Uterine distension media for outpatient hysteroscopy

Abstract

Background

Hysteroscopy done in an outpatient setting is the 'gold standard' method for evaluating the uterine cavity. Media used to distend the uterine cavity include gas as carbon dioxide and liquid as saline that can be used at room temperature or warmed to body temperature. Both media offer advantages as well as disadvantages.

Objectives

The objective of this review is to compare the effectiveness, tolerability, and safety of gas (carbon dioxide) and liquid (normal saline) used for uterine distension during outpatient hysteroscopy.

Search methods

We searched the Cochrane Gynaecology and Fertility (CGF) Group Specialised Register, CENTRAL, MEDLINE, Embase and PsycINFO on 28 April 2021. We checked references of relevant trials and contacted study authors and experts in the field to identify additional studies. CINAHL records and ongoing trials from the trial registries were included in the CENTRAL search.

Selection criteria

We included randomised controlled trials (RCTs) comparing saline with carbon dioxide, as well as RCTs comparing saline at different temperatures, for uterine distension in outpatient hysteroscopy done for any indication.

Data collection and analysis

We used standard methodological procedures recommended by Cochrane. Primary review outcomes were patient tolerability and adverse events or complications related to the distending medium. Secondary outcomes were quality of the hysteroscopic view and duration of the procedure.

Main results

We included 12 RCTs (1946 women). The quality of evidence ranged from very low to moderate: the main limitations were risk of bias due to absence of blinding due to the nature of the procedure, imprecision, and inconsistency.

Saline versus carbon dioxide

Analysis ruled out a clinically relevant difference in pain scores during the procedure between saline and carbon dioxide, but the quality of evidence was low (standardised mean difference (SMD) ‐0.07, 95% confidence interval (CI) ‐0.17 to 0.02; 9 RCTs, N = 1705; I² = 86%). This translates to differences of 0.39 cm (lower) and 0.05 cm (higher) on a 10‐cm visual analogue scale (VAS). Evidence was insufficient to show differences between groups in the proportion of procedures abandoned due to intense pain (Peto odds ratio (OR) 0.48, 95% CI 0.09 to 2.42; 1 RCT, N = 189; very low‐quality evidence). We are uncertain whether saline decreases the need for analgesia compared to carbon dioxide (Peto OR 0.34, 95% CI 0.12 to 0.99; 1 RCT, N = 189; very low‐quality evidence).

Saline compared to carbon dioxide is probably associated with fewer vasovagal reaction events (Peto OR 0.53, 95% CI 0.32 to 0.86; 6 RCTs, N = 1076; I² = 0%; moderate‐quality evidence) and fewer shoulder‐tip pain events (Peto OR 0.28, 95% CI 0.14 to 0.54; 4 RCTs, N = 623; I² = 0%, moderate‐quality evidence). Evidence suggests that if 10% of women undergoing outpatient hysteroscopy experience a vasovagal reaction event with the use of carbon dioxide, this rate would be between 3% and 9% with the use of saline. Similarly, if the rate of shoulder‐tip pain with carbon dioxide is 9%, it would be between 1% and 5% with saline. We are uncertain whether saline is similar to carbon dioxide in terms of endometrial bleeding (Peto OR 0.83, 95% CI 0.25 to 2.75; 2 RCTs, N = 349; I² = 0%; very low‐quality evidence). Infection was not reported by any study in this comparison.

Saline may result in fewer procedures with an unsatisfactory hysteroscopic view than carbon dioxide (Peto OR 0.51, 95% CI 0.32 to 0.82; 5 RCTs, N = 1082; I² = 67%; low‐quality evidence). The duration of the procedure was shorter with saline in three of the four studies that reported this outcome, and duration was similar in both arms in the fourth study.

Warm saline versus room temperature saline

Use of warm saline for uterine distension during office hysteroscopy may reduce pain scores when compared with room temperature saline (mean difference (MD) ‐1.14, 95% CI ‐1.55 to ‐0.73; 3 RCTs, N = 241; I² = 77%; low‐quality evidence). Evidence is insufficient to show differences between groups in either the proportion of procedures abandoned due to intense pain (Peto OR 0.97, 95% CI 0.06 to 15.87; 1 RCT, N = 77; very low‐quality evidence) or the need for analgesia (Peto OR 1.00, 95% CI 0.14 to 7.32; 1 RCT, N = 100; very low‐quality evidence).

Analysis ruled out a clinically relevant difference in duration of the procedure between warm and room temperature saline, but the quality of evidence is low (MD 13.17 seconds, 95% CI ‐12.96 to 39.29; 2 RCTs, N = 141; I² = 21%). No cases of infection were reported in either group (1 RCT, N = 100). No other adverse events and no information on quality of the hysteroscopic view were reported by any study in this comparison.

Authors' conclusions

Evidence was insufficient to show differences between different distension media used for uterine distension in outpatient hysteroscopy in terms of patient tolerability, operator satisfaction, or duration of the procedure. However, saline was superior to carbon dioxide in producing fewer adverse events (shoulder‐tip pain and vasovagal reaction).

Plain language summary

Substances used for expanding the womb cavity during hysteroscopy at outpatient sites

Review question

Cochrane authors wanted to determine which substance is best for expanding the womb cavity during outpatient hysteroscopy. We checked which substance is better tolerated by the patient, has fewer side effects, is more satisfactory to the operator, and is associated with a shorter procedural duration.

Background

The womb is a hollow organ. A hysteroscope is an apparatus that is introduced inside the womb to see inside the cavity. If one is to see, the cavity needs to be filled with a clear substance (distension medium). This substance can be liquid (saline solution) or gas (carbon dioxide). Warming liquid to body temperature was suggested to improve patient tolerability. Each substance has benefits and side effects, which we have compared here.

Study characteristics

We found 12 randomised controlled trials comparing distension media in a total of 1946 women undergoing outpatient hysteroscopy. Evidence is current to April 2021.

Key results

Pain during the procedure may be similar with saline and carbon dioxide. We are uncertain whether saline is as tolerable as carbon dioxide in terms of proportion of procedures abandoned due to intense pain and the need to use painkillers. Saline is probably associated with fewer side effects than carbon dioxide. Saline may be superior to carbon dioxide in terms of quality of the hysteroscopic view. Evidence is inconclusive for duration of the procedure.

