Adverse Events Associated with Nonsurgical Treatments for Urinary Incontinence in Women: a Systematic Review
Urinary incontinence (UI) is a common malady in women. Numerous nonsurgical treatments are available, each associated with risk of adverse events (AEs).
We systematically reviewed nonsurgical interventions for urgency, stress, or mixed UI in women, focusing on AEs. We searched MEDLINE®, Cochrane Central Trials Registry, Cochrane Database of Systematic Reviews, and Embase® through December 4, 2017. We included comparative studies and single-group studies with at least 50 women. Abstracts were screened independently in duplicate. One researcher extracted study characteristics and results with verification by another independent researcher. When at least four studies of a given intervention reported the same AE, we conducted random effects model meta-analyses of proportions. We also assessed the strength of evidence.
There is low strength of evidence that AEs are rare with behavioral therapies and neuromodulation, and that periurethral bulking agents may result in erosion and increase the risk of voiding dysfunction. High strength of evidence finds that anticholinergics and alpha agonists are associated with high rates of dry mouth and constitutional effects such as fatigue and gastrointestinal complaints. Onabotulinum toxin A (BTX) is also associated with increased risk of urinary tract infections (UTIs) and voiding dysfunction (moderate strength of evidence).
Behavioral therapies and neuromodulation have low risk of AEs. Anticholinergics and alpha agonists have high rates of dry mouth and constitutional effects. BTX is associated with UTIs and voiding dysfunction. Periurethral bulking agents are associated with erosion and voiding dysfunction. These AEs should be considered when selecting appropriate UI treatment options. AE reporting is inconsistent and AE rates across studies tended to vary widely. Trials should report AEs more consistently.
KEY WORDSurinary incontinence quality of life adverse events systematic review meta-analysis
This report is based on research conducted by the Brown Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-2015-00002-I). The Patient Centered Outcomes Research Institute (PCORI) funded the report (PCORI Publication No. 2018-SR-03). The authors gratefully acknowledge the contribution of Aysegul Gozu, MD, MPH, our AHRQ Task Order Officer; Jennifer Croswell, MD, MPH, our PCORI Senior Program Officer; and Kimberly Bailey, MS, our PCORI Program Officer. We would also like to thank and acknowledge the additional research associates and other staff who helped to conduct this systematic review: Valerie Rofeberg, ScM, Georgios Markozannes, MSc, Hannah Kimmel, MPH, Iman Saeed, ScM, Mengyang Di, PhD, Gowri Raman, MBBS, MS, Esther Avendano, MS, Andrew Zullo, PharmD, PhD, Jenni Quiroz, BS, and Anya Wallack, PhD.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they do not have a conflict of interest.
The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ or PCORI. Therefore, no statement in this report should be construed as an official position of PCORI, AHRQ, or of the U.S. Department of Health and Human Services.
- 1.Balk EM, Rofeberg V, Adam GP, et al. Pharmacological and Non-Pharmacological Treatments for Urinary Incontinence in Women: A Systematic Review and Network Meta-Analysis of Clinical Outcomes. Ann Intern Med. 2019; 170(7):465-479. https://doi.org/10.7326/M18-3227.
- 7.Balk E, Adam GP, Kimmel H, et al. Nonsurgical Treatments for Urinary Incontinence in Women: A Systematic Review Update. (Prepared by the Brown Evidence-based Practice Center under Contract No. 290–2015-00002-I for AHRQ and PCORI.) AHRQ Publication No. 18-EHC016-EF. PCORI Publication No. 2018-SR-03. Rockville, MD: Agency for Healthcare Research and Quality; August 2018. Available at: https://doi.org/10.23970/AHRQEPCCER212. Accessed 5 March 2019.
- 8.Methods Guide for Effectiveness and Comparative Effectiveness Reviews. AHRQ Publication No. 10(14)-EHC063-EF. Rockville, MD: Agency for Healthcare Research and Quality. January 2014. Chapters available at: https://effectivehealthcare.ahrq.gov/research-methods. Accessed 5 March 2019.
