised comparative studies, using Cochrane Collaboration Review Manager (RevMan 4.2) software, were conducted to directly compare the efficacy and safety of procedures using mesh versus procedures without mesh, and between different techniques that used mesh. Crude event rates for each of the intervention categories were tabulated for each outcome by study design (RCTs, non-randomised comparative studies, case series/registry) to illustrate the potential heterogeneity of event rates across different study designs. The median and range of the event rates for each study design were also reported, to express the variability of the data within each study design. Results From the initial 655 publications identified by the search strategy, 54 studies (reported in 60 publications) were included, of which 5 were full-text RCTs, 3 were RCTs available as conference abstracts, 17 were non-randomised comparative studies, and 29 were case series. Seven manufacturers provided data on mesh properties or related studies, all of which had already been identified by our searches. The table on the following page shows the 54 included studies by type of prolapse repair and by study design. The studies took place during the period in 16 countries. Overall, 7054 women were treated in total, of whom 4456 were treated with sacrocolpopexy, 976 with infracoccygeal sacropexy, 159 with uterine suspension sling, 520 with other mesh techniques (sacrocolpoperineopexy) or a mixture of the above mesh techniques, and 943 with no-mesh techniques. Across studies, the average age of the women was 61 years. Women who were treated with uterine suspension sling were younger (average age 37 years) than those treated with other techniques. Only six studies provided information on whether the procedures were primary or secondary. The average follow up was about two years for sacrocolpopexy, one year for infracoccygeal sacropexy, and three years for uterine suspension sling. xii

14 Number of studies and reports included Study design Studies Sacrocolpopexy Infracoccygeal sacropexy Uterine suspension sling Other mesh techniques or a mixture of mesh techniques Uterine repair RCTs (full text) RCTs (conference abstracts) Non-randomised comparative studies Case series with sample size Case series with sample size < Subtotal Vault repair RCTs (full text) RCTs (conference abstracts) Non-randomised comparative studies Case series with sample size Case series with sample size < Subtotal Uterine or vault repair RCTs (full text) RCTs (conference abstracts) Non-randomised comparative studies Case series with sample size Case series with sample size < Subtotal Total 54* *5 studies double counted: Three studies reported different types of prolapse repair separately. Two studies reported different mesh techniques separately. The methodological quality of the full-text studies only was assessed. For the five RCTs, all studies reported methods of randomisation. Treatment allocation was adequately concealed in three studies. All follow-up periods were one year or more. All studies used intention-totreat analysis in that women were analysed according to the group to which they were randomised. Among the 17 non-randomised comparative studies, only three studies collected data prospectively. Mean follow up was more than one year in 13 studies. The loss to follow up rates ranged from 4% to 55%. Most studies did not report the characteristics of women who were lost to follow up. For the 29 case series, 12 studies collected data xiii

15 prospectively. Mean follow up was one year or more in 25 studies. In 12 studies reporting loss to follow up, rates varied from 2% to 74% with follow up ranging from 2 to 66 months. Nine ongoing studies were also identified. Seven of these were RCTs. For studies reporting a follow-up period, all follow-up periods were one year or more. These studies are due to be completed between 2008 and Summary of evidence: sacrocolpopexy (mesh) Thirty two studies (4 full-text RCTs, 1 RCT available as a conference abstract, 15 nonrandomised comparative studies, and 12 case series with a sample size over 100) involving a total of 4456 women provided data on sacrocolpopexy. The average follow up was around two years across studies. Figures A and B show the ranges of event rates for efficacy and safety respectively for sacrocolpopexy, together with the number of women involved for each outcome. Efficacy Figure A Ranges of event rates across studies: sacrocolpopexy, efficacy 50 NA, 38/209, 94/429 NA, 4/9, 25/60 Event rates (%) /62, 8/306, 12/686 NA, 10/32, 3/193 NA, NA, 43/169 0/39, 15/60, 17/352 NA, NA, 7/54 0 Subjective failure Objective failure New prolapse at other sites Reoperation for prolapse Persistent urinary symptoms Persistent bowel symptoms Persistent sexual problems Uterine prolapse repair Vault prolapse repair Uterine and/or vault prolapse repair Notes: 1. Where only one study reported the outcome, a single horizontal bar reports its event rate; where more than one study reported the outcome, the range of the event rates across all studies is shown by a vertical bar. 2. The numbers in the figures are the number of events which occurred across all studies divided by the total number of women who received the treatment. 3. NA: no studies reported data for that outcome. xiv