Compared to room temperature saline, warm saline may reduce pain scores. Evidence is inconclusive for other outcomes in this comparison.

Quality of the evidence

Evidence is of very low to moderate quality. The main limitations of the evidence are inability to mask the intervention from the participant and the operator, lack of precision, and inconsistent results.

Background

Description of the condition

The uterine cavity is a virtual space that is lined by the endometrium. There is a need to assess the uterine cavity and the endometrium in women with abnormal uterine bleeding (AUB), infertility, or suspected genital tract congenital anomalies. In addition to performing assessment, obtaining an endometrial sample may be required in some cases (Munro 2011).

Several options are available to assess the inside of the uterus, including two‐dimensional ultrasonography, three‐dimensional ultrasonography, saline infusion sonohysterography, hysteroscopy, and magnetic resonance imaging (Bingol 2011; Farquhar 2003; Seshadri 2014). Dilatation and curettage (D&C) was used in the past to investigate the uterine cavity and to obtain an endometrial sample. However, D&C is considered obsolete because it is a blind method with low sensitivity for local and pedunculated intracavitary lesions. Further disadvantages of D&C include the need for hospital admission and general anaesthesia (Bettocchi 2001).

Description of the intervention

Hysteroscopy involves the introduction of a lighted scope through the cervix to visualise the uterine cavity. Hysteroscopy has replaced D&C for many cases requiring investigation of the uterine cavity. With direct visualisation of the uterine cavity, organic lesions are not missed and directed biopsy can be performed (Bedner 2007; Clark 2018). Hysteroscopy in an office setting was described in 1969 by Leidenheimer (Leidenheimer 1969). He used an instrument called the Silander hysteroscope, which was originally described by Torsten Silander in 1963 (Silander 1963). Office hysteroscopy in general is preferable, as it offers the advantages of being minimally invasive, can be done without general anaesthesia for diagnostic purposes, and has low cost and quick recovery time. In addition, some surgical interventions can be performed in the same setting ‐ 'see and treat' (Robinson 2013). Office hysteroscopy has a necessary role in the diagnostic workup for heavy menstrual bleeding (NICE guidelines 2018). The 'traditional' approach for hysteroscopy requires introduction of a vaginal speculum to separate vaginal walls and to visualise the cervix, followed by use of a forceps to grasp the cervix. On the other hand, the new 'vaginoscopic' approach is done by guiding the hysteroscope inside the vagina that is distended by the media without the use of vaginal instruments (Cooper 2010; Smith 2019).

Since this procedure was introduced, several modifications to outpatient hysteroscopy have been proposed, aimed at decreasing the associated pain and improving satisfaction for patients and operators. Decreasing the diameter of the hysteroscope (mini‐hysteroscope < 3.5 mm) and using the no‐touch 'vaginoscopic' approach are examples of such modifications that may result in less pain and better tolerability of outpatient hysteroscopy (Evangelista 2011).

How the intervention might work

As the uterine cavity is a virtual space, it needs to be distended by a medium under pressure if the whole cavity and the tubal ostia are to be visualised (Rioux 1984). Currently, the media in use include gas as carbon dioxide and liquid as saline that can be used at room temperature or warmed to body temperature (Brusco 2003). Problems linked to the type of distension media include pelvic pain, shoulder‐tip pain, and endometrial bleeding. These problems can negatively influence image quality and patient satisfaction (Evangelista 2011).

Why it is important to do this review

The search for the perfect gaseous or liquid distension media continues, as both methods offer advantages and disadvantages (Litta 2003; Nagele 1996; Paschopoulos 2004; Raimondo 2010). This review aims to summarise the evidence for all distension media in current use.

Objectives

The objective of this review is to compare the effectiveness, tolerability, and safety of gas (carbon dioxide) and liquid (normal saline) used for uterine distension during outpatient hysteroscopy.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) comparing any uterine distension medium versus another in outpatient hysteroscopy were eligible. We excluded non‐randomised and quasi‐randomised trials.

Types of participants

Women undergoing outpatient hysteroscopy for all indications were eligible for inclusion.

Types of interventions

Outpatient hysteroscopy using gas or liquid for uterine distension was eligible.

Types of outcome measures

We considered studies for inclusion in this review if they were appropriately designed to evaluate outcome measures relevant to patient and operator satisfaction when outpatient hysteroscopy using carbon dioxide or normal saline as a distension medium is performed.

Primary outcomes

1. Tolerability of the procedure, assessed as

   1. pain experienced by women during the procedure, excluding pain during introduction of the hysteroscope, based on pain scores

   2. proportion of procedures abandoned or terminated owing to patient pain or discomfort

   3. the need for analgesia

2. Operative and postoperative adverse events and complications, including shoulder‐tip pain, vagal symptoms (nausea, vomiting, dizziness, and fainting attack), bleeding from the endometrium, and infection

Secondary outcomes

1. Quality of the hysteroscopic view, assessed as

   1. operator's description of the clarity of the view on a specified scale

   2. proportion of procedures with an unsatisfactory hysteroscopic view

2. Length of time to complete the procedure

3. Cost implications

Search methods for identification of studies

We searched for all published and unpublished RCTs studying distension media in outpatient hysteroscopy in consultation with the Cochrane Gynaecology and Fertility Group (CGF) Information Specialist on 28 April 2021.

Electronic searches

We searched the following electronic databases for relevant trials:

1. Cochrane Gynaecology and Fertility Group (CGF) Specialised Register of Controlled Trials, ProCite platform (searched 28 April 2021) (Appendix 1);

2. CENTRAL via the Cochrane Register of Studies Online (CRSO), Web platform (searched 28 April 2021) (Appendix 2);

3. MEDLINE, Ovid platform (searched from 1946 to 28 April 2021) (Appendix 3);

4. Embase, Ovid platform (searched from 1980 to 28 April 2021) (Appendix 4);

5. Cumulative Index to Nursing and Allied Health Literature (CINAHL), Ebsco platform (searched from 1961 to 7 January 2020) (Appendix 5).CINAHL references from the April 2021 search were included in the CENTRAL search output.

