Outcomes After Female Urinary Incontinence and Pelvic Organ Prolapse Surgery

D 1258 OULU 2014 D 1258

UNIVERSITY OF OULU P.O.BR[ 00 FI-90014 UNIVERSITY OF OULU FINLAND ACTA UNIVERSITATIS OULUENSIS ACTA UNIVERSITATIS OULUENSIS ACTA

SERIES EDITORS DMEDICA Virva Nyyssönen

ASCIENTIAE RERUM NATURALIUM Nyyssönen Virva Professor Esa Hohtola TRANSVAGINAL MESH- BHUMANIORA AUGMENTED PROCEDURES University Lecturer Santeri Palviainen CTECHNICA IN GYNECOLOGY Postdoctoral research fellow Sanna Taskila OUTCOMES AFTER FEMALE URINARY DMEDICA INCONTINENCE AND PELVIC ORGAN PROLAPSE Professor Olli Vuolteenaho SURGERY ESCIENTIAE RERUM SOCIALIUM University Lecturer Veli-Matti Ulvinen FSCRIPTA ACADEMICA Director Sinikka Eskelinen GOECONOMICA Professor Jari Juga

EDITOR IN CHIEF Professor Olli Vuolteenaho PUBLICATIONS EDITOR

Publications Editor Kirsti Nurkkala UNIVERSITY OF OULU GRADUATE SCHOOL; UNIVERSITY OF OULU, FACULTY OF MEDICINE, INSTITUTE OF CLINICAL MEDICINE, ISBN 978-952-62-0562-5 (Paperback) DEPARTMENT OF OBSTETRICS AND GYNECOLOGY; ISBN 978-952-62-0563-2 (PDF) OULU UNIVERSITY HOSPITAL ISSN 0355-3221 (Print) ISSN 1796-2234 (Online)

ACTA UNIVERSITATIS OULUENSIS D Medica 1258

VIRVA NYYSSÖNEN

TRANSVAGINAL MESH-AUGMENTED PROCEDURES IN GYNECOLOGY Outcomes after female urinary incontinence and pelvic organ prolapse surgery

Academic dissertation to be presented with the assent of the Doctoral Training Committee of Health and Biosciences of the University of Oulu for public defence in auditorium L4 of Oulu University Hospital, on 10 October 2014, at 12 noon

Supervised by Docent Markku Santala Docent Anne Talvensaari-Mattila

Reviewed by Professor Seppo Heinonen Doctor Kari Nieminen

Opponent Docent Pentti Kiilholma

ISBN 978-952-62-0562-5 (Paperback) ISBN 978-952-62-0563-2 (PDF)

ISSN 0355-3221 (Printed) ISSN 1796-2234 (Online)

Cover Design Raimo Ahonen

JUVENES PRINT TAMPERE 2014 Nyyssönen, Virva, Transvaginal mesh-augmented procedures in gynecology. Outcomes after female urinary incontinence and pelvic organ prolapse surgery University of Oulu Graduate School; University of Oulu, Faculty of Medicine, Institute of Clinical Medicine, Department of Obstetrics and Gynecology; Oulu University Hospital Acta Univ. Oul. D 1258, 2014 University of Oulu, P.O. Box 8000, FI-90014 University of Oulu, Finland

Abstract Problems of female urinary incontinence and pelvic organ prolapse are common. Traditional operative techniques in the treatment of these conditions have unsatisfactory efficacy outcomes and involve complications. Attempts have been made to solve this problem with synthetic meshes, but with the use of meshes mesh-related complications have appeared. The situation is difficult because the number of different meshes, techniques and instrumentations is numerous. The present study was conducted to investigate the safety issues and complication rates of four structurally different polypropylene meshes used in transvaginal surgery when treating female urinary incontinence and apical or posterior vaginal prolapse. Vaginal mesh exposures were under special interest. Subjective outcome and patient satisfaction of tension-free vaginal tape (TVT) and transobturator tape (TOT) methods in the treatment of female urinary incontinence were reported. Objective and subjective cures of posterior intravaginal sling (PIVS) and Elevate®Posterior procedures were investigated. The incidence of vaginal mesh exposure varied between different meshes. The highest exposure incidence, 16–25%, was found with heavyweight microporous multifilament mesh. The lowest mesh exposure incidence, 0.9%, was seen with lightweight macroporous monofilament mesh. The subjective cures of the TVT and TOT procedures were 84% and 80%, and patient satisfaction rates were 79% and 74%, respectively. The objective cure of posterior IVS was only 69% and patient satisfaction rate 62%, while Elevate®Posterior reached 84–98% objective cure rate, depending on the definition used. Subjective efficacy of this procedure was 86%. According to this study, the use of heavyweight microporous multifilament should be abandoned because of the intolerably high vaginal mesh exposure incidence. The subjective efficacy and patient satisfaction of TVT and TOT procedures are satisfactory. Both objective and subjective cure rates of posterior IVS are poor, whereas the Elevate®Posterior technique with lightweight macroporous monofilament mesh presents promising results.

Keywords: mid-urethral sling, objective cure, patient satisfaction, pelvic organ prolapse, subjective cure, transvaginal mesh, urinary incontinence, vaginal mesh exposure

Nyyssönen, Virva, Verkkoavusteiset transvaginaaliset leikkaustekniikat gynekologiassa. Naisen virtsankarkailu- ja laskeumakirurgian tulokset Oulun yliopiston tutkijakoulu; Oulun yliopisto, Lääketieteellinen tiedekunta, Kliinisen lääketieteen laitos, Synnytys ja naistentaudit; Oulun yliopistollinen sairaala Acta Univ. Oul. D 1258, 2014 Oulun yliopisto, PL 8000, 90014 Oulun yliopisto

Tiivistelmä Virtsankarkailu ja emättimen monimuotoiset laskeumat ovat naisilla yleisiä. Näitä vaivoja perin- teisillä leikkaustekniikoilla hoidettaessa leikkaustulokset ovat olleet epätyydyttäviä sekä tehon että komplikaatioiden ilmaantuvuuden osalta. Ongelmaa on yritetty ratkaista synteettisien verkkojen avulla, mutta verkkojen käytön myötä niihin on havaittu liittyvän myös ongelmia. Tilan- netta hankaloittaa myös erilaisten verkkomateriaalien, tekniikoiden ja instrumentaatioiden run- saslukuisuus. Tässä tutkimuksessa selvitettiin neljän rakenteeltaan erilaisen polypropyleenistä valmistetun verkon turvallisuutta ja komplikaatioiden esiintyvyyttä hoidettaessa verkkoavusteisesti naisen virtsankarkailua ja emättimen pohjukan tai emättimen takaseinämän laskeumaa. Erityisenä kiin- nostuksen kohteena olivat verkkoihin liittyvät eroosiot. Virtsankarkailun hoidon subjektiivinen teho ja potilastyytyväisyys selvitettiin käytettäessä tension-free vaginal tape- (TVT) ja transobturator tape (TOT) -tekniikoita. Laskeumien hoidon objektiivinen ja subjektiivinen teho arvioi- tiin käytettäessä posterior intravaginal sling- (PIVS) ja Elevate®Posterior -tekniikoita. Verkon eroosioiden ilmaantuvuus vaihteli rakenteeltaan erilaisten verkkojen välillä siten, että tiivistä mikroporoottista multifilamenttinauhaa käytettäessä eroosioiden ilmaantuvuus oli 16–25 %, kun taas kevyttä makroporoottista monofilamenttiverkkoa käytettäessä eroosioprosentti oli 0.9. TVT-menetelmällä saavutettiin 84 %:n ja TOT menetelmällä 80 %:n subjektiivinen teho. TVT-potilaista hoitoon tyytyväisiä oli 79 % ja TOT-potilaista 74 %. Posteriorinen IVS saavutti vain 69 %:n objektiivisen tehon pohjukan laskeuman hoidossa. Potilastyytyväisyys oli samaa luokkaa, 62 %. Sen sijaan Elevate®Posterior-menetelmää käytettäessä saavutettiin käytetystä tehon määritelmästä riippuen 84–98 %:n objektiivinen teho. Subjektiivinen teho tällä menetel- mällä oli 86 %. Tämän tutkimuksen perusteella tiiviin mikroporoottisen multifilamenttiverkon käyttöön liit- tyvä verkkoeroosioiden määrä on sietämättömän suuri. Vakiintuneiden TVT- ja TOT-menetelmi- en subjektiivinen teho ja potilastyytyväisyys ovat hyväksyttäviä. PIVS-metodia käytettäessä sekä objektiivinen että subjektiivinen tulos on huono, kun taas Elevate®Posterior-menetelmän ja siinä käytetyn kevyen verkon käytöstä saadut tulokset ovat lupaavia.

Asiasanat: emättimen laskeuma, keskiuretraaliset nauhaleikkaukset, objektiivinen tulos, potilastyytyväisyys, subjektiivinen tulos, transvaginaalinen verkko, verkkoeroosio, virtsankarkailu

To my precious ones

8 Acknowledgements

This study was conducted at the Department of Obstetrics and Gynecology, University of Oulu, from 2004 to 2014. I express my deepest gratitude to my two magnificent supervisors, Docent Markku Santala and Docent Anne Talvensaari-Mattila, for their expert guidance and advice in the world of science through these years. Their amazing patience and never-ending support and optimism helped me to keep my spirits up also during tough times. The help and knowledge that Docent Santala has given me in statistics is invaluable. This study was mostly carried out “by email” as I have lived in Joensuu most of these years. I must say that the awesome linguistic virtuosity of Docent Santala in these emails has put a smile on my face numerous times. Despite the long distance, Docent Talvensaari-Mattila has always been available for me whenever I have been in urgent need of help. She has been my helping hand with all practical issues, which were challenging to handle because of the long distance. I am very grateful to Doctor Mervi Haarala and Doctor Seija Ala-Nissilä for their valuable advice and instructions regarding the last article of the thesis. I also thank my colleagues Eila Heiskanen, MD, Pekka Kulju, MD, Kirsi Kuismanen, MD, Päivi Selänne, MD, and Doctor Satu Tarjanne for providing the data for the last article. Risto Bloigu, PhD, is acknowledged for statistical help with the last manuscript. I am deeply appreciative to the reviewers of the thesis, Professor Seppo Heinonen and Doctor Kari Nieminen, for the precise observations and valuable comments, which truly improved the content of this thesis. I wish to thank the study nurses Irma Krankka and Eija Sorola for their important input in conducting studies II and III. Anna Vuolteenaho, MA, is acknowledged for her fast and expert revisions of both English and Finnish languages in all the articles and in the thesis. I am privileged to work with wise and skillful colleagues and friends in the Department of Obstetrics and Gynecology of North Karelia Central Hospital, in an atmosphere where both laughter and tears are allowed. I am deeply grateful to Jaana Fraser, MD, and Doctor Eeva Koistinen, for understanding the difficulties in integrating clinical work, research and family life. This study would never have been finished without the arrangements which allowed me to conduct this study during the daytime and not after bedtime. The companionship with Ulla Korhonen, MD, Anne Rissanen, MD, and Jonna Honkanen, MD, has given me

9 strength, support and perspective in all fields of life, and I am thankful for the joyful moments we have shared. Whenever my thoughts have been messed up, this group of ladies has had the capability to put everything into perspective, and suddenly the whole world seems like a better place. I also give my heartfelt thanks to Marjo Polso, MD, my dear colleague and friend, with whom I found a special connection during my resident years at Oulu University Hospital. My special thanks go to Ulla Korhonen, MD, for her unspeakably valuable peer support when sweat and tears were shed for this work. My friend Reetta Kuosmanen is very warmly thanked for her comprehensive friendship, which has lasted from upper secondary school. Even though we rarely see each other nowadays, our reunions always feel as if no time has passed since our last meeting. That is true friendship. My dear friends Aija Holopainen and Anne Leinonen are also sincerely thanked for being there for me, in the ups and downs of life. All these magnificent women know that a cup of coffee helps in every situation. I wish to thank my parents-in-law Mauri and Liisa Nyyssönen and my sister- in-law Tuija Nyyssönen for all the help and support they have given to our family during these busy years. My loving lifetime thanks go to my parents Kari and Anitta Kirves for giving me strong roots to lean on, and safe and loving surroundings to grow into adulthood. Their overwhelming and unconditional love is something I can always count on. I want to thank my dear little sister Petra Kirves for her true sisterhood. We know each other at our worst, and as blood is thicker than water, we know that we will be there for each other, no matter what happens. However, the amazing foursome, Iiris, Aaro, Pipsa and Peppi, are dearest to me of all. These kids are the ultimate reason for my excistence. Every day they show me what is truly important in life and my heart bursts with love as I cherish them. And Marko, I love you so much. Thank you for sharing your life with me, and for loving me as I am. Our thing is absolutely something special, now and in the future. This study was conducted with financial support from the North Karelia Central Hospital and Oulu University Hospital EVO-funding and the Department of Obstetrics and Gynecology of North Karelia Central Hospital. Private funding was given by Marko Nyyssönen.

10 Abbreviations

ASC Abdominal sacrocolpopexy ATFP Arcus tendineus fascia pelvic CARE Colpopexy and urinary reduction efforts CI Confidence interval DIS Detrusor instability score DNA Deoxyribonucleic acid EAS External anal sphincter FDA Food and Drug Administration GH Genital hiatus ICS International Continence Society IUGA International Urogynecological Association IVS Intravaginal slingplasty sling LMA Longitudinal muscle of anus LP Levator plate muscle force LSC Laparoscopic sacrocolpopexy MAUDE Manufacturer and user facility device experience MMK Marshall-Marchetti-Krantz MUI Mixed urinary incontinence MUS Mid-urethral sling NI Not informed NS Not significant OABS Overactive bladder symptoms OR Odds ratio PB Perineal body PCF Pubococcygeus muscle force PFDI Pelvic floor distress inventory PISQ Pelvic organ prolapse/Urinary incontinence sexual questionnaire PIVS Posterior intravaginal sling POP Pelvic organ prolapse POP-Q Pelvic organ prolapse – quantification PRM Puborectalis muscle PS Pubic symphysis PUL Pubourethral ligaments QoL Quality of life RCT Randomized controlled trial

11 RP Retropubic RR Risk ratio RSC Robotic sacrocolpopexy RVF Rectovaginal fascia SIMS Single incision mesh system SISTEr Stress incontinence surgical treatment efficacy trial SSLF Sacrospinous ligament fixation SUI Stress urinary incontinence TO Transobturator TOMUS Trial of mid-urethral slings TOT Transobturator tape TVL Total vaginal length TVM Transvaginal mesh TVT Tension-free vaginal tape TVT-O Tension-free vaginal tape obturator UI Urinary incontinence UISS Urinary incontinence severity score USL Uterosacral ligaments UTI Urinary tract infection VAS Visual analog scale

12 List of original articles

The present study is based on the following articles, referred to in the text by their Roman numerals:

I Nyyssönen V, Talvensaari-Mattila A & Santala M (2009) Intravaginal slingplasty sling is associated with increased risk of vaginal erosion. Acta Obstet Gynecol Scand 88(11): 1222–1226. II Nyyssönen V, Talvensaari-Mattila A & Santala M (2014) A prospective randomized trial comparing tension-free vaginal tape versus transobturator tape in patients with stress or mixed urinary incontinence: subjective cure rate and satisfaction in median follow-up of 46 months. Scand J Urol 48(3): 309–315. III Nyyssönen V, Talvensaari-Mattila A, Santala M (2013) Posterior intravaginal slingplasty versus unilateral sacrospinous ligament fixation in treatment of vaginal vault prolapse. ISRN Obstetrics and Gynecology. DOI: 10.1155/2013/958670. IV Nyyssönen V, Santala M, Ala-Nissilä S, Bloigu R & Haarala M (2014) Single incision posterior mesh without concurrent surgery: efficacy, safety and effect on untreated vaginal compartment. Manuscript.

14 Contents

Abstract Tiivistelmä Acknowledgements 9 Abbreviations 11 List of original articles 13 Contents 15 1 Introduction 19 2 Review of the literature 21 2.1 Normal pelvic floor ...... 21 2.1.1 Viscero-fascial layer ...... 21 2.1.2 Levator ani muscles ...... 22 2.1.3 Interplay between ligaments and muscular support ...... 22 2.1.4 Mid-urethral theory ...... 23 2.2 Abnormal pelvic floor – female urinary incontinence ...... 25 2.2.1 Definition of female urinary incontinence ...... 25 2.2.2 Epidemiology of female urinary incontinence ...... 25 2.2.3 Etiology of female urinary incontinence ...... 27 2.3 Abnormal pelvic floor – pelvic organ prolapse ...... 29 2.3.1 Definition of pelvic organ prolapse ...... 29 2.3.2 Epidemiology of pelvic organ prolapse ...... 29 2.3.3 Etiology of pelvic organ prolapse ...... 31 2.4 Mesh as a surgical material ...... 33 2.4.1 Textile ...... 34 2.4.2 Pore size ...... 36 2.4.3 Weight and density ...... 36 2.4.4 Coating ...... 37 2.4.5 Elasticity ...... 37 2.4.6 Degradation ...... 37 2.5 Tissue responses at mesh implantation ...... 38 2.5.1 Host response at cellular level ...... 38 2.5.2 Bacterial colonization and biofilm production ...... 38 2.5.3 Scar formation ...... 39 2.6 Mesh-augmented procedures in treatment of urinary incontinence ...... 39

15 2.6.1 History of mesh-augmented procedures in treatment of urinary incontinence ...... 39 2.6.2 Retropubic and transobturator approach ...... 40 2.6.3 Single-incision mini-sling ...... 40 2.7 Outcomes after mesh-augmented female incontinence surgery ...... 41 2.7.1 Efficacy of urinary incontinence surgery ...... 41 2.7.2 Safety ...... 44 2.7.3 Patient satisfaction ...... 50 2.8 Mesh-augmented procedures in pelvic organ prolapse surgery ...... 51 2.8.1 History of mesh-augmented pelvic organ prolapse surgery ...... 51 2.8.2 Abdominal approach...... 53 2.8.3 Transvaginal meshes with or without trocar-guidance ...... 53 2.8.4 Other vaginal methods ...... 54 2.9 Outcomes after mesh-augmented pelvic organ prolapse surgery ...... 55 2.9.1 Efficacy ...... 57 2.9.2 Safety ...... 61 2.9.3 Patient satisfaction ...... 70 3 Aims of the study 71 4 Materials and methods 73 4.1 Study subjects ...... 73 4.2 Methods ...... 75 4.2.1 Study designs and outcomes ...... 75 4.2.2 Data collection ...... 76 4.2.3 Questionnaires ...... 77 4.2.4 Used polypropylene meshes ...... 79 4.2.5 Surgical procedures (Studies II and IV) ...... 79 4.2.6 Statistics ...... 81 5 Results 83 5.1 Safety and complications ...... 83 5.1.1 Vaginal mesh exposure ...... 83 5.1.2 Intraoperative safety ...... 83 5.1.3 Other postoperative complications ...... 84 5.2 Subjective success and patient satisfaction after urinary incontinence surgery ...... 85 5.3 Objective and subjective outcomes after pelvic organ prolapse surgery ...... 85 5.4 Secondary study aims ...... 87

16 5.4.1 Changes in urge symptoms after female incontinence surgery ...... 87 5.4.2 Effect of posterior single incision mesh on untreated vaginal compartment ...... 87 5.4.3 Sexual functions after pelvic organ prolapse surgery ...... 87 6 Discussion 89 6.1 The main findings and their relation to current literature ...... 89 6.1.1 Safety and complication issues ...... 89 6.1.2 Outcomes after urinary incontinence surgery ...... 91 6.1.3 Outcomes after pelvic organ prolapse surgery ...... 92 6.1.4 Results for secondary study aims ...... 93 6.2 Strengths and limitations ...... 94 6.3 Clinical significance ...... 94 7 Conclusions 97 References 99 Appendices 121 Original publications 131