16 The objective failure rates ranged from 0% to 6.1% in 11 studies involving 1054 women, while the subjective failure rates ranged from 3.3% to 31% in 9 studies involving 638 women. In 4 studies involving 451 women, rates for those needing a further operation for recurrent or de novo prolapse ranged from 0% to 14.4%. Estimates for other outcomes were based on single studies only (shown as a single horizontal bar in the figure). Meta-analysis was carried out to compare subjective failure and objective failure in sacrocolpopexy versus sacrospinous colpopexy (no mesh). There was no evidence of a statistically significant difference in either outcome between the operations. Safety Figure B Ranges of event rates across studies: sacrocolpopexy, safety 70 3/39, 55/621, 158/ Event rates (%) /39, 5/473, 57/ /267, 45/969, 53/1686 NA, 2/22, 18/272 NA, NA, 12/87 30 NA, 14/427, 32/1296 7/143, 18/610, 47/1321 NA, NA, 2/ /62, 10/299, 68/1390 2/62, 30/309, 77/ Blood transfusion Organ damage Mesh erosion Operation for erosion New urinary symptoms New bowel symptoms New sexual symptoms Infection Other serious adverse effects Other adverse effects Uterine prolapse repair Vault prolapse repair Uterine and/or vault prolapse repair (not separated) Notes: 1. Where only one study reported the outcome, a single horizontal bar reports its event rate; where more than one study reported the outcome, the range of the event rates across all studies is shown by a vertical bar. 2. The numbers in the figures are the number of events which occurred across all studies divided by the total number of women who received the treatment. 3. NA: no studies reported data for that outcome. The proportion of women who required a blood transfusion for sacrocolpopexy ranged from 0% to 17% (19 studies, n=2080). The range for women with organ damage varied from 0% to 7.9% (15 studies, n=1723). Mesh erosion occurred in 0% to 12% of women (27 studies, n=2922), of whom 0% to 11% required an operation for mesh erosion (17 studies, n=2074). New urinary symptoms in women who did not have these symptoms at baseline occurred in 3.8% to 9.2% (4 studies, n=294). The estimate for new bowel symptoms (1.1%, 2/178) was based on a single study, and the estimate for new sexual symptoms (range 9.1% to 15%, xv

17 n=87) was based on two small studies. The range of infection was wide (0.8% to 68%, 17 studies, n=1391). The estimates for other serious adverse effects (not otherwise specified) ranged from 0% to 16% (21 studies, n=2059). The events that occurred included bowel obstruction, ureteral obstruction, wound dehiscence, incisional hernia, vesico-cutaneous fistula, deep vein thrombosis, pulmonary embolism, pneumonia, myocardial infarction, congestive heart failure, arrhythmia, and left ventricular failure. The proportion of women with other adverse effects (not otherwise specified) ranged from 0% to 16% (17 studies, n=1751). The events that occurred included voiding dysfunction, haematoma, persistent vaginal discharge, vaginal bleeding, phlebitis, wound complications, gastrointestinal complications, e.g. nausea, emesis, bloating or subacute intestinal obstruction, sciatica, and buttock pain. Meta-analysis was carried out to compare blood transfusion, damage to surrounding organs, infection, new urinary symptoms and other adverse effects (not otherwise specified) between sacrocolpopexy (mesh) and sacrospinous colpopexy (no mesh). There was no evidence of a difference in any of these outcomes between the operations. Meta-analysis was also conducted for other serious adverse effects (not otherwise specified): in four nonrandomised comparative studies, sacrocolpopexy (mesh) was associated with significantly more adverse events than sacrospinous colpopexy (no mesh) (pooled RR 6.94, 95% CI 1.02 to 26.38). Operation time and hospital stay The average operation time varied from 89 minutes to 267 minutes (based on 15 studies), whereas average hospital stay after sacrocolpopexy ranged from 1 to 7 days. The majority of the studies reported stays of 3 to 5 days (11/14 studies). Summary of evidence: infracoccygeal sacropexy (mesh) Fourteen studies (2 RCTs available as conference abstracts, 1 non-randomised comparative study, 2 case series with a sample size 100, and 9 case series with a sample size <100) involving 976 women provided data on infracoccygeal sacropexy. The average follow up was around one year across studies. The ranges of event rates for safety and efficacy, together with the number of women involved are shown in Figures C and D respectively. Meta-analysis was not possible because no studies used the same comparator. xvi

