Management of Mesh Complications
Taylor John Brueseke
Daniel Jacob Meller
HISTORICAL PERSPECTIVE
The potential value of surgical mesh can be traced to the late 19th century. In 1890, Viennese surgeon Theodor Billroth theorized that a new prosthetic material could efficiently close hernia defects.1 In the following years, unsuccessful attempts were made to create such a mesh from a wide variety of naturally occurring surgical materials (e.g., cotton, silk); however, these procedures failed due to infection, rejection, or recurrence.2 It was not until 1955 that Francis Usher at Baylor College developed the first successful mesh. The group evaluated new synthetic materials developed in the post-World War II period, including nylon, Orlon, Dacron, and Teflon. Shortcomings, including foreign body reaction, sepsis, rigidity, fragmentation, loss of tensile strength, and encapsulation, were noted in their work. One material made of polyethylene, Marlex, was discovered to be suitable for implantation. Over the next 2 years, the team worked to develop a safe and effective product, eventually settling on a woven mesh with large pores. This key feature encouraged interstitial growth of the tissue through the mesh. The team finally switched to knitted polypropylene, which could be autoclaved, had firm borders, permitted two-way stretching, and could be rapidly incorporated, and published their findings in 1958.2 This work was foundational for the development of modern mesh hernia repair techniques, the precursor to mesh-augmented vaginal prolapse repairs. History specific to sacrocolpopexy began in the late 19th century when Freund (1889) and Kustner (1890) described procedures in which the vaginal vault was fixed to the anterior longitudinal ligament by the interposition of an autologous graft. In 1958, Huguier and Scali used cutaneous flaps to successfully complete a similar procedure. Finally, in 1974, Scali was the first to report the use of a synthetic graft for abdominal repair of pelvic organ prolapse (POP).3,4
The modern era of pelvic mesh began in the 1990s and was defined by the meteoric rise and fall of vaginally placed mesh for the treatment of urinary incontinence and prolapse. In 1996, Boston Scientific received U.S. Food and Drug Administration (FDA) premarket approval for the ProteGen Sling, the first transvaginal mesh to be approved for marketing in the United States. By citing ProteGen as a direct or indirect predicate device, Mentor, Ethicon, American Medical Systems, Gyne Ideas, Tyco, and Caldera all gained approval for marketing under the FDA’s fast track 510(k) system which did not require any form of human study to gain marketing approval. In March of 1999, Boston Scientific pulled ProteGen from the market citing higher than expected vaginal erosion and dehiscence rates. However, devices that obtained FDA approval by using ProteGen as a predicate device were not required to be removed from the market, and numerous additional devices continued to be developed. In 2002, Ethicon began marketing Gynemesh PS, the first preconfigured surgical mesh for POP, opening the gates for wide-spread adoption of nearly 100 different “mesh kits” all marketed as less invasive alternatives to abdominal surgery but ultimately found to have high complication rates when brought into general use.
U.S. FOOD AND DRUG ADMINISTRATION RESPONSES TO COMPLICATIONS ASSOCIATED WITH VAGINAL MESH
The rapid and widespread adoption of mesh kits brought mesh-augmented pelvic floor disorder surgery to large number of surgeons with varying degrees of reconstructive surgical experience. This brought with it a growing concern for complications both within the medical community and literature. Between 2005 and 2007, the FDA received over 1,000 vaginal mesh-related medical device reports adverse events to the Manufacturer and User Facility Device Experience (MAUDE) database.5 As word spread and skepticism of safety claims by manufacturers grew, the FDA6 released a safety communication on October 20, 2008, calling attention to “rare but serious consequences” associated with transvaginal placement of surgical mesh to treat POP and stress urinary incontinence. These complications included erosion (more currently referred to as exposure) through vaginal epithelium, infection, pain, urinary problems, and recurrence of prolapse and/or incontinence. Initial recommendations to physicians included calls to obtain specialized training before implanting mesh kits for POP and recommendations for heightened vigilance for adverse effects.