18 1 Introduction

Treatment of female stress urinary incontinence and combinations of different pelvic organ defects is challenging and causes a significant burden on the gynecology field with major economic consequences to health care. There is a constant search for optimal surgical methods with low symptom recurrence rates, minimal adverse events and rapid recovery. Traditional techniques using abdominal approach for treatment of stress urinary incontinence (SUI) and pelvic organ prolapse (POP) are demanding for the surgeon, with rather a long learning curve, and for the patient, with a long recovery time. Traditional vaginal approaches in the treatment of POP are not optimal in terms of efficacy and postoperative complications (Maher et al. 2013). Dissatisfaction with operative results after conventional techniques has led to development of alternative methods. Mesh-augmented techniques in gynecological surgery have multiplied enormously during the last fifteen years. Development of mini-invasive approaches in surgical techniques aims at shorter learning curve for surgeons, short-term hospitalization with rapid recovery for patients, and better long-term efficacy compared to traditional techniques. Mesh-augmented urinary incontinence surgery provides all that, and today, synthetic tapes are in the first line when choosing the operative method for treatment of SUI. Based on the idea that vaginal prolapses are like hernias (Shull 1999) and on the success of mesh-augmented abdominal hernia repair, meshes were introduced in prolapse surgery as well. As better results of abdominal sacrocolpopexy were observed compared to traditional vaginal approaches in vaginal vault or uterine prolapse repair, the use of transvaginal mesh in all prolapse surgery started to increase. However, the use of differently structured synthetic mesh materials and various methods with variation of instrumentation in treatment of both female urinary incontinence and pelvic organ prolapse began to go “wild”, and to be based on “feelings” and “hunches”, without solid scientific knowledge of efficacy and safety aspects. The literature shows that the use of all artificial tapes and meshes can result in mesh-related adverse events. The incidence of complications varies between different mesh materials and different surgical methods. Surgical skills also play a major role in whether adverse events emerge or not. In July 2011, the United States Food and Drug Administration (FDA) released a safety communication

19 entitled “UPDATE on serious Complications Associated with Transvaginal Placement of Surgical Mesh for Pelvic Organ Prolapse” (FDA 2011). This pronouncement warns about mesh-related complications without benefits in efficacy after transvaginal mesh (TVM) surgery. This has led to carefulness in the use of transvaginal meshes. In some health care units transvaginal mesh use in the treatment of pelvic organ prolapse is now restricted to scientific use only. However, there are clinical situations where native tissue reconstruction is not sufficient and abdominal approach is not an option. In these situations transvaginal mesh-augmented approach is one alternative, but to ensure the best efficacy and safety results, more scientific data on TVM surgery and mesh behavior is required. As mesh-augmented urinary incontinence surgery is not free of mesh-related complications, either, research in this field is ongoing as well. The present study was carried out to report the efficacy, safety and patient satisfaction after transvaginal mesh-augmented techniques with polypropylene meshes with different structures and shapes in the treatment of female urinary incontinence and apical or posterior vaginal wall prolapse.

20 2 Review of the literature

2.1 Normal pelvic floor

Normal pelvic floor consists of fascial and muscular components that provide a dynamic support mechanism for pelvic organs, i.e., the bladder, vagina and rectum. There are two mechanisms that keep the pelvic organs in their normal place: the suspensory element of the endopelvic fascia, and the levator ani muscles that form an occlusive layer on which the pelvic organs rest. Levator ani muscles also close the lumens of pelvic organs by continuous constriction. (DeLancey 1994). On the other hand, the pelvic organs are not only suspended by the surrounding tissue elements, but they also play an important role in the pelvic floor through their connection with other pelvic floor structures (Wei & DeLancey 2004).

2.1.1 Viscero-fascial layer

The top layer of the pelvic floor is provided by the continuous, sheet-like endopelvic fascia, in order to suspend the pelvic organs to the pelvic walls. The fascial part of the endopelvic fascia, which attaches to the uterus, is called parametrium, made up of cardinal and uterosacral ligaments. (Bartscht & DeLancey 1998). The part that attaches the vagina is called the paracolpium. According to DeLancey (1994) the vaginal suspension is divided into three levels. The upper portion of the vagina (level I) consists of a sheet of tissue that suspends the vagina to the pelvic wall. In the mid-portion of the vagina (level II) the paracolpium attaches the vagina laterally and stretches it transversely. In this level the structural layer called pubocervical fascia supports the bladder; however, it is not a separate layer, consisting of anterior vaginal wall and its continuous attachment through the endopelvic fascia to the pelvic wall. In the same way, the so-called rectovaginal fascia is formed by the posterior vaginal wall and endopelvic fascia. In the distal vagina (level III) the vaginal wall is directly attached to surrounding structures. Anteriorly the vagina fuses with urethra, posteriorly with the perineal body, and laterally with the levator ani muscles. (DeLancey 1994). Urethra has a special support by the endopelvic fascia in order to achieve continence. This region is stronger than other parts of the pubocervical fascia and

21 it attaches laterally to the arcus tendineus fascia and also to the levator ani muscles. (DeLancey 1994). More recently, histological studies on vaginal walls have revealed that what has been termed as fascia, is actually vaginal muscularis in both the anterior and posterior segments (Farrell et al. 2001). Damage in parametrium and in level I paracolpium causes development of uterine or vaginal vault prolapse. When defect occurs in paracolpium level II anterior and posterior prolapse formation follows.

2.1.2 Levator ani muscles

The levator ani muscle consists of two muscles: pubovisceral and iliococcygeus muscles. The pubovisceral muscle arises from pubic bones forming a U-shaped, sling-like arrangement around the rectum. This pubovisceral muscle includes both pubococcygeus and puborectalis portions. The iliococcygeus muscles are situated laterally arising from the pelvic brim with a fibrous band called arcus tendineus. It forms a quite horizontal sheet spanning over the pelvic opening. (Lawson 1974). The fatigue-resistant feature of striated levator ani muscle enables the constant baseline activity of the muscle, which keeps the urogenital hiatus shut in normal situation (Gosling et al. 1981). When the levator ani muscle functions normally, the pelvic floor remains closed and prolapses cannot protrude. If pelvic floor muscles are damaged the pelvic floor opens and the vagina can no longer rest on it. Ligaments can hold the pelvic organs in their normal positions for a while, but eventually connective tissue will be damaged and prolapses occur. (DeLancey 1994). Damage of the pelvic nerves by any cause leads to dysfunction of pelvic muscles or loss of musculature. This situation can translate into eventual prolapse formation. (Smith et al. 1989).

2.1.3 Interplay between ligaments and muscular support

To achieve normal pelvic floor function the interplay of anatomical and physiological properties must be uninterrupted, and intact function of neural pathways is crucial. Balance between the powers of urethral resistance and forces of urinary expulsion is necessary in achieving continence. In women with normal pelvic floor muscles, the ligaments do not have to be strong, and formation of prolapse is unlikely. However, if the muscles are damaged, the ligaments are

22 forced to carry an increased load. In this situation, an individual with strong ligaments holds the normal anatomy while an individual with weak ligaments supposedly develops prolapse. Some women with very weak connective tissue will suffer from prolapse formation despite intact pelvic floor musculature. (DeLancey 1994).

2.1.4 Mid-urethral theory

In 1990, Petros and Ulmsten presented their anatomical classification for management of urinary dysfunction, integral theory, which was later termed mid- urethral theory. According to this theory, the mid-urethra is supported by pubourethral ligaments and the anterior vaginal wall. These elements form forward forces in the middle of the urethra while the muscular levator plate creates dorso-caudal forces on the bladder and bladder neck. Together these elements create a kinking effect on the urethra, resulting in continence during stress. (Petros & Ulmsten 1990). A schematic picture of the anatomy and forces of the pelvic floor is shown in Figure 1. Petros and Ulmsten stated that pelvic organ prolapse and abnormal pelvic symptoms including stress urinary incontinence are mainly caused by connective tissue laxity in the vagina or its supporting ligaments. They divided the pelvic floor into three zones: anterior, middle and posterior. Defect of anterior zone causes stress incontinence as lax mid-urethrally positioned pubourethral ligaments renounce. This mid-urethral movement has been demonstrated with magnetic resonance imaging by Finnish colleagues (Rinne et al. 2010). A middle zone defect (arcus tendineus fascial part defect) causes formation of anterior vaginal wall prolapse, abnormal emptying of the bladder, and frequency and urgency urinary symptoms. If the defect is in the posterior zone, meaning laxity of uterosacral ligaments, it leads to high vaginal wall prolapse detected as enterocele, or uterine or vaginal vault prolapse. Based on this theory, the most important anatomic structures in maintaining urinary continence are the suburethral vaginal wall, the pubourethral ligaments, the pubococcygeus muscle and the paraurethral connective tissue. (Petros & Ulmsten 1990).

23 Fig. 1. Schematic picture of the pelvic floor. ATFP: arcus tendineus fascia pelvis, EAS: external anal sphincter, LMA: longitudinal muscle of anus, LP: levator plate muscle force, PB: perineal body, PCF: pubocervical fascia, PCM: pubococcygeus muscle force, PRM: puborectalis muscle, PS: pubic symphysis, PUL: pubourethral ligaments, RVF: rectovaginal fascia, USL: uterosacral ligaments (reprinted with permission from Peter Petros: Fig 1-05, on the website Integral Theory of the Female Pelvic Floor – a revolution in diagnosis).

The relevance of integral theory lies in retropubic mid-urethral sling operation and posterior intravaginal slingplasty operation, both developed on the basis of this theory.

24 2.2 Abnormal pelvic floor – female urinary incontinence

2.2.1 Definition of female urinary incontinence

According to the most recent definition stated by the International Urogynecological Association (IUGA) and the International Continence Society (ICS), urinary incontinence is the complaint of any involuntary leakage of urine (Haylen et al. 2010). In this latest definition urinary incontinence is divided into eight subgroups. Stress urinary incontinence is involuntary leakage on exertion or effort such as sneezing, coughing or jumping, while urge urinary incontinence is involuntary leakage accompanied by immediate urgency. Mixed urinary incontinence (MUI) consists of both stress and urge urinary incontinence. Furthermore, incontinence can be defined as postural (involuntary loss of urine associated with change of body position), nocturnal (involuntary loss of urine occurs during sleep), continuous, insensible, and coital (Haylen et al. 2010).

2.2.2 Epidemiology of female urinary incontinence

Urinary incontinence is a common problem among women all over the world. The precise prevalence and incidence are, however, difficult to define, as studies on urinary incontinence suffer from differences in methodologies, definitions of urinary incontinence and study populations. A recently published meta-analysis showed that age and case definition account for 60% of variation in incidence rates among studies of female urinary incontinence conducted between 1996 and 2011. Specific incidence for urinary incontinence in this study was 2/1,000 person-years before age 40 and increased thereafter. (Stewart et al. 2014). In worldwide literature analysis the median prevalence of female urinary incontinence has been estimated to be 28% (Minassian et al. 2003). The same overall prevalence has been estimated in developing countries and also here in Finland (Mäkinen et al. 1992a, Walker & Gunasekera 2011), but wide variation in prevalences is also seen between studies (Table 1) (Møller et al. 2000, Oskay et al. 2005). The most common incontinence type is stress urinary incontinence, followed by mixed and urge incontinence (Minassian et al. 2003). This is true also for Finnish population (Mäkinen et al. 1992a).

26 26 Table 1. Epidemiological studies on female urinary incontinence.

Author Year n Design Age (y) Prevalence (%) CI or range UI distribution (stress/mixed/urge) Hulkko et al. 1999 4,937 Cross-sectional 25–60 20.1 CI: 18.8–21.4% 53.1/34.9/9.4% Matthews et al. 2013 64,396 Cross-sectional 62–87 45 Minassian et al. 2003 230,000 Review 15–79+ 27.6 Range: 4.8–58.4% 50/32/14% Møller et al. 2000 2,284 Observational 40–60 28.5 Mäkinen et al. 1992 5,247 Cross-sectional 25–55 20.1 Nuotio et al. 2003 227 Cross-sectional > 70 59 Oskay et al. 2005 500 Cross-sectional > 50 68.8 37.2/30.5/32.3% Walker & Gunasekera 2011 83,000 Review 14–99 28.7 Range: 5.2–70.8% CI: confidence interval, UI: urinary incontinence.

2.2.3 Etiology of female urinary incontinence

The etiological factors behind female urinary incontinence, gathered in Table 2, are numerous.

Table 2. Etiological factors behind female urinary incontinence and pelvic organ prolapse.

Female urinary incontinence Pelvic organ prolapse Age Age Obesity Obesity Smoking Parity and childbirth Parity and childbirth Levator muscle defect Hereditary factors Pudendal nerve neuropathy Matrix metalloproteinases Soft tissue changes Serine proteases Hereditary factors Elastin degradation/abnormal synthesis Laminin γ1 Growth factor-β Estrogen receptor α and β Progesterone receptor Collagen type III – alpha 1 Matrix metalloproteinase-9

Age

There are actually several studies giving age as an important risk factor for female urinary incontinence (Minassian et al. 2003, Peyrat et al. 2002). Among Finnish women the prevalence of urinary incontinence is estimated to be 20% in women aged 25–60 and 59% in women over 70 years (Hulkko et al. 1999, Mäkinen et al. 1992a, Nuotio et al. 2003). The trend of increasing prevalence of urinary incontinence by age is also ongoing in advanced age, which is shown in a cross- sectional analysis of the Nurses’ Health Study (Matthews et al. 2013).

Parity and childbirth

Parity is a known risk factor for SUI. Primiparous women seem to have three times higher prevalence of stress incontinence than their age-matched nulliparous controls (Hansen et al. 2012). A recent Swedish cohort study evidenced that parity increases the risk of forthcoming incontinence surgery. In this study, women with only vaginal deliveries had three times higher odds of suffering from urinary incontinence compared to women with only cesarean deliveries.

(Leijonhufvud et al. 2011). The same odds are also evidenced five to ten years after vaginal or cesarean childbirth (Handa et al. 2011). However, it has been calculated that 15 cesareans are needed in order to prevent one case of urinary incontinence (Press et al. 2007) and it is not relevant to use cesarean rather than vaginal birth in prevention of stress urinary incontinence (Koc & Duran 2012). If urinary incontinence is present during pregnancy, it correlates highly with incontinence symptoms also after delivery (Svare et al. 2014).

Lifestyle

Obesity results in increased intra-abdominal pressure, which leads to weakening of the pelvic floor innervations and musculature. Analysis of literature shows that weight loss through lifestyle modification and bariatric surgery improves SUI. The same analysis evidences that success of SUI surgery in obese women is similar to non-obese patients. (Osborn et al. 2013). As for other lifestyle SUI risk factors, Finnish colleagues studied the relationship of smoking and bladder symptoms, and they pointed that SUI is not associated with smoking whereas urgency and frequency are (Tähtinen et al. 2011). The status of smoking is also linked to the appearance of severe incontinence (Garcia-Perêz et al. 2013).

Hereditary factors

Some women suffer from urinary incontinence while others with similar risk factors do not. Now, scientific evidence suggests that patients with stress urinary incontinence have a genetic predisposition to abnormal extracellular matrix remodeling in their pelvic tissue. Data on collagen metabolism continue to support the hypothesis of increased turnover involving matrix metalloproteinases and serine proteases in affected individuals’ pelvic tissue. Increased degradation of elastin and abnormal elastin fiber synthesis are found in SUI patients, as are transforming growth factor-β pathways. These changes are modulated by reproductive hormones, trauma, mechanical stress load and aging. (Chen & Yeh 2011).

Aspects of mixed urinary incontinence

The prevalence of MUI among women suffering from urinary incontinence varies from 11% to 36% (Hannestad et al. 2000, Sandvik et al. 1995). The proportion of

MUI compared to other incontinence types increases with age (Mäkinen et al. 1992a). If urodynamics is performed, 21% of these patients have detrusor overactivity (Van Leijsen et al. 2011). Urge symptoms without detrusor overactivity may be a result of pelvic floor or voiding phase dysfunction, which easily leads to frequent voiding just in case, and this behavior gives the impression of urgency.

2.3 Abnormal pelvic floor – pelvic organ prolapse

2.3.1 Definition of pelvic organ prolapse

According to the IUGA/ICS joint report referred to, pelvic organ prolapse is defined as abnormal herniation or descent of pelvic organs from their normal attachment sites or positions in the pelvis (Haylen et al. 2010). The structures involved may be uterus, vaginal apex and vaginal anterior or posterior wall. Pelvic organ prolapse causes symptoms like vaginal bulging, pelvic pressure and low backache. If the prolapse is ulcerated, also bleeding, discharge and infection may occur. (Haylen et al. 2010).

2.3.2 Epidemiology of pelvic organ prolapse

As a condition, pelvic organ prolapse seems to reach epidemic levels, affecting up to 50% of women > 50 years when diagnosis is based on vaginal examination (Barber & Maher 2013a). If diagnosis is based on symptoms, the prevalence is much lower (Nygaard et al. 2008, Rortveit et al. 2007). Anterior vaginal wall prolapse is most common, accounting for two thirds of prolapses, and it is reported twice as often as posterior vaginal wall prolapse and three times more commonly than apical prolapse (Handa et al. 2004, Hendrix et al. 2002). Great diversity exists in prevalence within pelvic organ prolapse studies, mainly due to variation in definition. Studies on epidemiology of pelvic organ prolapse are gathered in Table 3.

30 30 Table 3. Epidemiological studies on pelvic organ prolapse.

Author Year n Design Age (y) Diagnose Epidemiological variable Result 95% Confidence Interval Bradley et al. 2007 259 Observational > 50 Vaginal examination Incidence (1 / 3-year) 26%/40% 20–33% / 26–56% Regression (1 / 3-year) 21%/19% Nygaard et al. 2008 1,961 Cross-sectional > 20 Symptoms Prevalence 2.9% 2.1–3.7% Olsen et al. 1997 395 Retrospective > 20 Surgery for POP Cumulative incidence 6.7% Rortveit et al. 2007 2,109 Cross-sectional > 40 Symptoms Prevalence 6% 4.8–6.8% Smith et al. 2010 44,728 Retrospective 40–69 Surgery for POP Cumulative incidence 19% 17.8–20.2% POP: pelvic organ prolapse.

The knowledge on natural history of POP is limited. Incidence rate increases over time, but also regression occurs (Bradley et al. 2007). In general, older parous women are more likely to develop new or progressive POP than to show regression. Lifetime risk for any POP surgery has been estimated to be between 6% and 19% (Olsen et al. 1997, Smith et al. 2010). Up to one third are at risk for reoperation (Olsen et al. 1997), but lower re-operation rate is presented later, which may be explained by improved surgical procedures (Clark et al. 2003). Frequency of vaginal vault prolapse after hysterectomy has been estimated to be 5–10% (Barrington & Edwards 2000).

2.3.3 Etiology of pelvic organ prolapse

Etiology behind pelvic organ prolapse is multi-factorial (Table 2). It can be divided into predisposing (e.g. hereditary factors, collagen distribution), decompensating (e.g. aging), inciting (e.g. vaginal delivery), and promoting factors (e.g. obesity) (Bump et al. 1998).