18 Figure C Ranges of event rates across studies: infracoccygeal sacropexy, efficacy 60 NA, NA, 3/7 50 0/10, 14/151, 10/127 Event rates (%) NA, 8/91, 28/171 2/89, 4/60, 18/253 NA, NA, 3/63 NA, NA, 5/ Subjective failure Objective failure New prolapse at other sites Reoperation for prolapse Persistent urinary symptoms Persistent bowel symptoms (no data) Persistent sexual problems Uterine prolapse repair Vault prolapse repair Uterine and/or vault prolapse repair (not separated) Figure D Ranges of event rates across studies: infracoccygeal sacropexy, safety Event rates (%) 10/79, 24/265, 33/ /10, 3/203, 1/492 10/79, 4/75, 32/ /10, 0/188, 1/185 0/55, NA, 0/27 NA, 6/183, 16/515 NA, 0/183, 11/ Blood transfusion Organ damage Mesh erosion Operation for erosion New urinary symptoms New bowel symptoms (no data) New sexual symptoms (no data) Infection Other serious adverse effects (no data) Other adverse effects Uterine prolapse repair Vault prolapse repair Uterine and/or vault prolapse repair (not separated) Notes: 1. Where only one study reported the outcome, a single horizontal bar reports its event rate; where more than one study reported the outcome, the range of the event rates across all studies is shown by a vertical bar. 2. The numbers in the figures are the number of events which occurred across all studies divided by the total number of women who received the treatment. 3. NA: no studies reported data for that outcome. The proportion of women with subjective failure ranged from 2.3% to 21% (n=262, 3 studies) after infracoccygeal sacropexy, whereas the range for objective failure was from 0% to 25% (9 studies, n=402). In 3 studies (n=288), 0% to 30% of women required re-operation for prolapse. Estimates for other outcomes were based on single studies including small numbers of women. xvii

19 The need for blood transfusion ranged from 0% to 2.3% (7 studies, n=383). The proportion of women with organ damage ranged from 0% to 2.7% (9 studies, n=684). The occurrence of mesh erosion ranged from 0% to 21% (11 studies, n=889), and 1.5% to 17% women needed an operation for mesh erosion (6 studies, n=678). Little evidence was available for new urinary symptoms, bowel symptoms, and sexual symptoms in women who did not have these symptoms at baseline. Infection ranged from 0% to 9.0% (8 studies, n=698). Other adverse effects (not otherwise specified) ranged from 0% to 10% (8 studies, n=675). The events that occurred included haematomas, urine retention, pain at skin incision, and vaginal pressure. Average operation times ranged from 10 minutes to 149 minutes with the majority of the studies (8/11) reporting operation time of less than one hour. Average hospital stays ranged from less than 24 hours to 5 days with the majority of the studies (7/11) reporting two days or less. Summary of evidence: uterine suspension sling (mesh) Six studies (one full-text RCT, one non-randomised comparative study, and four case series) involving 239 women reported uterine suspension sling, of which five studies involving 219 women reported sacrohysteropexy. The average follow up across the six studies was around three years across studies. Figure E (efficacy) and Figure F (safety) show the range of events across studies, together with the number of women involved. Meta-analysis was not possible because the studies used different comparators. The range for women reporting subjective failure was wide (0% to 39%, 3 studies, n=91). Women judged to have objective failure ranged from 0% to 7.7% (5 studies, n=136). The proportion of women who required a re-operation for prolapse ranged from 0% to 22% (3 studies, n=107). Little evidence was available for estimating other efficacy outcomes or any of the safety outcomes. The average operation time for uterine suspension sling ranged from 97 to 115 minutes (based on 3 studies). In one study, the average hospital stay was 7 days. xviii