Concerns continued to grow between January 1, 2008, and December 31, 2010, as the FDA’s MAUDE database received 2,874 additional reports of complications associated with vaginal mesh devices. On July 13, 2011, the FDA7 released a safety communication and a white paper citing surgical mesh for transvaginal repair of POP as an area of “continuing serious concern.” The most notable changes from their 2008 report include the statements: (1) Serious complications associated with surgical mesh for vaginal repair of POP are not rare and (2) it is not clear that transvaginal POP repair with mesh is more effective than traditional nonmesh repair. As such, the panel concluded in January 2012 (1) the risk/benefit profile of surgical mesh for transvaginal POP repair was not well established, (2) vaginally placed mesh for prolapse should be reclassified from class II (low- to moderate-risk devices) to class III (high-risk devices), and (3) companies must conduct postmarket surveillance studies to establish safety and effectiveness. Ultimately, 131 postmarket 522 study orders to 34 manufacturers of vaginal mesh were issued. Most manufacturers elected to cease marketing vaginal mesh after receiving the 522 orders, although Boston Scientific and Coloplast committed to women’s health by investing in the performance of these studies. Finally, on April 16, 2019, citing insufficient evidence “that the probable benefits of these devices outweigh their probable risks,” the FDA ordered all manufacturers of “surgical mesh intended for transvaginal repair of anterior compartment prolapse (cystocele)” to stop selling and distributing their products immediately.8 It is difficult to overstate the impact this regulation has had on the surgical management of pelvic floor conditions, but it is a strong reminder of the need to establish the safety and efficacy of medical devices prior to their widespread adoption.
The FDA’s willingness to grant premarket approval to dozens of new devices deemed “substantially equivalent” to existing products had a significant influence on the decisions of medical societies and governing bodies around the globe and international use of the procedures quickly became widespread in the late 2000s. However, regulation began to be imposed in the United Kingdom, Scotland, Wales, and Ireland soon after release of the influential 2017 PROSPECT study,9 in which patients with primary POP were randomized to conventional anterior colporrhaphy, anterior colporrhaphy with synthetic mesh implant, and anterior mesh repair with biologic implant. Although the procedures resulted in similar patient-oriented subjective treatment success, 12% of patients undergoing mesh-augmented repairs experienced a mesh-related complication. After publication, the United Kingdom, through the National Institute for Care and Health Excellence (NICE) committee, drafted new guidance recommending that mesh-augmented POP repair be restricted to clinical studies. In 2019, NICE expanded opportunities for mesh surgery providing certain requirements are met including (1) women be informed about the type of mesh to be used and whether or not it is permanent; (2) details of the procedure and its subsequent short- and long-term outcomes are recorded in a national registry; and (3) written information about the implant, including its name, manufacturer, and date of insertion, are provided to the patient.10 Responses in other countries have varied widely.11
CLASSIFICATION AND TERMINOLOGY OF VAGINAL MESH COMPLICATIONS
The use of commonly agreed on terms is critical to the expansion of standardized research into the causes and treatments for vaginal mesh complications. Currently, some terms have entered the common vernacular that may not accurately reflect the pathophysiology involved. For example, the term mesh “erosion” is commonly used to describe mesh that is visible in the vagina. However, the word erosion implies that friction or pressure has caused the tissue covering the mesh to wear away. Current evidence suggests exposure of mesh into the vagina is the result of a significantly more complex pathophysiologic host response to the graft that involves upregulation of matrix metalloproteinases and collagenases (see “Pathophysiology of Mesh Exposure” section). As such, the use of standardized terminology should be employed to accurately describe the complication that is present and terms that imply causation should be avoided unless accurately descriptive. American Urogynecologic Society/International Urogynecological Association (AUGS/IUGA) have developed a consensus-based terminology and classification report for prosthesis and graft complications that aims to improve clinical practice and research.12 That work is summarized in Table 53.1.
In addition to the anatomical mesh complications listed earlier, functional complications have been reported after the placement of vaginal mesh. These include the following:
Pain
Acute and chronic pelvic pain
Provoked and unprovoked
Dyspareunia
Partner dyspareunia
Vaginal bleeding/discharge
Infection of the implant
Fistula formation
Recurrent POP
Recurrent stress urinary incontinence
RISK FACTORS FOR VAGINAL MESH COMPLICATIONS
As described earlier, there are multiple potential complications that can result from the implantation of vaginal mesh, the most common of which is exposure of mesh into the vagina. Multiple risk factors for vaginal mesh exposure have been studied and is briefly reviewed here.
