The evidence for laser treatments to the vulvo- vagina: Making sure we do not repeat past mistakes

Transcription

1 Aust N Z J Obstet Gynaecol 2018; 58: DOI: /ajo REVIEW ARTICLE The evidence for laser treatments to the vulvo- vagina: Making sure we do not repeat past mistakes Sophia Song and Jason Abbott, Aaron Budden, Asha Short, Erin Nesbitt-Hawes, Rebecca Deans School of Women s and Children s Health, Gynaecological Research and Clinical Evaluation (GRACE) Unit, Royal Hospital for Women, UNSW, Sydney, NSW, Australia Correspondence: Professor Jason Abbott, Level 2, Department of Gynaecology, Royal Hospital for Women, Randwick, NSW 2031, Australia. j.abbott@unsw.edu.au Conflict of Interest: The authors report no conflicts of interest. Received: 30 August 2017; Accepted: 27 September 2017 Following menopause, up to 49% of women will experience genitourinary symptoms such as vaginal itching, dryness, dyspareunia and incontinence as a result of oestrogen deficiency. Treatments such as vaginal lubricants and moisturisers only temporarily relieve symptoms, while local oestrogen treatments are often unacceptable or unsafe for many women. Recently, a novel laser treatment has been proposed as a non- invasive, long- term solution to vulvo- vaginal and urinary symptoms. While preliminary histological results have been promising, its therapeutic, clinical effect has yet to be determined. However, despite the scarcity of evidence for its safety and long- term benefit, laser treatments are widely marketed for a range of genitourinary symptoms, with high uptake by both clinicians and women alike. This review aims to examine the evidence for laser treatments to the vulvo- vagina and to evaluate its safety and efficacy. Our results include 17 studies investigating the effect of laser therapy for vulvo- vaginal symptoms, seven for its effects on urinary incontinence and four for histology. These are limited to non- randomised, observational data with small sample sizes between 15 to 175 women and follow- up duration from none to two years. As such, strong evidence for laser efficacy and safety is limited and warrants more robust, placebo- controlled, randomised trials before widespread implementation. KEYWORDS vaginal laser, genitourinary syndrome of menopause, vulvo-vaginal atrophy, urinary incontinence INTRODUCTION Vulvo- vaginal symptoms (VVS) for the postmenopausal woman are a common cause of presentation to health care professionals, with up to 49% of postmenopausal women affected and causing a major impact on quality of life. 1 Specific symptoms such as dyspareunia may have a detrimental impact on relationships and contribute to reduced self- esteem and emotional wellbeing. 2 The local vulvo- vaginal atrophic changes lead to epithelial thinning, loss of vaginal rugae and decreased vaginal vascularisation. 3,4 In turn, this results in loss of elasticity and lubrication as well as shortening and narrowing of the vaginal canal, 3 with vulvo- vaginal atrophy (VVA) (more recently referred to as genitourinary syndrome of menopause/gsm), 5 manifesting as vaginal dryness, itching, irritation, abnormal discharge and dyspareunia, with associated urinary symptoms of frequency, urgency and incontinence. 6 Changes to the vaginal microbiome may also lead to an increased risk and recurrence of genitourinary infections. 7 Treatment of vulvo- vaginal symptoms may be hormonal or non- hormonal. Non- hormonal lubricants and moisturisers only provide short- term symptom relief and require regular application, but are safe for long- term use. 8 Local, low- dose oestrogen The Royal Australian and New Zealand College of Obstetricians and Gynaecologists wileyonlinelibrary.com/journal/anzjog