Other electronic sources were searched on the following Web platforms (28 April 2021), these include:

1. Epistemonikos (www.epistemonikos.org) and Google Scholar (scholar.google.com) (Appendix 6);

2. Database of Abstracts of Reviews of Effects (DARE), in the Cochrane Library, for reference lists from relevant non‐Cochrane reviews (onlinelibrary.wiley.com/o/cochrane/cochrane_cldare_articles_fs.html) (Appendix 7);

3. Latin American and Caribbean Health Science Information database (LILACS), found in the Virtual Health Library Regional Portal (VHL) (pesquisa.bvsalud.org/portal/) (Appendix 8);

4. OpenGrey for unpublished literature from Europe (www.open-grey.eu/) (Appendix 9);

5. Web of Science (another source of trials and conference abstracts (wokinfo.com)) (Appendix 10);

Searching other resources

We handsearched the reference lists of relevant trials and systematic reviews retrieved by the search and contacted experts in the field to obtain additional trials. We also handsearched relevant journals and conference abstracts that are not covered in the CGF Specialised Register, in liaison with the Information Specialist. Ongoing trials from trial registries (clinicaltrials.gov and the World Health Organization International Trials Registry Platform search portal) were included in the CENTRAL search.

Data collection and analysis

Selection of studies

Titles and abstracts of search results were initially screened independently by two review authors (KSA and MB), after which we retrieved the full texts of potentially eligible studies. Two review authors (KSA and MAG) independently examined all full‐text articles and selected studies meeting the Review eligibility criteria for inclusion. When papers contained insufficient information to permit a decision about eligibility, we attempted to contact study investigators to seek further details. We resolved disagreements by discussion with a third review author (BWJM). We documented the selection process by using a PRISMA flow chart.

Data extraction and management

Two review authors (KSA and MAG) independently extracted data from eligible studies using a data extraction form. We resolved disagreements by discussion. Extracted data included study characteristics and outcome data (see Characteristics of included studies tables). We collated multiple reports of the same trial under a single study ID with multiple references. We attempted to contact study investigators for further information on methods and/or results, if required. We included studies irrespective of whether outcomes were reported in a usable way. In multi‐arm studies, we excluded data from arms that did not meet eligibility criteria.

Assessment of risk of bias in included studies

Two review authors (KSA and MAG) independently assessed the included studies for risk of bias using the Cochrane 'Risk of bias' assessment tool (Higgins 2011). We assessed the following domains: selection bias (random sequence generation and allocation concealment); performance bias (blinding of participants and personnel); detection bias (blinding of outcome assessors); attrition bias (incomplete outcome data); reporting bias (selective reporting); and other bias. We assigned judgements as recommended in the Cochrane Handbook for Systematic Reviews of Interventions, Section 8.5 (Higgins 2011). We resolved disagreements by discussion. We described all judgements in detail and presented our conclusions in the 'Risk of bias' table in the Characteristics of included studies section. We incorporated these conclusions into our interpretation of review findings by means of sensitivity analyses (see Sensitivity analysis).

Measures of treatment effect

For dichotomous data, we used the numbers of events in both groups of each study to calculate Peto odds ratios (Peto ORs). For continuous outcomes, we calculated mean differences (MDs) between treatment groups when outcomes were reported with the same scale. We calculated standardised mean differences (SMDs) when outcomes were reported on different scales. We reversed the direction of effect of individual studies, when required, to ensure consistency across trials. We treated ordinal data as continuous data. We presented all outcomes with 95% confidence intervals (CIs). When data to calculate ORs and SMDs were not available, we utilised the most numerical data available (e.g. test statistics, P values). We assessed whether estimates calculated in the review for individual studies were compatible in each case with estimates reported in the study publications.

Unit of analysis issues

The primary analysis was per woman randomised. Data that did not allow valid analysis were briefly summarised in an additional table and were not meta‐analysed.

Dealing with missing data

We analysed data on an intention‐to‐treat basis as far as possible (i.e. including all randomised participants in analysis, in the groups to which they were randomised). Attempts were made to obtain missing data from the original trialists. We did not undertake imputation, and we analysed only available data.

Assessment of heterogeneity

We considered whether the clinical and methodological characteristics of included studies were sufficiently similar for meta‐analysis to provide a clinically meaningful summary. We assessed statistical heterogeneity using I². We considered I² greater than 50% to indicate substantial heterogeneity (Higgins 2011).

Assessment of reporting biases

In view of the difficulty of detecting and correcting for publication bias and other reporting biases, we aimed to minimise their potential impact by ensuring a comprehensive search for eligible studies and by being alert for duplication of data. We planned to use a funnel plot to explore the possibility of small‐study effects (i.e. tendency for estimates of the intervention effect to be more beneficial in smaller studies) if 10 or more studies were included in the same analysis.

Data synthesis

If studies were sufficiently similar, we combined the data using a fixed‐effect model in the following comparisons.

1. Saline versus carbon dioxide.

2. Warm saline versus room temperature saline.

We performed statistical analysis using Review Manager 5.3 (RevMan 2014).

Subgroup analysis and investigation of heterogeneity

We included no preplanned subgroup analyses in this review.

If we noted substantial heterogeneity (I² > 50%), we planned to explore differences between studies that might account for the heterogeneity. We took any statistical heterogeneity into account when interpreting the results, especially if we noted any variation in the direction of effect.

Sensitivity analysis

We conducted sensitivity analyses for the primary outcomes to determine whether conclusions were robust to arbitrary decisions made regarding eligibility and analysis. These analyses included consideration of whether review conclusions would have differed if:

1. eligibility had been restricted to studies at low risk of bias, defined as studies at low risk of selection bias;

2. a random‐effects model had been adopted; or

3. risk ratio had been used as the summary effects measure.