20 Figure E Ranges of event rates across studies: uterine suspension sling, efficacy Event rates (%) /91 4/136 10/107 3/19 1/5 3/27 0 Subjective failure Objective failure New prolapse at other sites (no data) Reoperation for prolapse Persistent urinary symptoms Persistent bowel symptoms Persistent sexual problems Uterine prolapse repair Figure F Ranges of event rates across studies: uterine suspension sling, safety 50 1/2 Event rates (%) /77 0/91 1/66 1/66 0/25 10/101 5/101 20/126 0 Blood transfusion Organ damage Mesh erosion Operation for erosion New urinary symptoms (no data) New bowel symptoms New sexual symptoms Infection Other serious adverse effects (no data) Other adverse effects Uterine prolapse repair Notes: 1. Where only one study reported the outcome, a single horizontal bar reports its event rate; where more than one study reported the outcome, the range of the event rates across all studies is shown by a vertical bar. 2. The numbers in the figures are the number of events which occurred across all studies divided by the total number of women who received the treatment. Summary of evidence: other mesh techniques or a mixture of mesh techniques Four studies (two non-randomised comparative studies and two case series) involving 520 women reported sacrocolpoperineopexy, or a mixture of techniques that used mesh but did not report them separately. None of the studies reported uterine and vault prolapse repair separately. Figure G (efficacy) and Figure H (safety) show the range of event rates across studies, together with the number of women involved. xix

21 Figure G Ranges of event rates across studies: other mesh techniques or a mixture of mesh techniques, efficacy 50 Event rates (%) /169 1/169 6/297 0 Subjective failure Objective failure New prolapse at other sites (no data) Reoperation for prolapse Persistent urinary symptoms (no data) Persistent bowel symptoms (no data) Persistent sexual problems (no data) Uterine and/or vault prolapse repair (not separated) Figure H Ranges of event rates across studies: other mesh techniques or a mixture of mesh techniques, safety Event rates (%) /45 11/342 27/415 14/415 4/9 18/173 9/342 12/342 0 Blood transfusion Organ damage Mesh erosion Operation for erosion New urinary symptoms New bowel symptoms (no data) New sexual symptoms (no data) Infection Other serious adverse effects (no data) Other adverse effects Uterine and/or vault prolapse repair (not separated) Notes: 1. Where only one study reported the outcome, a single horizontal bar reports its event rate; where more than one study reported the outcome, the range of the event rates across all studies is shown by a vertical bar. 2. The numbers in the figures are the number of events which occurred across all studies divided by the total number of women who received the treatment. The proportion of women who needed a re-operation for prolapse ranged from 0% to 4.7% (2 studies, n=297). Organ damage, mesh erosion, and operation for mesh erosion all occurred in less than 10% of women. In one study, the average operation time was 192 minutes, and in two studies, the average hospital stay ranged from 3 to 7 days. xx

22 Conclusions The review indicated that although sacrocolpopexy (mesh) is associated with an objective failure ranging from 0% to 6% at an average follow up of two years, the incidence of subjective failure (range 3% to 31%) and need for a further prolapse operation (range 2% to 14%) may be higher. There were risks from adverse effects such as blood transfusion (range 0% to 17%), infection (range 1% to 69%), mesh erosion (range 4% to 12%) and the need for a further operation for mesh erosion (range 1% to 11%). There was no evidence of a statistically significant difference between sacrocolpopexy (mesh) and sacrospinous colpopexy (no mesh) in subjective failure and objective failure but the numbers were small. For infracoccygeal sacropexy (mesh), subjective failure rates ranged from 2.3% to 21% at an average follow up of one year, objective failure 0% to 25%, mesh erosion 0% to 21%, and operation for mesh erosion 1.5% to 17%. Operation times (the majority were less than one hour) and hospital stays (the majority were two days or less) were relatively short compared with other operations that use mesh. For uterine suspension sling, the objective failure rates ranged from 0% to 7.7% at an average follow up of three years, whereas subjective failure ranged from 0% to 39%. However, little evidence was available for safety outcomes. Sacrocolpoperineopexy was another mesh technique that had been used, but there was little evidence available for assessing the efficacy or safety of this technique. It was not possible to compare the efficacy and safety between procedures using mesh (each type) and no mesh, between different procedures that use mesh, or between different types of mesh for the same procedure, because very few studies used the same comparator. It was also not possible to compare differences in efficacy and safety for women having primary versus recurrent prolapse repairs. Of the 54 included studies, only two exclusively reported on women having primary repairs, and the remainder did not report outcomes for these subgroups separately. Implications for future research The RCTs currently available only as conference abstracts may be available as full-text studies in the future. Full-text papers of the conference abstracts (RCTs published before 2005 and all non-randomised comparative studies and case series) that were excluded may xxi

