New avenues in the management of pelvic floor disorders: experimental secondary prevention and medium term outcomes of abdominal mesh surgery

Pelvic floor disorders (PFD) include pelvic organ prolapse (POP), urinary (UI) & fecal incontinence (FI), sexual dysfunction and pelvic pain. Twelve years after first vaginal delivery around 23% of women leak urine at least once a week, and around 24% of women have stage 2+ POP1 The prevalence of FI in women increases with age, from 6% in women < 40 years rising to 15% in older women. Up to 50% of the patients with FI also report UI.2 PFD greatly affects the health-related quality of life of these women: 6.2% of patients with UI suffer from depression, compared to 2.2% from those without3. Of women with symptomatic POP, 22% of cases have moderate to severe depressive symptoms, in comparison with 6% in controls. These symptoms  improve after surgery, suggesting a causal relationship.4 Moreover many women alter their daily routine due to social stigma and embarrassment. As the aging population continues to grow, it is expected that the prevalence of PFD will further increase emphasizing the need for more basic research and the development of new strategies for the treatment and prevention of PFD.

Current treatment options include conservative management such as physiotherapy, pharmacotherapy, the use of pessaries or surgery. While surgery for stress urinary incontinence (SUI) is successful, recurrence rates are high for prolapse repair 1 and surgical management of FI has failed to show long term results. The use of permanent synthetic meshes in prolapse repair has reduced the incidence of recurrence; however mesh-related complications occur in 10 to 15% of patients.5

Vaginal delivery causes pelvic floor muscle and connective tissue trauma, and mechanical and ischemic nerve injury.6 Therefore, it is logic to consider interventions that might prevent this trauma either around the time of delivery. Primary caesarean section has been proposed yet is unrealistic because of increased morbidity and mortality,7 cost, yet mainly because its protective effect is only partial. 8, 9 We therefore propose an alternative strategy using stem cells, to be administrated to high risk patients after delivery. We hypothesize that stem cells will boost the innate healing response to birth-induced injury and aid in repairing damaged pelvic striated muscle (the levator ani and external anal sphincter), the smooth muscle of the internal anal sphincter and/or pelvic neural cells. High risk patients can be identified by screening ultrasound for uni- or bilateral levator avulsion or major anal sphincter trauma. 10-12 Ideally, one would use autologous stem cells harvested and processed prior to delivery, because they will cause minimal side effects if they would engraft.13 Moreover, adult somatic stem cells have no tumorigenicity unlike embryonic stem cells.14 Several stem cell types come to mind. We earlier used adipose derived stem cells (ADSCs) to prevent erectile dysfunction induced in rats by crush injury of the cavernous nerve.15 Though ADSCs were homing to the pelvic ganglion, most effects were believed to be paracrine. We speculate that ADSCs are not ideal because of their low capacity for muscle tissue regeneration. Bone marrow derived mesenchymal stem cells (MSC) have already been extensively studied by Damaser et al in a rat model for simulated birth injury. Administration of MSC 1h after vaginal distension increased urinary leak point pressure as well as elastin and smooth muscle surrounding the urethra16. Administration of MSC 24h after anal sphincterotomy increased anal pressure.17 The effect of MSC on the vaginal smooth muscle layer or the levator ani muscle was not studied. Again homing was demonstrated, though no persistent cells could be shown 9 d after intramuscular or intravenous administration.16-18

Herein we will use mesangioblasts (MABs), also called pericytes or vessel-associated stem cells. These cells have the capacity to differentiate in to smooth and skeletal muscle tissue.19 We will use autologous cells so that eventual effects following engraftment are minimal. Autologous cell use would clinically also be acceptable as they can be isolated from minimally invasive “tru-cut” muscle biopsies 20. There is already clinical experience with stem cells in the treatment of stress urinary incontinence, on ongoing trial is using myoblasts (NCT01382602). In a mouse model for muscle dystrophy, two weeks after intra-arterial injection, LacZ labeled MABs were found in all the hind limbs.21 They were seen in the center of regenerating skeletal muscle fibers, in vessels expressing α- smooth muscle actin or endothelial markers, showing their capability to differentiate in striated and smooth muscle.21

Rat mesoangioblasts will be collected by punch needle biopsy, processed and injected intramuscular in the levator ani plate or anal sphincter or administrated systemically by intra-arterial route following simulated vaginal birth injury. Vaginal distension (VD) and pudendal nerve crush (PNC) in rats are two relevant trauma, associated to simulated childbirth, leading to a decrease in leak point pressure (LPP), denervation, hypoxia, and atrophy of the external urethral sphincter (EUS) on histology.22-25 For the study of FI, usually an anal incontinence model is preferred, consisting of sphincterotomy, though  pudendal nerve transection,26 intra-abdominal balloon inflation,27 but also vaginal distension have been used.28

1.         Olsen AL et al. Obstet Gynecol 1997; 89(4):501-6.

2.         Landefeld CS et al. Ann Intern Med 2008; 148(6):449-58.

3.         Melville JL et al. Obstet Gynecol 2005; 106(3):585-92.

4.         Ghetti C, Lowder JL, Ellison R, et al. Int Urogynecol J 2010; 21(7):855-60.

5.         Maher C et al. Cochrane Database Syst Rev 2013; 4:CD004014.

6.         Bortolini MA, et al. Int Urogynecol J 2010; 21(8):1025-30.

7.         Deneux-Tharaux C, et al. Obstet Gynecol 2006; 108(3 Pt 1):541-8.

8.         Rortveit G et al. N Engl J Med 2003; 348(10):900-7.

9.         MacArthur C et al. BJOG 2011; 118(8):1001-7.

10.       Schwertner-Tiepelmann N et al. Ultrasound Obstet Gynecol 2012; 39(4):372-83.

11.       Dietz HP. Aust N Z J Obstet Gynaecol 2013; 53(3):220-30.

12.       Meriwether KV et al. Int Urogynecol J 2014; 25(3):329-36.

13.       Prasongchean Wet al. N Biotechnol 2012; 29(6):641-50.

14.       Ben-David U, Benvenisty N. Nat Rev Cancer 2011; 11(4):268-77.

15.       Qiu X et al. Eur Urol 2012; 62(4):720-7.

16.       Dissaranan C et al. Cell Transplant 2013.

17.       Salcedo L et al. Stem Cell Res. 2013; 10(1):95-102. doi: 10.1016/j.scr.2012.10.002. Epub 2012 Oct 16.

18.       Salcedo L et al. Stem Cells Transl Med 2014.

19.       Roobrouck VD et al. Stem Cells 2011; 29(5):871-82.

20.       Quattrocelli M et al. Methods Mol Biol 2012; 798:65-76.

21.       Sampaolesi M, et al. Science 2003; 301(5632):487-92.

22.       Lin AS et al. Urology 1998; 52(1):143-51.

23.       Cannon TW et al. BJU Int 2002; 90(4):403-7.

24.       Damaser MS et al. J Urol 2003; 170(3):1027-31.

25.       Jiang HH et al. Handb Exp Pharmacol 2011(202):45-67.

26.       Zutshi M et al. Dis Colon Rectum. 2009; 52(7):1321-9. doi: 10.1007/DCR.0b013e31819f746d.

27.       Peirce C. et al. Obstet Gynecol. 2008; 112(4):943-4; author reply 944. doi: 10.1097/AOG.0b013e3181892ef2.

28.       Wai CY et al. Obstet Gynecol. 2008; 111(2 Pt 1):332-40. doi: 10.1097/AOG.0b013e318162f6a7.