Vaginal energy‐based devices for vulvovaginal dryness
Abstract
Objectives
This is a protocol for a Cochrane Review (intervention). The objectives are as follows:
To determine the benefits and harms of vaginal energy‐based devices for women with vulvovaginal dryness related to genitourinary syndrome of menopause (GSM) or hormone therapy.
Background
Description of the condition
Bothersome vaginal symptoms are common in women after menopause or after endocrine therapy for breast cancer. Vaginal dryness, itching, dyspareunia (painful intercourse) and other symptoms have been combined in a syndrome called genitourinary syndrome of menopause (GSM). GSM is now used to describe the condition known as 'vaginal atrophy' (Wańczyk‐Baszak 2018). The symptoms of GSM are believed to be caused by a lack of oestrogen and therefore vaginal oestrogen therapy has been used effectively as the gold‐standard treatment for this condition (Lethaby 2016). However, some women cannot tolerate local oestrogen – and some do not want it – so effective and safe alternatives could be valuable.
Description of the intervention
The types of energy‐based devices currently used to treat GSM can be divided into laser and radiofrequency devices.
Laser devices generate tiny laser beams that are applied to the vaginal wall through a series of mirrors and a vaginal probe. The lasers can use different sources and mediums. CO2‐fractional and ER:Yag (erbium‐doped yttrium aluminium garnet based) are the most commonly used. The ER:Yag laser differs from CO2‐fractional lasers in only causing a minimal thermal reaction to the epidermis. This may cause fewer side effects due to less epidermal injury and subsequent vaporisation of the mucosa (Huth 2021).
Radiofrequency devices also work by applying heat topically and thereby induce skin remodelling. The energy source is an alternating current from a radiofrequency generator that causes a charged electromagnetic field (Hong 2010).
All energy devices are applied by a probe in the vagina.
Each treatment takes a few minutes, requires no sedation and is usually repeated three times with a month between each treatment (Lang 2017).
How the intervention might work
Topically applied power (heat) from devices has been used in dermatology for various indications for decades. The power (heat) induces dermal remodelling; for example, by formation of new collagen and angiogenesis (formation of new blood vessels) through both photodermal and photochemical reactions, although the full mechanism behind the remodelling process has not been fully elucidated (Huth 2021; Preti 2019).
These findings have led to exploration of the use of laser and radiofrequency devices in the treatment of GSM (Lang 2017; Preti 2019; Salvatore 2014). Several published studies have suggested that these devices could not only effectively treat GSM (Salvatore 2014), but also improve urinary incontinence (Ogrinc 2015). Many other uses are being evaluated, for instance in the treatment of lichen sclerosus (Gómez‐Frieiro 2019).
A recent meta‐analysis concluded that CO2 laser treatment may be effective for GSM by improving quality of life and sexual function (Liu 2021). However, this review only included observational studies, excluded other energy‐based devices and did not have a published protocol.
Why it is important to do this review
Vaginal energy‐based devices have been introduced and are already in use. It is important to determine whether the benefits outweigh the harms. These are medical devices, which are not regulated as rigorously as pharmaceuticals. It is therefore important for there to be an independent review before a device is recommended. The US Food and Drug Administration (FDA) has warned against the use of these devices due to suspected serious adverse events, as well as few data on efficacy (FDA 2018).
As this is an active research area, a review that is continuously updated and reviewed by an independent group is therefore of importance.
Objectives
To determine the benefits and harms of vaginal energy‐based devices for women with vulvovaginal dryness related to genitourinary syndrome of menopause (GSM) or hormone therapy.
Methods
Criteria for considering studies for this review
Types of studies
We will include randomised controlled trials (RCTs), including cluster‐RCTs, assessing vaginal energy‐based devices for treating vaginal dryness in women.
We will exclude quasi‐randomised trials. We will also exclude cross‐over randomised trials because it is not known how long a washout period is needed for this intervention.
Types of participants
We will include studies of adult women with vulvovaginal dryness related to menopause (GSM) or after endocrine therapy (for instance, after breast cancer).
Types of interventions
We will include any studies that use a vaginal energy‐based device (laser or radiofrequency ablation) compared to local oestrogen, sham energy‐based treatment or no treatment.