Age

Aging is generally acknowledged as a POP risk factor, even though data on this matter are somehow complex. Lawrence et al. (2008) conducted a population- based study comparing age groups and found no increase in prevalences. Dietz (2008) found a weak and complex relationship between age and prolapse formation, with positive correlation before menopause and negative relationship thereafter. There is evidence that estrogen deprivation makes the tissue stiffer (Goh et al. 2002), which supports the negative postmenopausal correlation of age and POP. Some data point out that systemic estrogen increases the prevalence of POP (Baessler et al. 2006). Finally, no relationship has been found between aging and levator ani function and anatomy (Trowbridge et al. 2007, Weemhoff et al. 2008).

Childbirth and parity

Inciting risk factors of POP are, for example, childbirth and parity. Both epidemiological and observational cohort studies have shown that the main factor in the causation of prolapse is vaginal childbirth (Patel et al. 2007). Prolapse is

evidenced to be more common among parous versus nulliparous women (Kudish et al. 2011) and vaginal childbirth, especially operative vaginal delivery, increases the risk of pelvic organ descent to or beyond the hymen (Handa et al. 2011, Handa et al. 2012). Handa et al. (2012) found also that no increase in prolapse formation was observed in association with episiotomy while women with more than one spontaneous perineal laceration were more likely to exhibit a prolapse at or beyond the hymen. The association between vaginal delivery and POP formation is partly explained by levator ani muscle trauma. Vaginal delivery causes damage to the levator muscle, an important part of pelvic support system, in 20–36% of women giving birth (DeLancey et al. 2003, Dietz & Lanzarote 2005). On the other hand, levator defect is found in 36–55% of women seeking help for prolapse while the defect is identified in only 8–16% of women without symptomatic prolapse (DeLancey et al. 2007, Dietz & Simpson 2008). Another theory underlying the association of vaginal delivery and POP formation has been neuropathy of pudendal nerve leading to levator ani dysfunction (Allen et al. 1990). However, this area has turned out to be difficult to investigate, as measuring neuromuscular function is challenging, needle electromyography is painful, and interpretation of the results is cumbersome (Vodusek 2000). Animal models show that both vaginal distension and pudendal injury result in stress urinary incontinence, but urinary incontinence is transient unless the nerve is transected (Lin et al. 2010). The same is seen in clinical work, meaning temporary neuropathy on the post-natal ward. This impairment usually recovers within days to months. Permanent major pudendal neuropathy after childbirth seems rare. Undoubtedly, also soft tissue changes in delivery play role in POP formation. For example, repetitive stretching of the vaginal wall initiates a degradative collagen response and an increase in collagenase activity is seen (Zong et al. 2010). Also elastin degrades as a result of vaginal distension, and synthesis of elastin fibers is critical in recovery process after childbirth (Connell 2011).

Obesity

Several studies show an association between obesity and incidence of POP (Bradley et al. 2008, Marchionni et al. 1999, Uustal Fornell et al. 2004). One could assume that obesity is also a risk factor for operative failure. However, in prospective studies of both Clark et al. (2003) and Bradley et al. (2008) no evidence was found on increased surgical failure in obese women. Recently

published retrospective studies show the same result (Edenfield et al. 2013, Thubert et al. 2012) while opposite results are few (Kawasaki et al. 2013). Overall consensus is that obesity does not have an effect on surgical outcome after POP surgery.

Hereditary factors

There is growing evidence on the fact that hereditary factors are important in development of POP. Altman et al. (2008a) have investigated the prevalence of surgical treatment for POP in both di- and monozygotic twins, finding that the influence of genetic factors was substantial, attributing to 40% of the variation in liability for POP. Jack et al. (2006) performed an analysis on familiar inheritance pattern by studying ten families with young women presenting severe POP. The transmission of POP was dominant with high degree of penetrance (Jack et al. 2006). A recent meta-analysis substantiates the increased risk for POP in case of a positive family history (Lince et al. 2012). Underlying genetics has been under busy research. So far, six deoxyribonucleic acid (DNA) polymorphisms associated with POP have been identified (Table 2) (Chen et al. 2008a, Chen et al. 2008b, Chen et al. 2009, Chen et al. 2010, Kluivers et al. 2009, Martins Kde et al. 2011, Nikolova et al. 2007). However, the associations within the studies are not all the same. For example, collagen type III alpha 1 correlation in populations has been controversial, and it has been suggested that these differences could be explained by the fact that the studies were performed in ethnically different populations (Martins Kde et al. 2011).

2.4 Mesh as a surgical material

Development of synthetic meshes used in gynecology began with metallic meshes in late 1894, with silver as the first material used followed by tantalum and stainless steel in 1940 and 1952, respectively (Cosson et al. 2003). Since the 1940s numerous different materials, including polyvinyl, nylon, polytetrafluoroethylene, carbon, polyester and polypropylene, have been used in human grafts, as search for ideal synthetic material has continued (Cosson et al. 2003). Of these materials polypropylene has been proven to be the most useful in pelvic reconstructive surgery. Biomaterials are traditionally classified according to Amid, who created his classification of meshes for hernia surgery in 1997 (Amid 1997). This

classification was adopted in gynecology as well. Pore size of the materials is the basis of this classification. Amid’s classification for biomaterials is presented in Table 4.

Table 4. Amid’s classification for biomaterials.

Characteristic Type I Type II Type III Type IV Porosity Totally Totally microporous Macroporous, with Submicronic pore macroporous multifilamentous or size microporous components Pore size > 75µm < 10µm/dimension Material example Knitted Polytetrafluoroethylene Woven Pericardial polypropylene (Gore-Tex), polyethylene membrane (Prolene, IntelPro terephthalate Lite) (Dacron), woven polypropylene (IVS)

Meshes behave uniquely in vivo, and they also seem to continue this behavior after implantation. Mesh architecture, composed of pore size, weave, fiber structure and density, along with mechanical and other properties of the mesh, has special influence on mesh behavior, and this behavior leads to different biocompatibility of the meshes. In addition, there are always non-mesh factors that have their own influence on mesh behavior, such as individual patient characteristics and surgical technique. Characteristics of the mesh are also in a big role in the genesis of mesh-related complications, like mesh erosion, infection and pain.

2.4.1 Textile

The type of the mesh fiber can be monofilament or multifilament (Fig 2.) Multifilament offers easy access for bacteria to adhere and harbor into the craggy fiber surface whereas in smooth monofilament fibers this process is prevented by phagocytes and leukocytes (Bafghi et al. 2005). However, both fiber types have their uses in the surgical field, with advantages and disadvantages (Table 5).

Fig. 2. Multifilament and monofilament fibers (reprinted with permission from Springer; Fig 3. in the article: Cosson et al., Mechanical properties of synthetic implants used in the repair of prolapse and urinary incontinence in women: which is the ideal material? Int Urogyn J 2003;14(3):169–178).

The type of weave or knit of the mesh affects the amount of mesh surface area and tensile strength. Woven materials have good memory and strength. Disadvantages of these woven materials include fraying and poor conformity. (Chen et al. 2007). Knitted materials are flexible, versatile and have high conformity (Chen et al. 2007). If the material is unwoven, it is absorbed well but has no conformity, is poorly visible, and demands a higher level of treatment.

Table 5. Comparison of basic characteristics of mono- and multifilament fibers.

Monofilament Multifilament Advantages Disadvantages Advantages Disadvantages Less drag than Poor handling, knot-tying More pliable and flexible High capillarity multifilament more difficult Smooth surface Damaging with Better knot hold and Rough surface impairs instruments is possible better handling passage through tissue No interstices to support Tight weaving causes bacteria growth minimum friction

2.4.2 Pore size

Pore size is essential in achieving favorable tissue response after mesh implantation. We know that the average size of bacteria is 1 µm, and macrophages and neutrophils are unable to enter interstices or pores of less than 10 µm. If the pore size is 10 µm or smaller, the mesh gives the bacteria a possibility to multiply without disturbance of the body’s defence mechanisms (Amid 1997). It has also been shown that larger pores lead to better collagen deposition and capillary formation within the mesh (Chvapil et al. 1969, Taylor & Smith 1972). This way the pore size can also affect both the degree of mechanical interlock and the quality and strength of ingrown tissue.

2.4.3 Weight and density

The use of the terms weight and density are overlapping. Both properties are reported as grams per square centimeter (g/m2). The value depends on the diameter and closeness of the threads that form the mesh. In turn, the term porosity is expressed as a percentage of interstices to total area. Based on weight and density meshes can be divided into heavy- and lightweight or high and low density meshes. In studies made with inguinal hernia patients, lightweight mesh shows equally low recurrence rate but less pain and discomfort compared to heavyweight mesh (Agarwal et al. 2009). Significantly greater and prolonged inflammatory response with heavyweight compared to lightweight mesh has been established in animal studies, and lightweight structure has exhibited maximum tensile strength and double elasticity compared to heavyweight mesh (Klinge et al. 2002).

2.4.4 Coating

Coating of prosthetic implants is thought to resist degradation of the product used. In gynecology for example titanium and collagen-based biomaterials have been used in coating the meshes. However, studies show no enhancement on mesh biocompatibility when titanium coating is used (Scheidbach et al. 2004, Junge et al. 2005). With collagen the acute inflammatory response has appeared to be more intense than without it, which could cause greater local complications, such as mesh exposures and pain (Pierce et al. 2011). Opposite opinions also exist, suggesting that the use of collagen coating reduces postoperative complications (Sergent et al. 2011).

2.4.5 Elasticity

Elasticity is a physical property of a body to return into its initial shape after subjected to deformation. It has been a desirable property in mesh development. (Cosson et al. 2003). Lack of elasticity results in vaginal rigidity and may cause discomfort during coitus and produce symptoms of irritation during urination (Welty et al. 2001). Elasticity is influenced by mesh characteristics and mesh interaction with the host. In low-density mesh, the collagen fiber bundles adopt a distribution parallel to the filament interlacing giving greater elasticity to the scar (Klinge et al. 1998).

2.4.6 Degradation

As different biomaterials have been used in humans, stability of the material has been one of the properties pursued. Polypropylene has been long considered an inert material in vivo, but scanning electron microscope images of this material after exposure to ingredients like blood and saline show cracks, breakage and both shrinkage and expansion of the material. This evidences that polypropylene is actually a non-inert material in vivo (Coda et al. 2003, Jongebloed & Worst 1986). In light of these findings the unwanted problem of mesh shrinkage seems to be due to degradative processes of the mesh (Coda et al. 2003).

2.5 Tissue responses at mesh implantation

Both animal and human studies and implantation in both abdomen and vagina have been used to evaluate tissue response to graft materials. The abdominal wall and pelvic floor clearly represent two distinct anatomic regions, resulting in different histologic responses to grafts (Pierce et al. 2009). However, anatomical factors and variation between study subjects should be kept in mind when interpreting study findings on graft tissue response.

2.5.1 Host response at cellular level

Host response to foreign-body implantation occurs immediately after the biomaterial is introduced into the body. Interactions between blood and material lead to formation of transient matrix that surrounds the biomaterial used (Wilson et al. 2005). This matrix is rich with cytokines, chemoattractants and growth factors, which are important in the early wound-healing response (Gorbet & Sefton 2004). Matrix formation is followed by acute inflammatory response (Tang et al. 1998). In chronic inflammatory phase monocytes and lymphocytes enter the implant site and form foreign-body giant-cells. Cytokine activity influences macrophage migration into the implantation site and growth factors influence fibroblast proliferation; however, the subsequent fusion and tissue ingrowth into the mesh is dependent on the implanted material’s surface characteristics. (Pascual et al. 2008).

2.5.2 Bacterial colonization and biofilm production

Biomaterials-related infection is one of the main causes of implant failure (Nejadnik et al. 2007). Bacteria easily colonize surfaces of biomaterials, and bacterial contamination can lead to graft infection (Gristina 1987). The vagina, as a clean-contaminated field, is itself a possible risk in infectious adverse events. The location near the anus is also a risk factor for bacterial contamination (Boulanger et al. 2008). Preoperative antibiotic prophylaxis reduces the bacterial load in the vagina, but no additional advantage is achieved with repeated as compared to standard surgical-site disinfection in terms of the amount of bacterial colonization (Vollebregt et al. 2009). Biofilm formation may be a key determinant in the post-implantation infectious process. Biofilm is an aggregate of micro-organisms existing with a

self-produced protective polysaccharide matrix, surrounding the implanted graft. Within the biofilm, the bacteria can remain quiescent, shielded from antibiotics, but they have growth activity with the potential to change based on nutrient availability. (Costerton et al. 1999). Eradication of bacterial biofilm from the graft is impossible at present, and treating the infection requires removing the whole graft.

2.5.3 Scar formation

The amount and type of collagen production stimulated by different materials may vary owing to their respective properties and environment (Junge et al. 2006). For example, lightweight meshes with large pore sizes favor collagen type III formation compared to heavyweight mesh (Pascual et al. 2008), leading to better tensile strength of the scar.

2.6 Mesh-augmented procedures in treatment of urinary incontinence

2.6.1 History of mesh-augmented procedures in treatment of urinary incontinence

The first synthetic graft in the treatment of urinary incontinence was implantation of a tantalum plate in 1947 (Goldberger & Davids 1947). Exposure of the plate was common after this procedure, but this was not considered a problem by the researchers. The use of synthetic slings in incontinence surgery goes back to the 1960s as Moir used a polypropylene mesh sling placed under the bladder neck through abdominal and vaginal incisions, modifying Aldridge’s operation in which rectus sheath fascia was used as a sling (Aldridge 1942, Moir 1968). Traditional techniques such as Marshall, Marchetti and Krantz (MMK) and Burch colposuspensions used permanent sutures in suspending the urethra suprapubicly. However, the MMK technique suffered from osteitis pubis and the Burch technique caused voiding dysfunctions and formation of recto- and enterocele (Burch 1968). Dissatisfaction with the results of MMK and Burch colposuspension led to new thinking in treatment of urinary incontinence in the 1990s, and the mid-urethral sling was developed. (Ulmsten & Petros 1995). However, the use of mesh in SUI repair did not become common until after the

introduction of the Tension-Free Vaginal Tape System (TVT) in 1998 (Gynecare, Ethicon, Johnson & Johnson, Somerville, NJ, USA). Ethicon’s prolene hernia mesh was used as the mesh material in this surgical kit. This started massive development and marketing of ready-to-use kits for surgical treatment of SUI, with different instrumentations and different mesh properties. The retropubic approach in mesh-augmented treatment of SUI suffers from small but existing problem of bladder, visceral and vascular injury. In order to avoid these problems a sling suspension through transobturator route was invented by Delorme (Delorme 2001, Delorme et al. 2003). The position of the transobturator tape (TOT) is similar to natural hammock supporting the urethra based on DeLancey’s theory on pelvic anatomy (DeLancey 1994). The original insertion was performed via the outside-in transobturator route. In 2003, De Leval described a technique that allowed the tape to pass through the obturator foramen via the inside-out route. The intention of this technique was to reduce intraoperative complications, increase tape reproducibility and minimize tissue dissection (De Leval 2003). Again, the search for a method with fewer complications than the retropubic and transobturator approaches led to the invention of the so-called mini-sling. The first mini-sling was tested in an animal model in 2007 (Rezapour et al. 2007). The first data in humans were published in 2008 (Neuman 2008).

2.6.2 Retropubic and transobturator approach

Today, mini-invasive mesh-augmented techniques are the golden standard in surgical treatment of urinary incontinence. Even though the number of different devices, kits and meshes is enormous, the basic procedure in different approaches is nearly the same. The surgical techniques of retropubic and transobturator procedures are presented in detail later in this thesis (chapter 4.2.5).

2.6.3 Single-incision mini-sling

Mini-slings can be placed either U-shaped or H-shaped, mimicking the route of the original retropubic and transobturator approaches, respectively, without passage through these areas. This way the nerves and vessels in retropubic and transobturator spaces are not in danger. An incision of about 1.5 cm is made on the anterior vaginal wall 1 cm from the external meatus of the urethra. In U-type method, a paraurethral dissection is made at 45º from the sagittal mid-line upward

until the back edge of the pubic bone is reached. For the H-type method the dissection is made towards the obturator internus muscle parallel to the pelvic floor. Cystoscopy is performed when the U-type method is used. A short, eight- centimeter long tape is placed into desired position without exit through skin. (Neuman 2008).

2.7 Outcomes after mesh-augmented female incontinence surgery

Basically, outcome measures are divided into two categories: objective measurements independent of individuals’ perception and subjective measurements made from patients’ perspective. Outcome measures can also characterize safety and side effects. Objective efficacy measurements include, for example, cough test, pad test and urodynamics. Subjective outcome measures in monitoring efficacy of urinary incontinence treatment include voiding diary and symptom questionnaires. Patient satisfaction is also a subjective outcome. A good and enlightening example of the effect of different outcome measures to the reported result is the study by Richter et al. (2010). In this study the researchers compared results given by single objective or subjective measurement, and cure rates varied from 65% to 95%. They also created a composite outcome measure from all the measurements, which might be a useful tool in the future. However, the disunity of the outcome measurements used between the published studies should be kept in mind when comparing the study results.

2.7.1 Efficacy of urinary incontinence surgery

An enormous amount of data exists on outcomes after different mesh-augmented surgical methods in treatment of female urinary incontinence. The studies mentioned in this literature review are listed in Table 6 with detailed information on the studies. Long-term efficacy for both retropubic and transobturator approaches seems quite similar if studies involving only one surgical method are compared. TVT has the longest follow-up data with excellent objective and subjective cure rates of up to 90% (Nilsson et al. 2013). Follow-up times for TVTTM Obturator and TOT outside-in are shorter, but so far long-term objective and subjective data show convergent cure rates for both methods (Athanasiou et al. 2014, Heinonen et al. 2013, Serati et al. 2013).

The latest Cochrane review is from the year 2009 and it summarizes data on good or moderate quality studies comparing retropubic and transobturator routes (Ogah et al. 2009). No significant difference in risk ratios were found between the two approaches in terms of objective and subjective cure. A slight advantage in objective cure rates was found for the benefit of the retropubic approach, but the studies involved in this review had follow-up times of up to 12 months only. Studies published thereafter have not found any advantage for either approach in objective and subjective cure rates (Cerruto & Artibani 2011, Laurikainen et al. 2014, Richter et al. 2010). Difference between the two transobturator techniques has not been observed, either (Abdel-Fattah et al. 2012, Cheung et al. 2014, Madhuvrata et al. 2012). When monofilament tape is compared to multifilament tape the objective cure is significantly better after monofilament use, but subjective cures are equivalent (Novara et al. 2007, Ogah et al. 2009). Data on mini-slings have suggested that both patient-reported and objective cure rates are inferior to the cure rates of mid-urethral slings. The first meta- analysis comparing mini-slings to standard mid-urethral slings reported a risk ratio (RR) of 0.83 and 0.85 for patent-reported and objective cures, respectively (Abdel-Fattah et al. 2011b). Since then, TVT-SecurTM, one of the first mini- slings, has been removed from the market. The most recent meta-analysis, excluding TVT-SecurTM data and with longer follow-up, shows no difference between mini- and mid-urethral slings in objective and subjective cure rates, with risk ratios of 0.98 and 0.94, respectively (Mostafa et al. 2013). In surgical treatment of MUI the mid-urethral slings have good results at least for the stress component. A systematic review and meta-analysis from 2011 bunched six randomized trials and seven prospective studies with follow-ups from a few months to up to five years. The overall subjective cure was 56.4% and no difference was found between retropubic and transobturator approach (odds ratio (OR) 0.9, confidence interval (CI) 0.63–1.27). The cure rate of the stress component varied from 85 to 97% (Jain et al. 2011).

Table 6. Studies on the efficac y of mid-urethral slings.

