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Contents: Original Research

Long-term Device Outcomes of Mesh Implants in Pelvic Organ Prolapse Repairs

Chughtai, Bilal MD; Mao, Jialin MD, MS; Asfaw, Tirsit S. MD; Heneghan, Carl PhD; Rardin, Charles R. MD; Sedrakyan, Art MD, PhD

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doi: 10.1097/AOG.0000000000003689
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In the past two decades, more than 2 million women have been implanted with transvaginal mesh in the United States for both stress urinary incontinence and pelvic organ prolapse (POP).1 Transvaginal mesh devices were widely adopted to address the high failure rates of traditional POP repairs.2 However, on April 16, 2019, the U.S. Food and Drug Administration (FDA) ordered all mesh manufacturers to stop selling and distributing their products for transvaginal repair of anterior prolapse.3 Thousands of complications have been reported to the FDA and more than 73,000 federal lawsuits have been filed against manufacturers of transvaginal mesh products.4,5 Despite a 20-year journey from device approval to global adoption, there was no “reasonable assurance of safety and effectiveness for these devices.”3

There is evidence that mesh reduced some risks of surgical failure, but also led to unique complications such as mesh exposures or erosion into neighboring organs. We have previously demonstrated that mesh use has been associated with a higher risk of reintervention within 1 year after POP repair in the United States, and large randomized trials from Great Britain have confirmed this higher risk of reintervention.6–8 Accumulating evidence of harm has led to the restriction of mesh implants in Australia, New Zealand, and the United Kingdom.10

Given the previous widespread use of mesh implants for prolapse in the United States, the rates of associated adverse outcomes over the long term, such as reinterventions, are important to understand. We previously reported short-term outcomes of mesh in POP surgery over a 12-month follow-up period. In this study, we analyzed a population-based cohort to evaluate the long-term incidence of mesh-related complications and reintervention after POP repairs.

METHODS

We used data from the New York State Department of Health Statewide Planning and Research Cooperative System.12 The Statewide Planning and Research Cooperative System is a statewide, all-age, all-payer database that collects records of every hospital discharge, ambulatory and outpatient surgery, and emergency room admission. Data are submitted by health care facilities to New York State. The state conducts periodic audits to ensure data reliability and validity. The database captures patient characteristics, primary and secondary diagnoses and procedures, length of stay, and charges. A unique personal identifier is assigned to every patient and encrypted to allow longitudinal analyses without compromising the confidentiality of the records. This study has been approved by Weill Cornell Medicine Institutional Review Board.

We included all women undergoing surgeries for POP in inpatient and outpatient surgical settings between 2008 and 2016 in New York State. Procedures and the diagnosis of POP were identified using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM), International Classification of Diseases, 10th Revision, Procedure Coding System (ICD-10-PCS), and Current Procedural Terminology Coding System, 4th Edition (CPT-4) codes. The definition of mesh was consistent with our previous study6: any augmenting material, including synthetic and biological materials determined by specific ICD-9, ICD-10, and CPT-4 procedure codes. Every patient's first record of POP surgery was used. Before 2008, there were no mesh-specific codes and only general prolapse repair codes were available. Therefore, we included only procedures performed after 2008 and excluded patients who had any prior POP surgeries to ensure that the first POP repair procedure of each patient was identified as the index procedure. This study was limited to the transvaginal use of mesh; transabdominal procedures (eg, sacrocolpopexy) were excluded owing to their absence in the FDA safety communications.

The exposure of interest was the use of transvaginal mesh during POP repair. The primary outcome was reintervention after initial POP repair procedures—defined as a subsequent POP repair procedure, or a mesh revision or removal procedure. Patient characteristics assessed were age, race and ethnicity, insurance status, comorbidities, and procedural variables. Comorbidities were identified by diagnosis codes using algorithms validated by Elixhauser.13 Procedural variables identified were procedure year, concurrent hysterectomy, concurrent sling procedure, and apical support repair procedure. Hospital volume was calculated as the average annual volume of POP procedures, and categorized into low-, medium-, and high-volume centers based on tertiles.