Types of outcome measures
Primary outcomes
We have included all outcomes from the core outcome set for GSM (Lensen 2021), and we have chosen the following primary outcomes:
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Vulvovaginal dryness, measured with a visual analogue scale (VAS), or any other validated scale, at the end of treatment (continuous data). We will also assess the number of patients experiencing relief at the end of treatment (dichotomous data).
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Side effects of treatment (e.g. infections, scarring, dropout due to adverse events, vulvovaginal burning).
Both outcomes will be obtained at the end of treatment and if later follow‐up is available we will also report this. Long‐term follow‐up will be defined as > 8 months after the end of treatment.
Secondary outcomes
The following secondary outcomes will be measured with a VAS, or any other validated scale, at the end of treatment (continuous data). We will also assess the number of patients experiencing relief at the end of treatment (dichotomous data).
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Pain with sex.
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Vulvovaginal discomfort or irritation.
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Discomfort or pain when urinating.
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Change in most bothersome symptom.
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Distress, bother or interference of genitourinary symptoms.
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Satisfaction with treatment.
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Sexual function (as measured by a validated questionnaire such as the Female Sexual Function Index (FSFI) (Rosen 2000)).
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Urinary incontinence (as measured by a validated questionnaire such as the International Consultation on Incontinence Questionnaire‐Urinary Incontinence Short Form (ICIQ‐UI SF) (Avery 2004)).
We will only include outcomes that are defined as above. In case of doubt over whether an outcome is in line with our definitions, we will include the data and conduct a sensitivity analysis.
Outcomes 7) and 8) are not part of the core outcome set for GSM. Sexual function is clinically relevant and often the main reason for contact with a healthcare professional. We believe that it is not fully captured by 'Pain with sex' from the core outcome set. Laser treatment is currently being evaluated as a treatment for urinary incontinence and we have chosen to include this to provide information on this question, but we also acknowledge that it is an important clinical outcome.
Search methods for identification of studies
The search will be developed and performed by the Cochrane Gynaecology and Fertility (CGF) Information Specialist based on our predefined population, interventions, comparisons and outcomes (PICO). We will search for all published and unpublished RCTs of vaginal energy‐based devices without language or date restrictions.
Electronic searches
We will search the following electronic databases, trial registers and websites for all potential eligible studies:
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Cochrane Gynaecology and Fertility (CGF) Specialised Register of Controlled Trials, ProCite platform, from inception to present (Appendix 1);
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CENTRAL, via the Cochrane Central Register of Studies Online (CRSO), Web platform, from inception to present. CENTRAL now includes CINAHL as well as records from the World Health Organization International Clinical Trials Registry Portal (ICTRP) (https://trialsearch.who.int) and the ClinicalTrials.gov trials registry at the US National Institutes of Health (www.clinicaltrials.gov) (Appendix 2);
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MEDLINE (Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations), Ovid platform, from 1946 to present (Appendix 3);
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Embase, Ovid platform, from 1980 to present (Appendix 4);
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PsycINFO, Ovid platform, from 1806 to present (Appendix 5).
Searching other resources
We will check the references of included papers for eligible studies. We will search Google for unpublished theses and papers (grey literature) that could be relevant for inclusion in the review. We will also contact experts in the field for any additional studies.
Data collection and analysis
Selection of studies
Two authors will independently screen all studies in Covidence. Based on our predefined population, intervention and study design (from our PICO), they will independently select eligible studies. Disagreement will be resolved by discussion among the authors and a third author from the review team will determine whether the study is eligible for the review. We will document the study selection process in a PRISMA flow chart.
Data extraction and management
Two authors will independently extract data from the included studies. We will use a predesigned Excel sheet for data collection. We will report study details in a 'Characteristics of included studies' table in the review. Studies that are eligible, but do not have usable data for meta‐analysis, will be included and we will contact the authors for additional data. If no data are available, we will include the study in the qualitative review, but exclude it from the quantitative review.
One author will input data into RevMan Web 2023 and another author will review the data for potential errors.
Assessment of risk of bias in included studies
Two authors will independently assess all included studies for risk of bias using the revised Cochrane risk of bias 2 (RoB 2) tool, according to the following five domains (Higgins 2023; Sterne 2019):
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Bias arising from the randomisation process.
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Bias due to deviations from intended interventions.
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Bias due to missing outcome data.
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Bias in measurement of the outcome.
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Bias in selection of the reported result.
We will make assessments with the RoB 2 Excel tool and grade studies as 'low risk', 'some concerns' or 'high risk' according to published Cochrane guidelines for the RoB 2 tool (Higgins 2023). We will make an overall RoB 2 assessment for each outcome.
