Transvaginal mesh implants independent review: final report

Chapter 5: Review of the evidence from safety reviews and systematic reviews

Update Since Interim Report

Background

Since publication of the IR's Interim Report in October 2015, six further reports have been published which are within the scope of the review. These comprise two reports which are concerned with the Safety Reviews:

• Scientific Committee on Emerging and Newly Identified Health Risks ( SCENIHR). Opinion on the safety of surgical meshes used in urogynecological surgery. December 2015; and
• Kelly M, Macdougall K, Olabisi O, & McGuire N (2016). In vivo response to polypropylene following implantation in animal models: a review of biocompatibility. International Urogynecological Journal. DOI:10.1007/s00192-016-3029-1.

In addition there have been three updated Cochrane Reviews which focused on the effectiveness of mesh implants. These are:

• Lapitan MCM, Cody JD, (2016). Open retropubic colposuspension for urinary incontinence in women. Cochrane Database of Systematic Reviews 2016. DOI: 10.1002/14651858.CD002912.
• Maher C, Feiner B, Baessler K, Christmann-Schmid C, Haya N, Marjoribanks J, (2016a). Transvaginal mesh or grafts compared with native tissue repair for vaginal prolapse. Cochrane Database of Systematic Reviews 2016. DOI: 10.1002/14651858.CD012079;
• Maher C, Feiner B, Baessler K, Christmann-Schmid C, Haya N, Brown J, (2016b). Surgery for women with apical vaginal prolapse. Cochrane Database of Systematic Reviews 2016. DOI:10.1002/14651858.CD012376;

Finally, an update on the final report from the PROSPECT trial is included:

• Glazener CMA, Breeman S, Elders A, Hemming C, Cooper CG, Freeman RM, Smith ARB, Reid F, Hagen S, Montgomery I, Kilonzo M, Boyers D, McDonald A, McPherson G, MacLennan G, Norrie J (on behalf of the PROSPECT Group), (2016). Mesh, graft, or standard repair for women having primary transvaginal anterior or posterior compartment prolapse surgery: two parallel-group, multicentre, randomised, controlled trials ( PROSPECT). Lancet. DOI: http://dx.doi.org/10.1016/S0140-6736(16)31596-3.

This chapter provides an update on these documents and the impact they have on the conclusions of the interim report. The tabulated results from the interim report remain available on the website here http://www.gov.scot/Publications/2015/10/8485/downloads.

5.1 Evidence availability

This section of the IR was undertaken in line with a modified form of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses ( PRISMA) guideline ^[7] .

This review considered systematic review evidence of two sorts. The first were the reviews of evidence undertaken by those agencies responsible for the safety of medical devices on a national and international basis. The second were the published, peer-reviewed Cochrane systematic reviews and health technology assessments undertaken in relation to mesh devices for SUI and POP.

5.1.1 Safety reviews

Safety reviews of medical devices seek to determine if the device can continue to be used safely and how best to ensure that both patient safety and device effectiveness is maintained. One reviewed the evidence relating to adverse outcomes following mesh implantation; the other examined the toxicology of the product.

Safety reviews are most likely to focus mainly on the nature, severity and frequency of any surgical complications and adverse outcomes. They are also likely to consider aspects of efficiency and effectiveness in the delivery of care. Finally, they may consider whether there has been any failure in the regulatory system that was used to determine the original safety of the device as "safe" for health care use.

Different reviews may use varying methods. In most cases, the reviews use a "narrative" method, reporting on available evidence.

5.1.2 Cochrane Systematic reviews

Cochrane systematic reviews are produced by the Cochrane Collaboration. This is a global, independent network of researchers, professionals, patients, carers and people interested in health. It is formed as a not-for-profit organisation which spans contributors from more than 120 countries. Its work is always free from commercial sponsorship and other conflicts of interest.

Cochrane Collaborators produce reviews that summarise the best available evidence generated through research to inform decisions about health and health care. These Cochrane Reviews are a systematic synthesis of primary research in human health care and health policy. They are internationally accepted as providing health care evidence of the highest standard. Cochrane Reviews are updated as needed, ensuring the most up-to-date and reliable evidence is available.

The full text of Cochrane Review and Protocol are published online in the Cochrane Database of Systematic Reviews in the Cochrane Library ^[8] . In the UK, Cochrane Reviews are used to inform the National Institute for Health and Care Excellence ( NICE) and the Scottish Intercollegiate Guidelines, Network ( SIGN) guidelines, as well as informing policy and decision making in health care commissioning and development.

5.1.3 Randomised controlled trials

A randomized controlled trial is a clinical-epidemiological experiment in which subjects are randomly allocated into groups, usually called test and control groups, to receive or not to receive a preventive or a therapeutic procedure or intervention. The results are assessed by comparison of rates of disease, death, recovery, or other appropriate outcome in the study groups.

Randomised controlled trials are generally regarded as the most scientifically rigorous method of hypothesis testing available in epidemiology and medicine. Nonetheless, they may have limitations. These typically include a limitation of the trials findings being applied elsewhere due, for example, to the non-representativeness of patients who participate. ^[9]

5.2 Methods of reviewing evidence

Following discussions with both patients and clinicians, a number of key outcome areas were identified to provide a data extraction framework. These were:

• Effectiveness of SUI or POP procedure(s):
  • effectiveness in terms of objective SUI / POP cure at one year or more;
  • effectiveness in terms of subjective SUI / POP cure at one year or more;
  • need for repeat SUI or POP surgery; or
  • further conservative treatment for SUI.
• Reported safety issues with SUI or POP procedure;
  • mesh technology; or
  • proprietary brand of mesh.
• Patient-focussed outcomes: Quality of Life ( QoL):
  • measurable QoL at one year or more post procedure, specific to SUI or POP.
• Patient-focussed outcomes: adverse outcomes:
  • Short-term/postoperative complications;
  • long-term disability due to adverse effects;
  • surgical treatment for adverse effects.
• Relative efficacy of alternative therapy to mesh.

• Systems efficacy:
  • surgical capacity and competency issues;
  • service capacity and feasibility; and
  • other factors.

Data were extracted and tabulated for further interpretation. The overall quality of the evidence reviewed was assessed using the Scottish Intercollegiate Guidelines Network ( SIGN) on grades of evidence [ SIGN 50 reference].