2 S. Song et al. 149 is the mainstay of hormonal treatment; 3 however, these may be unacceptable or contra- indicated in women with increased risk of thromboembolic disease and those with oestrogendependent breast cancer. 8 Sixty- three percent of women with breast cancer surveyed experienced genitourinary symptoms associated with VVA, 9 but systemic absorption of topical vaginal treatments may increase circulating oestrogen levels, although the level of absorption is considered to be minimal. 8,10,11 Vulvo- vaginal laser treatment has been proposed as an alternative treatment for VVA, where microscopic areas of thermal necrosis to the vaginal skin induce a healing cascade to change a number of physical skin components. 12 Micro- ablative, fractional CO 2 and erbium- doped yttrium aluminium garnet (Er:YAG) lasers have been developed for superficial epithelial vaginal skin damage, remodelling and repair. Initial histological examination of vaginal tissue post- treatment demonstrates epithelial thickening, regeneration of indented papillae and increased glycogen storage and fibroblast activity However, evidence for symptom control and improvements to quality of life, duration of effect and safety is less concrete. This systematic review aims to assess the evidence for the clinical efficacy, safety and duration of effect of current marketed laser therapies to the vulvo- vagina, to ensure such proposed treatments are evidence- based. METHODS We performed a systematic review using a protocol registered with PROSPERO (#CRD ). SS searched MEDLINE, EMBASE and CENTRAL from database origin to April 2017 using the MeSH terms menopause, menopause related disorder, vagina, vagina disease, laser, urinary incontinence and laser surgery. Clinicaltrials.gov, the ANZ clinical trial registry and EU Clinical Trials Register were also searched for randomised controlled trials (RCT) underway. Reference lists of included articles were hand- searched to identify additional studies. Our search is reported according to the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) guidelines. Study selection Included studies assessed the effect of laser therapy on vaginal tissue, VVA and associated genitourinary symptoms. Studies that explored the use of laser therapy for neoplasia, infections and benign growths of the vulvo- vagina were excluded. Case- control studies, case reports, letters, conference papers and reviews were also excluded. Studies were selected independently by two reviewers who screened by title and abstract. Data collection from FIGURE 1 Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) flow diagram. Included Eligibility Screening Identification Records identified through database searching (n = 317) MEDLINE: 72 EMBASE: 227 CENTRAL: 18 Records after duplicates removed (n = 277) Records screened (n = 277) Full-text articles assessed for eligibility (n = 37) Studies included in qualitative synthesis (n = 28) Additional records identified through other sources (n = 5) Records excluded based on title or abstract (n = 240) Urology/ Nephrology: 48 Non gynaecology: 73 Non laser: 44 Non vagina: 18 Microbiology: 12 Infection (e.g. HPV): 14 Fistula: 8 Laparoscopy: 8 Cysts: 3 Condyloma: 2 Neoplasia: 2 Haematoma: 1 Hymen: 1 Conference Abstract: 6 Full-text articles excluded (n = 9) Non laser: 2 Laser for excision: 1 Non peer review: 1 Reviews: 5

3 150 Laser therapy for vulvo- vaginal atrophy TABLE 1 Laser therapy for treatment of vulvo- vaginal atrophy (VVA) symptoms and sexual function Author Year Study type Number of participants Follow-up duration Laser treatment Study measures Ostrzenski women in two groups symptomatic women healthy control women One treatment and final assessment six months later CO 2 Continuous mode of 8 10 W with defocus to create vaginal columnar rugae of depth 2 5 mm, width 5 8 mm, and 5 10 mm between crypts Pelvic organ prolapse/urinary incontinence sexual questionnaire (PISQ-12) Clinical neurosensory evaluation of vagina using cold and warm cotton balls Vaginal functional numeric rating scale Salvatore postmenopausal women with dyspareunia Three treatments one month apart with final assessment four weeks later Dot power 30 W, dwell time 1000 μs, dot spacing 1000 μm, smart stack parameter from 1 to 3 Dot power 20 W for introitus Vaginal Health Index Score (VHIS) Visual analogue scale (VAS) for VVA symptoms (burning, itching, dryness, dyspareunia, dysuria) Short Form-12 (SF-12) Female Sexual Function Index (FSFI) Salvatore 2014b 50 postmenopausal women unresponsive to local oestrogen Three treatments one month apart and final assessment four weeks later Dot power 30 W, dwell time 1000 μs, dot spacing 1000 μm, smart stack parameter from 1 to 3, 45 probe VHIS VAS for VVA symptoms (burning, itching, dryness, dyspareunia, dysuria) SF-12 Salvatore postmenopausal women unresponsive/unsatisfied with local oestrogen Three treatments one month apart and final assessment four weeks later Dot power 30 W, dwell time 1000 μs, dot spacing 1000 μm, smart stack parameter from 1 to 3 Dot power 20 W for introitus FSFI SF-12 VAS for VVA symptoms (vaginal burning, itching, dryness, dyspareunia, dysuria) Perino postmenopausal women Three treatments at least one month apart, with final assessment one month later Dot power 40 W, dwell time 1000 μs, dot spacing 1000 μm, SmartStak 2, D- pulse mode Dot power W for introitus VHIS VAS for VVA symptoms (itching, burning, dryness, dyspareunia) Gambacciani postmenopausal women with genitourinary syndrome of menopause (GSM) Three treatments 30 days apart with final assessment four weeks later 2940 nm erbium- doped yttrium aluminium garnet (Er:YAG) 7 mm spot size, 8.5 J, smooth mode, delivered through speculum for vaginal canal, 3 J for vestibule and introitus VHIS VAS for vaginal dryness and dyspareunia International Consultation on Incontinence Questionnaires- Urinary Incontinence Short Form (ICIQ-UI SF)