- 9.Shamliyan T, Wyman J, Kane RL. Nonsurgical Treatments for Urinary Incontinence in Adult Women: Diagnosis and Comparative Effectiveness. Comparative Effectiveness Review No. 36. (Prepared by the University of Minnesota Evidence-based Practice Center under Contract No. HHSA 290–2007-10064-I.) AHRQ Publication No. 11(12)-EHC074- EF. Rockville, MD. Agency for Healthcare Research and Quality; April 2012. Available at: https://effectivehealthcare.ahrq.gov/topics/urinary-incontinence-treatment/research. Accessed March 5, 2019.
- 10.Trikalinos TA, Hoaglin DC, Schmid CH. Empirical and Simulation-Based Comparison of Univariate and Multivariate Meta-Analysis for Binary Outcomes. Methods Research Report. (Prepared by the Tufts Evidence-based Practice Center under Contract No. 290–2007-10055-I.) AHRQ Publication No. 13-EHC066-EF. Rockville, MD: Agency for Healthcare Research and Quality; March 2013. Available at: https://effectivehealthcare.ahrq.gov/topics/methods-binary-outcomes-evaluation/research. Accessed 5 March 2019.
- 11.Berkman ND, Lohr KN, Ansari M, et al. Grading the Strength of a Body of Evidence When Assessing Health Care Interventions for the Effective Health Care Program of the Agency for Healthcare Research and Quality: An Update. Methods Guide for Comparative Effectiveness Reviews (Prepared by the RTI-UNC Evidence-based Practice Center under Contract No. 290–2007-10056-I). AHRQ Publication No. 13(14)-EHC130-EF. Rockville, MD: Agency for Healthcare Research and Quality. November 2013. Available at: https://effectivehealthcare.ahrq.gov/topics/methods-guidance-grading-evidence/methods. Accessed 5 March 2019.
- 12.Abdelbary AM, El-Dessoukey AA, Massoud AM, et al. Combined Vaginal Pelvic Floor Electrical Stimulation (PFS) and Local Vaginal Estrogen for Treatment of Overactive Bladder (OAB) in Perimenopausal Females. Randomized Controlled Trial (RCT). Urology. 2015;86:482–6. https://doi.org/10.1016/j.urology.2015.06.007.Google Scholar
- 13.Alves PG, Nunes FR, Guirro EC. Comparison between two different neuromuscular electrical stimulation protocols for the treatment of female stress urinary incontinence: a randomized controlled trial. Rev Bras Fis 2011;15:393–8.Google Scholar
- 14.Baker J, Costa D, Guarino JM, et al. Comparison of mindfulness-based stress reduction versus yoga on urinary urge incontinence: a randomized pilot study. with 6-month and 1-year follow-up visits. Female Pelvic Med Reconstr Surg. 2014;20:141–6. https://doi.org/10.1097/spv.0000000000000061.Google Scholar
- 19.Ferreira M, Santos PC. Impact of exercise programs in woman's quality of life with stress urinary incontinence. Rev Port Saúde Pública 2012;30:3–10.Google Scholar
- 21.Galea MP, Tisseverasinghe S, Sherburn M. A randomised controlled trial of transabdominal ultrasound biofeedback for pelvic floor muscle training in older women with urinary incontinence. Aust N Z Continence J 2013;19:38-44.Google Scholar