5.3 Safety Reviews

5.3.1 The Scientific Committee on Emerging and Newly Identified Health Risks Safety Review

5.3.1.1 Aims

The SCENIHR report is the European Safety Review commissioned by the Commission of the European Union. The report aims to answer a series of specific questions. In this case the review's scope was to consider the:

• risks associated with the use of surgical meshes for treating SUI and POP;
• identification of high-risk patient groups;
• risks associated with mesh use for non-urogynecological surgery;
• need for further assessment in this field; and
• scientific rationale for the use of synthetic surgical mesh for the management of urinary incontinence, POP and colorectal functional disorders.

The scope of the European Review is slightly broader than that of the Independent Review ( IR), which is limited to the use of surgical mesh in SUI and POP.

5.3.1.2 Update since interim report

The IR included evidence derived from the earlier, preliminary opinion from SCENIHR published in June 2015. This preliminary opinion document was subsequently subject to a formal consultation by the SCENIHR before the final version was published in December 2015.

5.3.1.3 Describe included studies

The surgical mesh component of the safety review considered 24 studies. Four studies were in humans (n= 64 in total), and the rest were in animals.

5.3.1.4 Outcomes

For this evidence update, a comparison between the conclusions reached in the preliminary and the final versions of the European Review has been undertaken for those areas which were included into the IR. The text below provides a narrative between the relevant conclusions and recommendations of the preliminary and final version of the European Review.

5.3.1.5 Follow up period

The follow up period of all studies included in the surgical mesh element of the this safety review varied from 14 days to 3 years.

5.3.1.6 Quality of evidence

The quality of this evidence has been assessed as very good.

5.3.1.7 Findings

In the main differences between the preliminary opinion of the SCENIHR and the final opinion are in the wording and there is no substantive difference in the underlying meaning of the opinion. Additional detail has been added to improve clarity of the opinion made in several cases.

There are differences between the preliminary and final opinion regarding the specific sub-groups of women who are identified as having greater risk of adverse outcomes in the use of synthetic mesh. The final report has removed mention of both an association between smoking and mesh exposure and the potential need for greater consideration prior to mesh use in younger age groups. The final report highlights an increased risk associated with age and obesity.

5.3.1.8 Conclusions

Risks associated with the use of surgical meshes for treating SUI and POP include various complications of poor tissue integration, such as tissue extrusion, exposure of the mesh and shrinkage of the mesh. High-risk patient groups are associated with age and obesity. There is insufficient evidence to comment on the risk of meshes other than for urogynecological surgery.

The factors influencing the surgical outcomes are mesh properties (biocompatibility, tissue integration, long-term stability, and mechanical performance over time which includes flexibility, elasticity, aging and resistance to deformation) product design ( e.g. physical characteristics of the mesh, size of the pore as a predisposing factor to infection in particular with a pore size less than 75 microns) overall mesh size (which is greater for POP than for SUI), route of implantation, ( e.g., vaginal or transabdominal), patient characteristics ( e.g., age, obesity, smoking), associated procedures ( e.g., hysterectomy) and surgeon's experience.

5.3.2 Kelly et al (2016). In vivo response to polypropylene following implantation in animal models: a review of biocompatibility.

5.3.2.1 Aims

This paper reports on a Literature Review undertaken by staff within the MHRA. The focus of the review is research on polypropylene devices after implantation in the body.

5.3.2.2 Update since interim report

This safety review has been published since the interim report.

5.3.2.3 Description of included evidence

46 articles investigating the response of mesh in live subjects were reviewed.

5.3.2.4 Outcomes

The specific areas considered were: the type of material selected; the impact of anatomical location; and the structure, weight and size of polypropylene mesh types. In all cases the studies focussed on animal models.

5.3.2.5 Follow up period

The studies included have a limited follow up period, with few long-term studies possible.

5.3.2.6 Quality of evidence

The quality of this evidence has been assessed as very good.

5.3.2.7 Findings

While this review only focusses on research evidence drawn from animal studies, the findings are consistent with other safety reviews. Specifically, the review concluded:

• polypropylene meshes are less likely to evoke an inflammatory or similar host response than other synthetic materials and polypropylene composite meshes;
• using a light-weight mesh with large pores results in fewer complications; and
• current evidence, although limited, suggests that mesh implants in the pelvic region are more susceptible to complications than the abdominal region.

There are limitations of applying data from animal studies to humans, and the review itself acknowledges this shortcoming. However, the use of animal models in such situations is well-accepted in research literature.

5.3.2.8 Conclusions

In summary, this review concludes that the biocompatibility of synthetic polypropylene mesh for use in SUI and POP is comparable with or better than other synthetic meshes, composite meshes and biologically-derived meshes when examining complication rates. While more research is indicated, the overall findings from the animal studies are consistent with existing evidence, suggesting that mesh type, size and location of implantation are all risk factors for complications.

5.4 Systemic Review - Stress Urinary Incontinence

5.4.1 Lapitan & Cody (2016). Open retropubic colposuspension for urinary incontinence in women

5.4.1.1 Aims

This systematic review considers the effectiveness of surgical techniques for retropubic colposuspension as a treatment for SUI or SUI mixed with other urinary symptoms in women.

5.4.1.2 Update since interim report

This review adds new evidence since the interim report was published regarding the comparison of open retropubic colposuspension ( ORC) with self-fixing sling procedures using either retropubic or transobturator mesh tapes.

5.4.1.3 Description of included trials

Overall, the review found 22 trials that compared ORC with sling procedures; of which 12 related to retropubic and 4 to transobturator mesh tape procedures.

5.4.1.4 Outcomes

Across all studies there were 27 different outcomes considered, these varied considerably between the studies that consider mesh procedures. Those reported were:

• reported cure;
• incontinence rate;
• outcomes associated with surgical characteristics ( e.g. length of stay);
• quality of life measures;
• health economic outcomes; and
• adverse outcomes.

5.4.1.5 Follow up period

Less than one year to more than five years.

5.4.1.6 Quality of Evidence

The overall quality of the evidence included was not well described and the potential bias in the included trials was generally assessed as "uncertain". The additional evidence of interest to the IR, may be of low quality at best. The review's authors comment on the ",,,urgent need for further trials of adequate power to assess the effectiveness, safety and cost-effectiveness of open retropubic colposuspension in comparison with (a) suburethral slings, using both traditional and minimally invasive approaches, and (b)the laparoscopic technique. In addition, the long-term outcomes of existing trials could and should be reported". (Lapitan & Cody (2016). Pg 26).