Baseline characteristics were assessed for patients undergoing POP repair with or without mesh. We used chi-square tests and Student's t test to examine differences in patient characteristics between groups. We performed propensity score matching to account for differences in patients' baseline characteristics between these two groups. To obtain the propensity scores for each individual, we used a multivariable logistic regression based on patient demographics, comorbidities, procedural characteristics (procedure year, concurrent hysterectomy, concurrent sling procedure, and apical support repair procedure), and hospital volume. A missing category was created for missing race information. We then performed nearest neighbor matching of the two groups at a 1:1 fixed ratio, using a caliper width of 0.2 of the SD of the logit of the propensity score. Balance in baseline covariates in the matched cohort was examined using standardized differences.14 A covariate is considered balanced between groups when the absolute value of standardized difference is less than 0.1.

We analyzed reintervention as a time-to-event outcome. The estimated cumulative risks of reintervention at 5 years after the index POP repair procedure were obtained using Kaplan-Meier analysis for the unmatched and matched cohort with 95% CIs. We further examined the primary diagnosis related to patients' first reintervention. A Cox proportional hazard model was used to assess the differences in risks of reintervention between the mesh and nonmesh groups. For matched data, a robust sandwich variance estimator was used in the Cox model to account for the paired data structure. The proportional hazards assumption was tested to confirm the adequacy of the model. All analyses were performed using SAS 9.3 (Cary, NC).

RESULTS

We identified 54,194 women undergoing POP repairs (12,989 with mesh, and 41,205 without mesh). Mean age at surgery was 59.8 (±13.1) years. Patients undergoing POP repair with mesh were older (61.9 vs 59.1 years, P<.001) and more likely to have comorbidities than those undergoing POP repair without mesh (Table 1). Patients undergoing POP repair with mesh were more likely to have concurrent sling procedure (52.2% vs 38.1%, P<.001) and apical support (72.3% vs 55.0%, P<.001); but less likely to have concurrent hysterectomy (45.2% vs 51.3%, P<.001), when compared with those undergoing POP repair without mesh. After propensity score matching, 12,284 pairs of women were formed, and baseline characteristics in the two groups were balanced.

Table 1.
Table 1.:
Characteristics of Patients Undergoing Pelvic Organ Prolapse Repair With and Without Mesh in New York State, 2008–2016

The number of mesh-based POP repairs decreased from 2,118 in 2011 to 1,078 in 2014 (P<.001, Fig. 1) but remained unchanged from 2014 to 2016 (P=.07). The overall number of prolapse repairs, with or without mesh, decreased from 6,984 in 2008 to 5,097 in 2016.

Fig. 1.
Fig. 1.:
Number of mesh- and nonmesh-based transvaginal pelvic organ prolapse repair procedures among New York State residents between 2008 and 2016.Chughtai. Long-term Mesh Implants in Pelvic Organ Prolapse. Obstet Gynecol 2020.

The median length of follow-up after the index procedure was 4.7 years (interquartile range: 2.4–6.8 years). Median follow-up in the matched cohort was 5.0 years for patients undergoing POP repair without mesh and 4.9 years for patients undergoing POP repair with mesh. In the matched cohort, 717 women who received POP repair without mesh and 992 patients who received POP repair with mesh had at least one reintervention.

Using Kaplan Meier analysis (Fig. 2), the estimated risk of undergoing reintervention at 5 years was 8.8% (95% CI 8.2–9.3%) in the mesh group and 6.3% (5.9–6.8%) in the nonmesh group in the matched cohort. When compared with POP repair without mesh in the matched cohort, POP repair with mesh was associated with a higher overall risk of reintervention during follow-up (hazard ratio [HR] 1.40, 95% CI 1.27–1.54, P<.001). In the subgroup analysis stratifying by hospital volume of POP repair, POP repair with mesh was consistently associated with a higher risk of reintervention during follow-up (low volume: HR 1.30, 95% CI 1.08–1.57, P=.006; medium volume: HR 1.61, 95% CI 1.32–1.96, P<.001; high volume: HR 1.36, 95% CI 1.19–1.56, P<.001).

Fig. 2.
Fig. 2.:
Cumulative risks of reintervention after initial pelvic organ prolapse surgery with and without mesh.Chughtai. Long-term Mesh Implants in Pelvic Organ Prolapse. Obstet Gynecol 2020.