23 also be available in the future. The expected completion times of the nine on-going studies (seven RCTs, one registry, and one case series) range from 2008 to A further review incorporating these studies may be informative. Subjective symptoms (including quality of life related to prolapse) are important to women. Identifying the need for further operations for recurrent prolapse and adverse effects requires long term follow up over many years. The RCTs included in the present review were relatively small. Therefore, high quality longterm RCTs, with adequate power to detect clinically meaningful differences, with validated patient-reported outcome measures, primarily comparing the failure rate between mesh and no-mesh techniques, and between different types of mesh techniques and between different types of mesh, taking account of the outcomes important to women, are required to determine the comparative efficacy of mesh techniques and their optimal place in clinical practice. In addition, prospective data collection should be considered in which the operative and clinical details of women undergoing prolapse surgery with mesh can be recorded so that sufficient efficacy and safety data can be gathered to guide the use of mesh or grafts in the future. In particular, long term outcomes need to be considered as it may be many years before a prolapse recurrence becomes symptomatic. xxii

24 LIST OF ABBREVIATIONS BMI CENTRAL CI GATE PFMT pivs POP POP-Q RCOG RCT ReBIP RR SCI SMD Body Mass Index Cochrane Central Register of Controlled Trials Confidence interval Generic Appraisal Tool for Epidemiology Pelvic Floor Muscle Training Posterior intravaginal slingplasty (= infracoccygeal sacropexy) Pelvic Organ Prolapse Pelvic Organ Prolapse Quantification System Royal College of Obstetricians and Gynaecologists Randomised Controlled Trial Review Body for Interventional Procedures Relative risk Science Citation Index Standardised Mean Difference xxiii

25 1 OBJECTIVE OF THE REVIEW The aim of this study was to systematically review the evidence for the efficacy and safety of mesh in surgery for uterine or vaginal vault pelvic organ prolapse. The specific objectives were to: (a) Report efficacy and safety of procedures using mesh (each type); (b) Compare efficacy and safety between procedures using mesh and no mesh; (c) Compare efficacy and safety of different procedures that use mesh; and (d) Compare efficacy and safety of different types of mesh for the same procedure. 1

26 2 BACKGROUND 2.1 Description of the underlying health problem Epidemiology Pelvic organ prolapse (POP) is a protrusion of one or more pelvic organs (bladder, rectum, uterus, vaginal vault, bowel) through vaginal fascia into the vagina and the downward displacement ( prolapse ) of the associated vaginal wall from its normal location to or outside the vaginal opening. 1 POP can be classified, according to the compartment affected, as: 1. Anterior vaginal wall prolapse (urethrocele, cystocele), 2. Posterior vaginal wall prolapse (rectocele, enterocele), 3. Prolapse of the uterus (cervix if the remaining part of the uterus was removed previously), 4. Prolapse of the vaginal vault (which can only occur after hysterectomy). A woman can present with prolapse of one or more of these sites. The present review focuses on uterine and vault prolapse. We focused on anterior and/or posterior vaginal wall prolapse in a previous review. 2 In the UK, around 48,500 women undergo hysterectomy each year, of which about 15,000 are vaginal procedures, and 8000 of these are for vaginal prolapse. 3 Approximately 2,800 women will require further surgery at a later time for vault prolapse (35% of the women who have a vaginal hysterectomy for prolapse). 4 Uterine or vault prolapse has a major impact on quality of life and on the use of NHS services Burden of disease POP affects a woman s quality of life by its local physical effects (pressure, bulging, heaviness or discomfort) or its effect on urinary, bowel or sexual function. Urinary symptoms include both symptoms related to incontinence or urinary retention (incomplete emptying), bowel symptoms include constipation or faecal incontinence, and symptoms of sexual dysfunction include dyspareunia (pain during intercourse) or avoiding intercourse due to embarrassment. There is no symptom which is specific to uterine or vault prolapse alone. Women may present with any or none of these symptoms. 2