The data from one trial, which considered the use of the Gynecare TVT ^TM procedure, was sufficiently large to dominate the analysis relating to retropubic mesh tapes. This may be a potential bias.

5.4.1.7 Findings

The summarised results from the individual comparisons made in this systematic review are included below.

5.4.1.8 Conclusions

Open retropubic colposuspension is an effective treatment modality for stress urinary incontinence, especially in the long-term. Within the first year of treatment, the overall continence rate is approximately 85% to 90%. After five years, approximately 70% of women can expect to be dry. Newer minimal access sling procedures look promising in comparison with open colposuspension but more evidence is required. Open colposuspension is associated with a higher risk of pelvic organ prolapse compared to sling operations and anterior colporrhaphy, but with a lower risk of voiding dysfunction compared to traditional sling surgery. Laparoscopic colposuspension should allow faster recovery but its relative safety and long-term effectiveness is not yet known.

Table 5.1 Summary overview of Systematic Review on Stress Urinary Continence by Lapitan & Cody 2016.

Author(s) (Year) & Title	Effects	Colposuspension	Mesh Tape	RR, 95% CI, number of studies and participants
Lapitan MCM & Cody JD (2016) Open retropubic colposuspension for urinary incontinence in women	Short-term efficacy (1 year)	Subjective: 75.4%	71.1%	0.88 [ 0.67, 1.16 ], 5 RCTs, 547 participants
		Objective: 82.4%	83.4%	1.08 [ 0.74, 1.57 ], 4 RCTs, 515 participants
	Medium term efficacy (1-5 year)	Subjective: 74.0%	70.0%	0.91 [ 0.68, 1.22 ], 4 RCTs, 427 participants
		Objective: 84.0%	85.9%	1.14 [ 0.69, 1.88 ], 3 RCTs, 348 participants
	Long-term efficacy (>5 year)	Subjective: 69.7%	63.3%	0.83 [ 0.54, 1.26 ], 1 RCT, 177 participants
		Objective: 89.8%	80.6%	0.52 [ 0.20, 1.36 ], 1 RCTs, 121 participants
	Repeat continence surgery	3.4%	2.4%	1.46 [ 0.40, 5.32 ], 1 RCTs, 316 participants

Table 5.2 Extracted Data from Systematic Review on Stress Urinary Incontinence by Lapitan & Cody 2016.

Author(s) & Title	Aim Review type, Evidence quality	Level of evidence & Description of studies	Findings Surgical Adverse QoL	Conclusions
Lapitan MCM & Cody JD (2016) Open retropubic colposuspension for urinary incontinence in women. Cochrane Database of Systematic Reviews 2016. DOI: 10.1002/14651858.CD002912.pub6 Last assessed as complete at 12 th February 2016	To assess the effects of open retropubic colposuspension for the treatment of urinary incontinence. Cochrane Systematic Review. This is a full search update to Lapitan & Cody (2012). In this table, only the comparison of surgical open retropubic colposuspension ( ORC) with self-fixing sling procedures using either tension-free vaginal tape ( TVT) or transobturator tape ( TOT) forms of mesh implants are considered. The potential bias in the included trials was generally assessed as "uncertain". The quality of the relevant evidence may be assumed to be low at best.	Systematic Review based on evidence ranging from SIGN 1++ (High quality meta-analysis, systematic reviews of Randomised Controlled Trials ( RCTs) ,or RCTs with a very low risk of bias) to SIGN 1+.( Well conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias) In total 55 studies which were either randomised or quasi-randomised controlled trials which involved ORC in at least one arm of the trial In total these 22 trials randomised 2343 women to surgical interventions. Data from one of the new trials could not be included in pooled data analyses as there was insufficient information.	All results refer to comparisons between ORC and Mesh self-fixing slings. Where possible TVT or TOT procedures as comparators are shown. Outcomes are described using the terms adopted in the update review. 1. Women's' Observations (Subjective cure) Short-term (<1y). Comparisons including five trials (n=547) showed no differences between OTC and TVT ( RR = 0.88; 95% CI.67 to 1.16) for any short-term women's outcomes; Mid-term (1-5y). Analysis for ORC v TVT for subjective incontinence (five trials) ( RR = 1.18; 95% CI 1.01 to 139) and for improvement in incontinence (two trials) ( RR = 1.11; 95% CI 0.64 to 1.91) were inconclusive. The significant finding of superior subjective cure with TVT being a consequence of 1 large trail in that comparison. Long-term (>5y). Pooled data from three trials showed no significant differences between ORC and TVT ( RR = 1.11; 95% CI 0.97 to 1.27). 2. Clinician's Observations Data for: Short-term (<1y) ( RR = 1.11; 95% CI 0.97 to 1.27, four trials); Mid-term (1-5y). ( RR = 1.14; 95% CI 0.69 to 1.88, three trials); Long-term (>5y). ( RR = 0.52; 95% CI 0.20 to 1.36, 1 trial ) showed no significant differences in objective cure. Surgical outcomes showed that Mesh procedures were superior to ORC for length of operative time ( RR = 18.06; 95% CI 14.67 to 21.46, 3 trials); length of hospital stay of 4 days ( MD=3.99; 95% CI 3.71 to 4.28, 6 trials); and time to catheter removal ( MD = 4.51; 95% CI 3.05 to 5.97, 1 trial). 3. Adverse outcomes No significant differences were found between ORC and TVT procedures in relation to: perioperative (7d) surgical complications ( RR = RR 1.11; 95% CI 0.66 to 1.87, 4 trials); (n= voiding dysfunction ( RR = 0.85; CI 0.47 to 1.53, 6 trials); or repeat incontinence surgery ( RR = 1.46; 95% CI 0.40 to 5.32, 1 trial); TVT procedures were found to be superior to ORC in relation to: the rate of new or recurrent prolapse post-surgery ( RR = 1.85; 95% CI 1.25 to 2.75, three trials), though this superiority was not observed if only symptomatic prolapse was analysed; bladder perforation ( RR=0.20; 95% CI 0.08 to 0.49, 7 trials); and other complications ( RR =0.24 95% CI 0.09 to 0.62, 4 trials); There was insufficient pooled data to assess if there were differences between TVT and ORC procedures relating: to de novo symptoms of urgency ( RR = 1.28; 95% CI 0.51 to 3.16, 2 trials); or de novo detrusor over-activity ( RR = 1.28 95% CI 0.71 to 2.32). 3 trials). One trial reported a case of vascular injury associated with TVT procedure. 4. Quality of Life Outcomes Two trials included formal assessment of QoL using standardised instruments. All showed no differences between ORC and TVT surgery safe for one trial that showed a significant improvement in the emotional and social functioning sub-scale of the SF36 associated with TVT.	"… [There is an] urgent need for further trials of adequate power to assess the effectiveness, safety and cost-effectiveness of open retropubic colposuspension in comparison with (a) suburethral slings, using both traditional and minimally invasive approaches, and (b)the laparoscopic technique. In addition, the long-term outcomes of existing trials could and should be reported". (Pg. 26). "The minimally invasive sling procedures confer similar success rates in comparison to open colposuspension. However, traditional slings provide better cure rates at the expense of more voiding dysfunction in the short-term. The long-term adverse event profile of the sling procedures, in particular with the use of the TVT, is still unclear." (Pg. 26).