TABLE 53.1 AUGS/IUGA Definitions and Descriptions for Anatomical Mesh Complications | ||||||||||||||||||
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Graft Material
As recognized from the inception of graft-augmented reconstructive surgery, the material used in surgical management of POP has been shown to directly influence risk of exposure. Perhaps the most widely cited complication rates for various mesh types are published in the Colpopexy and Urinary Reduction Efforts (CARE) trial,13 a randomized surgical trial of 322 stress-continent women with stages 2 to 4 POP that investigated the benefit of an adjuvant Burch colposuspension at the time of open sacral colpopexy. In addition to allograft material (cadaveric rectus facia or fascia lata), and xenograft material (hexamethylene diisocyanate cross-linked porcine dermis [Pelvicol, CR Bard, Murray Hill, NJ]), a variety of synthetic materials were used in the study. These include woven polyester (Mersilene, Ethicon, Somerville, NJ), polypropylene (Prolene, Ethicon, Somerville, NJ), soft weave polypropylene (Gynemesh, Ethicon Women’s Health & Urology, Cincinnati, OH), and expanded polytrafluroethylene (ePTFE, Gore-Tex, GORE Medical, Newark, DE). Synthetic mesh was the most common graft, used in 92% of trial procedures. Of those cases, the most commonly used materials were woven polyester (42%) (Mersilene, Ethicon, Somerville, NJ) and polypropylene (48%), with minimal usage of ePTFE (6%). At 2 years after surgery, the study found a significantly higher risk of mesh erosion in women who had ePTFE mesh (alone or in combination) compared to those without ePTFE mesh (4 of 21 [19%] vs. 16 of 301 [5.3%]; odds ratio [OR] 4.2, 95% confidence interval [CI] 1.3 to 13.9). The extended CARE study13 reported 7-year follow-up data, including mesh exposure rates, but unfortunately, loss to follow-up was high. Of the originally enrolled 322 women, only 122 were available for data collection at 7 years. Given the high loss to follow-up, the authors employed modeling with right censoring and projected that 10.5% of patients would have experienced mesh exposure by 7 years postsurgery. Although this is the most robust data available regarding mesh exposure rates, debate continues among surgeons regarding how to apply it when counseling patients given that many of the meshes used in this study are no longer in clinical use and the right censoring employed in the model development may inherently exclude patients less likely to have had a mesh-related complication.
Concomitant Hysterectomy
Concomitant hysterectomy at the time of mesh-augmented prolapse repair is a debated risk factor for vaginal mesh exposure in patients undergoing sacrocolpopexy. In the CARE trial,13 concurrent hysterectomy was performed in 83 of 322 (26%) of participants and the risk of mesh/suture exposure was higher in this group (60% exposure rate in patients with concomitant hysterectomy vs. 24% in those with prior hysterectomy [OR 4.9, CI 1.9 to 12.4]). Hysterectomy was also associated with increased risk of mesh exposure in a retrospective cohort study of 188 women who underwent minimally invasive sacrocolpopexy between November 2004 and January 2009 at the University of California, San Diego or Kaiser Southern California.16 Nineteen (10%) of these women experienced mesh erosion with a higher rate seen in patients who underwent concomitant total vaginal hysterectomy compared with women who had a prior hysterectomy (23% vs. 5%, P = .003). In contrast, other studies suggest that concomitant hysterectomy with robotic sacrocolpopexy (RSCP) may be protective or not associated with mesh exposure. In a study comparing mesh exposure rates 6 weeks after surgery that included 230 participants, 118 (51.7%) had RSCP only, and 112 (48.7%) had RSCP with hysterectomy.17 Of the nine mesh exposures identified, three occurred in the concomitant hysterectomy with RSCP group, whereas six occurred in the RSCP only group. There was no significant difference in the mesh exposure rate between total and supracervical hysterectomy. Similarly, in a retrospective comparison of exposure rates between commercial mesh kits and
surgeon-fashioned mesh-augmented vaginal repairs, no significant difference in exposure rate was seen between patients who underwent concomitant hysterectomy compared to previous hysterectomy.18
surgeon-fashioned mesh-augmented vaginal repairs, no significant difference in exposure rate was seen between patients who underwent concomitant hysterectomy compared to previous hysterectomy.18
Although the debate continues over whether performing hysterectomy at the time of prolapse repair increases the risk of mesh exposure, this potentially increased risk of mesh exposure should be used for counseling and not preclude apical suspension in patients with indications for graft-augmented apical prolapse repair.