Author Methods Year n Design Follow-up Objective cure Subjective cure Abdel-Fattah et al. TO inside-out/outside-in 2012 341 RCT 3 years 73.2%/72.3% Athanasiou et al. TVT-O 2014 124 Retrospective 90.3 months 81.5% 83.5% Cheung et al. TO inside-out/outside-in 2014 213 Observational 5 years 82.6%/82.5% 81.7%/84.1% Heinonen et al. TOT 2013 191 Observational 6.5 years 89% 83% Laurikainen et al. TVT/TVT-O 2014 131/123 RCT 5 years 84.7%/86.2% Madhuvrata et al. TO inside-out/outside-in 2012 573/559 Review, meta-analysis 1 y ear OR 1.66, CI 0.8–3.34 OR 1.25, CI 0.78–1.99 (RCTs) OR 1.03, CI 0.48–2.22 Nilsson et al. TVT 2013 90 Observational 17 years 90% 87% Novara et al. TVT/IVS 2007 206/205 Review, meta-analysis 1–2 year OR 0.47, CI 0.28– 0.83 OR 0.63, CI 0.37–1.09 Ogah et al. RP/TO 2009 2,434 Review 1 year 88%/84% 83%/83% monofilament/multifilament 409 83%/72% 83%/77% Richter et al. RP vs. TO 2010 597 RCT 1 year 80.8%/77.7% 62.2%/55.8% Serati et al. TVT-O 2013 191 Observational 5 years 90.3% 90.8% CI: confidence interval, IVS: intravaginal slingplasty sling, OR: odds ratio, RCT: randomized controlled trial, RP: retropubic, RR: risk ratio, TO: transobturator, TVT: tension-free vaginal tape, TVT-O: tension-free vaginal tape – obturator.

2.7.2 Safety

Complications of mid-urethral slings can appear intra- or postoperatively. They can also be categorized as complications related to mesh or not (Table 7). Studies on complications after mid-urethral sling surgery with detailed information are bunched in Table 8.

Table 7. Complications after mesh-augmented female incontinence surgery.

Not mesh-related complications Mesh-related complications Need for reoperation Mesh exposure to vagina Short-term or long-term voiding dysfunction Mesh erosion into the bladder or urethra Overactive bladder symptoms Pain Urinary tract infections Dyspareunia Intraoperative bladder, urethral and bowel Infection perforations Intraoperative vaginal perforations Intraoperative vascular injuries

Need for reoperation

The overall reoperation rate of 8.8% after SUI surgery has been reported in a register study from the United Kingdom. The risk for repeated surgery after mid- urethral sling in this study was 3.2%. (Abdel-Fattah et al. 2011a). Jonsson et al. (2012) reported an almost 15% cumulative nine-year incidence for repeat surgery in women who had undergone SUI surgery, with mid-urethral slings accounting for 70% of the cases (Jonsson et al. 2012). After TVT procedure the reported reoperation rate is low (Svenningsen et al. 2014) and the Cochrane review found no difference in reoperation rates between the retropubic and transobturator route (Ogah et al. 2009). Single-incision mini-slings present a non-significant trend towards a higher rate of repeat incontinence surgery compared to mid-urethral slings (RR 2.00, 95% CI 0.93–4.31) (Mostafa et al. 2014).

Table 8. Studies reporting complications after mid-urethral operations.

Author Year n Design Method Follow-up Complication and result Abdel-Fattah et al. 2011 342 Register MUS NI Reoperation: 3.2% Angioli et al. 2010 37/35 RCT TVT/TVT-O 60 months De novo urge: 3%/6%; Vaginal mesh exposure 5%/3%; Dyspareunia 2% Balakrishnan et al. 2007 62 RCT subanalysis IVS 30 months Vaginal mesh exposure: 13% Barber et al. 2006 213/205 Retrospective TVT/TOT > 6 weeks Bladder perforation: 5%/0% Barber et al. 2008 88/82 RCT TVT/TOT 18 months Bladder perforation: 7%/0%, Abnormal bladder function: 47%/43%, Brubaker et al. 2011 298/299 RCT TVT/TO 24 months Organ perforation 5.3%/0%, Vaginal mesh exposure 4.7%/3.0%, Pain: 2.3%/2.0% Collinet et al. 2008 984 Register TVT-O 12 weeks Dyspareunia: 2.7% Deffieux et al. 2010 75/74 RCT TVT/TVT-O 24 months Bladder perforation: 5%/2%, Vaginal mesh exposure: 0%/1% Domingo et al. 2005 65 Observational TO (Uratape) 290 days Vaginal mesh exposure: 13.8% Doo et al. 2006 134 Observational TVT 5 years Bladder perforation: 3.7%, Pain: 2.2%, De novo urge: 11.5% Feng et al. 2008 102 Retrospective TVT-O 12 months Vaginal mesh exposure: 1%, Pain: 17% Jonsson et al. 2012 127,848 Observational MUS 9 years Reoperation: 13% Kaelin-Gambirasio et al. 2009 233 Observational TO 27 months Voiding dysfunction: 10.2%, Vaginal mesh exposure: 7.6%, Dyspareunia: 9% Laurikainen et al. 2014 131/123 RCT TVT/TVT-O 5 years De novo urge: 3.1%/2.4%, Vaginal mesh exposure 0%/0.7%, UTI (> 3) 6.3% Meschia et al. 2006 95/95 RCT TVT/IVS 2 years Vaginal mesh exposure: 9%/0% Mellier et al. 2007 341 Observational TOT 17 months Organ perforation 0%, Hemorrhage 0.9%, Vaginal mesh exposure 0.9% Morton & Hilton 2009 3,587/ 4,459 Review RP/TO NI Urethral injury: 0.88%/1.09% Nguyen et al. 2012 3,747 Register MUS 21 months Voiding dysfunction 1.3%, Bladder perforation 1.4%, Urethral perforation 0.05%, Vaginal mesh exposure 0.8% 45

46 46 Author Year n Design Method Follow-up Complication and result Novara et al. 2010 1,627/ 1,559 Review RP/TO NI Voiding dysfunction: OR 1.35, Organ perforation: OR 2.5, Hematoma: OR 2.62, Vaginal mesh exposure: OR 0.64, Reoperation: OR 1.1 Ogah et al. 2009 2,434 Review RP / TO 1 year Pain: 1.7%/12%, Bladder perforation: 5.5%/0.3%, De novo urge: 6%/7%, Voiding dysfunction: 7%/4% Richter et al. 2010 298/299 RCT TVT /TOT 1 year Surgery for voiding dysfunction: 2.7%/0%, De novo urge: 0%/0.3%, Persistent urge: 12%/10%, Dyspareunia: 4%/9.4%, UTI 12.2%/7.7% Ross et al. 2009 105/94 RCT TVT/TO 1 year Pain 6%/15% Svenningsen et al. 2014 483 Register TVT 10 years Reoperation 2.3% Tamussino et al. 2007 2,543 Register TO NI Reoperation: 2.5%, Voiding dysfunction: 0.9%, Bladder perforation: 0.4%, Urethral perforation: 0.07%, Hemorrhage: 3.3%, Vaginal mesh exposure: 0.07%, Dyspareunia: 0.5%, Mesh related infection: 0.03% Wang et al. 2008 160/155 RCT TVT/TVT-O 3 years De novo urge: 5.8%/4.1%, Mesh exposure: 1.9%/2.1%, Pain: 2.6%/8.2% IVS: intravaginal slingplasty sling, MUS: mid-urethral sling, NI: not informed, OABS: overactive bladder symptoms, OR: odds ratio, RCT: randomized controlled trial, RP: retropubic, TO: transobturator, TOT: transobturator tape, TVT: tension-free vaginal tape, TVT-O: tension-free vagina l tape–obturator, UTI: urinary tract infection.

Voiding dysfunctions and overactive bladder symptoms

Short-term voiding dysfunction after mid-urethral sling surgery is common. In Trial of Mid-urethral Slings (TOMUS) 24% of patients were discharged with self- catheterization. However, only 6% reported any need for catheter after two weeks. (Richter et al. 2010). Among the patients surgically treated for complications almost half of the patients report lower urinary tract obstruction symptom (Petri & Ashok 2012). It seems that the rate of voiding dysfunction is lower after the transobturator approach compared to the retropubic approach (Barber et al. 2006, Richter et al. 2010). Of all late postoperative complications, overactive bladder symptoms seem to be the most common, affecting more than half of the patients who undergo surgery for mid-urethral sling complication (Petri & Ashok 2012). However, no difference in postoperative overactive bladder symptoms has been demonstrated between the retropubic and transobturator approach (Ogah et al. 2009, Richter et al. 2010).

Urinary tract infections

Urinary tract infection (UTI) is a common complication after mid-urethral slings reported in 5–34% of patients within three months after surgery (Anger et al. 2007, Dieter et al. 2012). This condition is significantly more common after the retropubic approach than after the transobturator approach (Richter et al. 2010). Postoperative catheterization is a risk for postoperative UTI affecting 30% of these patients, compared to 5% without catheterization (Dieter et al. 2012).

Urinary tract, vaginal and bowel perforations

Intraoperative urinary tract perforations are significantly more common after the retropubic than transobturator approach, which is easy to understand in view of the differences between the two techniques. Incidences vary from less than one per cent for the transobturator approach to a few per cent for the retropubic approach (Nguyen et al. 2012, Ogah et al. 2009). Urethral perforation is a rare complication affecting less than one per cent of patients undergoing either retropubic or transobturator mid-urethral sling surgery (Morton & Hilton 2009, Nguyen et al. 2012).

Trocar perforation can also occur in the vagina, and this type of perforation is more common with the transobturator than the retropubic approach, as the course of the sling is flatter and closer to the anterior vaginal fornices. The rates for vaginal perforation in retropubic and transobturator groups were 2% and 4% in the study of Richter et al. (2010). In trials comprising a transobturator approach only the reported vaginal perforation rates are around one per cent (Collinet et al. 2008, Tamussino et al. 2007). Bowel perforation concerns only the retropubic approach so far. It is a rare but serious event, as it can result in abdominal catastrophe and death (Deng et al. 2007). Incidence of this feared complication is 3/12,000 procedures (Agostini et al. 2006).

Hemorrhage

It is generally thought that hemorrhage is more common with the retropubic than the transobturator technique. In the trial of Richter et al. (2010) hemorrhage over 100 ml occurred twice as frequently in the retropubic group than in the transobturator group. However, in the Cochrane review there was no difference in major postoperative hemorrhage between the two techniques (RR 0.35, CI 95% 0.06–2.19) (Ogah et al. 2009), and individual studies also show the same trend (Brubaker et al. 2011, Mellier et al. 2007, Tamussino et al. 2007). However, postoperative hematomas are more common after a retropubic than a transobturator approach (Novara et al. 2010).

Vaginal mesh exposure

Although non-absorbable meshes in mid-urethral sling surgery are the golden standard in the treatment of female urinary incontinence, their use is associated with complications such as vaginal exposure, urethral or bladder erosion, dyspareunia, groin pain and infections. Incidence of mesh-related complications is influenced by both the properties of the mesh used and the surgical technique used. The rate of vaginal exposure in RCTs involving TVTTM and TVT-OTM has been 2.8–5% (Angioli et al. 2010, Deffieux et al. 2010, Laurikainen et al. 2014). With the transobturator MonarcTM tape the risk has been assessed at the same level (But 2005, Mellier et al. 2007). In the Cochrane review analysis no statistical difference was found between a retropubic and transobturator approach

in terms of vaginal mesh exposure (RR 1.58, 95% CI 0.83–3.00) (Ogah et al. 2009). When unwoven microporous monofilament (ObtapeTM) or woven microporous multifilament tape (IVSTM) are used, the risk of vaginal exposure is far higher, 7–14% and 9–13 %, respectively (Balakrishnan et al. 2007, Domingo et al. 2005, Kaelin-Gambirasio et al. 2009, Meschia et al. 2006). In contrast to these results is the Cochrane analysis comparing monofilament and multifilament tapes, showing no statistically significant difference in vaginal mesh exposure between the monofilament and multifilament tapes, but variation was wide (RR 0.36, 95% CI 0.01–14.16). Deeper inspection reveals that only two studies are included in this analysis (Ogah et al. 2009).

Urethral mesh exposure

Urethral mesh exposure is a rare late complication of synthetic meshes. After tension-free placement of the tape the incidence of urethral exposure varies from 0.003 to 0.8% (Velemir et al. 2008). A case report on urethral erosion after placement of mini-sling has been published, and the removed sling was 24% shorter than before insertion (Minaglia & Oyama 2012). Velemir et al. (2008) identified five possible causal factors of urethral erosion: excessive tensioning of the sling during placement, postoperative urethral dilatation, misplacing the sling under the urethra, perioperative urethral injury, and mesh material. Intravesical erosion seems to be the most rare adverse event, as no estimated incidence was found in the literature, but case reports have been published (Foley et al. 2010, Macedo et al. 2013). However, the risk for urethral or bladder mesh exposure is very small. In fact, in studies included in the Cochrane review not a single case of these adverse events were found. On the other hand, these complications should be kept in mind as they represent 8.2% of all mid-urethral sling complications (Petri & Ashok 2012).

Pain and dyspareunia

Persistent pain is more of a problem with the transobturator approach. The Cochrane review analysis showed a significant difference when comparing the incidence of groin pain to suprapubic pain (RR 5.95, 95% CI 3.22–11.02) (Ogah et al. 2009). After retropubic approach prolonged pain is reported to occur in up to 7.5%, in the vagina or the suprapubic region (Doo et al. 2006, Ross et al. 2009, Wang et al. 2009). Persistent groin pain is one of the most important

complications of the transobturator technique (Feng et al. 2008, Wang et al. 2009). The higher incidence of groin pain is associated with the passage of the trocars through tissues like muscles, tendons and sometimes nerves in transobturator surgery as compared to the retropubic technique, as muscles and tendons do not exist in the retropubic space (Petri & Ashok 2012). The reasons behind the groin pain include adductor muscle injury, osteitis pubis, regional abscess, nerve entrapment and structural adhesion (Roth 2007). Data on dyspareunia after mid-urethral slings are controversial. In a recent reanalysis of the TOMUS study, dyspareunia decreased significantly from 38% to 27% at 12 months after surgery, without difference between retropubic and transobturator routes (Zyczynzki et al. 2012). On the other hand, the incidence of de novo dyspareunia after the retropubic approach was 14.5% in the study of Mazouni et al. (2004) and 9% after the transobturator approach (Kaelin- Gambirasio et al. 2009). Finally, De Souza et al. (2012) found no change in the prevalence of dyspareunia before and after mid-urethral sling surgery using TVTTM and MonarcTM sling.

Tape-related infections

Tape-related infections include swelling, redness and pus formation in the skin puncture area, and abscess formation in the skin, retropubic space and deep tissues. Randomized controlled trials comparing the retropubic to the transobturator approach have found a risk of wound infections up to two per cent, with no difference between the two techniques (Barber et al. 2008, Richter et al. 2010, Ross et al. 2009). Necrotizing fasciitis is the most feared infectious complication described after mid-urethral sling operations, but fortunately it is extremely rare (Connolly 2004, Flam et al. 2009). Traditionally, antibiotic prophylaxis is used in mid-urethral sling operations. This habit has recently been questioned, with data showing no difference in incidence of infections with or without prophylaxis (Harmanli et al. 2012, Shepherd et al. 2014).

2.7.3 Patient satisfaction

Even though the amount of data on outcomes after mid-urethral sling surgery is overwhelming, there are relatively little data regarding patient satisfaction. So far it is known that the nature of patient satisfaction is multifactorial. In 2008 Mallett et al. reported that patients with inappropriate treatment expectations are at

increased risk for dissatisfaction after surgery. This result was not repeatable in Wai’s study, which did not find preoperative expectations to have an effect on patient satisfaction (Wai et al. 2013). In the same study, reduction of urinary incontinence symptoms and symptom bother had a positive connection with patient satisfaction. This result is in line with the Stress Incontinence Surgical Treatment Efficacy Trial (SISTEr). (Burgio et al. 2010, Wai et al. 2012). Greater baseline urge urinary incontinence symptoms and postoperative complications have been linked to lower patient satisfaction (Burgio et al. 2010, Davis et al. 2004, Trabuco et al. 2011). Studies on mid-urethral slings show patient satisfaction rates of 80–94% with a retropubic approach (Dyrkorn et al. 2010, Laurikainen et al. 2014, Lee et al. 2010, Olsson et al. 2010,) and 77–92% with a transobturator approach in long- term follow-up (Dyrkorn et al. 2010, Heinonen et al. 2013, Laurikainen et al. 2014). Data on patient satisfaction in patients fitted with a mini-sling are limited as in Barber et al.´s study (2012) satisfaction rate of 91% was measured with one year follow-up.

2.8 Mesh-augmented procedures in pelvic organ prolapse surgery

The basic surgical techniques for mesh-augmented pelvic organ prolapse surgery are presented below. In real life, however, various variations on these methods exist. Moreover, surgeons’ personal skills and differences in materials used, in terms of mesh structure or shape between techniques, result in even larger diversity in the methods used in the trials.

2.8.1 History of mesh-augmented pelvic organ prolapse surgery

Pelvic reconstructive surgery aims at restoring normal anatomy and function and reinforcing the weakened ligaments and soft tissue. Methods of pelvic reconstructive surgery have been under constant change, as the optimal method has still not been found. Synthetic graft use is based on the idea that the body’s own tissue is not strong enough to reinforce already weakened tissue support. For this purpose both native body tissue and allogeneic or synthetic grafts have been used. The first traceable description of using synthetic graft material in prolapse surgery was the use of tantalum mesh in cystocele repair in 1955 (Moore 1955), inspired by tantalum plate use in incontinence surgery. The problem of mesh

exposure existed with tantalum mesh, even though the defects were eventually covered by granulation tissue. Other materials suitable for use in humans were searched for. Since the early 1960s synthetic meshes have been used in the abdominal approach in posthysterectomy vaginal vault prolapse treatment (Lane 1962), termed abdominal sacrocolpopexy. The laparoscopic approach in sacrocolpopexy was first described in 1994 in order to reduce morbidity, length of hospital stay and convalescence (Nezhat et al. 1994). Several synthetic materials have been used in abdominal approaches: polytetrafluoroethylene (Gore-Tex®), polyethylene tetraphalate (Mersilene®) and polypropylene. However, sacrocolpopexy is demanding for the surgeon regardless of the technique used, and is not suited for all patients. This fact induced the growing use of synthetic meshes in transvaginal POP surgery in order to reinforce the affected vaginal compartment. In the beginning of transvaginal mesh surgery the grafts were placed “free”, just on top of the prolapse in traditional colporraphy. The first polypropylene mesh in transvaginal POP treatment was crystalline polypropylene (Marlex®) in cystocele repair (Julian 1996), followed by the use of the fully absorbable materials polyglactin 910 and polyglycolic acid (Sand et al. 2001). These materials have poor long-term results, which led to the abandonment of these meshes; today, all transvaginally assessed synthetic meshes are made of polypropylene. The crucial role of apical support in prolapse repair was first demonstrated in 1992 (DeLancey 1992). As the use of meshes became more popular, there was a wish to solve the problem of apical support by using grafts as well. At first, the dissection of the vaginal walls was made more laterally to achieve arcus tendineus fascia pelvic (ATFP) and sacrospinous ligaments, and the mesh was placed onto these structures (Dwyer & O’Reilly 2004). Integral theory was the basis behind the development of infracoccygeal sacropexy in the late 1990s (Petros 1997), the idea being to attempt to correct vaginal vault prolapse with the insertion of a prosthetic tape to mimic the path of uterosacral ligaments. Later, in 2004, the problem of apical support was solved by introducing trocar-guided transvaginal mesh-augmented methods, where meshes are fixed to ATFP, sacrospinous ligaments or nearby, by passing the prosthetic arms of the mesh from the vagina to the skin (Debodinance et al. 2004). The blind setting, with trocars guided close to nerves, vessels and rectum, caused a risk for injury of these organs, leading to development of single-incision transvaginal meshes with controlled apical fixation of the mesh to the sacrospinous ligament.