Summary of findings and assessment of the certainty of the evidence

We prepared a 'Summary of findings' table using GRADEpro and Cochrane methods (GRADEpro GDT 2015; Higgins 2011). This table evaluated the overall quality of the body of evidence for the main comparison (saline versus carbon dioxide) while addressing the review outcomes: patient tolerability (pain during the procedure, procedures abandoned due to intense pain, need for analgesia), adverse events and complications (vasovagal reaction, shoulder‐tip pain, endometrial bleeding, infection), quality of the hysteroscopic view (clarity of the view on a scale, procedures with an unsatisfactory view), and duration of the procedure. An additional 'Summary of findings' table was prepared for the main review outcomes for the other comparison (warm saline versus room temperature saline). We assessed the quality of evidence using GRADE criteria: risk of bias, consistency of effect, imprecision, indirectness, and publication bias. Two review authors working independently (KSA and MAG) made judgements about evidence quality (high, moderate, low, or very low), with disagreements resolved by discussion. We justified, documented, and incorporated judgements into reporting of results for each outcome. We extracted study data, formatted our comparisons in data tables, and prepared 'Summary of findings' tables before writing the results and conclusions of our review.

Results

Description of studies

Results of the search

The search yielded 730 records, in addition to two records identified through other sources. Twenty‐four studies were potentially eligible and were retrieved in full text (Figure 1); 12 of these met our inclusion criteria (Characteristics of included studies). We excluded eight studies (Characteristics of excluded studies), and four are awaiting classification (Characteristics of studies awaiting classification).

1.

Study flow diagram.

Included studies

Study design and setting

We included 12 trials in this systematic review. All studies were parallel‐designed randomised controlled trials (RCTs). Of theses 12 trials, one was a conference abstract (Garbin 2000), and the other 11 were published as full articles (Almeida 2008; Diniz 2009; Evangelista 2011; Isaat 2017; Mazzon 2014; Paschopoulos 2004; Pellicano 2003; Pluchino 2010; Raimondo 2010; Shankar 2004; Tawfek 2019).

Three were multi‐centre trials (Pellicano 2003; Pluchino 2010; Raimondo 2010), and nine trials were conducted in single centres (Almeida 2008; Diniz 2009; Evangelista 2011; Garbin 2000; Isaat 2017; Mazzon 2014; Paschopoulos 2004; Shankar 2004; Tawfek 2019). Four trials were conducted in Italy (Mazzon 2014; Pellicano 2003; Pluchino 2010; Raimondo 2010), three in Brazil (Almeida 2008; Diniz 2009; Evangelista 2011), one in Egypt (Tawfek 2019), one in France (Garbin 2000), one in Greece (Paschopoulos 2004), one in Poland (Isaat 2017), and one in United Kingdom (Shankar 2004).

Participants

The studies included 1946 women who had undergone outpatient hysteroscopy. Mean patient age ranged across studies from 33 to 58 years.

Interventions

Nine studies compared saline versus carbon dioxide as distension media for outpatient hysteroscopy (Almeida 2008; Diniz 2009; Garbin 2000; Mazzon 2014; Paschopoulos 2004; Pellicano 2003; Pluchino 2010; Raimondo 2010; Shankar 2004). Three studies compared warm versus room temperature saline (Evangelista 2011; Isaat 2017; Tawfek 2019).

The vaginoscopic approach for introducing the hysteroscope was used for both arms in eight trials (Evangelista 2011; Isaat 2017; Mazzon 2014; Paschopoulos 2004; Pellicano 2003; Pluchino 2010; Raimondo 2010; Tawfek 2019), the traditional approach for both arms was used in two studies (Garbin 2000; Shankar 2004), and two studies used the vaginoscopic approach for the saline group and the traditional approach for the carbon dioxide group (Almeida 2008; Diniz 2009). Hysteroscopies with different outer sheath diameters ranging from 2.8 to 5.1 mm were used across studies.

Saline at different temperatures was used in studies comparing warm saline with room temperature saline: 37.5°C in two studies (Evangelista 2011; Tawfek 2019), and 36°C in one study (Isaat 2017). One of the trials comparing saline with carbon dioxideused warm saline at 36°C (Almeida 2008).

Outcomes

All 12 studies included in the analysis reported pain during the procedure. A standardised 10‐cm visual analogue scale (VAS), with 0 indicating no pain and 10 indicating worst pain, was used to measure pain in 11 studies (Almeida 2008; Diniz 2009; Evangelista 2011; Garbin 2000; Isaat 2017; Mazzon 2014; Pellicano 2003; Pluchino 2010; Raimondo 2010; Shankar 2004; Tawfek 2019). One study used ranking from 0 to 3 to measure pain experienced during the procedure, with 0 indicating no pain and 3 indicating severe pain not allowing completion of the procedure (Paschopoulos 2004). One study measured pain using another scale (present pain intensity (PPI) scale from 0 to 5), with 0 indicating no pain and 5 indicating excruciating pain, as well as a VAS (Shankar 2004).

Two studies reported procedures abandoned due to intense pain (Pellicano 2003; Tawfek 2019). Two studies reported the need for analgesia (Isaat 2017; Pellicano 2003).

Seven studies reported adverse events and complications (Almeida 2008; Isaat 2017; Paschopoulos 2004; Pellicano 2003; Pluchino 2010; Raimondo 2010; Shankar 2004). Studies did not report the total adverse events per woman randomised. As more than one of these adverse events could have occurred in one woman, we analysed each adverse event individually. These seven studies reported vasovagal reactions; four of them also reported shoulder‐tip pain (Almeida 2008; Paschopoulos 2004; Pluchino 2010; Shankar 2004), two reported bleeding from the endometrium (Almeida 2008; Pluchino 2010), and one reported infection (Isaat 2017).

Quality of the hysteroscopic view was reported in seven trials (Almeida 2008; Diniz 2009; Garbin 2000; Mazzon 2014; Pellicano 2003; Raimondo 2010; Shankar 2004). Two trials reported the quality of the hysteroscopic view on a scale; one trial used a 4‐point scale (0 to 4) to rank the hysteroscopic view, with 0 indicating worst view and 4 indicating best view (Garbin 2000); the other trial used a 10‐cm standardised VAS to measure the quality of the hysteroscopic view, with 0 indicating worst view and 10 indicating best view (Raimondo 2010). The other five trials reported the proportions of procedures with an unsatisfactory view (Almeida 2008; Diniz 2009; Mazzon 2014; Pellicano 2003; Shankar 2004). Seven studies reported the duration of the procedure: four in minutes (Almeida 2008; Evangelista 2011; Pellicano 2003; Tawfek 2019), and three in seconds (Isaat 2017; Mazzon 2014; Raimondo 2010).

Excluded studies

We excluded eight studies from the review for the following reasons (Characteristics of excluded studies).