27 2.1.3 Aetiology, pathology and prognosis Vaginal delivery is the greatest risk factor for POP. Neuromuscular injury 6,7 and mechanical injury during labour (for example damage to the fascial connective tissue or pelvic floor muscles) 8 has been identified as the main reason for POP. Nulliparous women with connective tissue disorders (e.g., Ehlers-Danlos or Marfan s syndrome) or women with spina bifida and poorly functioning pelvic floor muscles are susceptible to POP and can present with advanced POP at a young age. A number of objective clinical classification or grading systems are in use. The simplest include the ordinal grading of prolapse as first, second and third degree such as the Baden- Walker 9 and Beecham 10 classification systems. In an attempt to improve the accuracy of prolapse assessment, the International Continence Society has devised the POP quantification (POP-Q) System with proven inter-observer and intra-observer reliability. 11,12 It allows for a standardised, accurate objective description of physical findings, and provides a means of quantification of change in individual patients, and comparison between series of patients. The staging depends on the position of the leading edge of the prolapse: the lowest or worst level of maximum protrusion is used. The Baden-Walker and POP-Q classifications are summarised in Table 1. Table 1 Classification of uterine or vault prolapse stages Baden-Walker classification system POP-Q system - - Stage 0 No descent of pelvic structures during straining First degree The cervix or vaginal apex descends halfway to the hymen. Stage I The leading edge of the prolapse is >1 cm above the hymenal ring. Second degree The cervix or vaginal apex extends to the hymen or over the perineal body. Stage II The leading edge of the prolapse extends from 1 cm above the hymen to 1 cm below the hymenal ring. Third degree The cervix and corpus uteri extend beyond the hymen or the vaginal vault is everted and protrudes beyond the hymen. Stage III The leading edge of the prolapse extends to between 2 and 3 cm below the hymenal ring, but there is not complete vaginal eversion. - - Stage IV The vagina is completely everted. 3

28 2.2 Current management and alternative procedures Current treatment options for uterine or vault prolapse include pelvic floor muscle training (PFMT), use of pessaries (mechanical devices such as rings or shelves), and surgery. 13 Surgery is usually considered when the prolapse is more severe and is causing symptoms or because conservative treatment or a pessary do not work or are unacceptable to patients. Recent developments to try to reduce the need for re-operation have been the development of new operations such as sacrocolpopexy and infracoccygeal sacropexy which involves the use of mesh. 2.3 The interventional procedure under review Description of the technology (mesh) A variety of types of mesh are used for POP repair 2. Table 2 summarises the most common types of mesh according to their absorbability, material, and structure. Absorbable synthetic mesh (polyglactin) loses 75% of its strength after 21 days. Its purpose is to act as a supportive material for the formation of granulation tissue, and therefore is not suitable for operations which depend on the mesh to form a permanent bridge between two anatomical structures e.g. ligament, fascia, and organs. Biological grafts show a spectrum of absorbability, and are eventually absorbed by the host tissues to a greater or lesser degree. Some may be so long lasting that they are suitable for use as a bridge between two anatomical structures. Combined mesh/graft materials use the permanent strength of a non-absorbable mesh to provide the bridge function but are covered with other materials which are thought to decrease the risk of erosion and promote integration with the host tissues (e.g. collagen, and polyglactin). Non-absorbable synthetic mesh does not degrade and acts as a mechanical bridge between tissues. It can be made from knitted single-fibre filaments (monofilament materials) or they can be braided with monofilament yarns, or woven as multifilament fibres in different ways. Non-absorbable synthetic mesh is usually further classified according to its pore size, and can be divided into four types (Amid types): totally macroporous with a pore size of >75μm (type I), totally microporous (type II), a mixture of macro and microporous (type III), 4