- 25.Jha S, Walters SJ, Bortolami O, et al. Impact of pelvic floor muscle training on sexual function of women with urinary incontinence and a comparison of electrical stimulation versus standard treatment (IPSU trial): a randomised controlled trial. Physiotherapy. 2017; 104:91–7. https://doi.org/10.1016/j.physio.2017.06.003.Google Scholar
- 30.Manonai J, Kamthaworn S, Petsarb K, et al. Development of a pelvic floor muscle strength evaluation device. J Med Assoc Thail 2015;98:219–25.Google Scholar
- 31.McLean L, Varette K, Gentilcore-Saulnier E, et al. Pelvic floor muscle training in women with stress urinary incontinence causes hypertrophy of the urethral sphincters and reduces bladder neck mobility during coughing. Neurourol Urodyn 2013;32:1096–102. https://doi.org/10.1002/nau.22343.PubMedCentralGoogle Scholar
- 32.Oldham J, Herbert J, McBride K. Evaluation of a new disposable “tampon like” electrostimulation technology (Pelviva(R)) for the treatment of urinary incontinence in women: a 12-week single blind randomized controlled trial. Neurourol Urodyn 2013;32:460–6. https://doi.org/10.1002/nau.22326.Google Scholar
- 33.Olmo Carmona MV, González Molleja ÁM, Luque Ríos I, et al. Neuroestimulación percutánea del nervio tibial posterior frente a neuroestimulación de B 6 (Sanyinjiao) en incontinencia urinaria de urgencia. Rev Int Acupuntura 2013;7:124–30.Google Scholar
- 48.Burgio KL, Locher JL, Goode PS, et al. Behavioral vs drug treatment for urge urinary incontinence in older women: a randomized controlled trial. JAMA. 1998;280:1995–2000.Google Scholar
- 56.Samuelsson E. Treatment of Stress Urinary Incontinence Via Smartphone; 2017. https://clinicaltrials.gov/ct2/show/NCT01848938. Accessed 5 March 2019.
- 58.Terlikowski R, Dobrzycka B, Kinalski M, et al. Transvaginal electrical stimulation with surface-EMG biofeedback in managing stress urinary incontinence in women of premenopausal age: a double-blind, placebo-controlled, randomized clinical trial. Int Urogynecol J 2013;24:1631–8. https://doi.org/10.1007/s00192-013-2071-5.PubMedCentralGoogle Scholar
- 61.Abdulaziz K, Hasan T. Role of pelvic floor muscle therapy in obese perimenopausal females with stress incontinence: A randomized control trial. Int J Gynecol Obstet 2012;16:34–42.Google Scholar
- 65.Dmochowski RR, Davila GW, Zinner NR, et al. Efficacy and safety of transdermal oxybutynin in patients with urge and mixed urinary incontinence. J Urol 2002;168:580–6.Google Scholar
- 70.Homma Y, Paick JS, Lee JG, et al. Clinical efficacy and tolerability of extended-release tolterodine and immediate-release oxybutynin in Japanese and Korean patients with an overactive bladder: a randomized, placebo-controlled trial. BJU Int 2003;92:741–7.Google Scholar
- 73.McMichael J. Safety and Efficacy Study of a New Treatment for Symptoms of Urinary Incontinence; 2013. https://clinicaltrials.gov/ct2/show/NCT01340066. Accessed 5 March 2019.