4 S. Song et al. 151 Main outcomes Adverse events Comments Mean PISQ-12 increased from 27.2 to 32 (18.7%) Intact neurosensory faculties of vaginal walls post-treatment Sensation of smooth vagina resolved by six weeks post-treatment Group one selection bias for women who demanded treatment All women treated with vaginal oestrogen six weeks before treatment and continued post-study Significant improvement in VHIS from baseline to follow-up (12.9 ± 30 vs 22.1 ± 2.3, P < 0.001) Significant improvement in VAS scores in all domains from baseline to follow-up (P < for dyspareunia, P < 0.05 all others) Significant improvement in SF-12 and FSFI from baseline to follow-up (P < 0.05 and P < 0.001, respectively) Assessor bias Significant improvement in VHIS, VAS scores and SF-12 from baseline to follow-up (P < 0.001) Procedure pain at first treatment with probe insertion and movement but significantly reduced by second and third treatments Assessor bias 17/20 women who were not sexually active due to VVA symptoms resumed activity after first laser treatment Significant improvement in FSFI score from baseline to follow-up (14.8 ± 7.7, 95% CI vs 27.2 ± 5.6; 95% CI , P < 0.001) with individual domains all significant (P < 0.001) Significant improvement in VAS in all domains (P < 0.001) and in SF-12 (P = and P = 0.002, physical and mental, respectively) Significant improvement in VHIS baseline to follow-up (median/interquartile range 10.5/3 vs 21.5/2, P < ) Significant improvement in VAS scores across all domains from baseline to follow-up (P < ) Questionnaire results anonymous Sample size arbitrarily defined due to lack of available literature Selection bias for women more motivated to return to sexual activity Vaginal lubricant use may not have been well controlled Assessor bias 8/48 patients used hormone replacement therapy six months to one year before laser treatment Significant improvement in VAS, VHIS and ICIQ-UI SF score from baseline to follow-up (P < 0.01) Additional treatment to anterior vaginal wall for 21/67 women with concurrent stress urinary incontinence (SUI) (Continues)

5 152 Laser therapy for vulvo- vaginal atrophy TABLE 1 (Continued) Author Year Study type Number of participants Follow-up duration Laser treatment Study measures Gambacciani 2015b Prospective longitudinal 70 postmenopausal women in two groups laser therapy vaginal oestrogen control Three treatments one month apart with final assessment six months later 53 postmenopausal women with GSM symptoms Three treatments one month apart with final assessment one month later 2940 nm Er:YAG7 mm spot size, fluence 6.0 J/cm 2, 1.6 Hz, smooth mode (thermal, non- ablative) VHIS ICIQ-UI SF VAS (vaginal dryness, dyspareunia) Pitsouni 2016 Objective ph VHIS Cytology for vaginal maturation value (VMV) VAS for VVA symptom severity (dryness, burning, itching, dyspareunia, dysuria, urinary frequency and urgency) Sexual intercourse frequency FSFI ICIQ Female Urinary Tract Symptoms (ICIQ-FLUTS) and ICIQ-UI SF Urogenital Distress Inventory (UDI-6) King s Health Questionnaire (KHQ) Patient Global Impression of Improvement (PGI-I) Sokol 2016 and Sokol 2017 (one year follow- up of Sokol 2016) 30 postmenopausal women with VVA symptoms Three treatments six weeks apart with final assessment one year later. 40 W, 1000 ms dwell time, 1000 μm spacing, normal scan mode, 90, four point probe VHIS Primary outcome: VAS (0 10) for vaginal pain, burning, itching, dryness, dyspareunia, dysuria FSFI SF-12 PGI-I Maximal tolerable dilator size for vaginal wall elasticity Questionnaire of orgasm function, vaginal moisturisation and tightening, and treatment acceptability Alinsod sexually active, anorgasmic or slow to orgasm with normogasmic history Three treatments one month apart Trancutaneous temperature controlled radiofrequency S- shaped probe with radiofrequency emitter on one tip surface Pieralli breast cancer survivors in oncological menopause experiencing dyspareunia due to VVA Three treatments 30 days apart with final assessment four weeks later. Dot power 30 W, dwell time 1000 μs, dot spacing 1000 μm, smart stack parameter 1 Objective ph VHIS (only in first 36 patients) VAS for dyspareunia (score 1 5)