29 and submicronic (type IV). It is thought that the various fibre structures and pore sizes result in different mesh attributes (e.g. risk of infection, rejection and erosion), but it is not clear how function is affected by these attributes. The choice of mesh therefore depends on a balance between strength and degree of absorbability and the risk of infection, rejection or erosion. Table 2 The different mesh types in pelvic organ prolapse repair Type of mesh and grafts Material Examples (commercial or trade name) Absorbable synthetic mesh Polyglactin Vicryl (multifilament) Biological graft Autograft Fascia lata Rectus sheath NA (patient s own tissue used) NA (patient s own tissue used) Allograft Fascia lata Dura mata Dermis Tutoplast Duraderm AlloDerm Xenografts Porcine dermis Porcine small-intestine submucosa Pelvicol SIS Combined mesh/graft Polyglactin and polypropylene Porcine collagen and Vypro II (mono-multifilament) Avaulta (monofilament) polypropylene Non-absorbable synthetic mesh Type I (totally macroporous) Polypropylene Marlex (monofilament) Prolene (monofilament) Type II (totally microporous) Polytetrafluoroethylene Goretex (multifilament) Type III (macro-microporous) Polyethylene tetraphalate Mersilene (multifilament) Type IV (submicronic pore size) Silicone or silicone-coated mesh Polyatex Description of the interventional procedure Types of surgical repair which necessarily involve the use of mesh include sacrocolpopexy, infracoccygeal sacropexy, uterine suspension sling, and other mesh techniques such as colpoperineopexy. Types of surgeries which do not involve mesh include hysterectomy, cervical amputation, and uterine/vault suspension. 5

30 The procedures, with or without mesh, are usually conducted as an inpatient procedure under a general or spinal anaesthetic. Some women may have other gynaecological problems which require surgical correction at the same time. These concomitant procedures include anterior or posterior vaginal wall prolapse repair or surgery for urinary incontinence. These are usually conducted under the same anaesthetic. Sacrocolpopexy (mesh) Sacrocolpopexy can be carried out for vault prolapse or at the same time as hysterectomy for uterine prolapse with the aim of preventing vault prolapse. It involves attachment of the vaginal vault to the sacrum with the use of mesh as a necessary bridge. The mesh is attached to both the vault and the sacrum with sutures. This procedure is carried out abdominally (open or by laparoscope). Infracoccygeal sacropexy (mesh) Infracoccygeal sacropexy (also known as Posterior IntraVaginal Slingplasty, IVS) can be carried out for either uterine or vault prolapse. In women who have a uterine prolapse, the uterus can be preserved. Infracoccygeal sacropexy is usually carried out under local or regional anaesthesia. An incision is made in the posterior wall of the vagina and a small puncture incision is made in each buttock. A tape is introduced through the buttock incision and a tunnelling device is used to take it up around the rectum, along one side of the vagina, across the top of the vagina, down along the other side of the vagina and out through the incision in the other buttock. The tunneller is guided by a finger in the vaginal incision. The tape is sutured to the top of the vagina and acts as a tension-free sling to suspend the vaginal vault in its natural position. Delayed absorbable sutures are used to close the vaginal incision. Uterine suspension sling (including sacrohysteropexy) using mesh 'Uterine suspension sling' involves the attachment of the uterus, using mesh, either to the sacrum or ligaments. Two main variants of the procedure exist (both necessitating an abdominal approach, using either open or laparoscopic techniques): Firstly, sacrohysteropexy, which involves the attachment of the uterus to the sacrum using a mesh bridge. In sacrohysteropexy, the mesh can be attached to the uterus in two different ways: either in the midline, and usually at the level of the back of the uterine cervix; or bilaterally from the insertion points of each uterosacral ligament at the uterus. (In both cases the other 6