- 74.Moore KH, Hay DM, Imrie AE, et al. Oxybutynin hydrochloride (3 mg) in the treatment of women with idiopathic detrusor instability. Br J Urol 1990;66:479–85.Google Scholar
- 80.Szonyi G, Collas DM, Ding YY, et al. Oxybutynin with bladder retraining for detrusor instability in elderly people: a randomized controlled trial. Age Ageing 1995;24:287–91.Google Scholar
- 81.Tapp AJ, Cardozo LD, Versi E, et al. The treatment of detrusor instability in post-menopausal women with oxybutynin chloride: a double blind placebo controlled study. Br J Obstet Gynaecol 1990;97:521–6.Google Scholar
- 82.Thuroff JW, Bunke B, Ebner A, et al. Randomized, double-blind, multicenter trial on treatment of frequency, urgency and incontinence related to detrusor hyperactivity: oxybutynin versus propantheline versus placebo. J Urol 1991;145:813–6.Google Scholar
- 84.Anderson RU, Mobley D, Blank B, et al. Once daily controlled versus immediate release oxybutynin chloride for urge urinary incontinence. OROS Oxybutynin Study Group. J Urol. 1999;161:1809–12.Google Scholar
- 85.Anderson RU, MacDiarmid S, Kell S, et al. Effectiveness and tolerability of extended-release oxybutynin vs extended-release tolterodine in women with or without prior anticholinergic treatment for overactive bladder. Int Urogynecol J Pelvic Floor Dysfunct 2006;17:502–11. https://doi.org/10.1007/s00192-005-0057-7.Google Scholar
- 86.Appell RA. Clinical efficacy and safety of tolterodine in the treatment of overactive bladder: a pooled analysis. Urology. 1997;50(6A Suppl):S90–6.Google Scholar
- 89.Bodeker RH, Madersbacher H, Neumeister C, et al. Dose escalation improves therapeutic outcome: post hoc analysis of data from a 12-week, multicentre, double-blind, parallel-group trial of trospium chloride in patients with urinary urge incontinence. BMC Urol 2010;10:15. https://doi.org/10.1186/1471-2490-10-15.PubMedCentralGoogle Scholar
- 90.But I, Goldstajn MS, Oreskovic S. Comparison of two selective muscarinic receptor antagonists (solifenacin and darifenacin) in women with overactive bladder--the SOLIDAR study. Coll Antropol 2012;3:1347–53.Google Scholar
- 91.Butt F, Badar N, Rana M. Comparison of Side Effects of Solifenacin Vs Tolteridine in Patients with Urinary Incontinence. Pakistan J Med Health Sci 2016;10:590–3.Google Scholar
- 93.Chu FM, Dmochowski RR, Lama DJ, et al. Extended-release formulations of oxybutynin and tolterodine exhibit similar central nervous system tolerability profiles: a subanalysis of data from the OPERA trial. Am J Obstet Gynecol 2005;192:1849–54. https://doi.org/10.1016/j.ajog.2005.03.036.Google Scholar
- 95.Davila GW, Daugherty CA, Sanders SW. A short-term, multicenter, randomized double-blind dose titration study of the efficacy and anticholinergic side effects of transdermal compared to immediate release oral oxybutynin treatment of patients with urge urinary incontinence. J Urol 2001;166:140–5.Google Scholar
- 98.Gupta SK, Sathyan G, Lindemulder EA, et al. Quantitative characterization of therapeutic index: application of mixed-effects modeling to evaluate oxybutynin dose-efficacy and dose-side effect relationships. Clin Pharmacol Ther 1999;65:672–84. https://doi.org/10.1016/s0009-9236(99)90089-9.Google Scholar
- 99.Gupta SK, Sathyan G. Pharmacokinetics of an oral once-a-day controlled-release oxybutynin formulation compared with immediate-release oxybutynin. J Clin Pharmacol 1999;39:289–96.Google Scholar
- 103.Lackner TE, Wyman JF, McCarthy TC, et al. Randomized, placebo-controlled trial of the cognitive effect, safety, and tolerability of oral extended-release oxybutynin in cognitively impaired nursing home residents with urge urinary incontinence. J Am Geriatr Soc 2008;56:862–70. https://doi.org/10.1111/j.1532-5415.2008.01680.x.Google Scholar
- 104.Madersbacher H, Halaska M, Voigt R, et al. A placebo-controlled, multicentre study comparing the tolerability and efficacy of propiverine and oxybutynin in patients with urgency and urge incontinence. BJU Int 1999;84:646–51.Google Scholar