6 S. Song et al. 153 Main outcomes Adverse events Comments Significant improvement in VHIS and VAS scores in both groups (P < 0.01) Laser group significantly better than oestrogen from three months for VHIS and six months for VAS (P < 0.05) Significant decrease in ICIQ-UI SF scores after laser treatment from baseline to six month follow-up (12.0 ± 1.8 vs 5.0 ± 2.6, P < 0.01) One experienced burning sensation starting 36 h after first treatment and lasting for a couple of days Inclusion and exclusion criteria for control group not defined Uneven distribution between control and laser group 19/25 completed follow-up Additional treatment to anterior vaginal wall provided to 19/45 patients who experienced SUI Significant improvement in VHIS and VMV from baseline to follow-up (8.4 ± 2.5 vs 20.1 ± 3.0 and 11.7 ± 15.6 vs 44.2 ± 13.7, P < 0.001) Significant decrease in VAS (7.4 ± 2.1 vs 1.8 ± 1.8, P < 0.001, effect size 3) but 8/53 unchanged from baseline Clinically significant improvement in FSFI from baseline to follow-up (13.7 ± 8.1 vs 25.9 ± 4.6, P < 0.001, effect size 1.5) 15/16 women with no sexual activity at baseline due to VVA resumed activity post- treatment Significant improvement in FLUTS and quality of life (P < 0.05) except in treating difficult bladder emptying and lower abdominal pain Mild irritation of introitus immediately after laser treatment to two hours post which resolved spontaneously Two blinded assessors Clinically meaningful improvements in genitourinary symptoms, sexual function and general health perception Not representative of women with history of urinary tract infections (UTI) or vaginitis Significant improvement (P < 0.05) in all VAS domains from baseline to end of treatment (dryness and dyspareunia most improved (P < 0.001)) Significant improvement in VHI and FSFI reported from baseline to one year follow-up (average change 7.0 ± 3.7 and 10.6 ± 10.0, P < ) 83% women increased their maximum tolerable dilator size from baseline to three month follow-up but declined to 73.7% at one year follow-up No significant change in SF-12 Two women: mild to moderate pain lasting two to three days Two women: minor bleeding less than one day duration Genetically homogenous Treatment parameters modulated downward to suit participant tolerance if required Vaginal elasticity results may be confounded by women lost to follow-up being those who could tolerate greater dilator size 24/30 completed follow-up 23/25 reported average reduction of at least 33% 23/25 reported achieving orgasm after treatment All reported vaginal canal tightening and satisfaction with treatment 20/25 reported improvements in vaginal moisturisation No follow-up No baseline measurements No validated assessments Treatment to both external genitalia and vaginal canal Significant improvement in VHIS from baseline to follow-up (8.9 ± 1.7 vs 21.6 ± 1.6, P < ) with no significant difference between subgroups undergoing different adjuvant therapy (P < 0.3) Significant improvement in VAS dyspareunia from baseline to follow-up (median 5 vs 3, P < 1.86 e 22 ) 12/50 pain with probe insertion Highly variable long-term follow-up time Variable adjuvant therapy (tamoxifen, aromatase inhibitors or none) (Continues)

7 154 Laser therapy for vulvo- vaginal atrophy TABLE 1 (Continued) Author Year Study type Number of participants Follow-up duration Laser treatment Study measures Pagano 2016 Retrospective observational 26 women with surgically treated hormone-receptor positive breast tumours experiencing VVA Three treatments days apart with final assessment 30 days later Dot power 30 W, dwell time 1000 μs, dot spacing 1000 μm, smart stack parameter 1 to 3 Gynaecological exam VAS (0 10) of VVA symptoms (vaginal laxity, reduced sensitivity during intercourse, vaginal flatulence and/or leucorrhoea, dryness, itching, stinging, bleeding, dyspareunia and dysuria) and procedure discomfort Murina women in two groups women experiencing vestibulodynia menopausal women >50 years experiencing vulvar pain secondary to GSM Three treatments at least 30 days apart with final assessment four months later Prospective cohort study 50 women with GSM in two groups women on oestrogen for eight weeks women laser Three treatments three weeks apart with final assessment 18 months later Biopsies from 12 patients Dot power 30 W, dwell time 1000 μs, dot spacing 700 μm, smart stack parameter 2, DP pulse mode Four point score for vestibular health VAS vulvar pain Vaginal pain reported on scale of 0 3 with physician pushing on various points with Q-tip Marinoff score of dyspareunia Objective Gaspar nm Er:YAG Two phases Laser speculum for vaginal canal Vestibule and introitus Smooth mode Vaginal biopsy Vaginal ph Cytology for vaginal maturation index and maturation value (MV) VAS 0-3 scale for GSM symptoms (dyspareunia, dryness, irritation, leucorrhoea) Gambacciani 2017 Prospective longitudinal 43 breast cancer survivors with severe GSM Three treatments one month apart with final assessment 18 months later 2940 nm Er:YAG 7 mm spot size, 1.6 Hz, fluence 6.0 J/cm 2, smooth mode Laser speculum used for vaginal canal VHIS VAS for GSM symptoms (vaginal dryness and dyspareunia) Behnia- Willison postmenopausal women with GSM unresponsive or contra- indicated to oestrogen Three treatments six or more weeks apart with final assessment months later Dot power 30 W, dwell time 1000 μs, dot spacing 1000 μm, smart stack parameter 2, D- pulse mode for full vaginal canal Smart stack parameter 1 for vestibule and fourchette Vaginal exam for elasticity, fluid volume, epithelial integrity and moisture to define atrophy Australian Pelvic Floor Questionnaire for evaluation of bladder, bowel, sexual function and prolapse GSM symptom frequency and severity questionnaires (vaginal dryness, dyspareunia, tightness, prolapse symptoms, bladder function, urge and stress incontinence)