1. 4 of 8 were quasi‐randomised trials (Brusco 2003; Kapur 2020; Litta 2003; Nagele 1996).

2. 3 of 8 did not assess the intervention of interest (Campo 2005; Nagele 1996; Salazar 2019).

3. 1 of 8 had protocol breaks and was not published (Santos 2012).

Risk of bias in included studies

Assessment of risk of bias of included studies can be found in the Characteristics of included studies tables, as well as in Figure 2 and Figure 3.

2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

We rated nine trials at low risk of bias related to sequence generation. Seven studies used computer randomisation (Almeida 2008; Evangelista 2011; Isaat 2017; Mazzon 2014; Pellicano 2003; Pluchino 2010; Raimondo 2010), one used a random number table (Shankar 2004), and one randomised by choosing from two identical sealed envelopes containing either of the interventions (Paschopoulos 2004). On the other hand, three trials did not describe the method used and were considered to have unclear risk of this bias (Diniz 2009; Garbin 2000; Tawfek 2019).

We assessed seven studies as having low risk of bias related to allocation concealment, as they used sealed opaque envelopes (Almeida 2008; Evangelista 2011; Isaat 2017; Mazzon 2014; Paschopoulos 2004; Raimondo 2010; Shankar 2004). The other five studies did not mention how allocation concealment was ensured; therefore we rated them as having unclear risk of bias for this domain (Diniz 2009; Garbin 2000; Pellicano 2003; Pluchino 2010; Tawfek 2019).

Blinding

For studies comparing saline with carbon dioxide, the type of intervention could not be blinded from neither patients nor operators. As all outcomes were patient‐ or operator‐reported, unmasking could influence the findings of outcomes, so we rated all studies in this comparison as having high risk of bias for these domains (Almeida 2008; Diniz 2009; Garbin 2000; Mazzon 2014; Paschopoulos 2004; Pellicano 2003; Pluchino 2010; Raimondo 2010; Shankar 2004).

Among the three studies comparing warm saline with room temperature saline, one study was patient‐blinded (Evangelista 2011); we rated this study as having low risk of performance and detection bias, as primary outcomes were patient‐reported and operators' knowing of the intervention is hardly likely to influence the results. The two other studies did not mention blinding of patients nor operators, and we rated them as having unclear risk of bias for these domains (Isaat 2017; Tawfek 2019).

Incomplete outcome data

Eleven studies included all or most of the randomised women, and reasons for dropouts were explained and accounted for. We rated these studies as having low risk of attrition bias (Almeida 2008; Diniz 2009; Evangelista 2011; Garbin 2000; Isaat 2017; Mazzon 2014; Pellicano 2003; Pluchino 2010; Raimondo 2010; Shankar 2004; Tawfek 2019). We assessed one study as having high risk of attrition bias because 5 of 79 women were excluded after they were randomised and had received the intervention (Paschopoulos 2004); two exclusions were due to adverse events, and adverse events were unequally distributed between groups.

Selective reporting

We considered 11 studies to be at low risk of reporting bias (Almeida 2008; Evangelista 2011; Garbin 2000; Isaat 2017; Mazzon 2014; Paschopoulos 2004; Pellicano 2003; Pluchino 2010; Raimondo 2010; Shankar 2004; Tawfek 2019). We checked the registered protocols of three trials and found that all pre‐specified outcomes were reported in these publications (Isaat 2017; Mazzon 2014; Tawfek 2019). Authors of two studies were contacted and confirmed that no other outcomes of interest were assessed and not reported (Evangelista 2011; Garbin 2000). For the other six studies, protocols were not available, but the primary outcomes of this review ‐ including adverse events and complications ‐ were mentioned in the methods section and were fully reported in the results (Almeida 2008; Paschopoulos 2004; Pellicano 2003; Pluchino 2010; Raimondo 2010; Shankar 2004).

We rated one study as having unclear risk of bias in this domain, as its protocol was not available and study authors did not provide information on complications and adverse events (Diniz 2009).

Other potential sources of bias

We rated two studies as having high risk of other bias due to unusually low standard deviations of means for pain during the procedure (Pellicano 2003; Pluchino 2010).

Effects of interventions

See: Table 1; Table 2

Summary of findings 1. Saline vs carbon dioxide for uterine distension in outpatient hysteroscopy.

Saline vs carbon dioxide for uterine distension in outpatient hysteroscopy
Population: women undergoing outpatient hysteroscopy Setting: outpatient hysteroscopy clinics Intervention: saline Comparison: carbon dioxide
Outcomes		Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№. of participants (studies)	Certainty of the evidence (GRADE)	Comments
		Risk with carbon dioxide	Risk with saline
Tolerability of the procedure	Pain during the procedure assessed with different scalesa; higher values mean worse pain (on a scale from 0 to 10, 0 indicates no pain and 10 indicates worst pain)	Mean (SD) pain score during the procedure was 2.74 (2.3) cm on 10‐cm VASb	SMD 0.07 SD lower (0.17 lower to 0.02 higher)		1705 (9 RCTs)	⊕⊕⊝⊝ LOWc,d	This translates to a difference of 0.16 cm lower on 10‐cm VAS with saline (0.39 cm lower to 0.05 cm higher)b
	Procedures abandoned due to intense pain	43 per 1000	21 per 1000 (4 to 99)	Peto OR 0.48 (0.09 to 2.42)	189 (1 RCT)	⊕⊝⊝⊝ VERY LOWe,f
	Need for analgesia	120 per 1000	44 per 1000 (16 to 119)	Peto OR 0.34 (0.12 to 0.99)	189 (1 RCT)	⊕⊝⊝⊝ VERY LOWe,f
Adverse events and complications	Vasovagal reaction	100 per 1000	56 per 1000 (34 to 88)	Peto OR 0.53 (0.32 to 0.86)	1076 (6 RCTs)	⊕⊕⊕⊝ MODERATEc
	Shoulder‐tip pain	92 per 1000	28 per 1000 (14 to 52)	Peto OR 0.28 (0.14 to 0.54)	623 (4 RCTs)	⊕⊕⊕⊝ MODERATEc
	Endometrial bleeding	34 per 1000	29 per 1000 (9 to 89)	Peto OR 0.83 (0.25 to 2.75)	349 (2 RCTs)	⊕⊝⊝⊝ VERY LOWc,f
	Infection	Not reported by any study in this comparison
Quality of hysteroscopic view	Procedures with unsatisfactory view	94 per 1000	51 per 1000 (32 to 79)	Peto OR 0.51 (0.32 to 0.82)	1082 (5 RCTs)	⊕⊕⊝⊝ LOWc,d
Duration of the procedure assessed in seconds	Saline resulted in shorter procedures in 3 out of 4 studies that reported this outcome; duration was similar to carbon dioxide in the fourth study
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; OR: odds ratio; RCT: randomised controlled trial; SD: standard deviation; SMD: standardised mean difference; VAS: visual analogue scale.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