5.5 Systematic Reviews - Pelvic Organ Prolapse

5.5.1 Maher et al (2016a). Transvaginal mesh or grafts compared with native tissue repair for vaginal prolapse.

5.5.1.1 Aim

This Cochrane systematic review provides a partial update on the initial Cochrane systematic review by Maher C et al (2013): " Surgical management of POP in women". The update focusses only on studies that consider transvaginal mesh or grafts compared with native tissue repair for vaginal prolapse.

5.5.1.2 Update since interim report

Twelve new trials were included in the systematic review and data from the three year follow up of a study previously included in the 2013 review.

5.5.1.3 Description of included trials

In total, 37 trials were included, representing data from 4,023 adult women who had sought treatment for symptomatic POP (either primary or recurrent). Of these 1,986 had been treated with colporrhaphy augmented with transvaginal implant (synthetic mesh or biological graft) and 2,037 with traditional native tissue repair (colporrhaphy).

5.5.1.4 Outcomes

The studies included a range of primary and secondary outcomes. These can be summarised as:

• Primary outcomes:
  • subjective awareness of prolapse;
  • repeat surgery - for prolapse, SUI; or composite; and
  • recurrent prolapse.
• Secondary outcomes:
  • adverse events: death (related to surgery); mesh exposure; bladder or bowel; surgery for mesh exposure;
  • prolapse outcomes: objective failure by compartment) objective failure by POPQ score; total vaginal length;
  • bladder function: recurrent or SUI; recurrent or de novo overactive or urge incontinence;
  • bowel function: de novo faecal incontinence or obstructed defecation;
  • sexual function: de novo dyspareunia; PISQ-12;
  • quality of life and satisfaction measured by questionnaire ( PG1-1, PQOL, PFDI-20, or PFIQ-7); and
    measures associated with surgery: operating time; blood transfusion; length of hospital stay.

5.5.1.5 Follow up period

The trials varied in their follow up periods. While one only reported a six month follow up, there were 25 reporting after one year, eight with after two years and three after three years.

5.5.1.6 Quality of evidence

Overall the quality of evidence was assessed to be:

• permanent transvaginal mesh compared with native tissue: was low to moderate for most outcomes;
• absorbable mesh compared with native tissue repairs: was generally very low to low, reflecting smaller, older studies; and
• biological grafts compared with native tissue repairs: was very low to low, reflecting poor reporting of study methods, lack of clarity with regard to blinding of assessors, and imprecision.

The main limitations were poor reporting of study methods, inconsistency, and imprecision.

The risk of bias in the main studies was considered to be low.

5.5.1.7 Findings

The summarised results from the individual comparisons made in this systematic review are shown below.

5.5.1.8 Conclusions

The general conclusions from this systematic review are:

1. Permanent transvaginal mesh surgery is associated with lower rates of awareness of prolapse and prolapse on examination than native tissue repair. However, it is also associated with increased morbidity. There is a complex risk-benefit profile which suggests that transvaginal mesh has limited utility in primary surgery. In cases where there is a high risk of recurrence, some women and their clinical team may feel that the benefits may outweigh the risks. This systematic review, however, has no evidence to support this position.

2. There is limited evidence that absorbable mesh may reduce the risk of recurrent prolapse on examination compared with native tissue repair. Existing evidence from trials using absorbable mesh was insufficient to allow any further conclusions to be drawn.

3. Many of the permanent transvaginal mesh devices reviewed have now been removed from clinical use by their manufacturers. This review does not include RCT data for any of the more recently introduced, lightweight transvaginal meshes for permanent insertion. Until such RCT data become available, these newer transvaginal meshes should be utilised under the discretion of the ethics committee. Unfortunately, at least two such ethically approved trials have been terminated due to difficulty in recruitment or funding.

4. Other urgent research needs include: an updated cost-benefit analysis of transvaginal mesh surgery; and long-term outcome studies should be undertaken for existing mesh procedures.

Table 5.3 Summary Table of Systematic Review on Pelvic Organ Prolapse by Maher et al 2016 (a)

Author(s) (Year) & Title	Effects	Native Tissue Repair	Mesh Repair	RR ( 95% CI, number of studies and participants
Maher C, Feiner B, Baessler K, Christmann-Schmid C, Haya N, Marjoribanks J.(2016) Transvaginal mesh or grafts compared with native tissue repair for vaginal prolapse.	Short-term efficacy (1-3 years)	Subjective: 81%	85-90%	0.66 (0.54-0.81), 12 RCTs, 1614 participants
		Objective: 62%	80-89%	0.40 (0.30-0.53), 21 RCTs, 2494 participants
	Need for further POP surgery after 1 year	3.2%	1.7%	0.53 (0.31-0.88), 12 RCTs, 1674 participants
	Development of de novo SUI	9.6%	13.3%	1.39 (1.06-1.82), 12 RCTs, 1512 participants
	Need for SUI surgery after 1 year	2.6%	2.8%	1.07 (0.62 to 1.83), 9 RCTs, 1284 participants
	Combined need for further surgery ( POP, SUI or mesh removal) at 1 year	4.8%	11.4%	2.40 (1.51-3.81), 7 RCTs, 867 participants
	Development of de novo dyspareunia	9.5%	8.8%	0.92 (0.58-1.47), 11 RCTs, 764 participants
	Bladder injury	0.5%	2.1%	3.92 (1.62-9.50), 11 RCTs, 1514 participants
	Length of hospital stay			0.06 days (0.03-0.18),7 RCTs, 953 participants
	Blood transfusion			1.55 (0.88-2.72), 6 RCTs, 723 participants