8 S. Song et al. 155 Main outcomes Adverse events Comments Significant decrease in median VAS scores from baseline to last treatment EXCEPT in vaginal laxity (P < for all, P < for dysuria) Significant, progressive improvement in dyspareunia and pain scores at each treatment and follow-up (P < 0.05) Vestibular health index score improved after each treatment with no difference between groups 67.6% of Group 1 reported improved symptoms and 43.4% reported no change 3/70 transient burning sensation post-treatment which resolved in five to six days No tabular or graphical breakdown of scores or statistical analysis No satisfaction results presented for GSM group Subjective outcome measures Significant reduction in VAS scores across all domains at six months in both groups (P < 0.05) with improvements maintained and better in laser than oestrogen by 12 and 18 months Significant improvement in MV and ph in both groups at three months (P < 0.001) but laser maintained a significant and better improvement at 12 months (P < 0.001) while oestrogen group ph returned to baseline Histology: thickening of epithelial tissue (basal cell hyperplasia) with improvements in vascularisation, increased fibrillar components of extracellular matrix, angiogenesis and papillomatosis Significant decrease in VAS from baseline to end of treatment, (P < 0.01) with significant difference (although reduced) maintained at 12 months up (P < 0.01) Significant improvement in VHIS score reported from baseline to end of third treatment (8.1 ± 1.3 vs 21.0 ± 1.4, P < 0.01) No significant difference in VAS or VHIS by 18 months follow-up 84% of patients with moderate or severe symptoms experienced improvement to mild or non-atrophic categories Statistically significant improvement in sexual function, dyspareunia and sexual issues from baseline to end of treatments (P < 0.001) Statistically significant improvements in prolapse symptoms, vaginal sensation and lubrication and bladder function/urge incontinence after treatments which were maintained at months follow-up (all P < 0.05 or lower) 2/50 sensation of warmth related to mild to moderate pain.transient oedema, spotting and transitory pain after laser treatment No events reported 3/102 post- coital UTI 2/102 vaginal discharge/ infection 3/102 lower pelvic pain for 2 3 days requiring simple analgesia 1/102 genital herpes breakout 2/102 postmenopausal bleeding (four and six months after third treatment) Allocation method unknown Laser group treated with vaginal oestrogen two weeks before laser No measure of function Positive changes maintained up to 12 months post-treatment All procedures performed by one gynaecologist No example of questionnaire for GSM symptom frequency and intensity Sexual issues not defined Large follow-up margin (12 24 months) Large loss to follow-up (exact number unknown)