Measures of treatment effect
We will report continuous data as the mean difference between groups after treatment. Both ordinal and continuous scales will be included. If studies have used ordinal scales we will analyse the data as continuous. We will report the standardised mean difference if the included studies use different scales. We will report dichotomous data as a risk ratio.
The minimally important difference (MID) will be set to 20 mm (absolute scale) or a 32% difference (relative scale) on a 100 mm VAS, based on studies for pain and itch (Olsen 2001; Reich 2006), as a MID has not been established in the literature for vaginal dryness and dyspareunia.
Unit of analysis issues
Individuals randomised will be the unit of analysis. We will correct for any errors arising from the inclusion of cluster‐randomised controlled trials in the statistical analysis. The review will not include studies with cross‐over designs.
Dealing with missing data
If studies lack data we will contact the authors and ask for the missing data. If it is not possible to retrieve the missing data we will include the study in the analysis where possible. We will highlight missing data as a limitation for the remaining analyses. No statistical imputations are planned.
Assessment of heterogeneity
We will create forest plots and initially inspect these visually. We will explore heterogeneity by looking for clinical and methodological differences between studies.
We will use the Chi2 test for heterogeneity and the I2 statistic for quantifying the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error. We will use the following thresholds to guide the interpretation of heterogeneity:
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0% to 40%: might not be important;
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30% to 60%: may represent moderate heterogeneity;
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50% to 90%: may represent substantial heterogeneity;
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75% to 100%: considerable heterogeneity.
Assessment of reporting biases
If more than 10 studies are included in an analysis, we will create a funnel plot to visually check for potential publication bias and report the findings in the review.
We will also screen the protocols of included studies, if available, or the clinical trial registration (e.g. clinicaltrials.gov or the WHO portal) to detect potential selective reporting of outcomes.
Data synthesis
We will perform data analysis in RevMan Web 2023 using appropriate effect measures and 95% confidence intervals with an alpha level of 0.05. We will present the primary analysis with the inclusion of studies judged to be at low risk of bias for all domains.
If the studies are sufficiently similar, we will combine the data using a fixed‐effect model for the main analysis in the following comparisons, stratified by type of intervention (ER:YAG lasers, CO2‐fractional lasers, radiofrequency devices).
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Vaginal energy‐based device versus no treatment/sham energy‐based treatment
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Vaginal energy‐based device versus local oestrogen
The combined estimate for all vaginal energy‐based devices will be the main analysis estimate.
If studies are substantially different in patient characteristics and interventions, we will use a random‐effects model in a sensitivity analysis and report the results together with the fixed‐effect model results.
Where we are unable to present results in a meta‐analysis, we will report the findings using a narrative approach.
Subgroup analysis and investigation of heterogeneity
We will investigate heterogeneity by assessing differences in the study characteristics (clinical and methodological) between the outlier(s) and the rest of the included studies.
We plan to conduct a subgroup analysis to assess whether the effect differs between women with natural menopause versus surgically associated menopause versus medically induced menopause. However, we will only conduct this subgroup analysis if there are at least three studies in each group (to ensure statistical power for the analysis). We will analyse the data using the formal test for subgroup effects in RevMan Web 2023.
We will conduct no other subgroup analyses, as guided by the Cochrane recommendations to limit these (Higgins 2022).
Sensitivity analysis
The main analysis will only include studies with a low risk of bias, therefore for the primary outcomes we will carry out a sensitivity analysis by including studies with a high risk and/or some concerns of bias.
Summary of findings and assessment of the certainty of the evidence
We will create summary of findings tables for the two main comparisons:
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Vaginal energy‐based device versus no treatment or sham energy‐based treatment
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Vaginal energy‐based device versus local oestrogen
We will present the following outcomes in the summary of findings tables:
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Vulvovaginal dryness
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Side effects of treatment
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Pain with sex
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Vulvovaginal discomfort or irritation
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Discomfort or pain when urinating
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Satisfaction with treatment
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Urinary incontinence
Two independent authors will assess the certainty of evidence using GRADE (Schünemann 2013). Disagreements will be resolved by discussion with a final decision by a third author within the author team. If many studies are judged to have 'some concerns' or 'high risk of bias', we will also show the results of the sensitivity analysis in the summary of findings tables.