While the very basics of POP surgery have remained the same, the characteristics of the polypropylene mesh have developed. The first polypropylene meshes used were heavyweight and the type of the mesh could vary. Today, all polypropylene meshes used in POP surgery are type I monofilament and aim at reducing the overall mesh load (Ostergard 2010). The latest meshes are ultra-light weight, and the next question is perhaps “how light is too light?”

2.8.2 Abdominal approach

In abdominal sacrocolpopexy the vaginal vault is connected and supported to the sacrum. Abdominal, laparoscopic and robot-assistant techniques can be used (Lane 1962, Nezhat et al. 1994, Paraiso et al. 2011). The vagina is freed from the rectum and the bladder is mobilized for 6–8 cm from the vault and anterior vaginal wall. The peritoneum above the sacrum is dissected. The mesh is designed to cover the front and the back surfaces of the vagina and is attached to these surfaces and the sacral anterior longitudinal ligament with stitches or staples. The peritoneum is used in covering the mesh (Lane 1962, Nezhat et al. 1994). It has been suggested that besides benefits for the patient, the laparoscopic approach provides surgically easier access and placement of the mesh down the posterior vaginal wall compared to the open procedure. Recently also extraperitoneal mesh placement has been used (Onol 2011).

2.8.3 Transvaginal meshes with or without trocar-guidance

In vaginal trocar-guided methods the mesh is secured and anchored outside the afflicted tissue by mesh arms, which are passed through desired structures with trocars. In the anterior section a sagittal colpotomy is performed with full- thickness lateral dissection of the bladder. As paravesical fossae are opened, the ATFP is identified. Four skin incisions are made: two at the anteromedial edge of the obturator foramen at the level of urethra and another two 2 cm below and 1 cm lateral to the first ones. Guides are inserted from the skin incisions to the vagina, mimicking the route of ATFP, and the prosthetic arms of the mesh are pulled from the vagina through the obturator foramen. The mesh is placed in a tension-free manner. In the posterior compartment, a short posterior colpotomy is performed with entire dissection of the posterior vaginal wall. The pararectal spaces are opened and dissection is performed until sacrospinous ligaments can

be palpated. Two skin incisions are made 3 cm lateral and 3 cm down from the anus. The guides are inserted from the skin incisions, passed through the buttocks and ischiorectal fossae until they reach the middle part of the sacrospinous ligament, through which the prosthetic arm of the mesh is pulled. Tension-free placement is used. The meshes are usually secured with a few knots and covering of the mesh is performed in traditional manner without trimming the mucosa. Separate anterior and posterior meshes are available. Also total vaginal mesh exists for three-compartment reconstructions (Johnson & Johnson Inc, 2006) In single incision transvaginal mesh placement the dissection of the anterior and posterior vaginal wall is performed in the same manner as in trocar-guided methods, but dissection of sacrospinous ligaments or ischiopubic rami is also performed when an anterior mesh is used. In anterior techniques the shorter arms of the meshes are fixed with special tools into soft tissue covering ischial spines, fascia of internal obturator muscle, or sacrospinous ligaments, depending on the kit used. In posterior approach the mesh arms are fixed to sacrospinous ligaments only (Azaïs et al. 2012).

2.8.4 Other vaginal methods

The technique of infracoccygeal sacropexy, also called posterior intravaginal slingplasty, starts with a 4–5 cm wide full-thickness incision made on the posterior vaginal wall, after which adherent rectocele and enterocele are freed from adjoining tissues. Perineal 1-cm incisions are made 2 cm lateral to and below the external anal sphincter. A special tunneler is placed into the ischiorectal fossa at a distance of 4 cm, turned inwards and passed through the rectovaginal fascia, reaching the transverse incision. The procedure is repeated on the other side. The tape is secured with sutures to the vaginal vault and also to the remnants of the uterosacral ligaments. (Petros 1997). At least nylon and polypropylene with multifilament and monofilament type have been used in this technique.

Fig. 3. POP-Q measure points (reprinted with permission from Female_anatomy.svg: Tsaitgaistderivative work: Huckfinne (talk) - Female_anatomy.svg. Licensed under Creative Commons Attribution-Share Alike 3.0 via Wikimedia Commons - http://commons.wikimedia.org/wiki/File:Pelvic_Organ_Prolapse_Quantification_Syste m.svg#mediaviewer/File:Pelvic_Organ_Prolapse_Quantification_System.svg).

2.9 Outcomes after mesh-augmented pelvic organ prolapse surgery

The division into objective and subjective outcomes is present also in evaluating the efficacy of POP surgery. The lack of standardized definitions for surgical success following pelvic organ prolapse surgery has resulted in highly variable estimates of success (Maher et al. 2013). Objective anatomical outcomes can be measured by pelvic organ prolapse quantification (POP-Q) measurements (Bump et al. 1996), or defined for example as no re-treatment for POP. The measure points in the POP-Q system are given in Figure 5, and the point descriptions and stage criteria in Tables 9 and 10.

Table 9. Descriptions of POP-Q points.

Point Description Range of values Aa Anterior vaginal wall 3 cm proximal to the hymen −3cm to +3cm Ba Most distal position of the remaining upper anterior vaginal wall −3cm to +tvl C Most distal edge of cervix or vaginal cuff scar D Posterior fornix (N/A if post-hysterectomy) Ap Posterior vaginal wall 3 cm proximal to the hymen −3cm to +3cm Bp Most distal position of the remaining upper posterior vaginal wall −3cm to +tvl Gh (genital hiatus) Measured from middle of external urethral meatus to posterior midline hymen Pb (perineal body) Measured from posterior margin of gh to middle of anal opening Tvl Depth of vagina when point D or C is reduced to normal position (total vaginal length)

The definition of “optimal anatomical outcome” requires perfect anatomic support with POP-Q stage 0. “Satisfactory anatomic outcome” requires support higher than 1 cm proximal to the hymen (POP-Q stage 0–I). However, data on symptom-free women from gynecological exams show that almost 75% do not meet POP-Q stage 0 and almost 40% fail to meet POP-Q stage I criteria (Swift et al. 2005). Today, objective outcome can also be defined as leading POP-Q measurement beyond or above hymen, as hymen has proved to be an important “cut-off point” in the prevalence of pelvic organ prolapse. Women with prolapse beyond the hymen have more pelvic floor symptoms and are more likely to report a vaginal bulge than women with prolapse at or above the hymen (Barber 2005, Barber et al. 2009, Tan et al. 2005). Moreover, the absence of vaginal bulge symptoms has a strong correlation with patients’ assessment of overall improvement and treatment success (Barber et al. 2009). The presence of vaginal bulge symptom is, however, one of the subjective outcomes used in symptom- based and quality of life (QoL) questionnaires. In this review on the present literature only studies with polypropylene mesh are included.

Table 10. POP-Q staging criteria.

Stage Criteria Stage 0 Aa, Ap, Ba, Bp = −3 and C or D ≤ - (tvl–2) cm Stage I Stage 0 criteria are not met and leading edge < −1cm Stage II Leading edge ≥ −1 but ≤ 1 Stage III Leading edge > +1cm but < + (tvl–2) cm Stage IV Leading edge ≥ + (tvl–2) cm

2.9.1 Efficacy

Evaluation of studies on efficacy of pelvic organ prolapse surgery is demanding because of the variation in populations, study designs and methods used and in definitions. However, the studies on the efficacy of mesh-augmented pelvic organ prolapse surgery mentioned in this literature review are listed in Table 11.

Treatment of apical compartment

For post-hysterectomy vaginal vault prolapse abdominal sacrocolpopexy (ASC) is regarded as golden standard. Barber and Maher concluded in their review that the success of ASC, defined as lack of apical prolapse, varies from 78% to 100%, and when success is defined as no recurrent prolapse in any segment, the published success rates are 56–100% (Barber & Maher 2013b). However, the cure rate depends greatly on the chosen definition, as among the same population cure can vary from 19% (perfect anatomic support) to 97% (no re-treatment) (Barber et al. 2009). Nygaard et al. (2013) created a composite definition for failure including both objective and subjective outcomes, and in their study one-third of the women met the criteria of failure after five years’ follow-up. Laparoscopic sacrocolpopexy (LSC) shows objective cure of 60–100% and subjective cure of 79–98% in short and mid-term case series (Barber & Maher 2013b). Both open and laparoscopic procedures appear equally effective when these two techniques are compared (Klauscie et al. 2009). However, there exists so far only one randomized, controlled trial comparing ASC and LSC. This study of Freeman et al. (2013) shows subjective outcome of 90% and 80% for open and laparoscopic techniques, respectively, with equal objective cure. Currently available, quite limited data on robotic sacral colpopexy (RSC) report objective cure of 60–100% and subjective cure of 91–97% (Barber & Maher 2013b). One randomized comparison on RSC to LSC exists (Paraiso et al. 2011), providing data of equally significant improvement of vaginal support and functional outcomes one year after surgery. Transvaginal trocar-guided total mesh in treatment of apical prolapse shows objective cure of 37–43% in two randomized controlled trials where the mesh group was compared to native tissue or laparoscopic sacrocolpopexy (Maher et al. 2011, Sokol et al. 2012). The recurrence rate was significantly higher in the mesh group compared to LSC (Maher et al. 2011). No difference compared to native tissue was obtained, but it is noticeable that the number or patients who received

total vaginal mesh was only eight in this study (Sokol et al. 2012). One randomized study compared total mesh to sacrospinous colpopexy, reporting better objective cure for total mesh group compared to sacrospinous ligament fixation group. Subjective outcomes in the form of QoL questionnaires were similar. (Halaska et al. 2012). Posterior intravaginal slingplasty (PIVS) in treatment of apical prolapse reveals success ranging from 83% to 100% with follow-up ranging from three to 120 weeks (Barber & Maher 2013b, Feiner et al. 2009) Also longer follow-up exists, reporting good objective success (Capobianco et al. 2014, Heinonen & Nieminen 2011). With elderly women the success after PIVS is worse (Mattox et al. 2006).

Treatment of anterior compartment

Mesh augmentation into anterior compartment has shown better anatomical cure compared to native tissue repair in randomized controlled trials (Altman et al. 2011, Nguyen & Burchette 2008, Nieminen et al. 2010). The recent Cochrane review calculated RR 3.3 (CI 2.6 to 4.2) comparing objective recurrence rates (46% and 14%) following anterior colporrhaphy to any transvaginal anterior polypropylene mesh (Maher et al. 2013). According to RCTs and the Cochrane review, there is less awareness of prolapse after anterior transvaginal mesh repair, indicating better subjective outcome compared to anterior colporraphy alone (Altman et al. 2011, Maher et al. 2013, Nieminen et al. 2010). The success data on single incision transvaginal anterior mesh is scarce, reported objective success being approximately 90% (Moore et al. 2012, Stanford et al. 2013).

Table 11. Studies on efficacy of mesh-augm ented pelvic organ prolapse surgery.

Author Year n Compartment Design Method Follow-up Objective cure definition Objective Subjective cure cure Altman et al. 2011 189/200 Anterior RCT Native / mesh 1 year Composite cure 34.5–60.8% Azaïs et al. 2012 70 Multicompartment Observational SIMS 1 year POP-Q stage ≤ I 79% Anterior 88% Posterior 86% Barber & Maher 2013 Apical Review ASC Lack of apical prolapse 78–100% Lack of any prolapse 56–100% LSC 60–100% 79–98% RSC 60–100% 91–97% PIVS 83–100% Barber et al. 2009 322 Apical RCT ASC 2 years Anatomy – no 19–97% (+/- Burch) retreatment Capobianco et 2014 44 Apical Observational PIVS 9 years POP-Q point C 93% al. Carey et al. 2009 70/69 Multicompartment RCT Native/mesh 1 year POP-Q stage ≤ I 65.6/81% 89–95% Feiner et al. 2009 2,653 Apical Review TVM 26–78 weeks POP-Q stage ≤ I 87–95% PIVS Baden-Walker gr ≤ I 88% Freeman et al. 2013 27/26 Apical RCT ASC/LSC 15 months POP-Q point C NS 90/80% Halaska et al. 2012 83/85 Apical RCT SSLF/TVM 1 year POP-Q stage ≤ I 61/83% Heinonen & 2011 12/8 Apical RCT SSLF/PIVS + 3 years POP-Q stage ≤ I 79/87% Nieminen anterior mesh Klauschie et al. 2009 41/43 Apical Retrospective ASC/LSC 10 months POP-Q point C NS Lukban et al. 2012 139 Posterior Observational SIMS 1 year POP stage ≤ I post 92.5% posterior Maher et al. 2011 53/55 Apical RCT LSC/TVM 2 years Lack of any prolapse 77–43% 59 Reoperation rate 5–22%

60 60 Author Year n Compartment Design Method Follow-up Objective cure definition Objective Subjective cure cure Mattox et al. 2006 21 Apical Observational PIVS 6 weeks Lack of any prolapse 37% Moore et al. 2012 60 Anterior Observational SIMS anterior 13.4 months POP-Q stage ≤ I 91.7% Nguyen & 2008 38/37 Anterior RCT Native/mesh 1 year Anterior POP-Q stage ≤ I 55/87% Burchette Nieminen et al. 2010 202 Anterior RCT Native/mesh 3 years Anterior POP-Q stage ≤ I 59/87% Paraiso et al. 2011 38/40 Apical RCT LSC/RSC 1 year POP-Q points NS Sokol et al. 2012 32/33 Multicompartment RCT Native/mesh 1 year POP-Q stage ≤ I 37–30% 96/91% Anterior 39–53% Posterior 82–78% Stanford et al. 2013 128 Anterior Observational SIMS anterior 1 year POP-Q stage ≤ I 87.7% ASC: abdominal sacrocolpopexy, LSC: laparoscopic sacrocolpopexy, NS: not significant, PIVS: posterior intravaginal slingplasty, POP-Q: pelvic organ prolapse quantification, RCT: randomized controlled trial, RSC: r obotic sacrocolpopexy, SIMS: single-incision mesh system, SSLF : sacrospinous ligament fixation, TVM: transvaginal mesh.

Treatment of posterior compartment

Data concerning repair of posterior vaginal wall with polypropylene mesh are limited, but current data show no statistically significant benefit for the use of mesh on anatomical outcome concerning posterior vaginal wall prolapse (Carey et al. 2009, Sokol et al. 2012), Transvaginal trocar-guided methods were used in these studies, and they also involved other vaginal compartments. Carey reported better success with than without mesh with patients with concomitant anterior and posterior vaginal wall repair (Carey et al. 2009). In Sokol’s previously mentioned study, success after posterior compartment surgery was slightly lower with mesh compared to native tissue. However, posterior compartment surgery involved only eight patients (Sokol et al. 2012). When recurrent POP is operatively treated, the present data suggest that mesh-augmented surgery with polypropylene mesh provides statistically significant improvement in anatomical outcome and fewer recurrences in both anterior and posterior vaginal wall repair (Withagen et al. 2011). In fact, there are no randomized controlled trials comparing purely posterior native tissue reconstruction to polypropylene mesh graft. Single incision transvaginal methods for posterior compartment report an objective cure rate of more than 90% (Lukban et al. 2012). In Azaïs et al.’s study (2012) the success rate for anterior or posterior single incision transvaginal mesh, or their combinations, was lower, only 79%.

2.9.2 Safety

Adverse events after transvaginal pelvic organ prolapse surgery can be divided into not mesh-related and mesh-related complications (Table 12). Recently, IUGA and ICS published a specific classification of complications related to pelvic reconstructive surgery (Haylen et al. 2012). The aim in this classification is that from now on, all parties refer to the same clinical issue. This classification provides a large number of possible complication scenarios by using category (C), time (T) and site (S). Seven categories are used: three for vaginal complications, followed by urinary tract, rectal or bowel, skin and/or muscular, and patient compromises. Time periods are intraoperative to 48 hours, two months, 12 months, and over 12 months. Site divisions are systemic, vaginal area of suture line, vaginal away from suture line, trocar passage, other skin or musculoskeletal site, or intra-abdominal site. (Haylen et al. 2012). Again, there are a number of studies reporting complications of mesh-augmented pelvic organ prolapse

surgery; the studies mentioned in this review of literature are gathered in Table 13.

Table 12. Complications after mesh-augmented POP surgery.

Not mesh-related complications Mesh-related complications Recurrence/reoperation Mesh exposure/extrusion Pain Mesh shrinkage Infection Infection Bleeding Organ perforation Urinary problems

Reoperations for recurrence

Reoperation for apical prolapse using abdominal sacrocolpopexy is needed in 0– 18% of cases (Nygaard et al. 2004). Review on current literature reports a small advantage in reoperation rates for laparoscopic sacrocolpopexy compared to abdominal approach (deTayrac & Sentilhes 2013). In Maher et al.’s RCT (2011) the number of reoperations was significantly higher in the TVM group than in the group receiving LSC. In the study of Sokol et al. (2012) apical reoperation was needed in one of ten cases while there were no surgical interventions in the conventional surgery group. Repeat surgery rates after PIVS vary from 0% to 14% (Capobianco et al. 2014, Cosma et al. 2011, Jordaan et al. 2006). When the anterior vaginal wall is reconstructed with or without mesh, the reoperation rates for prolapse in RCT:s vary from 0% to 6% in mesh groups and from 0% to 10% in native tissue groups (Nieminen et al. 2010, Sivaslioglu et al. 2008, Vollebregt et al. 2011). However, the Cochrane review found no significant difference in further prolapse surgery between native tissue and mesh-augmented surgery for anterior compartment, the rates being 3% versus 1.3%, respectively (RR 2.18, 95% CI 0.93–5.10) (Maher et al. 2013). No RCTs are found comparing posterior vaginal wall native tissue and mesh- augmented surgery alone. From studies involving also other compartments, no posterior vaginal wall reoperations in patients with mesh were made within the follow-up time of one year (Carey et al. 2009, Sokol et al. 2012). Single-incision methods also show low rates of reoperations for prolapse in both anterior and posterior compartment (Lukban et al. 2012, Moore et al. 2012, Stanford et al. 2013).