9 156 Laser therapy for vulvo- vaginal atrophy full text publications was abstracted and included study design, participant population, laser type and duration of treatment, measures of vulvo- vaginal and urinary symptoms, quality of life or sexual function and adverse events. RESULTS Figure 1 reports the results of our systematic review. All studies were published between 2012 and 2017, with no published RCTs to date, although three were identified as being underway through trial registries. Of the included studies, four investigated the effect of laser therapy on vaginal tissue histology (not tabulated), on vulvo- vaginal symptoms with two 22,30 concurrently examining the effect on incontinence, and seven on urinary incontinence only. Sample sizes were generally small, ranging from 15 to 175 women, with a total of 761 women who underwent treatment for vulvo- vaginal symptoms and 408 for urinary incontinence. The non- histology studies were all observational, with one retrospective 25 and the remaining, prospective studies. Followups ranged from none to two years post- treatment with a 45% to 100% completion rate. Table 1 summarises the characteristics of studies that measured laser therapy effects on VVA and Table 2 summarises those related to urinary incontinence. DISCUSSION From published data, women having vulvo- vaginal laser treatments are primarily postmenopausal women and those with a history of breast cancer experiencing GSM or urinary incontinence. These are populations who should have most benefit from such treatments given the theoretical benefits. Alternative treatments for GSM are limited, with many women not wanting to use hormones in any form and others who have not had a response to topical treatments having few alternatives. Should this treatment prove effective, then the ideal treatment interval, the need for retreatment, the complications and cost factors must all be established and made available to women with these symptoms. The current data are limited by length of follow- up, with no long- term data available and no comparison against placebo. Therefore, treatment should only be administered under an ethics- approved clinical trial until such information is available. Currently in Australia, more than treatments have been undertaken (personal communication) and if only a fraction of these were included in a large- scale study or RCT, these data would already be available. An evidence- based approach to new, novel treatments such as vulvo- vaginal laser treatments involves integrating physician experience and judgement with reliable, external evidence. 40,41 The traditional evidence pyramid should progress efficiently from initial case reports and series that determine that an innovative treatment with biological plausibility may be performed and may have a clinical effect, to controlled, robust studies such as RCTs that establish the validity of the procedure within the clinical context. The speed at which this occurs is determined by a number of factors including local regulatory requirements, availability of the novel equipment or drug, clinician factors, commercial factors, including advertising and patient factors often involving information availability. History has demonstrated the volatile nature of clinicians and data alike, with a good example being the proposal for internal mammary artery ligation as a potential surgical intervention for angina pectoris 42 in the 1950s. There was very positive media around the intervention as it was doing something, 43 with preliminary data demonstrating significant symptomatic improvement. 44 Subsequently, two randomised, placebo- controlled trials showed no difference between the placebo and the intervention groups. 45,46 Even for treatments proven effective in the short term, post- market monitoring may reveal long- term adverse events, as was the case with many vaginal mesh kits that has led to multiple cancellations of the devices by the Therapeutic Goods Administration and a senate enquiry into a variety of procedures in the pelvic floor. This is not to say that all new treatments are ineffective and should not be used. However, safe, rational and appropriate use by critically appraising the literature for sound evidence before using a treatment is imperative to ensure patient safety and benefit. While the availability of levels of evidence may be in flux, 47 the need for that evidence is not. studies are the predominant evidence currently available for laser treatments of VVS and these report an effect that is an excellent springboard to the next level of evidence, the placebo- controlled study, and since none are currently available, the essential data for clinicians, patients and industry alike remain uncertain. 48 There are currently four studies 26,27,30,37 that use a control group for comparison, but none of these are randomised and none have a placebo control. While placebo- controlled trials are registered, large- scale treatment using vulvo- vaginal laser is already being marketed and provided as a solution when the trials are still incomplete. Studies without blinded, control groups are highly susceptible to the placebo effect that is documented to cause positive physiological and/or physical changes without actual treatment due to participant expectation of a response. 49 Responses may even be seen when participants are aware of taking a placebo 50 and the effect is particularly prominent in subjective, patient- reported outcomes 51 the predominant outcome measures in studies of laser treatment so far. The studies to date do examine histology in a small series and this provides some objective data; however, it is longitudinal, symptomatic improvement that is the final arbiter of success for this problem and with less than 50 women having follow- up to two years, 32 the success of the treatment cannot be considered more than hypothesis. Furthermore, selection bias and the small numbers preclude determination of safety and substantive efficacy, which must be established before being offered to women