Among mesh patients who had reinterventions, 18.5% had a reintervention related to mesh-related complications, with the remaining 81.5% receiving reinterventions related to new or recurrent prolapse, urinary complications and other reasons (Table 2). A time-to-event analysis showed that the risk of reintervention related to mesh complications persisted throughout the entire study period (Fig. 3). The estimated risk of reintervention associated with mesh complication at 5 years was 1.7% among patients undergoing POP repair with mesh compared with 0.7% among patients undergoing POP repair without mesh. The estimated risk of reintervention associated with repeat POP diagnosis was 5.8% in the mesh group and 4.5% in the nonmesh group.

Table 2.
Table 2.:
Primary Diagnosis Associated With Reintervention for Patients Who Underwent Mesh- and Nonmesh-Based Pelvic Organ Prolapse Repair in the Matched Cohort
Fig. 3.
Fig. 3.:
Cumulative risks of reintervention-related mesh complications after initial pelvic organ prolapse surgery with mesh.Chughtai. Long-term Mesh Implants in Pelvic Organ Prolapse. Obstet Gynecol 2020.

DISCUSSION

Our findings suggest that patients who underwent POP repair with mesh had a significantly higher risk of overall reintervention at 5 years (8.8% vs 6.3%) compared with a matched nonmesh cohort. This increased risk was observed across all levels of hospital volume in performing POP procedures. Almost one in five of the surgical reinterventions were coded as resulting from mesh-related complications. Further, there was no decline in mesh erosion rates over the study period, implying this is an ongoing risk. These rates almost double those published by a Cochrane Review in 2016, where only 8% of repeat surgical interventions were for mesh-related complications.15 This comprehensive review contained 37 randomized controlled trials (4,023 women) comparing transvaginal grafts compared with traditional native tissue repair for vaginal prolapse, which are typically performed by high-volume surgeons and centers. This rate of mesh complication may actually be underestimated given that only women who underwent reintervention are captured and not any of the women who had mesh erosions and complications that were conservatively managed in the office setting. Furthermore, our study included more than 12,000 matched patients and may better reflect a more real-world estimate.

Our group previously had reported that reintervention was higher after mesh-based repair of POP compared with nonmesh over a 12-month follow-up period.6 There is a continuous accumulation of mesh erosions and almost a 40% higher risk of reinterventions in patients receiving a mesh implant at a median follow-up of 5 years. Contrary to the traditional belief that mesh procedures reduce the recurrence of POP through good apical support, our results showed a higher rate of repeat POP surgery overall in women with mesh (652 patients; 5.3% of all patients) than in women without mesh (513 patients; 4.2% of all patients). Our more current data represent some of the longest follow-ups for POP repair in the United States and worldwide. For example, a systematic review of the complication and reintervention rates after apical vaginal prolapse repair included 24 studies and 3,425 patients with a mean follow-up of only 17.1 months (±SD 13.8 months).16 A Scottish study found that anterior and posterior compartment prolapse mesh procedures had significantly higher complication rates than nonmesh procedures over a median follow-up period of 5 years.8

Globally, there has been a public outcry and concern amongst regulators and governments about the use of transvaginal mesh. In March of 2017, the Scottish government released its report on mesh concluding, “current evidence does not indicate any additional benefit from the use of transvaginal implants (polypropylene mesh or biological graft) over native tissue repair for POP.”8,17 In December of 2017, the United Kingdom's National Institute for Health and Care Excellence published, “current evidence on the safety of transvaginal mesh repair of anterior or posterior vaginal wall prolapse shows there are serious but well-recognized safety concerns. Evidence of long-term efficacy is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research.”10 The Australian Therapeutic Goods Administration reported that “benefits of using transvaginal mesh products in the treatment of POP do not outweigh the risks these products posed to patients.”18 Transvaginal mesh for prolapse was removed from the market. The Ministry of Health in New Zealand requested manufacturers to stop marketing their products in the country, resulting in an effective ban of all transvaginal mesh.19

The first warning the FDA issued in 2008 was based on reports of more than 1,000 adverse events reported to the agency, but only after 2011 a stronger language in a second communication led to reduced mesh use.9 In 2016, the FDA reclassified transvaginal mesh for POP repair from a moderate-risk class II to high-risk class III device and required manufacturers to submit premarket approval applications to provide strong scientific evidence for their devices' safety and effectiveness.3 The FDA asked manufacturers to conduct postmarking studies on mesh in 2012. These studies progressed very slowly and did not accumulate the necessary long-term outcomes needed to answer key questions, which at least partially are related to the reluctance of surgeons to engage actively in these efforts. Consequently, the most recent FDA decision in 2019 against the use of transvaginal mesh for POP was justified based on a lack of manufacturers providing “reasonable assurance” of the long-term safety and effectiveness for POP.