Pelvic pain and mesh shrinkage

Bothersome pain symptoms after mesh-augmented prolapse surgery include dyspareunia; pelvic, vaginal or buttock pain; and signs of obturator or pudendal neuralgia (Marcus-Braun et al. 2012). Overall incidence of postsurgery pelvic pain varies from 0% to 30% in case series involving patients treated with transvaginal mesh (Rigaud et al. 2008, Sentilhes et al. 2008). Studying postoperative de novo dyspareunia is challenging as dyspareunia exists also preoperatively in patients with POP, and moreover, the nature of dyspareunia is multifactorial. The reported dyspareunia rate after conventional native tissue POP surgery is 19% (Weber et al. 2000). Generally, dyspareunia rates of up to 9% have been reported after ASC (Baessler & Schuessler 2001, Benson et al. 1996), but markedly higher dyspareunia incidence has also been disclosed (Virtanen et al. 1994). For LCS, Price et al. (2011) observed a dyspareunia rate of less than ten per cent. In studies comparing ASC and LSC in an observational manner and in RCT, no difference in dyspareunia rates between the two methods has been found, even though there is wide variation in dyspareunia rates between the studies (Freeman et al. 2013, Khan et al. 2013). Limited data exist on PIVS and dyspareunia. In the study of Heinonen & Nieminen (2011) comparing PIVS and sacrospinous ligament fixation with concomitant anterior mesh, the dyspareunia rates did not differ between the groups. Capobianco reported dyspareunia in 11.4% with long follow-up; however, the preoperative dyspareunia rate in their study was 100% (Capobianco et al. 2014). Cosma et al. (2011) found no cases of dyspareunia while buttock pain did occur. Dyspareunia rates have been reported in a broad spectrum in mesh- augmented anterior and posterior repairs. Nieminen et al. (2008) reported reduction in dyspareunia when comparing anterior mesh to traditional colporraphy. The review made by the Society of Gynecologic Surgeons included 70 studies with mesh augmented vaginal repair reporting dyspareunia rates, concluding an overall dyspareunia rate of 9.1% (Abed et al. 2011). All in all, dyspareunia rates do not rise after mesh-augmented transvaginal surgery compared to traditional native tissue surgery involving the anterior compartment. Data on posterior compartment are insufficient to draw any conclusions (Dietz & Maher 2013). Dyspareunia or other pelvic pain after placement of single incision mesh for anterior compartment appears in 5 to 7.1% of the cases (Moore et al. 2012,

Stanford et al. 2013). For posterior compartment single incision mesh the reported prevalences of postoperative pain (buttock, pelvic, back) and dyspareunia are also low. In fact, dyspareunia has been reported to resolve in 67% of the patients. (Lukban et al. 2012). Shrinkage of the mesh is one cause of vaginal pain and dyspareunia. The reported percentages on painful shrinkage vary from 4% to 11%, according to the definition used (deTayrac & Sentilhes 2013). In Maher’s study mesh contraction was significantly greater after vaginal mesh surgery than after LSC (Maher et al. 2011). It is also possible that shrinkage causes concomitant contracture of the underlying pelvic floor musculature leading to chronic pelvic pain, even though the prevalence of pelvic floor muscle spasms following reconstructive vaginal surgery has not been studied (Gyang et al. 2013). The incidence of pudendal neuralgia following pelvic reconstructive surgery is also unknown even though signs of it are seen in patients suffering from postoperative pain (Gyang et al. 2013, Marcus-Braun et al. 2012). The trocars of trocar-guided mesh kits are designed to pass through the obturator space apically at the level of ischial spines, and because of the immediate proximity of the pudendal nerve unrecognized nerve injury can occur (Hibner et al. 2012).

Intraoperative blood loss and organ perforations

Vaginal mesh-augmented methods seem to produce more intraoperative blood loss than other techniques. Total vaginal mesh shows more blood loss compared to LSC (Maher et al. 2011). When anterior mesh is compared to native tissue repair, blood loss is significantly smaller in conventional treatment. As RCTs comparing posterior compartment mesh and native tissue do not exist, comparative data on blood loss are not available. Concerning the abdominal sacrocolpopexies, mean blood loss is significantly higher after ASC than LSC (Freeman et al. 2013, Coolen et al. 2013). Posterior intravaginal slingplasty might show less blood loss than traditional sacrospinous ligament fixation; however, findings of equal blood loss also exist (Cosma et al. 2013, Maher et al. 2013). A recently published cohort study showed a statistically significant difference in mean blood loss favoring native tissue repair over single incision transvaginal mesh (Su et al. 2014). The Cochrane review concluded intraoperative bladder injury rate to be 0.3% and 2.4% after anterior colporraphy and transvaginal mesh, respectively. However, the difference was not significant. (Maher et al. 2013). A recent meta-

analysis included 1,508 trocar-guided procedures and no trocar-related injuries whatsoever were found. Dissection-related bladder injuries occurred in 1% and dissection-related bowel injuries in 0.2% (Nguyen et al. 2012). All in all, rectal perforation seems very rare. In Altman’s study, rectum perforation occurred in 1/48 patient with posterior mesh (Altman et al. 2008b), while no bowel perforations in the posterior mesh groups were detected in other studies (Carey et al. 2009, Withagen et al. 2011). When single incision mesh is compared to native tissue, bladder and rectal perforations occur equally (Su et al. 2014). The percentages for organ perforations in other studies including only single incision mesh are in line with this result (Lukban et al. 2013, Moore et al. 2012, Stanford et al. 2013). Severe complications seem more common after open compared to laparoscopic sacrocolpopexy (Freeman et al. 2013, Coolen et al. 2013). The RCT of Freeman showed one bladder perforation in the LSC group while no bowel perforations were observed. (Freeman et al. 2013). Coolen et al. (2013) compared ASC and LSC in a cohort study, and found 2.4% fatal bowel complications in the ASC group, while bladder lesions emerged equally in both groups (Coolen et al. 2013). Other studies report similar complication rates (Klauschie et al. 2009, Paraiso et al. 2005). Rectal perforations in patients receiving PIVS seem also rare, as this adverse event is not detected in most studies (Capobianco et al. 2014, Cosma et al. 2011, Heinonen et al. 2011).

66 66 Table 13. Studies reporting complications after mesh-augmented pelvic organ prolapse surgery.

Author Year n Compartment Design Method Follow-up Complication and result Abdel-Fattah et al. 2008 289 Multicompartment Retrospective TVM 3 months Bladder injury: 1.3%, Rectal injury: 1.1%, Mesh exposure: 10%, Buttock pain: 5.2%, Serious infection: 0.7% Abed et al. 2011 Multicompartment Review TVM Mesh exposure 10.3%, Dyspareunia 9.1% Altman et al. 2011 189/200 Anterior RCT Native/mesh 1 year Hemorrhage: 0%/2%, Bladder perforation 0.5%/3.5%, De novo SUI: 6.3%/12.3%. Mesh exposure: 3.2% Baessler & Maher 2013 Anterior Review Native/mesh De novo SUI 8%/14%, De novo OABS: 10%/7% Baessler & Schuessler 2001 33 Apical Observational ASC 26 months Dyspareunia: 8.7% Caquant et al. 2008 684 Multicompartment Retrospective TVM 6 months Bladder perforation: 2%: Rectal perforation 0.15%, Hemorrhage: 1%, Pelvic abscess: 0.29%, Pelvic cellulitis 0.15%, De novo SUI: 5.4%, Mesh exposure: 11.3% Capobianco et al. 2014 44 Apical Observational PIVS 9 years Mesh exposure: 2.3%, Dyspareunia 11.4% Carey et al. 2009 70/69 Multicompartment RCT Native/mesh 1 year Dyspareunia: 15%/17%, Mesh exposure: 5.6% Coolen et al. 2013 42/43 Apical Observational ASC/LSC Hemorrhage: 0%/4.7%. Bowel perforation: 2.4%/0%, Bladder perforation: 4.8%/4.7% Cosma et al. 2011 118 Apical Retrospective PIVS/SSLF 24–84 mo Mesh exposure 8.5%, Dyspareunia: 0%, Buttock pain: 2.5% De Tayrac & Sentilhes 2013 Multicompartment Review ASC Mesh exposure 3%, Reoperation 4% LSC Mesh exposure 2.5%, Reoperation 1.7% Freeman et al. 2013 27/26 Apical RCT ASC/LSC 1 year Dyspareunia: 3.8%/7.4% Gauruder-Burmester 2007 120 Multicompartment Observational TVM 1 year Mesh exposure: 8% et al. Heinonen & Nieminen 2011 14/8 Apical RCT PIVS/SSLF 3 years Dyspareunia: 7%/0% Jordaan et al. 2006 42 Apical Retrospective PIVS 13 months Rectum perforation: 2.4%

Author Year n Compartment Design Method Follow-up Complication and result Khan et al. 2013 794/176 Apical Retrospective ASC/LSC 1 year Dyspareunia 23.7%/18.2% Lukban et al. 2012 139 Posterior Observational SIMS posterior 1 year Reoperation: 0%, Mesh exposure: 6.5% Nguyen et al. 2012 858 Multicompartment Observational Synthetic graft 21 months Mesh exposure: 3%, Pelvic abscess in one patient Nieminen et al. 2010 97/105 Anterior RCT Native/mesh 3 years Reoperation: 18%/11%, De novo SUI: 5%/7%, Mesh exposure: 19% Maher et al. 2011 53/55 Apical RCT LSC/TVM 2 years Mesh exposure: NS, Reoperations 5%/22% Moore et al. 2012 60 Anterior Observational SIMS anterior Mesh exposure 0%, Dyspareunia: 5% Price et al. 2011 84 Apical Observational LSC 24 months Dyspareunia: 8% Sivaslioglu et al. 2008 45/45 Anterior RCT Native/mesh 1 year Mesh exposure: 6.9%, Dyspareunia 0%/4.6% Sokol et al. 2012 32/33 Multicompartment RCT Native/TVM 1 year Reoperation (apical) 0%/9% Stanford et al. 2011 128 Anterior Observational SIMS anterior 1 year Mesh exposure 6.3%, Dyspareunia: 3.2%, Buttock pain: 3.9%, De novo SUI 3.9% Su et al. 2014 101/100 Multicompartment Observational Native/SIMS 1 year Vaginal mesh exposure: 3%, Bladder perforation: 3%/3%, Rectal perforation 2%/1% Virtanen et al. 1994 30 Apical Observational ASC 3 years Dyspareunia: 37.5% Vollebregt et al. 2011 64/61 Anterior RCT Native/mesh 1 year Reoperation: 5%/0%, Mesh exposure 4%, De novo dyspareunia: 9%/15% Withagen et al. 2010 97/93 Multicompartment RCT Native/mesh 1 year Mesh exposure: 16.9% ASC: abdominal sacrocolpopexy, LSC: laparoscopic sacrocolpopexy, OABS: overactive bladder symptoms, RCT: randomized clinical tri al, SIMS: single incision mesh system, SUI: stress urinary incontinence, TVM: transvaginal mesh. 67

Postoperative de novo urinary symptoms

The risk for de novo SUI after traditional POP surgery was recently estimated to be as high as 37% (Al-Mandeel et al. 2011), compared to previous estimates varying from 2% to 22% (Borstad & Rud 1989, Colombo et al. 1996, Stanton et al. 1982). Baessler & Maher concluded in their review (2013) that conventional anterior repair yields lower rates of de novo SUI than transvaginal mesh procedure. The studies included had relatively short follow-ups, and indeed, Nieminen reported that after three years’ follow-up the percentages for de novo SUI were similar (Nieminen et al. 2010). In the Colpopexy and Urinary Reduction Efforts (CARE) trial de novo SUI was reported in 41% of patients who had undergone ASC (Brubaker et al. 2006, Brubaker et al. 2008). After LSC about half of the patients have reported de novo SUI, one out of six of them requiring surgery for it (Leruth et al. 2013). The recent Cochrane review calculated that overactive bladder symptoms develop in 12% of women with various types of prolapse surgery. The cumulative rate of de novo overactive bladder symptoms (OABS) in women who underwent a transvaginal anterior mesh procedure is lower than in studies involving conventional anterior repair (Baessler & Maher 2013, Maher et al. 2013). However, this difference was not significant. OABS are reported in 7.6% of patients after ASC (Costantini et al. 2007).

Mesh exposure

Mesh exposure is the most commonly reported mesh complication, according to the Manufacturer and User Facility Device Experience (MAUDE) database (FDA 2011). This phenomenon is now defined by IUGA/ICS as vaginal mesh visualized through separated epithelium, and extrusion is defined as the gradual passage of mesh out of the body structure or tissue (Haylen et al. 2012). Rates for exposure or extrusion are various, and data on this matter is heterogeneous and huge. According to a recent study on 858 mesh-augmented procedures in the treatment of POP, the reoperation rate for vaginal mesh erosion is 3%. This study also reported that exposure requiring surgical excision most commonly exists in the anterior compartment. (Nguyen et al. 2012). The review of the Society of Gynecologic Surgeons analyzing 110 studies revealed an overall exposure rate of 10.3% (Abed et al. 2011).

Similar mesh exposure rates have been calculated for ASC and LSC (deTayrac & Sentilhes 2013). The only study comparing LSC to total vaginal mesh did not show a significant difference in exposure rates between the two methods (Maher et al. 2011). In the latest Cochrane review the vaginal exposure rate was 11.4% in mesh augmented treatment of anterior compartment. As RCTs concerning the posterior compartment do not exist, no meta-analysis on mesh- augmented posterior vaginal wall surgery can be given. However, taking together the scarce data on posterior vaginal mesh, exposure rates between 0% and 11% are reported (Abdel-Fattah et al. 2008, Gauruder-Burmester et al. 2007, Withagen et al. 2010). Exposure rates were higher, up to 18%, in RCTs involving multicompartment mesh surgery (Maher et al. 2013). The PIVS method also shows wide variation in vaginal exposure rates, from 0% to 21% (Cosma et al. 2011). Actually, one could expect even higher exposure rates for this method as in most of the studies involving PIVS the mesh used is multifilament and microporous in nature. In studies involving single incision mesh, exposure rates of up to 6% have been reported for both anterior and posterior compartments (Lukban et al. 2012, Moore et al. 2012, Stanford et al. 2013).

Infection

The actual rate of infections after mesh-augmented surgery for pelvic organ prolapse is unknown. Bacterial mesh colonization occurs in up to 80% of the cases (Vollebregt et al. 2009) and the incidence of vaginal mesh infections ranges from 0% to 8% (Falgas et al. 2007). Infections may or may not be associated with mesh exposure, but clinically evident infections are frequently associated with erosion or other uncommon clinical manifestations, such as vesicovaginal fistula, rectovaginal fistula, pelvic abscess, sigmoid bowel-vaginal fistula, osteomyelitis, spondylodiscitis and cellulitis. The incidences of severe infections, such as abscess, spondylodiscitis or cellulitis, do not exceed 1% after both sacrocolpopexy and transvaginal meshes. In a cohort of 685 polypropylene mesh implants pelvic abscess and cellulitis were reported to occur in only 0.29% and 0.15%, respectively (Caquant et al. 2008). In Nguyen’s review only one pelvic abscess occurred after sacrocolpopexy, in a patient with concomitant hysterectomy (Nguyen et al. 2012).

2.9.3 Patient satisfaction

Patient satisfaction has risen to be an important outcome after surgical procedures just in recent years. However, data on patient satisfaction following mesh- augmented surgical interventions for POP are limited. No comprehensive reviews or meta-analyses have been conducted on this issue. Only one RCT involving transvaginal mesh included a question on patient satisfaction in their study protocols. Carey et al. (2009) reported a non-significant difference in patient satisfaction rates, 91.5% and 81%, with or without transvaginal mesh, respectively. In an observational study by Alperin the median global satisfaction rate was as high as 9.3 (2.0–10.0) after two years’ follow-up when ProliftTM was used for total, anterior and posterior prolapse treatment (Alperin et al. 2013). Feiner et al. (2012) reported equal patient satisfaction indexes for anterior ProliftTM and PerigeeTM in prospective comparison. A direct answer to the question on patient satisfaction following ASC is not given in the current studies. In the RCT of Freeman comparing ASC and LSC, quality of life measurements were similar between the groups, but overall satisfaction was not asked (Freeman et al. 2013). Lee et al. (2014) reviewed literature on LSC and RSC, and these techniques showed similar patient satisfaction rates, 92%, when analyzing 1,221 patients with a mean follow-up of 26 months. In the RCT comparing LSC to total vaginal mesh, the median patient satisfaction measured with VAS was significantly higher, 8.1, following LSC (95% CI 0.2 to 16.0) (Maher et al. 2011). Patient satisfaction has not been asked directly in studies concerning PIVS except for one study, which reported the satisfaction rate to be 89.9% (Neuman & Lavy 2007). In deTayrac’s RCT comparing PIVS and sacrospinous ligament fixation no difference in postoperative quality of life questionnaires was observed (deTayrac et al. 2008). Quality of life measurements improved equally in a cohort study comparing single incision mesh to native tissue repair, but patient satisfaction was not asked in this study (Su et al. 2014). Lukban reported 81% satisfaction in patients receiving posterior single incision mesh when satisfaction was defined as “very” or “extremely” satisfied. Overall, 96% of the patients would recommend the procedure to a friend. (Lukban et al. 2012).

3 Aims of the study

The purpose of the present study was to view safety issues and determine complication rates of heavyweight and lightweight macroporous monofilament meshes and microporous multifilament mesh in treatment of female urinary incontinence and apical and posterior vaginal wall prolapse. Vaginal mesh exposure rate was under special interest. Patient-oriented outcomes were under evaluation after treatment of urinary incontinence with tension-free vaginal tape (TVT) and transobturator tape (TOT) methods. Objective and subjective outcomes after treatment of pelvic organ prolapse with posterior intravaginal slingplasty (PIVS) and posterior single incision mesh were investigated. The specific aims of the study were as follows:

1. To detect the late postoperative complication rate, especially vaginal mesh exposure rate, after treatment of urinary incontinence with heavyweight macroporous monofilament mesh (TVT) and heavyweight microporous multifilament mesh (intravaginal slingplasty sling, IVS) using a retropubic approach (I). 2. To find out whether there is a difference in subjective cure and patient satisfaction when female urinary incontinence is treated with a retropubic (TVT) or transobturator (TOT) approach. Two structurally different heavyweight, macroporous monofilament meshes were used. Information about the safety of the procedures was gathered (II). 3. To evaluate the objective outcome after surgical treatment of apical prolapse with heavyweight microporous multifilament mesh (PIVS) in comparison to traditional sacrospinous ligament fixation. Complication rate and patient satisfaction were also investigated (III). 4. To study the short-term efficacy and safety of lightweight macroporous monofilament mesh in single incision mesh repair of posterior vaginal wall (Elevate®Posterior) (IV).

4 Materials and methods

4.1 Study subjects

For the study on late postoperative complications of TVT and IVS (Study I) we collected retrospective data on 403 patients who were operatively treated for stress urinary incontinence in Oulu University Hospital between January 2000 and June 2004. A total of 293 patients underwent TVT and 80 patients underwent IVS operation. Other procedures were used in 30 operations and they were excluded from the final analysis. Both TVT and IVS groups were similar in terms of age, body mass index, parity and use of hormone replacement therapy. There was no difference in previous surgical operations or concomitant diseases, either. The groups were also similar concerning the type of incontinence. In the TVT group 27 (9%) patients had undergone anterior colporrhaphy, 116 (39%) had prior hysterectomy and 38 (13%) previous incontinence operation. Corresponding numbers in the IVS group were 10 (13%), 17 (22%) and 4 (5%). The patients for the prospective and randomized study comparing TVT and TOT in the treatment of stress or mixed urinary incontinence (Study II) were recruited in the outpatient clinic of the Department of Obstetrics and Gynecology of Oulu University Hospital between January 2004 and November 2006. A total of 100 women who were evaluated to benefit from operative treatment were enrolled in the study. Written information on the trial was given to all patients before agreeing to the study and the participating patients gave a written consent. The patients were randomized either to the TVT or to the TOT group, and randomization was performed with sealed and numbered envelopes. Inclusion criteria were SUI or MUI with a predominant stress component, insufficiency of conservative treatment, and patient’s willingness to participate in the study. Exclusion criteria were urge incontinence, previous mini-invasive operation for SUI, and necessity of other concomitant surgical procedure. An attempt was made to enroll all patients fulfilling the criteria and attending operative treatment in the study as the aim was “real-life” patients. SUI was diagnosed with positive cough test with full bladder or specific questionnaires. Urodynamic testing was not mandatory for the study protocol; it was carried out in five patients (10%) in both groups only when the decision regarding operative treatment could not be made without urodynamic findings.