10 S. Song et al. 157 TABLE 2 Author Year Ogrinc 2015 Fistonic 2015 Laser therapy for treatment of stress urinary incontinence (SUI) Study type No. of participants Follow-up duration Type of laser Outcome measures Main outcomes Adverse events Comments 175 women in two groups 1. Stress urinary incontinence (SUI) (66%) 2. Mixed urinary incontinence (MUI) (34%) Two treatments four to six weeks apart, third treatment six months later, with final assessment 12 months after first treatment 2940 nm erbium- doped yttrium aluminium garnet (Er:YAG) Fluence 10.0 J/cm 2, four pulses per packet, pulse duration 250 ms, spot size 7 mm, repetition rate 1.6 Hz Three phases Vaginal canal Anterior vaginal wall Urethra Objective Muscular strength using perineometrical measurement (PFX Biofeedback Kegel exercisers) Clinical exam Echosonography for residual volume and bladder wall thickness International Consultation on Incontinence Questionnaires- Short Form (ICIQ-SF) Incontinence Severity Index (ISI) Visual analogue scale (VAS) for procedure pain Significant improvement in ISI from baseline to 12 months (women with very severe UI experienced greatest ISI decrease) 108/175 patients had no incontinence at one year 38/175 patients had worsening UI after therapy Improvements in SUI significantly better than in MUI group (77% of SUI cases vs 34% of MUI cases, P < 0.001) Mild discomfort (max. VAS pain 3 on 0 10 scale) with less discomfort over successive treatments Treatment timing poorly controlled (planned second treatment at four to six weeks but average time between treatments was 77.6 days) Uneven groups Parity uncontrolled Variable treatment number (12/175 received one, 54/175 received two and 109/175 received all three) Data poorly presented in graphs, difficult to interpret Prospective cohort 73 consecutive women with SUI One treatment with final assessment two to six months later 2940 nm Er:YAG Smooth mode Three phases Anterior vaginal wall Vaginal canal Vestibule ICIQ-UI SF Significant decrease in ICIQ-UI SF score from baseline to two to six month follow-up (median 12 vs 4, P < 0.001) Younger age (<39 years) and normal body mass index (BMI) associated with decrease in ICIQ-UI SF score (median score baseline vs follow-up, 8.0 vs 0, P < and 10.5 vs 0, P = for age and BMI, respectively) Warmth, pricking or irritation during treatment. Slight vulva oedema which resolved 48 h post-treatment. 1/43 de novo urgency which resolved after eight days 45/73 completed follow-up Large range for second follow-up (two to six months) although authors claim no statistically significant differences between months Did not account for menopausal status and activity/pelvic floor strength in analysis (Continues)

11 158 Laser therapy for vulvo- vaginal atrophy TABLE 2 (Continued) Author Year Study type No. of participants Follow-up duration Type of laser Outcome measures Main outcomes Adverse events Comments Perino postmenopausal women with VVA and overactive bladder (frequency and urgency) Three treatments at least 30 days apart with final assessment 30 days later Dot power 40 W, dwell time 1000 μs, smart stack 2, D- pulse mode for vaginal canal Dot power W for introitus Vaginal Health Index (VHI) VAS for vulvo-vaginal atrophy (VVA) (vaginal itching, burning, dryness and dyspareunia) Patient s Perception of Intensity of Urgency Scale Overactive Bladder Questionnaire Short Form (OAB-Q SF) Significant improvements (P < ) across all VAS domains, VHI and OAB-Q SF from baseline to end of treatment (VHI median/ interquartile range 11/3 vs 22/3.25, OAB-Q 18.5/4.25 vs 8/2.25, P < ) Tien, Yi-Wen consecutive, sexually active women with SUI One treatment with final assessment six months later 2940 nm Er:YAG Smooth mode Three phases Vaginal canal Anterior vaginal wall Vestibule mucosa and introitus Objective Urodynamic study (uroflowmetry, filling and voiding cystometry) 20min pad test Partner reported Modified Male Sexual Activity questionnaire Clinical exam Three day bladder diary Interview for lower urinary tract symptoms (LUTS) Sexual function 39.3% (11/28) objective cure 39.3% (11/28) objective improvement Significant reduction in pad weight from baseline to six month follow-up (14.0 ± 18.2 g vs 3.1 ± 5.6 g, P < 0.001) Urodynamic values unchanged Significantly improved sexual desire from baseline to six month follow-up (2.5 ± 0.7 vs 2.7 ± 1.0 6, P = 0.03) but no functional improvement Symptom alleviation not as extensive as compared to standard mid-urethral sling surgery 28/35 women completed follow-up Objective cure defined as <1 g pad weight Objective improvement defined as pad weight reduction >50% (Continues)