The United States was late in the removal of mesh implants for POP despite the numerous safety warnings and adverse events reported from patients' narratives. We suggest that the factors that prevented timely response to the FDA warning might be related to patient-reported outcomes favoring mesh use in specific subgroups such as those with recurrent prolapse or specific conditions such as levator avulsion.20 Furthermore, the Society of Gynecologic Surgeons released a systematic review of mesh use in transvaginal prolapse repair, which concluded that, “Synthetic mesh augmentation of anterior wall prolapse repair improves anatomic outcomes and bulge symptoms compared with native tissue repair. Biological grafts do not improve prolapse repair outcomes in any compartment. Mesh erosion occurred in up to 36% of patients, but reintervention rates were low.”21 Reported higher failure rates of some nonmesh repairs such as sacrospinous vaginal colpopexy may have also supported continued mesh use.22

The limitations of the current dataset do not permit comparison of relative morbidity of reintervention for recurrent prolapse compared with reintervention for mesh complications and do not account for the morbidity of recurrent POP when the patient does not seek or receive surgical reintervention. We were not able to detect recurrent POP symptoms among patients choosing not to undergo surgical reintervention, or to detect patients opting for nonsurgical treatments of recurrent prolapse, such as pessaries. Because procedure codes for reoperations were not specific to whether it was removal or revision, we were not able to report mesh removal separately. Unfortunately, information regarding the severity of POP and symptoms and patient characteristics such as smoking status cannot be captured through our data. Furthermore, the location of the mesh is unknown, along with the type of mesh being used; this study is unable to distinguish biological from synthetic mesh, or ultralight compared with other types of synthetic mesh. Also, this dataset does not provide information about the training or experience of the implanting surgeon, nor of the optimal management of patients experiencing mesh complications. There might be residual confounding as a result of not matching on these unmeasured variables. Follow-up of patients was limited to within New York State. We were not able to capture reoperation if patients sought care in other states. We limited to New York State residents for this reason, but might have missed some of the reoperations. Owing to the matching design, nondifferential censoring was more likely, which would lead to bias toward null (ie, HR). We excluded patients who had transabdominal procedures (eg, sacrocolpopexy) owing to their absence in the FDA safety communications and the unique side-effect profile of transabdominal procedures for POP.

There are several lessons learned from the mesh experience. First, although there is no doubt of the importance of traditional academic studies such as randomized controlled trials, the use of transvaginal mesh for prolapse is an example of how difficult it can be to understand the relative benefits and risks of new interventions. Second, the ability to study real-world effectiveness and safety concerns will play an increasingly vital role in the future. Negative news travels faster and longer, and without solid evidence of benefits in real word settings, adverse events will get most of the attention of policy makers. Third, it is critically important to make national investments in device surveillance, systems that include more comprehensive information about the nature and burden of POP recurrence, different types of re-treatment, patient-reported outcomes, and information about implanting surgeons. The physicians should actively engage in data collection if they like their devices and see benefits associated with their use. One such initiative is the “ACQUIRE” registry,23 which is, “a national urogynecology-focused registry open to all physicians that is designed to measure and report health care quality and patient outcomes” and is supported by an FDA grant from the Medical Device Epidemiology Network (MDEpiNet).24 In the United Kingdom, the National Institute for Health and Care Excellence has recommended that “if a synthetic polypropylene mesh is inserted, the details of the procedure and its subsequent short- and long-term outcomes must be collected in a national registry.”25

Even though transvaginal mesh has been removed from the market, our data suggest that the risk of mesh complications does not diminish over time and these women warrant close follow-up. Continued surveillance of mesh in POP repairs is essential to ensure safety for the women who have already been implanted. Registries should include comprehensive information about the nature and burden of POP recurrence, different types of re-treatment, patient-reported outcomes, and information about implanting surgeons.

REFERENCES

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