Table 5.4 Extracted Data from Systematic Review on Pelvic Organ Prolapse by Maher et al 2016 (a)

Author(s) & Title	Aim Review type, Evidence quality	Level of evidence & Description of studies	Findings Surgical Adverse QoL	Conclusions
Maher C et al. Transvaginal mesh or grafts compared with native tissue repair for vaginal prolapse. Cochrane Database of Systematic Reviews 2016 DOI: 10.1002/14651858.CD012079.pub2 Last assessed as complete at 6 th July 2015.	To determine the safety and effectiveness of transvaginal mesh ( TM) or biological grafts compared to native tissue repair ( NTR) for vaginal prolapse Cochrane Systematic Review This is a full search update on Maher et al (2013). The comparison of TM repairs versus NTR for vaginal prolapse are relevant. Overall the quality of evidence was assessed to be: permanent transvaginal mesh compared with native tissue - low to moderate; and absorbable mesh or biological grafts compared with native tissue repairs - very low to low. The main limitations were poor reporting of study methods, inconsistency, and imprecision. The risk of bias in the main studies was considered to be low.	Systematic Review based on evidence ranging from SIGN 1++ (High quality meta-analysis, systematic reviews of Randomised Controlled Trials ( RCTs) ,or RCTs with a very low risk of bias) to SIGN 1+.( Well conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias) In total 37 trials were included with data from 4,023 women who had sought treatment for symptomatic pelvic organ prolapse (either primary or recurrent). Of these 1,986 had been treated with transvaginal graft repairs and 2,037 with traditional NTR (colporrhaphy). Twelve new trials were include in this 2016 systematic review and data from the three year follow up of a study previously included in the 2013 systematic review was included.	All results refer to comparisons between NTR and TM repairs. Where possible permanent ( pTM) or absorbable ( aTM) Mesh procedures are shown. 1. NTR v pTM Primary Outcomes Awareness of prolapse - no significant differences were found at mid-term review (1-3y) ( RR = 0.66; 95% CI 0.54 to 0.81, 12 trials); Surgery for prolapse - rate of repeat surgery was lower for pTM ( RR = 0.53; 95% CI 0.31 to 0.88, 12 trials); Surgery for SUI - rate of repeat surgery was not significantly different between pTM and NTR ( RR = 1.07; 95% CI 0.62 to 1.83, 9 trials); Surgery for prolapse, SUI or pTM erosion -repeat surgery was less likely in NTR than pTM ( RR = 2.40; 95% CI 1.51 to 3.81, 7 trials); Recurrent prolapse at mid-term review (1-3y) -was less likely for pTM versus NTR ( RR = 0.40; 95% CI 0.30 to 0.53, 21 trials). Sub analysis suggested this benefit of pTM was maintained for both anterior repairs alone ( RR = 0.33; 95% CI 0.26 to UL+0.40, 15 trial) or multi-compartment repairs ( RR = 0.59; 95% CI 0.40 to 0.87, 6 trials). Secondary (Adverse) Outcomes o POPQ scores - pTM repairs at the mid-anterior vaginal wall were superior to NTR ( MD = -0.93; 95% CI -1.27 to -0.59, 10 trials). No differences were found between procedures at other vaginal sites; Mesh exposure at mid-term review (1-3y) -was reported in 10% of anterior repairs and 17% of multi-compartment repairs; Surgery for mesh exposure at mid-term review (1-3y) - the rate was 8% for all pTM procedures; Prolapse at mid-term review (1-3y) -less in pTM repair vs NTR ( RR = 0.45; 95% CI 0.36 to UK=0.55, 13 trials). Sub-analysis associated this with anterior repairs ( RR = 0.36; 95% CI 0.28 to 0.47, 9 trial), but not multi-compartment repairs ( RR = 0.73; 95% CI 0.51 to 1.06, 4 trials); Prolapse in the posterior vaginal compartment - no significant differences in procedures ( RR = 0.64; 95% CI 0.29 to 1.42, 3 trials); Bladder or bowel injury - Bladder injury was more likely with pTM and NTR ( RR = 3.92; 95% CI 1.62 to 9.50, 11 trials). No significant differences were reported in one trial that reported on bowel injury; De novo bladder voiding problems - no differences between procedures were found ( RR = 0.75; 95% CI 0.35 to 1.63, 3 trials); De novo dyspareunia - there was no evidence of a difference between the procedures ( RR = 0.92; 95% CI 0.58 to 1.47, 11 trials); Secondary (Surgical) Outcomes Operating times - only data relating to multi-compartment repairs were suitable for analysis. The mean operating time was shorter for pTM procedures ( MD = 7.48m; 95% CI -10.87 to UL = -4.08, 3 trials); No differences were found in relation to blood transfusion use during the procedure ( RR = 1.55; 95% CI 0.88 to 2.72, 6 trials) or length of hospital stay ( MD = -0.06d; 95% CI -0.03 to UL = 0.18, 7 trials). Secondary ( QoL) Outcomes No significant differences in either the PSSFQ scores ( MD= -0.13, 95% CI -0.40 to 0.13, 7 trials), or combined scores from the PQLQ (3 trials) and the PFIQ (4 trials) (Standard MD = 0.05; 95% CI -0.20 to 0.30). 2. NTR v aTM Primary Outcomes Awareness of prolapse (2y review) -no evidence of a difference between NTR and aTM repair ( RR = 1.05,;95% CI 0 .77 to 1.44, 1 trial); Repeat surgery (2y review) -no evidence of differences for prolapse ( RR = 0.47; 95% CI 0.09 to 2.40, 1 trial); Recurrent prolapse (3m to 2y review) -rates at review were lower for aTM ( RR = 0.71, 95% CI 0.52 to 0.96, 3 trials) However, this finding was sensitive to statistical analysis, if a random-effects model was used the difference was not significant ( RR = 0.74, 95% CI 0.51 to 1.06); Secondary (Adverse) Outcomes Death - none reported; Post-operative SUI - there was no evidence of a difference between aTM and NTR ( RR = 1.38; 95% CI 0.95 to 2.00, 1 trial). Secondary (Surgical) Outcomes No differences in NTR and aTM, at 1-2 yr review, in failure of anterior compartment ( RR = 0.72; 95% CI 0.53 to 0.98, 2 trials) or failure of posterior compartment ( RR = 1.13; 95% CI 0.40 to 3.19, 1 trial); Secondary ( QoL) Outcomes Prolapse Quality of Life Questionnaire (2y review) -no difference between aTM and NTR ( MD = 0.00, 95% CI -2.82 to 2.82, 1 trial).	"… while permanent transvaginal mesh is associated with a greater reduction in prolapse on examination, awareness of prolapse and reoperation for prolapse than native tissue repairs, it is associated with increased morbidity, including a higher rate of bladder injury, de novo stress urinary incontinence, and reoperation rates for prolapse, stress urinary incontinence, and/or mesh exposure. The rate of mesh exposure was 12%, and surgery for mesh exposure was required in 8%, accounting for most of the reoperations for mesh complications." (pg. 17)