12 S. Song et al. 159 TABLE 2 (Continued) Author Year Study type No. of participants Follow-up duration Type of laser Outcome measures Main outcomes Adverse events Comments Fistonic women with SUI One treatment with final assessment six months later 2940 nm Er:YAG 7 mm spot size, fluence of 3,6 and 10 J/cm 2 up to four consecutive pulses at 1.6 Hz, smooth mode Three phases Anterior vaginal wall Vaginal canal Vestibule Objective Perinometry for pelvic diaphragm muscle strength Residual volume with DC-8 ultrasound unit ICIQ-UI SF VAS scale for treatment pain (0 10) Treatment discomfort, tolerability Significant improvement in ICIQ-UI SF score from baseline to one month post-treatment (12.9 ± 5 vs 6.6 ± 6.1, P < 0.001) and remained significant but less pronounced by six months (7.8 ± 5.7, P = 0.01) 32.52% (10/31) reported no incontinence by one month follow-up Significant reduction in post-void residual volume at two month follow-up (P = 0.04) but no significant difference by six months (P = 0.07) No statistically significant improvement in perineometry Warmth or teasing during treatment Increased vaginal discharge following procedure Vulva oedema which resolved 48 h post-treatment 17/31 completed two month follow-up 14/31 completed six month follow-up Pardo 2016 Prospective longitudinal 42 women with SUI Two treatments days apart with final assessment three to six months later 2940 nm Er:YAG Three phases Vaginal canal Anterior vaginal wall Vestibule and introitus ICIQ-UI SF Discomfort, treatment tolerability Statistically significant improvement in ICIQ-UI SF scores per patient (P < 0.001) 78.6% (33/42) of patients reported symptom improvement independent of age or parity 81.8% of sexually active women (27/33) reported improvement in sexual gratification Improvement considered as lowered ICIQ-SF score without necessarily a change in severity category Large range follow-up Postmenopausal women treated with local oestrogen before laser

13 160 Laser therapy for vulvo- vaginal atrophy outside of clinical studies. Selection and reporting bias are a frequent occurrence in longitudinal data and this has been repeatedly demonstrated in clinical studies for example, endometrial ablation where initial results showed amenorrhea rates of 99% and no failures 52 but subsequent RCTs dropped this rate to 43% and a clinical failure rate of 11.7%. 53,54 Using evidence- based care benefits women s health and ensures clinician integrity. The potential for a non- invasive way to treat stress urinary incontinence is very attractive, particularly in the current setting of litigation and class actions that involve midurethral slings. 55 This is in the face of good evidence that the procedures are highly effective in well- conducted large- scale randomised trials. 56 However, to date, the evidence for laser treatment for stress urinary incontinence is tenuous at best with a small number of women treated and only followed up in the short term (up to six months and one study to one year). 36 While statistically significant improvements in subjective scores were noted, the improvements often diminished by six months. 37,39 Since urinary incontinence is a chronic issue, the determination that it is indeed better than placebo and the duration of its effect, the need to repeat treatments, their efficacy and costs compared with current standard treatments must be considered. All studies included for urinary incontinence investigated changes in stress urinary incontinence with one 36 studying mixed incontinence and reporting a reduced effect in this setting (77% vs 34% improvement in stress vs mixed incontinence, respectively, P < 0.001) and caution must be given in areas where the data are limited or extrapolated. 36 Of the 26 studies involving vaginal treatment (excluding one 14 ex vivo study), 12 15,17,20,21,24,26,29,31,33 35 reported no adverse events. Reported events included procedure pain with probe insertion and movement, introitus irritation post- treatment, a burning sensation and minor bleeding. All adverse events noted were transient and spontaneously resolved within a few hours or days of treatment. No long- term adverse events were recorded and it is perhaps this simple approach in an ambulatory setting with many applications that make the treatment attractive for both clinician and patient alike. Certainly media reports suggest benefit 57 and this often advertorial rather than editorial approach must be tempered by science and the clinical community must impose that science. TABLE 2 (Continued) Study type No. of participants Follow-up duration Type of laser Outcome measures Main outcomes Adverse events Comments Author Year ICIQ-UI SF score 0 = cure Clinically meaningful improvement in pad weight defined as 50% reduction in pad weight from baseline Local oestrogen used as needed two weeks before laser Mild, transient symptoms resolved within 24 h after procedure 1/22 pelvic pain 2/22 dysuria Significant improvement in ICIQ-UI SF score from baseline to three months (mean 18 vs 5, P < 0.001) but effect reduced at six months (18 vs 8, P < 0.001) Significant weight reduction in pad test from baseline to three months and remained significant but reduced by six months (mean baseline 23 vs 10 vs 14, P < 0.001) 18/22 patients showed clinical improvement at three months and 11/22 at six months Objective Er:YAG 2 mm spot size, 6.0 J/cm 2, 1.4 Hz in smooth mode in four passes along the entire urethral canal delivered via a cannula 22 women with severe type III SUI Two treatments three weeks apart with final assessment six months later Gaspar 2017 One hour pad weight ICIQ-UI SF CONCLUSION Urogenital symptoms associated with VVA are a significant burden on women and the development of non- invasive, simple treatment methods such as laser therapy, is welcome. However, current, scientific evidence in support of laser therapy is limited by observational data and is not enough to demonstrate robust clinical safety and efficacy. While this treatment may well be safe and efficacious, these claims must be validated through largescale randomised controlled trials, which can provide stronger evidence, to ensure responsible representation of this new treatment to the public.

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