As intravaginal slingplasty tape was also used in the treatment of apical prolapse in the form of the PIVS method, we enrolled sixteen patients who had undergone PIVS for treatment of apical prolapse between February 2001 and March 2005 into our retrospective study in Oulu University Hospital. As a control group we enrolled seventeen patients who had undergone traditional sacrospinous ligament fixation (SSLF) for apical prolapse as well, at the same time period (Study III). These groups were similar as regards age, body mass index and parity. Prior hysterectomy was performed in all patients in the PIVS group and in fifteen patients in the SSLF group. Two patients with SSLF had concomitant hysterectomy. For the trial of single incision mesh repair in treatment of symptomatic posterior vaginal wall prolapse, 113 patients were recruited at four university hospitals and four central hospitals in Finland between September 2010 and August 2013. All attending patients gave a written consent after oral and written counseling. Exclusion criteria were concomitant surgery, immunosuppressive treatment of any kind, previous or forthcoming bowel operation with low anastomosis creation, and previous vaginal radiation therapy. Two patients were excluded from the final analysis, one due to receiving a concomitant transobturator tape and the other because of intraoperative rectum perforation. However, rectum perforation was included in the safety analysis. (Study IV) Patients’ baseline demographics and study designs are gathered in Table 14.

Table 14. Study designs and patient demographics.

Characteristic Study I Study II Study III Study IV TVT/IVS TVT/TOT PIVS/SSLF Elevate®Posterior Design Retrospective Prospective, Retrospective Prospective, observational randomized observational observational Number of subjects 293/80 50/50 16/17 111 Follow-up (mo) 40 (12–72) 46 (27–62) 16 (6–52) 3 Age (y) 55 (26–82)/ 51 (33–70)/ 70 (52–80)/ 63 (47–87) 55 (34–80) 54 (36–70) 62 (48–75) BMI (kg/m2) 27 (17–48)/ 25 (20–38)/ 29 (20–33)/ 27 (19–44) 26 (19–42) 28 (21–35) 27 (24–39) Parity 2 (0–16)/ 2 (0–11)/ 3 (0–7)/ 2 (0–12) 2 (0–13) 3 (0–16) 3 (1–13) Values are given as median (range), when appropriate.

4.2 Methods

4.2.1 Study designs and outcomes

The study concentrating on late postoperative complications of monofilament macroporous mesh (TVT) and multifilament microporous mesh (IVS) in treatment of female urinary incontinence was a retrospective study (Study I). The main outcome was the incidence rate of vaginal mesh exposure. Postoperative urge and treatment failure were defined as a contact to gynecological outpatient clinic because of this symptom. The comparison of retropubic and transobturator approaches in treatment of female stress or mixed urinary incontinence was designed as a prospective and randomized study (Study II). The main outcomes were subjective cure and patient satisfaction. Subjective cure was defined as a postoperative urinary incontinence severity score (UISS) under eight and patient satisfaction was asked with a direct question. Secondary outcome was the change in the urge symptoms during the follow-up. A score of seven on the detrusor instability score (DIS) was used as a cut-off point in evaluating the alterations in urge. Information was also collected on vaginal mesh erosions that emerged. Comparing the microporous multifilament IVS tape in treatment of apical prolapse to traditional unilateral SSLF was performed in a retrospective observational manner. In this study the main outcome was the objective success after surgery, measured using the POP-Q system. Apical prolapse failure was defined as point C ≥ −1 and overall failure was defined as any POP-Q point ≥ −1. Secondary outcomes in this study were the incidence of vaginal exposure after the PIVS method and patient satisfaction after surgical interventions. (Study III) The trial on short-term efficacy and safety of lightweight macroporous monofilament mesh in treatment of posterior vaginal wall prolapse with single incision technique was designed as a prospective multicenter national study (Study IV). In addition to reporting efficacy and safety, the secondary aim of this study was to evaluate the effect of the surgical method on the non-affected and untreated anterior vaginal compartment. Two different objective cures were used as definitions: POP-Q stage ≤ I or postoperative leading edge at or above the hymen in preoperatively affected posterior compartment with or without apical descent. De novo anterior vaginal wall prolapse was also qualified by two definitions: stage ≥ II, or postoperative leading edge beyond the hymen in anterior compartment, including patients with preoperative stage 0 or I on anterior vaginal

wall. Subjective cure was defined as absence of bulge symptoms asked within the PFDI-20 questionnaire. Dyspareunia in this study was defined as patient response “usually” or “always” to the question “Do you feel pain during intercourse?” in the PISQ-12 questionnaire, or answering yes to direct question on pain during intercourse. We obtained approval to prospective Study II from the Regional Ethics Committee. The study protocol for Study IV was approved by the Ethics Committees of all participating hospitals. Studies I and III did not require ethical approval as these study designs were retrospective without any interventions.

4.2.2 Data collection

Data for the study involving TVT and IVS were collected from patients’ case records. All patients had a visit in the gynecological outpatient clinic preoperatively. Gynecological examination was performed with special interest in cough test and gynecological ultrasound in revealing possible retention of urine. The outcome of urethrocystometry was denoted if it was conducted. The results of preoperatively filled UISS and DIS questionnaires were collected. Data concerning postoperative visits to gynecological outpatient clinic because of complications were gathered. (Study I) As for the comparison of the retropubic and transobturator approach using TVT and TOT methods, the preoperative evaluation consisted of a detailed interview on patient’s medical and gynecological history and a physical examination of the patient, including a standardized cough test to reveal urinary leakage, a finger test to examine the force of the pelvic floor muscles, and a pelvic ultrasound scan for the detection of a full bladder before the cough test and possible urinary retention. UISS and DIS questionnaires were used in assessing baseline bother of urinary incontinence and the degree of urge symptoms. The follow-up data were gathered at a median of 3, 14 and 46 months after the operation using postal collection of UISS and DIS questionnaires together with a question on overall satisfaction. (Study II). The preoperative data on the study subjects who had undergone PIVS and SSLF were collected from the patient database. Furthermore, they were invited to attend a postoperative follow-up visit. Clinical examination included the provocation of the maximal size of the prolapse using the Valsalva maneuver or cough test, and POP-Q scores were measured to evaluate the anatomical outcome of the surgical intervention. Information on patients’ subjective urinary, bowel

and sexual dysfunctions and difficulties were gathered with a specific questionnaire. Overall satisfaction with the treatment was asked. (Study III). Baseline data on subjects in Study IV were gathered using a detailed and structured interview. Clinical examination with baseline POP-Q measurements was performed, condition of the vaginal mucosa was inspected and gynecological ultrasound was performed to exclude possible pelvic pathologies. Patients filled in pelvic floor distress inventory (PFDI-20) and pelvic organ prolapse/urinary incontinence sexual questionnaires (PISQ-12), which were used in the follow-up as well. Three months postoperatively gynecological examination was repeated with measurement of POP-Q points, and possible complications were documented. PFDI-20 and PISQ-12 questionnaires were also filled in once more. (Study IV).

4.2.3 Questionnaires

Detrusor instability score (DIS)

The detrusor instability score was developed by the Finnish colleagues Kauppila et al. (1982). This questionnaire is standardized and validated (Klovning et al. 1996, Kujansuu & Kauppila 1982) and it is used in estimating the degree of overactive bladder symptoms. The DIS questionnaire is a common tool in clinical practice in Finland, recommended by the Finnish Society of Obstetrics and Gynecology. The questionnaire consists of ten questions with three possibilities to answer, rated as 0, 1 and 2 points. The maximum score of the DIS is 20 points. When evidence of stress incontinence has been found, a sum score above seven on the DIS questionnaire justifies diagnosing the type of urinary incontinence as mixed incontinence.

Pelvic floor distress inventory 20 (PFDI-20)

The pelvic floor distress inventory was developed by Barber et al. in 2001 to investigate all symptoms related to pelvic floor disorders and the severity of inconvenience they cause. In 2005, a shorter version, PFDI-20, was developed and proved to be a valid and reliable condition-specific questionnaire (Barber et al. 2005). PFDI-20 consists of 20 items which can be divided into three subscales including the pelvic organ prolapse distress inventory-6 (POPDI-6), the colo-

rectal-anal distress inventory-8 (CRADI-8), and the urinary distress inventory-6 (UDI-6). If a subject answers yes to a questionnaire item the symptom severity is graded with a further scale as follows: 1 = unimportant, 2 = little, 3 = moderate and 4 = a lot. The mean of the answers in each subscale is calculated and multiplied with 25, giving a possible score from 0 to 100. The score of the PFDI- 20 is calculated as a sum of the three subscale scores. This questionnaire has so far not been validated in Finnish population.

Pelvic organ prolapse/urinary incontinence sexual questionnaire 12 (PISQ-12)

The pelvic organ prolapse/urinary incontinence sexual questionnaire, validated in 2001, was the first condition-specific instrument for evaluating sexual function in women with prolapse or urinary incontinence (Rogers et al. 2001). In 2003 a 12- item short version of the PISQ was developed and validated (Rogers et al. 2003). Items 1–4 concern emotional and behavioral factors, items 5–9 deal with physical aspects, while items 10–12 address the relationship with partner. The Likert scale is used to grade responses which range from “never” to “always” with scores 0 to 4. For items 1–4 inverse scoring is used. The maximum score possible is 48, and higher scores indicate better sexual function. This questionnaire has not been validated in Finnish population, either.

Questionnaire study III

This detailed non-validated, standardized questionnaire covers satisfaction with the operation, current urinary and bowel function, symptoms involving urinary incontinence, and questions on sexual function. We adopted this questionnaire into our study from colleagues in Tampere (Nieminen & Heinonen 2001) who have used it in their studies involving issues associated with pelvic organ prolapse.

Urinary incontinence severity score (UISS)

Urinary incontinence severity score is used in evaluating social, hygienic and professional disability. It was first introduced into clinical practice by Finnish colleagues in 1992 (Mäkinen et al. 1992a) and further validated in 2001 (Stach- Lempinen et al. 2001). Today, it is widely used in clinical practice in Finland as it

is recommended by the Finnish Society of Obstetrics and Gynecology. This questionnaire consists of ten questions with three possible answers, which are graded from 0 to 2. Maximum score of the UISS questionnaire is 20 points. Local guidelines exist in determining the UISS score which justifies intensive treatment of urinary incontinence. At the time of our study, the cut-off point eight represented a bother severe enough to consider intensive care of urinary incontinence, for example operative treatment.

4.2.4 Used polypropylene meshes

Below in Table 15 are listed all the meshes used in this study with structure properties of importance.

Table 15. Study meshes and their properties.

Property TVT® IVS®/PIVS® Monarc® Elevate® Filament monofilament multifilament monofilament monofilament Pore size 1379µm < 10µm 1000µm 1120µm Structure knitted woven knitted knitted Weight 95 g/m2 84.2 g/m2 120 g/m2 25.5 g/m2

4.2.5 Surgical procedures (Studies II and IV)

The treatment of female urinary incontinence using retropubic (TVT) and transobturator (TOT) approaches (Study II) and the treatment of posterior vaginal wall prolapse with single incision mesh (Study IV) were performed as follows.

TVT

TVT was performed by one qualified surgeon. A local anesthetic, prilocaine hydrochloride with adrenalin diluted to 0.25%, was infiltrated in the midline of the anterior vaginal wall and then through the route of the tape insertion instrument. Fentanyl or alfentanyl hydrochloride was used intravenously when extra pain medication was needed. Intravenous cefuroxime 1.5 g antibiotic prophylaxis was used in all operations. A sagittal vaginal incision about 1.5 cm in length was made starting approximately 1.0 cm from the outer urethral meatus. Two small 0.5 cm paraurethral dissections and two abdominal 0.5–1.0 cm skin incisions were made

on each side of the midline, just above the symphysis, not more than 4–5 cm apart. The empty bladder and urethra were moved contralaterally to the side of the needle passage with a rigid catheter guide. The TVTTM introducer was attached to the end of the needle. The needle passing paraurethrally penetrating the urogenital diaphragm was controlled and guided by the non-dominant hand and introduced into the retropubic space. After the needle tip was passed through the urogenital diaphragm, the needle was moved upwards towards the abdominal skin incision while pressing the needle against the back of the pubic bone. When the needle tip reached the abdominal incision, cystoscopy was performed to confirm bladder integrity. The procedure was repeated on the other side. The sling was placed loosely under the mid-urethra and adjusted to the right position with intraoperative full bladder cough test. The plastic sheaths of the tapes were removed and abdominal ends of the tape were cut and left in the subcutis. Skin incisions and vaginal incision were sutured. (Ulmsten et al. 1996)

TOT

The same qualified surgeon who performed the TVT procedures operated on TOT patients as well. The use of local anesthetic, antibiotic prophylaxis and handling the extra pain were accomplished as described in the TVT section. A suburethral incision was made under the mid-urethra and dissection was extended laterally until the interior portion of the inferior pubic ramus was reached. Stab skin incisions were made bilaterally at the level of the clitoris laterally to the pubic ramus and just inferior to the tendon of the adductor longus muscle. A MonarcTM needle was pointed perpendicular to the skin incision with the index finger of the other hand in the vaginal incision palpating the bone, and the thumb on the outside curve of the needle to control the needle movement as it perforated the obturator membrane and muscle. The needle shaft and handle were positioned at 45º angle to the patient’s vertical axis. The needle was first pushed through the obturator muscle and membrane and then rotated so that the needle tip reached the vaginal incision. The mesh was attached to the needle, which was reverse-rotated back through the skin incision, pulling the mesh into position. The procedure was repeated on the other side. The mesh was properly tensioned by placing scissors or a small instrument between the mesh and the urethra, and plastic sheaths were removed. The mesh was trimmed at the level of subcutaneous tissue and skin incisions as well as vaginal incision were closed. (American Medical System Inc, 2006)

Elevate®Posterior

The vaginal wall was opened in midline and full-thickness dissection was used. After clearance of both sacrospinous ligaments, a special fixating arm was inserted onto the needle tip. With palpation of the sacrospinous ligament under action, the self-fixating tip was driven into the ligament two to three centimeters medially from the ischial spine. The needle tip was inserted up to the first bend and the needle was then gently removed from the self-fixating tip. This procedure was repeated on the patient’s other sacrospinous ligament. The graft was attached to the vaginal apex or posterior cervix with two or more absorbable sutures. The distal end of the mesh was trimmed appropriately for the patient’s anatomy, and absorbable sutures were placed through the proximal portion of the graft. When the adjustment was final the fixation arms were locked with eyelets and fixating arms were trimmed. Trimming of the vaginal mucosa was avoided as much as possible and the vaginal incision was closed using absorbable monofilament string. (American Medical Systems Inc, 2009). (Study IV) Qualified surgeons (n = 9), familiar with transvaginal mesh surgery, performed the operations, and they received hands-on training for this specific technique before patient enrollment. One dose of prophylactic intravenous antibiotic was used in all operations, according to local practice. Cefuroxime 1.5 g was used in 82 (73%) cases and metronidazole 500 mg was combined with it in 25 (22%) operations. In case of penicillin allergy (n = 5, 5%) clindamycin 600 mg was used. Vaginal packing and transurethral catheter were placed intraoperatively and removed on the first postoperative day. (Study IV).

4.2.6 Statistics

The data were analyzed with SPSS versions 16.0, 17.0 and 22.0. Descriptive statistical analysis of continuous variables was performed using mean with standard deviation or median with range. A p-value under 0.05 was considered as statistically significant. For Study I Fisher’s Exact test, Pearson’s chi-squared test, Mann-Whitney U-test and log linear test were used as appropriate. Risk ratios with 95% confidence intervals were used for categorical variable. In Study III Mann-Whitney U-test was the most appropriate for skewed distribution of most variables. However, Fisher’s Exact test was used for contingency tables of the discrete variables. Analyses for Study II were performed according to intention to

treat. Paired t-test, Fisher’s exact test and Mann-Whitney U-test were used to evaluate changes in outcome scores in both Study II and Study IV. Sample size calculation for Study IV was performed with G*Power program (version 3.1.5) (Faul et al. 2007). Based on previously published data, we estimated the clinically significant difference to be two centimeters in POP-Q measurements, with standard deviation of one centimeter. To reach 90% power in detecting effect size of 0.30 with one-tailed type-α error 0.05 the G*Power analysis calculated 97 as the number of patients needed.

5 Results

5.1 Safety and complications

5.1.1 Vaginal mesh exposure

Symptomatic vaginal exposure was found in 3 (1%) of the TVT patients and in 13 (16%) of the IVS patients, and this difference was statistically significant (p < 0.001; RR 13.7, 95% CI 4.03–46.8). The median time to onset of symptoms was nine (8.5–24.5) months in the TVT group and 11.5 (2.5–41) months in the IVS group. (Study I) Within the prospective study concerning TVT and TOT procedures, mesh exposures occurred in two TOT patients; both cases were treated operatively by removing the visible part of the tape. No tape erosions were found in the TVT group. (Study II) As for Study III, vaginal mesh exposure rate after PIVS was 25%, affecting four patients. All of them required surgical removal of the tape and approximation of vaginal edges. Posterior single incision mesh was safe in view of the incidence of mesh exposure. At three months only one (0.9%) 1-mm erosion was detected without need for operative treatment (Study IV).

5.1.2 Intraoperative safety

Data on intraoperative safety of mid-urethral slings for treatment of urinary incontinence were gathered from a prospective study concerning TVT and TOT. (Study II). Significant differences in intraoperative surgical data were found in median operative time (29 min vs. 15 min), intraoperative blood loss (100 mL vs. 50 mL), and intraoperative (5 vs. 0) and immediate postoperative (3 vs. 1) visual analogue scale (VAS) score for pain, in favor of TOT compared to TVT. However, major intraoperative adverse events like bladder, bowel or vascular injuries were not observed. There were no intraoperative bladder or vascular injuries among our study populations treated for pelvic organ prolapse with PIVS, SSLF or Elevate®Posterior. Median intraoperative blood loss was 50 mL (0–350 mL) in both PIVS and SSLF groups with no need for transfusions.

Considering the patients receiving Elevate®Posterior intraoperative blood loss over 300 mL was observed in three (3%) patients without need for transfusions. Hemostatic sponge was used in one case. The one intraoperative dissection- related rectum perforation occurred in posterior Elevate®Posterior study.

5.1.3 Other postoperative complications

Incontinence surgery

Postoperative infections were seen in 15 (5%) patients in the TVT and eight (10%) in the IVS group. Further evaluation of infections evidenced 12 urinary tract infections and three wound infections in the TVT patients, and two urinary tract infections, three wound infections, two tape infections and one pyelonephritis among the IVS patients. The differences between infections were not significant. (Study I) A total of 2% of the TVT and 5% of the IVS patients suffered from aggravated urge symptoms in Study I population. This difference was not significant (p = 0.3). (Study I) Moving on Study II, de novo urge was detected in five (17%) TVT patients and six (17%) TOT patients in the subgroup of pure stress incontinence after the 46-month follow-up. The rate of de novo urge was also calculated for SUI patients without division by the operative method, also resulting in 17% urge symptoms rate in the final follow-up.

Prolapse surgery

Postoperative urinary and bowel symptoms were frequent after PIVS and SSLF procedures. The rates for urinary symptoms were 50% and 47%, and for bowel symptoms 38% and 47% among PIVS and SSLF patients, respectively. (Study III). Postoperative complications of Elevate®Posterior included granulation tissue formation (n = 5), asymptomatic hematoma (n = 3), urinary tract infection (n = 2), and pain at the operative region (n = 1). One hematoma was evacuated with puncture but other surgical interventions were not required in treating complications. (Study IV).