5.5.2 Maher et al (2016b). Surgery for women with apical vaginal prolapse

5.5.2.1 Aim

This second Cochrane systematic review by Maher et al focusses on apical vaginal prolapse, included cases which occurred post-hysterectomy.

5.5.2.2 Update since interim report

As such, it also provides updated evidence alongside studies previously considered in the Maher C et al (2013) review.

5.5.2.3 Description of included trials

52 papers from 30 trials were included in the review, though only six trials that compared vaginal surgery with or without mesh were included. In total these trials included 598 women: 297 had a sacrospinous colpopexy as a native tissue repair, and 301 a mesh repair. In all trials polypropylene mesh was used, with monofilament mesh used in four trials and multi-filament mesh in the remaining two. Of the six studies, two included only those with post-hysterectomy prolapse and four included those with both uterine and vaginal apical prolapse.

5.5.2.4 Outcomes

As with Maher et al (2016a), a range of primary and secondary outcomes were considered (see section 3.1 above).

5.5.2.5 Follow up

Follow up periods were between 1 and 3 years post-surgery.

5.5.2.6 Quality of evidence

The quality of the evidence contained within the six trials included in this review was assessed as very low to moderate, though the risk of bias in the six trials was assessed at being mainly low or uncertain.

5.5.2.7 Findings

Overall the review found little or no difference between native tissue repairs and mesh repairs in relation to the primary outcomes of:

• awareness of prolapse;
• the need for repeat surgery for prolapse;
• an increased need for repeat surgery for SUI following mesh repair; or
• a decrease in recurrent prolapse following mesh surgery.

No significant differences were noted in any of the secondary outcomes except that the rate of mesh exposure after transvaginal mesh was 18% and rate associated with the need for further surgery for mesh exposure was 9.5%.

5.5.2.8 Conclusions

Sacral colpopexy is associated with lower risk of awareness of prolapse, recurrent prolapse on examination, repeat surgery for prolapse, postoperative SUI and dyspareunia than a variety of vaginal interventions. The limited evidence does not support use of transvaginal mesh compared to native tissue repair for apical vaginal prolapse. Most of the evaluated transvaginal meshes are no longer available and others currently lack evidence of safety. The evidence was inconclusive when comparing access routes for sacral colpopexy and comparing uterine preserving surgery versus vaginal hysterectomy for uterine prolapse.

Table 5.5 Summary of Systematic review on Pelvic Organ Prolapse by Maher et al 2016 (b)

Author(s) (Year) & Title	Effects	Native Tissue Repair	Biological Graft Repair	RR, 95% CI, number of studies and participants
Maher C, Feiner B, Baessler K, Christmann-Schmid C, Haya N, Brown J. (2016) Surgery for women with apical vaginal prolapse.	Short-term efficacy (1-3 years)	Subjective: 89.5%	89.8%	0.97 (0.65-1.43), 7 RCTs, 777 participants
		Objective: 70.5%	72.3%	0.94 (0.60-1.47), 7 RCTs, 587 participants
	Need for further POP surgery at 1-2 years	4.3%	5.2%	1.22 (0.61-2.44), 5 RCTs, 306 participants
	Development of de novo dyspareunia (1-3 years)	17.7%	15.0% (3.5-64.8%)	0.85 (0.20-3.67), 1 RCTs, 37 participants

Table 5.6 Extract data from Systematic review on Pelvic Organ Prolapse by Maher et al 2016 (b)