Surgeon Volume and Intraoperative Complications
Among the multitude of factors that influence adverse outcomes after mesh surgery, the most striking may be the risk of complication stratified by low-, intermediate-, and high-volume surgeons. In a 5% random national sample of female Medicare beneficiaries obtained from the Centers for Medicare and Medicaid Services, medium- and high-volume surgeons performed only 25% and 22% of the cases, respectively, but had rates of reoperation of 2% and 3%. However, low-volume surgeons performed the majority of cases (53%) and had the highest rates of reoperation (6%).19 The high relative risk of complication seen in low- versus high-volume surgeons has been identified repeatedly in other publications.20,21,22,23 On a related note, intraoperative complications, such as organ perforation, have been associated with mesh complications. In a study of 77 patients experiencing vaginal mesh exposure or bladder/urethra mesh perforation, trocar injury during surgery was associated with an increased risk of mesh perforation.24 This concern requires the surgeon to thoughtfully consider how to manage complications such as trocar perforation during midurethral sling placement or cystotomy during sacrocolpopexy. Intraoperative factors will guide high-volume surgeons in determining if a midurethral sling mesh can still be placed and the trocar safely repositioned away from the perforation site during midurethral sling placement and that sacrocolpopexy mesh can be placed if the cystotomy can be closed in a tension-free manner with overlapping layers and not in juxtaposition to the mesh. For surgeons with limited experience in these procedures, data suggest that graft placement should be deferred in the event of an intraoperative complication.
Radiation
Pelvic floor disorders are common in gynecologic cancer survivors,25 and radiation therapy is frequently indicated to obtain cure or remission of these malignancies. The long-term effects of radiation include progressive vascular damage, obliterative arteritis, ischemia, and fibrosis.26 Intuitively, this reduction in tissue quality is thought to predispose women to developing vaginal mesh exposure, but limited data exist to guide reconstructive surgeons when counseling patients on the degree of increased relative risk of complication in this scenario.27,28
Vaginal Estrogen Exposure
Vaginal estrogen (VE) exposure is known to stimulate growth of the stratified squamous epithelium resulting in a thickening of the vaginal wall.29 Despite these observations, perioperative estrogen exposure has not been shown to be protective against vaginal mesh exposure. A randomized controlled trial of 186 women who underwent a single surgeon noninferiority study compared 93 women who received twice weekly VE cream with 93 women who did not. Mesh exposure was documented in 16.1% (15 of 93) in the VE group versus 12.9% (12 of 93) in the non-VE group. At 1 year, the study concluded that no VE therapy before surgery was noninferior to VE therapy.30 Similar findings were observed in a retrospective study of 1,544 patients, of which 248 (16%) used estrogen preoperatively. Thirtyseven (2.4%) of total patients experienced mesh exposure, but no significant difference was seen in the mesh exposure rate between women who used estrogen preoperatively compared to those who did not (OR 0.79, CI 0.26 to 2.38).31 It is not clear why preoperative estrogen treatment does not reduce the risk of mesh exposure; however, the explanation is likely multifactorial.
Age
Age is an interesting risk factor for mesh exposure. As vaginal atrophy becomes more prevalent with age,32 one may expect that older patients would be more likely to experience mesh exposure. However, studies of women undergoing transvaginal mesh-augmented prolapse repair33 and midurethral mesh slings34 have shown that younger age is associated with an increased risk of mesh exposure. Although the reasons for this observation are not certain, it is possible that younger patients are more likely to engage in sexual activity and that this activity may introduce a mechanical stress on the tissues. Alternatively, it has been hypothesized that the increased vascularity present in younger women may predispose to hematoma formation which impairs wound healing.
Smoking
Although studies have reported differing associations between smoking and mesh exposure,14,16,20,24,31,34,35,36,37 most surgeons agree that smoking is a risk factor for mesh exposure. Smoking is well known to cause microvascular dysfunction which impairs wound healing38 presumably promoting epithelial degradation of vaginal tissue overlying vaginal mesh.
PATHOPHYSIOLOGY OF MESH EXPOSURE
Although multiple mechanisms for mesh exposure have been proposed, including mechanical erosion, infection, or hematoma formation, it is likely that the full explanation of vaginal mesh exposure is complex and multifactorial. A detailed explanation of the cellular response to graft implantation is beyond the scope of this chapter, but one key element may be macrophage invasion, which is a common host response to the implantation of a foreign body, including polypropylene. Two major macrophage subtypes that are involved in the response to vaginal mesh include the M1 and M2 subtypes. The M1 macrophage response results in chronic inflammation which can result in tissue damage and destruction. M2 macrophage activity results in chronic fibrosis and encapsulation of the mesh. Current research suggests that placement of polypropylene vaginal mesh can alter the balance of the M1 versus M2 macrophage activity39 and that this disruption of homeostasis contributes to the degradation of vaginal epithelium overlying vaginal mesh. T cells also appear to play a critical role in the long-term host response and may be a central pathway that leads to complications.40 Additional basic science research is needed to more fully elucidate the cellular and molecular host response to the implantation of vaginal mesh.
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