5.2 Subjective success and patient satisfaction after urinary incontinence surgery

We collected data on recurrent SUI after TVT and IVS operations. The outcome of subjective failure was defined as a contact to gynecological outpatient clinic because of SUI. During the median of 40 months’ follow-up period stress urinary incontinence was aggravated in three (1%) women in the TVT and three (10%) in the IVS group, and this difference was significant (p < 0.001). We evaluated subjective cure of TVT and TOT in three follow-up steps in Study II. The number of patients within each follow-up step and subjective cure defined as UISS < 8 are gathered in Table 16. Significant differences between TVT and TOT cannot be found in these terms. A statistically significant difference in median UISS scores was observed at 14 months of follow-up between the main groups (p = 0.013) and between the SUI subgroups (p = 0.003) in favor of TVT. Other median UISS scores were equal.

Table 16. Subjective cure of TVT and TOT and subgroups during the follow-up steps.

Groups 3 month 14 month 46 month TVT TOT TVT TOT TVT TOT Number of patients 49 49 43 43 47 46 UISS < 8 46 (95) 44 (90) 40 (93) 36 (84) 38 (84) 37 (80) MUI subgroup (n) 18 10 19 11 UISS < 8 17 (94) 8 (80) 14 (74) 9 (82) SUI subgroup (n) 25 33 28 35 UISS < 8 23 (92) 28 (85) 24 (86) 28 (80) Values are given as number (percentage).

At the final follow-up 79% and 74% of the patients in the TVT and TOT groups were satisfied or quite satisfied with the operative result. When treatment failed (UISS ≥ 8) 22% of the patients were satisfied or quite satisfied; when de novo urge emerged satisfaction rate was 55%. (Study II)

5.3 Objective and subjective outcomes after pelvic organ prolapse surgery

Median anatomical POP-Q scores were equal for both posterior intravaginal slingplasty and sacrospinous ligament fixation in Study III. Median point C after surgery was −5.5 (−10–9) among the PIVS patients and −5 (−8–1) among the

SSLF patients. Surgical procedures did not have a negative effect on vaginal length as median total vaginal length was eight for both study groups. Stage ≥ II prolapses were frequently seen postoperatively (Table 17), both isolated and combined compartment prolapses existed. Recurrences were also detected in all compartments. Reoperation for anatomical apical failure was needed in three patients who had undergone a PIVS procedure, while no apical reoperations were needed among SSLF patients. Altogether, reoperation was significantly (p = 0.042) more frequent among PIVS than SSLF patients, as eight (50%) patients in the PIVS group were reoperated, compared to the two (12%) who had undergone SSLF. The reoperations needed in the SSLF group were repairs of recurrent anterior vaginal wall prolapse.

Table 17. Postoperative stage ≥ II after PIVS and SSLF.

Compartment PIVS SSLF p Apical 5 (31) 2 (12) 0.25 Anterior vaginal wall 6 (38) 8 (47) 0.73 Recurrent 4 (66) 4 (50) 1.00 Posterior vaginal wall 8 (50) 4 (24) 0.16 Recurrent 5 (62) 3 (75) 0.44 Overall 8 (50) 9 (53) 1.00 Values are given as number (percentage).

Subjective cure defined in Study III was the rate of patient satisfaction. Among the PIVS and SSLF patients these rates were 62% and 76%, respectively. Anatomical failure was observed in half of the unsatisfied patients who had undergone PIVS and in all patients who had undergone SSLF. (Study III) Considering the patients receiving posterior single incision mesh (Study IV), the posterior and apical compartment objective cure rates reached by 109 patients at three months are gathered in Table 18. Reoperations for treatment failure were not performed. Among Study IV patients a total of 98 patients completed the PFDI-20 questionnaire at three months and subjective cure, defined as absence of bulge symptoms, was observed in 84 (86%) patients. Two of the fourteen (14%) patients with persistent bulge symptoms had leading edge beyond the hymen. Quality of life of the patients, measured by changes in median PFDI-20 questionnaire scores, improved significantly. This significant improvement was also seen in all PFDI- 20 subgroup scores.

Table 18. Objective cure after Elevate®Posterior at three months follow-up.

Compartment Stage 0–I Leading edge ≤ 0 Posterior compartment 92 (84) 107 (98) Primary (n = 58) 47 (81) 57 (98) Recurrent (n = 51) 45 (88) 50 (98) Apical compartment 109 (100) 109 (100) Values are given as number (percentage).

5.4 Secondary study aims

5.4.1 Changes in urge symptoms after female incontinence surgery

In the mixed urinary incontinence subgroup in Study II, the DIS score diminished to ≤ 7 in 13 (68%) TVT and eight (73%) TOT patients at the final follow-up. We also compared SUI and MUI subgroups without division by the operative method. In the MUI subgroup DIS ≤ 7 was noticed in 70% of the patients at the 46-month follow-up. Incidence of de novo urge symptoms is reported in the Complications section.

5.4.2 Effect of posterior single incision mesh on untreated vaginal compartment

For anterior compartment a trend of stage ≤ I turning into stage II or worse was noticed as 85% were in stage 0–I was at the baseline and 77% at three months. However, this difference was not significant. Depending on the definition de novo anterior prolapse was detected in 15 (16%) or three (3%) patients. One patient was treated with anterior mesh for de novo prolapse by the time of the follow-up, and for another patient operative treatment for anterior prolapse was scheduled.

5.4.3 Sexual functions after pelvic organ prolapse surgery

In Study III a total of 38% of the patients in the PIVS group and 41% in the SSLF group were sexually active at the time of the follow-up visit. The operation worsened sexual life of one (6%) patient while improvement was observed in two (13%) patients in the PIVS group. Corresponding numbers in the SSLF group were two (12%) and four (24%).

Among the patients who received a posterior mesh, 53% of the 108 PISQ-12 questionnaire respondents were sexually active at the follow-up. Median PISQ-12 scores increased from 33 (18–45) to 37 (13–46); this improvement was statistically significant (p = 0.007). Preoperative dyspareunia (7%) was cured at three months, while de novo dyspareunia occurred in 4%.

6 Discussion

In the treatment of female urinary incontinence and pelvic organ prolapse there are issues to consider when operative treatment is chosen: the method should be effective and it should be safe. During our research period the focus on outcomes has changed from anatomical success towards patient-oriented outcomes. Knowledge on behavior of meshes in vivo has increased enormously, and development of surgical methods has been ongoing. More and more attention is paid to mesh-related complications, with the result of more cautious attitudes towards the use of synthetic meshes. Moreover, interpreting the current literature has been challenging, as definitions of cure and failure change from one study to another. Also terminology of adverse events has been heterologous. Fortunately, international guidelines have recently been provided to make the terminology and definitions used uniform (Toozt-Hobson et al. 2012). In the present study various perspectives have been used in investigating safety and efficacy issues. This study shows a cross-section of the development of polypropylene meshes in the past decade and provides safety and efficacy information on both established and novel mesh-assisted methods in the treatment of urinary incontinence and pelvic organ prolapse.

6.1 The main findings and their relation to current literature

6.1.1 Safety and complication issues

Our data present an intolerably high vaginal exposure rate for microporous multifilament mesh, 16% among the IVS patients and 25% among the PIVS patients. This is even higher than presented in current literature (Balakrishnan et al. 2007, Cosma et al. 2011, Meschia et al. 2006). For heavyweight macroporous monofilament meshes the exposure rates were 0–1% (TVT) and 4% (TOT), which are in line with other studies and the most recent Cochrane review (But et al. 2005, Deffieux et al. 2010, Laurikainen et al. 2014, Mellier et al. 2007, Ogah et al. 2009). The mesh exposure rate (0.9%) reported in this study for lightweight macroporous monofilament mesh is lower than presented for posterior single incision mesh or trocar-guided methods (Abdel-Fattah et al. 2011b, Lukban et al. 2012, Withagen et al. 2011).

Small pore size and multifilament structure result in easy access for bacteria to adhere to the craggy fiber surface without disturbance of macrophages and neutrophils which are unable to enter pores 10 µm or less in diameter (Amid 1997). It has become evident that these structural properties of IVS mesh result in more vaginal exposure than other mesh materials used, and IVS tape is today off the market, but the PIVS method is still used with macroporous monofilament tape (Cosma et al. 2011). The nature of the tape favoring bacteria over defensive mechanisms in the operative area can also explain the higher but non-significant rate of postoperative infections among IVS patients compared to TVT patients. The mesh properties of TVTTM and MonarcTM meshes seem to be close to each other as no difference in exposure rates between these materials was detected. The low mesh exposure rate was an expected result for Elevate®Posterior as the lightweight property of the mesh should result in even better infiltration of macrophages and formation of fibrous capsule after implantation of the mesh (Sanders et al. 2000). The assessment where concomitant hysterectomies were denied and the use of local estrogen was frequent might have diminished the mesh exposure rate in Study IV. It should be kept in mind that postoperative clinical examination was lacking in both Study I and Study II, which could have resulted in a decreasing effect on the actual mesh exposure rate. Methods assisted by polypropylene meshes in treatment of urinary incontinence and pelvic organ prolapse seem safe when intraoperative results of present study are concerned. All intraoperative complications were minor in character. Trocar guidance of the meshes is generally considered a risk factor for various perforating problems. In our study we could not confirm the higher bladder perforation rate of the retropubic approach compared to the transobturator approach (Nguyen et al. 2012, Ogah et al. 2009), but there was a significant difference in intraoperative blood loss in TOT’s favor. However, results from other studies are conflicting as to whether or not there is a difference in blood loss between retropubic and transobturator approaches (Ogah et al. 2009, Richter et al. 2010). According to the Cochrane review (Maher et al. 2013) PIVS shows less blood loss than SSLF, which was not confirmed by the results in the present study. The median blood loss of Elevate®Posterior was similar to PIVS and SSLF and in line with published literature (Lukban et al. 2012 McLennan et al. 2013). The low rate of rectal perforations among patients receiving PIVS or posterior single incision mesh (Cosma et al. 2011, Lukban et al. 2012) was supported by

the present data. The one rectum perforation that occurred was dissection-related and would probably have occurred in native tissue reconstruction as well. Two different results on incidence of de novo urge symptoms in studies I and II were observed. In the retrospective study (Study I) the incidences of urge for TVT and IVS were 2% and 4% and in the prospective questionnaire based study (Study II) 17% for both TVT and TOT, and also in SUI patients without division by the operative method. This difference is however within limits of the 3–25% suggested by current literature (Lleberia-Juanós et al. 2011, Palva & Nilsson 2011). In our study and in the literature, the high diversity in urge symptom rates can at least partly be explained by the differences in definitions and study designs. Urinary and bowel symptoms were exceptionally frequent among PIVS and SSLF patients compared to current data (deTayrac et al. 2008), which possibly reflects the poor anatomical success within this study. (Study III). The low postoperative complication rate after Elevate®Posterior on the other hand is in line with the good operative result and previous studies (Lukban et al. 2012, Su et al. 2014). The good outcome is also explained by lighter mesh structure and controlled apical fixation. (Study IV)

6.1.2 Outcomes after urinary incontinence surgery

The IVS method was significantly worse in treating SUI in terms of the number of patients seeking help for recurrent SUI compared to TVT patients. This result directs us again to the different properties of the IVS tape. As the IVS tape is less extensible and more flexible, it might slide to a less optimal position shortly after placement, resulting in greater risk for SUI recurrence. However, subjective cure for IVS by this definition (90%) was better than the 71% reported in the literature (Prien-Larsen & Hemmingsen 2009). This difference is due to our definition and the study design. The subjective cure of the TVT and TOT methods was evaluated using “real- life” patients and in definition of subjective cure we used an every-day tool, the UISS questionnaire score, as it is used in clinical practice. It was a considered decision to choose this national questionnaire for our study. Both TVT and TOT have diverse subjective cure rates in current literature, 62–93% for TVT and 56– 99% for TOT (Lee et al. 2010, Olsson et al. 2010, Richter et al. 2010, Ross et al. 2009), and our data are consistent with these results. In Dyrkorn’s study with eight months of follow-up the subjective cure rate was significantly better in TVT patients (Dyrkorn et al. 2010) compared to TOT. As a matter of fact, in our study

concerning TVT and TOT patients a similar trend was observed at 14-month follow-up, but this difference eased out later. Based on these data one could say that the transobturator approach may have slightly inferior short-term success compared to TVT but this difference evens out later. This difference is probably due to the difference in technique. Patient satisfaction rates for TVT and TOT were similar and in line with subjective cure rates. No difference compared to current literature could be noticed (Dyrkorn et al. 2010, Laurikainen et al. 2014, Olsson et al. 2010). The result of poor satisfaction among patients with treatment failure and de novo urge is understandable, and has also been shown elsewhere (Wai et al. 2013). However, not all failure patients were dissatisfied, which only shows the complexity of the formation of patient satisfaction (Mallett et al. 2008).

6.1.3 Outcomes after pelvic organ prolapse surgery

Most published studies have used POP-Q stage 0–I as a definition of objective cure even though this practice has been argued. Criticism is based on the fact that 40% of asymptomatic patients do not meet these criteria (Swift et al. 2005). However, this definition was also used in our studies concerning pelvic organ prolapse. For PIVS and SSLF the achieved anatomical cure rate for apical prolapse was clearly worse than that presented in current literature, which gives cure rates of 82–98% for PIVS and 96–100% for SSLF (Capobianco et al. 2014, deTayrac et al. 2008, Eckhard & Kiran 2011, Nieminen & Heinonen 2001). Overall success involving all vaginal compartments was unsatisfactory as well, only 50% for both procedures. However, when the definition of anatomical failure is changed to reoperation rate, SSLF was significantly preferable to PIVS. Formation of recurrent and de novo anterior vaginal wall prolapse after SSLF with various incidences has previously been evidenced (Nieminen et al. 2003, Sze & Karram 1997). Our data are consistent with that as almost half of the SSLF patients developed anatomical anterior prolapse during the follow-up. For our study population the single incision posterior mesh worked fine in repair of apical descent, providing 100% cure in three-month follow-up, but the number of patients with apical defect was low, only nine (8%). Actually, the main outcome was the anatomical cure of the posterior compartment. Results on this matter were good, with success varying from 81% to 98%, depending on the definition used. Stage 0–I results were consistent with those published for posterior single incision mesh and trocar-guided methods (Gabriel et al. 2007,

Gauruder-Burmester et al. 2007, Lukban et al. 2012, Sokol et al. 2012, Su et al. 2014, Withagen et al. 2011). Our poor anatomical result and high mesh exposure rate reflects the patient satisfaction rates among the PIVS and SSLF patients, demonstrating worse results than the only other study reporting satisfaction (Neuman et al. 2007) for PIVS and pooled data reporting satisfaction with SSLF (Morgan et al. 2007), with satisfaction rates of 90% and 87%, respectively. Patient satisfaction was not asked for patients receiving Elevate®Posterior as follow-up time was short, but the absence of bulge symptoms, a recommended definition for subjective cure after POP surgery by ICS/IUGA (Toozs-Hobson et al. 2012), was investigated. An interesting observation was that our subjective cure rate, 86%, was consistent with our objective stage 0-I cure rate and not the leading edge at or above hymen result, which is recently suggested to be better a cut-off point in cure than stage 0- I (Barber et al. 2009, Toozs-Hobson et al. 2012). The difficulty in interpreting the bulge symptoms against the operative success lies, of course, in that bulge can result from any compartment prolapse – not only the operatively treated one.

6.1.4 Results for secondary study aims

Conflicting opinions exist concerning the effect of incontinence surgery on urge symptoms. It is known that urgency can persist and de novo urge can appear, with poor patient satisfaction with the operative treatment. However, a resolution rate of 50–80% has been reported for urge symptoms (Paick et al. 2008, Palva & Nilsson 2011). Among MUI patients in Study II, the resolution for urge was in line with current data and both operative methods were equally good in resolving urge symptoms. It is suggested that prolapse surgery might produce de novo prolapse formation in the untreated vaginal compartment (Withagen et al. 2010, Withagen et al. 2012). This trend was noticed among Elevate®Posterior patients and the percentage was higher than previously observed for this method. The data are not fully comparable as precise POP-Q measurements for anterior compartment were not presented in the previous study. (Lukban et al. 2012). However, it is possible that severe de novo prolapse can occur very shortly after index operation, as two patients in our series needed operative treatment for symptomatic anterior de novo prolapse within three months of follow-up. A negative impact of pelvic organ prolapse on sexual function is typically reported by patients suffering from POP. Improvement in sexual function and in

body image has been documented for the majority of patients with native tissue and graft repair. Our data for PIVS, SSLF and Elevate®Posterior are equivalent with current data: more improvement than worsening was noticed among study groups, PISQ-12 scores improved, dyspareunia resolved and de novo dyspareunia rate was low.

6.2 Strengths and limitations

This study is the first one to report the efficacy and safety of microporous multifilament mesh in treatment of urinary incontinence and of lightweight macroporous monofilament mesh in treatment of posterior vaginal compartment prolapse among Finnish female population. National data concerning posterior intravaginal slingplasty is also scarce (Heinonen & Nieminen 2011). Special interest in this whole study lies on vaginal mesh exposure rate, and this study was able to demonstrate the difference between structurally different polypropylene meshes in vaginal exposure rates. In both retrospective and prospective studies the operations were performed by qualified surgeons with extensive experience on both native tissue repair and the use of synthetic mesh. In the study concerning TVT and TOT the use of “real-life” patients gives information on how the methods actually work in clinical practice, and measuring subjective cure by only UISS score is unique. The strength in using UISS is that we use the same questionnaire daily in clinical practice and yet very little data on this questionnaire are published. However, this also means that a precise definition for how to use this questionnaire is lacking. Based on this it is easy to dispute the way the UISS is used in Study II. Furthermore, other limitations exist as well. The study populations in articles II and III are small. Follow-up periods are quite decent except in Study IV. Postoperative objective evaluation is missing for study populations I and II, which leads to probability of underestimating mesh exposure rates – the main outcome of this study. In addition, direct comparison of different mesh materials is impossible because operative methods vary. However, a different design would have been difficult to organize as not all mesh materials are available for a single operative method.

6.3 Clinical significance

Our retrospective studies I and III show the plain truth of what happens when a clinical tool enters practise without sufficient clinical research. This should teach

us to treat new methods with caution, but should not prevent us from innovating and developing procedures and materials towards more effective and safe gynecological surgery. Also, conclusions as to whether a certain medical practice – in this case, transvaginal mesh – is to be condemned, should not be made based on results of a single method. In this study the results of PIVS are poor while those of Elevate are decent. It is known that not all patients with pelvic organ prolapse will be helped by native tissue repair, and the abdominal approach is not always an option. Thus, it is fortunate that the development of methods and materials has progressed.

7 Conclusions

Vaginal mesh exposure rate is intolerable high for heavyweight microporous multifilament and it should be abandoned in transvaginal surgery. Heavyweight macroporous monofilament polypropylene meshes used in mid-urethral sling procedures are safe both intra- and postoperatively and provide decent subjective cure and patient satisfaction. Lightweight macroporous monofilament mesh provides promising results in treatment of posterior compartment prolapse in terms of both efficacy and safety whereas posterior intravaginal slingplasty sling and sacrospinous ligament fixation resulted poor objective and subjective outcomes.

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Appendix 1 PFDI-20

PFDI short form – suomennettu

Nimi:______päiväys:______tutkimusnro ______

1. Tunnetko yleensä painon tunnetta alavatsalla?En☐ kyllä ☐ Jos vastasit kyllä, kuinka paljon tämä haittaa Sinua?