Author(s) & Title	Aim Review type, Evidence quality	Level of evidence & Description of studies	Findings Surgical Adverse QoL	Conclusions
Maher C et al. Surgery for women with apical vaginal prolapse. Cochrane Database of Systematic Reviews 2016, DOI: 10.1002/14651858.CD012376.pub10 Last assessed as being up to date at 6 th July 2016.	To evaluate the safety and efficacy of any surgical intervention compared to another intervention for the management of apical vaginal prolapse. Cochrane Systematic Review This is a full search update on Maher et al (2013). In this table only the analysis of the comparison of vaginal surgery with or without transvaginal mesh is considered. The quality of the evidence contained within the trials included in these comparisons was considered very low to moderate. The risk of bias was assessed as being mainly low or uncertain.	Systematic Review based on evidence ranging from SIGN 1++ (High quality meta-analysis, systematic reviews of Randomised Controlled Trials ( RCTs) ,or RCTs with a very low risk of bias) to SIGN 1+.( Well conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias) In total 30 trials were included with data from 3414 women who had sought apical vaginal prolapse. Of these, 6 trials representing 598 women who had been treated with either transvaginal mesh ( TM) repairs or varying approaches to native tissue repairs ( NTR).	All results relate to the comparisons between NTR and TM repairs at one to two year review. Primary Outcomes No significant differences were found between TM and NTR in relation to: Awareness of prolapse (3y review) - ( RR = 1.08; 95% CI 0.35 to 3.30, 1 trial); Repeat surgery for prolapse (1-3y review) - ( RR = 0.69; 95% CI 0.3 to 1.60, 5 trials); Repeat surgery for SUI (2y review) - ( RR = 4.91; 95% CI 0.86 to 27.94, 2 trials); There was possible, marginal evidence rates of recurrent prolapse (1-3y) were lower for TM repairs - ( RR = 0.36; 95% Ci 0.09 to 1.40, 3 trials) Secondary Outcomes Mesh exposure - rates for mesh exposure associated with TM repairs were 18%. Of these 9.5% required surgical intervention; No significant differences were found for: Bladder injury - RR 3.00 (0.91 to 9.89) (4 studies) De novo SUI (1-3y) - (1.37 (0.94 to 1.99) (4 studies) De novo dyspareunia (1 to 3y) - ( RR = 1.21; 95% CI 0.55 to 2.66, 5 trials).	"In those not suitable for sacral colpopexy and in those with uterine prolapse, we were unable to detect an advantage to utilising transvaginal mesh as compared to vaginal colpopexy, and the transvaginal mesh was associated with a one in 10 risk of a sub-sequent surgical intervention for the management of mesh exposure. All the transvaginal mesh kits that have been evaluated in this review have been voluntarily removed from the market following transvaginal mesh alert issued by the American Food and Drug Administration. The principal concern raised by the FDA related to vaginal pain and dyspareunia that accounted for36% of adverse events reported to the FDA. These concerns have not been realised in this analysis with the rate of dyspareunia and sexual function scores on the validated Pelvic organ prolapse/urinary Incontinence Sexual Questionnaire ( PISQ) being the same between native tissue and transvaginal mesh interventions. There were no reports of mesh being removed in any of these trials except for the management of mesh exposure." (pg. 38)

5.6 Pelvic surgery : PROSPECT Trial

5.6.1 Glazener et al (2016). Mesh, graft, or standard repair for women having primary transvaginal anterior or posterior compartment prolapse surgery: two parallel-group, multicentre, randomised, controlled trials ( PROSPECT)

5.6.1.1 Aim

The PROSPECT study aimed to compare the outcomes of prolapse repair involving either synthetic mesh inlays or biological grafts against standard repair in women.

5.6.1.2 Update since interim report

The interim report included some early data from the PROSPECT trial relating to the experiences of women who had undergone POP repair using mesh implants. In December 2016 the final report from the trial was published in The Lancet.

5.6.1.3 Description of trials

The PROSPECT study comprised two randomised controlled trials that were undertaken in 35 UK hospitals, including both secondary (General) and tertiary (Regional Specialist) Hospitals. Women undergoing primary transvaginal anterior or posterior compartment prolapse surgery were recruited and randomly assigned one of the two trials. The first trial compared native tissue repair alone with standard repair augmented with synthetic mesh (the Mesh Trial - MT). The second compared native tissue repair alone with biological graft (the Graft Trial - GT). In total 65 surgeons participated. These were either surgeons who were subspecialist urogynaecologists or general gynaecologists with a special interest in the field; all had experience of transvaginal anterior and posterior prolapse repair. The trial standardised the types of mesh and biological grafts used for augmented repairs.

5.6.1.4 Outcomes

Primary outcomes assessed were women's report of prolapse symptoms and a measure of quality of life. Secondary outcomes assessed using patient reports included generic quality of life, adverse events/complications, and bladder, bowel and sexual function. In all cases validated approaches were used. In addition objective assessment of prolapse stage was undertaken. Were possible, adverse event reports were verified from a secondary source.

5.6.1.5 Follow up

Trial follow up continued for two years post-surgery. and was found to be robust, with high levels of patient participation at six month (93% native tissue, 88% mesh), one year (92%, 89%), and two year (81%, 79%) reviews.

5.6.1.6 Quality of evidence

Overall, the authors considered that the study produced high quality evidence; "….pragmatic effectiveness design allowed PROSPECT to generate, using a well done study, high quality evidence for the real-world comparison of these surgical options." (Glazener et al (2016) pg 10) This would seem to be the case as the quality of the data is markedly better than many trials included in systematic reviews.

5.6.1.7 Findings

For the purposes of this update, the results of the MT are considered. The summarised results from the individual analyses made are shown below. Overall, however, the results of the MT can be summarised as:

• no significant differences were found between standard native tissue repairs and repairs augmented by mesh in any of the primary outcomes (at one year) or secondary outcomes (at one and two years) formally analysed;
• overall the rate of mesh complications was 12% amongst women in the MT or who had mesh as an additional procedure. In the MT, surgical mesh removal occurred for 25 women during the first year and 17 women between one to two years. In the GT, a further three women needed surgical mesh removal during the first year following concomitant use of mesh; and
• most of the mesh complications were reported as asymptomatic by the women involved and most mesh exposures were small, requiring only partial removal in all but one case.

5.6.1.8 Conclusions

Augmentation of a vaginal repair with mesh or graft material did not improve women's outcomes in terms of effectiveness, quality of life, adverse effects, or any other outcome in the short-term, but more than one in ten women had a mesh complication. Therefore, follow-up is vital to identify any longer-term potential benefits and serious adverse effects of mesh or graft reinforcement in vaginal prolapse surgery.

Table 5.7 Extracted Data from the Randomised Controlled tRial by Glazener et al(on behalf of the PROSPECT group) (2016)