- 105.Milani R, Scalambrino S, Milia R, et al. Double-Blind Crossover Comparison of Flavoxate and Oxybutynin in Women Affected by Urinary Urge Syndrome. Int Urogynecol J 1993;4:3–8.Google Scholar
- 110.Sand PK, Miklos J, Ritter H, et al. A comparison of extended-release oxybutynin and tolterodine for treatment of overactive bladder in women. Int Urogynecol J Pelvic Floor Dysfunct 2004;15:243–8.Google Scholar
- 112.Zellner M, Madersbacher H, Palmtag H, et al. Trospium chloride and oxybutynin hydrochloride in a german study of adults with urinary urge incontinence: results of a 12-week, multicenter, randomized, double-blind, parallel-group, flexible-dose noninferiority trial. Clin Ther 2009;31:2519–39. https://doi.org/10.1016/j.clinthera.2009.11.005.Google Scholar
- 115.Dmochowski RR, Sand PK, Zinner NR, et al. Comparative efficacy and safety of transdermal oxybutynin and oral tolterodine versus placebo in previously treated patients with urge and mixed urinary incontinence. Urology. 2003;62:237–42.Google Scholar
- 116.Drutz HP, Appell RA, Gleason D, et al. Clinical efficacy and safety of tolterodine compared to oxybutynin and placebo in patients with overactive bladder. Int Urogynecol J Pelvic Floor Dysfunct 1999;10:283–9.Google Scholar
- 120.van Kerrebroeck P, Abrams P, Lange R, et al. Duloxetine versus placebo in the treatment of European and Canadian women with stress urinary incontinence. BJOG. 2004;111:249–57.Google Scholar
- 124.Cardozo L, Drutz HP, Baygani SK, et al. Pharmacological treatment of women awaiting surgery for stress urinary incontinence. Obstet Gynecol 2004;104:511–9. https://doi.org/10.1097/01.AOG.0000134525.86480.0f.Google Scholar
- 127.Ghoniem GM, Van Leeuwen JS, Elser DM, et al. A randomized controlled trial of duloxetine alone, pelvic floor muscle training alone, combined treatment and no active treatment in women with stress urinary incontinence. J Urol 2005;173:1647–53. https://doi.org/10.1097/01.ju.0000154167.90600.c6.Google Scholar
- 132.Millard RJ, Moore K, Rencken R, et al. Duloxetine vs placebo in the treatment of stress urinary incontinence: a four-continent randomized clinical trial. BJU Int 2004;93:311–8.Google Scholar
- 133.Norton PA, Zinner NR, Yalcin I, et al. Duloxetine versus placebo in the treatment of stress urinary incontinence. Am J Obstet Gynecol 2002;187:40–8.Google Scholar
- 138.Robinson D, Abrams P, Cardozo L, et al. The efficacy and safety of PSD503 (phenylephrine 20%, w/w) for topical application in women with stress urinary incontinence. A phase II, multicentre, double-blind, placebo controlled, 2-way cross over study. Eur J Obstet Gynecol Reprod Biol 2011;159:457–60. https://doi.org/10.1016/j.ejogrb.2011.07.030.Google Scholar
- 141.Jabs C, Carleton E. Efficacy of botulinum toxin a intradetrusor injections for non-neurogenic urinary urge incontinence: a randomized double-blind controlled trial. J Obstet Gynaecol Can 2013;35:53–60.Google Scholar
- 143.Lightner D, Rovner E, Corcos J, et al. Randomized controlled multisite trial of injected bulking agents for women with intrinsic sphincter deficiency: mid-urethral injection of Zuidex via the Implacer versus proximal urethral injection of Contigen cystoscopically. Urology. 2009;74:771–5. https://doi.org/10.1016/j.urology.2009.05.034.Google Scholar
- 147.Futyma K, Miotla P, Galczynski K, et al. An Open Multicenter Study of Clinical Efficacy and Safety of Urolastic, an Injectable Implant for the Treatment of Stress Urinary Incontinence: One-Year Observation. Biomed Res Int 2015;2015:851823. https://doi.org/10.1155/2015/851823.PubMedCentralGoogle Scholar
- 149.Toozs-Hobson P, Al-Singary W, Fynes M, et al. Two-year follow-up of an open-label multicenter study of polyacrylamide hydrogel (Bulkamid®) for female stress and stress-predominant mixed incontinence. Int Urogynecol J 2012;23:1373–8. https://doi.org/10.1007/s00192-012-1761-8.PubMedCentralGoogle Scholar