^aScales used were 10‐cm VAS from 0 to 10, with 0 indicating no pain and 10 indicating worst pain (8 studies), and a rank from 0 to 3, with 0 indicating no pain and 3 indicating severe pain necessitating stopping the procedure (1 study).

^bThis is based on the mean (SD) pain score on 10‐cm VAS in the carbon dioxide group reported in Mazzon 2014; MD was calculated by multiplying the SMD by the SD from the carbon dioxide group in this study.

^cDowngraded by one level due to serious risk of bias; unclear method of randomisation and allocation concealment in some studies, and inadequate blinding in all studies.

^dDowngraded by one level due to serious inconsistency (high heterogeneity, I² = 57% to 86%).

^eDowngraded by one level due to serious indirectness: only women with infertility were studied.

^fDowngraded by two levels due to very serious imprecision: very few events and very wide confidence interval.

Summary of findings 2. Warm saline vs room temperature saline for uterine distension in outpatient hysteroscopy.

Warm saline vs room temperature saline for uterine distension in outpatient hysteroscopy
Population: women undergoing outpatient hysteroscopy Setting: outpatient hysteroscopy clinics Intervention: warm saline Comparison: room temperature saline
Outcomes		Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№. of participants (studies)	Certainty of the evidence (GRADE)	Comments
		Risk with room temperature saline	Risk with warm saline
Tolerability of the procedure	Pain during the procedure assessed with VAS Scale from 0 to 10 (worst)	Mean pain during the procedure ranged from 3.05 to 4.31	MD 1.14 lower (1.55 lower to 0.73 lower)		241 (3 RCTs)	⊕⊕⊝⊝ LOWa,b
	Procedures abandoned due to intense pain	26 per 1000	26 per 1000 (2 to 300)	Peto OR 0.97 (0.06 to 15.87)	77 (1 RCT)	⊕⊝⊝⊝ VERY LOWa,c
	Need for analgesia	40 per 1000	40 per 1000 (6 to 234)	Peto OR 1.00 (0.14 to 7.32)	100 (1 RCT)	⊕⊝⊝⊝ VERY LOWa,c
Adverse events and complications	Vasovagal reaction	No cases occurred in both groups (1 RCT, 100 participants)
	Shoulder‐tip pain	Not reported by any study in this comparison
	Endometrial bleeding	Not reported by any study in this comparison
	Infection	No cases occurred in both groups (1 RCT, 100 participants)
Quality of hysteroscopic view		Not reported by any study in this comparison
Duration of the procedure assessed in seconds		Mean duration of the procedure ranged from 167 to 230 seconds	MD 13.17 seconds higher (12.96 lower to 39.29 higher)	‐	141 (2 RCTs)	⊕⊕⊝⊝ LOWa,d
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; OR: odds ratio; RCTs: randomised controlled trial; VAS: visual analogue scale.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

^aDowngraded by one level for unclear risk of selection, performance, and detection bias domains in some or all studies.

^bDowngraded by one level due to serious inconsistency (high heterogeneity, I² = 77%).

^cDowngraded by two levels due to very serious imprecision: one RCT with very few events and a wide confidence interval.

^dDowngraded by one level due to imprecision and wide confidence interval.

See Table 1 and Table 2.

Saline versus carbon dioxide

Primary outcomes

1. Tolerability of the procedure

(Analysis 1.1; Analysis 1.2; Analysis 1.3; Figure 4)

1.1. Analysis.

Comparison 1: Saline vs carbon dioxide, Outcome 1: Tolerability of the procedure ‐ Pain during the procedure

1.2. Analysis.

Comparison 1: Saline vs carbon dioxide, Outcome 2: Tolerability of the procedure ‐ Procedures abandoned due to intense pain

1.3. Analysis.

Comparison 1: Saline vs carbon dioxide, Outcome 3: Tolerability of the procedure ‐ Need for analgesia

4.

Forest plot of comparison: 1 Saline versus carbon dioxide, outcome: 1.1 Tolerability of the procedure ‐ Pain during the procedure.

1.1. Pain during the procedure

Analysis ruled out a clinically relevant difference between both media in pain scores, but the quality of evidence was low (standardised mean difference (SMD) ‐0.07, 95% confidence interval (CI) ‐0.17 to 0.02; 9 randomised controlled trials (RCTs), N = 1705; I² = 86%; Analysis 1.1; Figure 4). This translates to a difference of 0.39 cm (lower) and 0.05 cm (higher) on a 10‐cm visual analogue scale (VAS).

1.2. Proportion of procedures abandoned due to intense pain

Evidence was insufficient to show differences between groups in the proportion of procedures abandoned due to intense pain (Peto odds ratio (OR) 0.48, 95% CI 0.09 to 2.42; 1 RCT, N = 189; very low‐quality evidence; Analysis 1.2): 2 of 97 (2%) in the saline group and 4 of 92 (4%) in the carbon dioxide group.

1.3. The need for analgesia

We are uncertain whether saline lowers the need for analgesia when compared to carbon dioxide (Peto OR 0.34, 95% CI 0.12 to 0.99; 1 RCT, N = 189; very low‐quality evidence; Analysis 1.3): 4 of 97 (4%) in the saline group and 11 of 92 (12%) in the carbon dioxide group.