Author(s) & Title	Aim Review type, Evidence quality	Level of evidence & Description of study	Findings Surgical Adverse QoL	Conclusions
Glazener CMA et al. (on behalf of the PROSPECT Group) Mesh, graft, or standard repair for women having primary transvaginal anterior or posterior compartment prolapse surgery: two parallel-group, multicentre, randomised, controlled trials ( PROSPECT). Lancet. DOI: http://dx.doi.org/10.1016/S0140-6736(16)31596-3.	To compare the outcomes of prolapse repair involving either synthetic mesh inlays or biological grafts against standard repair in women. Pragmatic, parallel-group, multicentre, randomised controlled trials. The authors state that the evidence generated was of a high quality. The potential for bias was considered to be low.	The trial is of a standard that would be suitable for inclusion in a Systematic Review based on evidence ranging from SIGN 1++ (High quality meta-analysis, systematic reviews of Randomised Controlled Trials ( RCTs) ,or RCTs with a very low risk of bias) to SIGN 1+.( Well conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias). The trial ran from 2010 to 2013, with follow up for 2 years post-surgery. In total 1,348 women were included in the trial, with 856 allocated to the transvaginal mesh ( TM) versus native tissue repair ( NTR). Follow up was found to be robust the trial 79% or women followed up at two year review.	In this table, only the analyses which compared TM v NTR are presented. Objective Prolapse Outcomes (1y review) Assessment by Pelvic Organ Prolapse Questionnaire (by site of repair, mean treatment effect). - No significant differences between NTR and TM at : Anterior edge - (Mean = 0·06; 95% CI -0·17 to 0·29); Cervix/vault - (Mean = -0·03; 95% CI -0·36 to 0·31); Posterior edge - (Mean = -0·03; 95% CI -0·21 to 0·15); Total vaginal length - (Mean = 0·12; 95% CI -0·07 to 0·30). Overall POP-Q stage (by stage, mean treatment effect) - No significant differences between procedures were found: Stage 0 (no prolapse) - (Mean = 1·11; 95% CI 0·83 to 1·47); Stage 2b,3 or4 - (prolapse) - (Mean = 1·12; 95% CI 0·79 to 1·60) ; Clinical Outcomes 6 month outcomes - no difference was found for clinical symptoms: POP-SS - (Mean = 0·57, 95% CI (-0·12 to 1·26); Symptomatic prolapse - (Mean = 1·07, 95% CI 1 to 1·14); 'Something coming down' ( SCD) - (Mean = 1·09, 95% CI 0·90 to 1·34). 1 year outcomes - no differences were found between procedures: POP-SS - (Mean = 0·00, 95% CI -0·70 to 0·71); Symptomatic prolapse - (Mean = 1·01, 95% CI 0·95 to 1·08); Women with any report of SCD - (Mean = 0·98, 95% CI 0·82 to 1·18); Severe urinary incontinence - (Mean = 1·34, 95% CI 0·79 to 2·26); Faecal incontinence - (Mean = 0·92, 95% CI 0·74 to 1·13); ICI Vaginal Symptoms Score - (Mean = 0·52, 95% CI -0·64 to 1·68); Severe dyspareunia - (Mean = 1·73, 95% CI 0·52 to 5·78). 2 year outcomes - No significant differences found between NTR and TM: POP-SS - (Mean 0·32, 95% CI -0·39 to 1·03); Symptomatic prolapse - (Mean = 1·04, 95% CI 0·97 to 1·11); Women with any report of SCD - (Mean = 1·06, 95% CI (0·85 to 1·32); Severe urinary incontinence - (Mean = 1·01, 95% CI (0·51 to 1·99); Faecal incontinence - (Mean = 1·13, 95% CI 0·92 to 1·41); ICI Vaginal Symptoms Score- (Mean = -0·18, 95% CI -1·34 to 0·98); Severe dyspareunia - (Mean = 0·49, 95% CI 0·15 to 1·55). Adverse Outcomes 6 month outcomes - no differences were found: Number readmitted (0-6 m - (Mean = 1·15; 95% CI 0·51 to 2·57); 1 year outcomes - no differences between procedures were found: Number readmitted (6-12m) - (Mean = 1·32; 95% CI 0·36 to 4·81); New prolapse operation - (Mean = 1·99 ; 95% CI 0·76 to 5·24); Same compartment (Mean = 2·55; 95% CI 0·68 to 9·53); Different compartment - (Mean = 1·35; 95% CI 0·31 to 5·96); New continence operation - (Mean = 0·40; 95% CI 0·08 to 2·04); Adverse effects in year 1 - no differences between NTR and TM were found: Serious adverse effects (exc. TM) - (Mean = 1·08; 95% CI 0·68 to 1·72); Any mesh complications ( NTR <1% v TM 7%); Surgical removal ( NTR <1% v TM 5%); Conservative treatment ( NTR 0% v TM 2%); No treatment ( NTR 0% v TM <1%); De novo mesh procedure ( NTR <1% v TM 6·2%); Concomitant mesh procedure ( NTR <1% v TM 1%); 2 year outcomes - no differences were found: Number readmitted (12-24m) - ( NTR <1% v TM 0%); New prolapse operation - (Mean = 0·94; 95% CI 0·47 to 1·88); Same compartment - t(Mean = 0·79; 95% CI 0·30 to 2·11); Different compartment - (Mean = 1·14; 95% CI 0·42 to 3·10); New continence operation - (Mean = 1·28; 95% CI 0·35 to 4·73); Adverse effects in second year - no differences found between procedures: Serious non mesh adverse effects - (Mean = 0·66; 95% CI 0·19 to 2·30); Any mesh complications - ( NTR <1% v TM 6%); Surgical removal - ( NTR 0% v TM 4%); Conservative treatment - ( NTR <1% v TM <1%); No treatment - ( NTR 0% v TM <1%); De novo mesh procedure - ( NTR 0% v TM 5·3%) Concomitant mesh procedure - ( NTR <1% v TM <1%). Quality of Life Outcomes Prolapse-related QoL score - no significant differences noted at: 6 months - (Mean = 0·22, 95% CI -0·16 to 0·60); 1 year - (Mean = 0·13, 95% CI -0·25 to 0·51); 2 years - (Mean = 0·15, 95% CI -0·23 to 0·54); EQ-5D-3L score - no significant differences noted at: 6 months - (Mean = 0·01, 95% CI -0·02 to 0·04); 1-year - (Mean = 0·01, 95% CI -0·02 to 0·04); 2-years - (Mean = 0·02, 95% CI -0·02 to 0·06).	"The PROSPECT study showed that augmenting a primary transvaginal anterior or posterior prolapse repair with non-absorbable synthetic mesh or biological graft confers no symptomatic or anatomical benefit to women in the short term. More than one in ten women had a mesh complication, but most were asymptomatic, and most of the mesh exposures measured less than 1 cm². Although no evidence was apparent of differences between standard, mesh, or graft repair in other adverse effects up to 2 years after surgery, mesh use did result in the need for additional surgical procedures for exposures and extrusion in the first 2 years, which might be considered to be an unnecessary risk. This additional risk suggests that in the future mesh should only be used in the context of trials aimed at identifying benefit from modifying mesh type or insertion techniques, or in defined categories of high-risk women." (pg. 11-12).