2. Adverse events and complications

(Analysis 1.4)

1.4. Analysis.

Comparison 1: Saline vs carbon dioxide, Outcome 4: Adverse events and complications

2.1. Vasovagal reaction

Saline is probably associated with fewer vasovagal reaction events than carbon dioxide when used as distension media for outpatient hysteroscopy (Peto OR 0.53, 95% CI 0.32 to 0.86; 6 RCTs, N = 1076; I² = 0%; moderate‐quality evidence). This suggests that if the chance for a vasovagal reaction with carbon dioxide is 10%, the chance with saline would be between 3% and 9%.

2.2. Shoulder‐tip pain

Saline probably causes fewer shoulder‐tip pain events than carbon dioxide when used as distension media for outpatient hysteroscopy (Peto OR 0.28, 95% CI 0.14 to 0.54; 4 RCTs, N = 623; I² = 0%; moderate‐quality evidence). This suggests that if the chance for occurrence of shoulder‐tip pain with carbon dioxide is 9%, the chance with saline would be between 1% and 5%.

2.3. Endometrial bleeding

We are uncertain whether saline is similar to carbon dioxide in terms of endometrial bleeding events (Peto OR 0.83, 95% CI 0.25 to 2.75; 2 RCTs, N = 384; I² = 0%): 5 of 174 events (3%) with saline and 6 of 175 events (3%) with carbon dioxide among participants.

2.4. Infection

This outcome was not reported by any study in this comparison.

Secondary outcomes

3. Quality of the hysteroscopic view

(Analysis 1.5; Analysis 1.6; Analysis 1.7)

1.5. Analysis.

Comparison 1: Saline vs carbon dioxide, Outcome 5: Quality of hysteroscopic view ‐ Clarity of the view on a scale

1.6. Analysis.

Comparison 1: Saline vs carbon dioxide, Outcome 6: Quality of hysteroscopic view ‐ Procedures with unsatisfactory view

1.7. Analysis.

Comparison 1: Saline vs carbon dioxide, Outcome 7: Duration of the procedure

3.1. Clarity of the hysteroscopic view on a scale

Two RCTs measured this outcome, but each used a different scale (Results; Included studies). The two studies reported different directions of the treatment effect; Garbin 2000 reported better clarity of the view with use of saline (3 ± 1.07) than with carbon dioxide (2.47 ± 1.24) on a 5‐point scale (P = 0.003); Raimondo 2010 reported that carbon dioxide (8.9 ± 1.85) was better than saline (7 ± 0.7) on a 10‐cm VAS (P < 0.001). Consequently, we did not pool the data in this analysis.

3.2. Proportion of procedures with an unsatisfactory view

Saline may be associated with fewer procedures with an unsatisfactory hysteroscopic view than carbon dioxide (Peto OR 0.51, 95% CI 0.32 to 0.82; 5 RCTs, N = 1082; I² = 67%; low‐quality evidence; Analysis 1.6). This suggests that if the chance of an unsatisfactory hysteroscopic view with carbon dioxide is 9%, this chance would be between 3% and 8% with saline.

4. Duration of the procedure

(Analysis 1.7)

Four studies reported duration of the procedure in this comparison; two studies reported the duration in minutes (Almeida 2008; Pellicano 2003), and two other studies reported the duration in seconds (Mazzon 2014; Raimondo 2010). Due to marked heterogeneity in reported results (I² = 95%), we did not pool the results in this analysis. The procedure was shorter with saline in three studies: Almeida 2008 (MD ‐55.80 seconds, 95% CI ‐99.15 to ‐12.45; N = 64), Mazzon 2014 (MD ‐26.50 seconds, 95% CI ‐33.17 to ‐19.83; N = 392), and Pellicano 2003 (MD ‐120.00 seconds, 95% CI ‐178.28 to ‐61.72; N = 189], and the duration was similar in both arms in the fourth study (Raimondo 2010) (MD ‐3.00 seconds, 95% CI ‐6.15 to 0.15; N = 264).

5. Cost implications

None of the studies in this comparison reported any cost implications.

Subgroup and sensitivity analyses for comparison 1 (saline versus carbon dioxide)

No pre‐specified subgroup analyses were conducted for this comparison.

Sensitivity analyses

When analysis of primary outcomes was restricted to studies with low risk of selection bias, the rate of vasovagal reaction for both interventions (Analysis 1.4), but other primary outcomes did not substantially change (Analysis 1.1; Analysis 1.2; Analysis 1.3). Therefore, our conclusions for this comparison have not changed.

When the random‐effects model was used for Analysis 1.1, the results did not substantially change. We could not use the random‐effects model for analyses of other primary outcomes because these analyses were done by the Peto method.

Use of the Mantel–Haenszel method to calculate risk ratios for dichotomous primary outcomes showed results similar to those obtained by the Peto method for primary analyses (Analysis 1.2; Analysis 1.3; Analysis 1.4).

Warm saline versus room temperature saline

Primary outcomes

1. Tolerability of the procedure

1.1. Pain during the procedure

(Analysis 2.1; Analysis 2.2)

2.1. Analysis.

Comparison 2: Warm saline vs room temperature saline, Outcome 1: Tolerability of the procedure ‐ Pain during the procedure

2.2. Analysis.

Comparison 2: Warm saline vs room temperature saline, Outcome 2: Tolerability of the procedure ‐ Procedures abandoned due to intense pain

Use of warm saline for uterine distension during office hysteroscopy may reduce pain scores when compared with room temperature saline (MD ‐1.14, 95% CI ‐1.57 to ‐0.73; 3 RCTs, N = 241; I² = 77%; low‐quality evidence; Analysis 2.1). However, this result should be interpreted with caution because the sensitivity analysis restricted to studies with low risk of selection bias failed to show a difference between groups.

1.2. Proportion of procedures abandoned due to intense pain

Evidence was insufficient to show a difference between groups in the proportion of procedures abandoned due to intense pain (Peto OR 0.97, 95% CI 0.06 to 15.87; 1 RCT, N = 77; very low‐quality evidence; Analysis 2.2): 1 of 39 (3%) in the warm saline group and 1 of 38 (3%) in the room temperature saline group.

1.3. The need for analgesia

Evidence was insufficient to show a difference between groups in the need for analgesia (Peto OR 1.00, 95% CI 0.14 to 7.32; 1 RCT, N = 100; very low‐quality evidence): 2 of 50 (4%) in the warm saline group and 2 of 50 (4%) in the room temperature saline group.

2. Adverse events and complications

2.1. Vasovagal reaction

Only one study reported this outcome (Isaat 2017). No cases of vasovagal reaction were observed in either group; therefore data were not pooled in this analysis.

2.2. Shoulder‐tip pain

This outcome was not reported by any study for this comparison.

2.3. Endometrial bleeding

This outcome was not reported by any study for this comparison.

2.4. Infection

Only one study reported this outcome (Isaat 2017). No cases of infection were observed in either group; therefore data were not pooled in this analysis.

Secondary outcomes

3. Quality of the hysteroscopic view

3.1. Clarity of the hysteroscopic view on a scale

This outcome was not reported by any study for this comparison.

3.2. Proportion of procedures with an unsatisfactory view

This outcome was not reported by any study for this comparison.

4. Duration of the procedure

(Analysis 2.4)

2.4. Analysis.

Comparison 2: Warm saline vs room temperature saline, Outcome 4: Duration of the procedure

Analysis ruled out a clinically relevant difference in procedural duration between warm and room temperature saline, but the quality of evidence was low (MD 13.17 seconds, 95% CI ‐12.96 to 39.29; 2 RCTs, N = 141; I² = 21%; Analysis 2.4).

5. Cost implications

None of the studies for this comparison reported any cost implications.

Subgroup and sensitivity analyses for comparison 2 (warm saline versus room temperature saline)

No pre‐specified subgroup analyses were conducted for this comparison.

Sensitivity analyses

When the analysis of primary outcomes was restricted to studies with low risk of selection bias, pain during the procedure differed substantially and became similar in both interventions (Analysis 2.1). This sensitivity analysis could not be performed for other primary outcomes because the analyses included only one study (Analysis 2.2; Analysis 2.3).

2.3. Analysis.

Comparison 2: Warm saline vs room temperature saline, Outcome 3: Tolerability of the procedure ‐ Need for analgesia

When the random‐effects model was used for Analysis 2.1, the results did not change substantially. We could not use the random‐effects model for analyses of other primary outcomes because these analyses were done by the Peto method (Analysis 2.2; Analysis 2.3).

Use of the Mantel–Haenszel method to calculate risk ratios for dichotomous primary outcomes showed results similar to those obtained by the Peto method for primary analyses (Analysis 2.2; Analysis 2.3).

Assessment of heterogeneity

Heterogeneity was high in analyses for some outcomes (Analysis 1.1, I²= 86%; Analysis 1.6, I² = 67%; Analysis 1.7, I² = 95%; Analysis 2.1, I² = 77%). Pain during the procedure is a subjective outcome that is greatly influenced by many clinical variables (clinical heterogeneity) that varied across studies (e.g. age and parity of participants, operator experience, size of the hysteroscope, hysteroscopic approach, additional interventional techniques along with endometrial biopsy) (Analysis 1.1; Analysis 2.1), and data were insufficient for subgroup analyses to be performed.

No explanation for the high heterogeneity was discovered in analyses of the quality of the hysteroscopic view (Analysis 1.6). The high heterogeneity in analysis of duration of the procedure may be related to the difference in operator experience (clinical heterogeneity) (Analysis 1.7), but because of marked heterogeneity and non‐overlap of confidence intervals, we did not perform the meta‐analysis.

Assessment of publication bias

We did not construct a funnel plot for any analysis because all analyses included fewer than 10 studies.

Discussion

Summary of main results

Saline versus carbon dioxide for uterine distension in women undergoing outpatient hysteroscopy

We are uncertain whether saline and carbon dioxide are similarly tolerable among patients undergoing outpatient hysteroscopy because the quality of evidence is very low to low. However, carbon dioxide probably causes more adverse events (vasovagal reaction and shoulder‐tip pain) than saline (moderate‐quality evidence).

Saline may provide a better hysteroscopic view than carbon dioxide (low‐quality evidence). Evidence on duration of the procedure is insufficient. No studies have reported any cost implications.

Warm saline versus room temperature saline for uterine distension in women undergoing outpatient hysteroscopy

Pain scores during the procedure using warm saline might be lower than those when room temperature saline is used (low‐quality evidence). However, studies with low risk of selection bias failed to show a difference in pain scores between the two interventions. Therefore, extreme caution should be taken when results for this outcome are interpreted. We are uncertain of the effects of warm saline on the proportion of procedures abandoned due to intense pain and on the need for analgesia because the quality of evidence is very low. Infection, the only adverse event reported for this comparison, did not occur with either medium.

Procedural duration may be similar with warm and room temperature saline (low‐quality evidence). No studies for this comparison reported on quality of the hysteroscopic view nor on cost implications.

Overall completeness and applicability of evidence

Outpatient hysteroscopy is a widely used tool that allows diagnosis and a few therapeutic interventions. It provides the benefit of visualisation of intrauterine lesions. Moreover, it is done in an outpatient setting without general anaesthesia. As a result, the patient is aware of what is happening, and this makes it more difficult for both the patient and the operator to perform than other procedures done under general anaesthesia. Searching for the best uterine distension medium that is most tolerable, has the fewest side effects, and at the same time gives the best hysteroscopic view is challenging.

Randomised controlled trials (RCTs) investigating the uterine distension media identified in this review are few. Most of these trials have investigated saline versus carbon dioxide. Studies included participants with different characteristics (nullipara and multipara, reproductive age and menopausal women) undergoing hysteroscopy for any indication (infertility or abnormal uterine bleeding (AUB)) without analgesia or anaesthesia in an outpatient setting. This variation gives results the advantage of generalisability, along with clinical heterogeneity, as most outcomes are dependent on these factors. Hysteroscopes used across studies varied in the diameter of their outer sheaths. These differences, as well as variation in operator experience, can affect patient tolerability (Pluchino 2010). The approach of the introduction of the hysteroscope into the vagina and the cervix also varied across studies. Some studies used different approaches in different study groups. In other studies, patients underwent surgical procedures or endometrial biopsies in the same setting when necessary. All these clinical differences might have given rise to different treatment effects and could have accounted for the high statistical heterogeneity noted in subjective outcomes. None of the studies reported cost implications of both media, which might be important in considering the best medium, especially if other outcomes show similar results.

Quality of the evidence

We used the GRADE approach to assess the overall evidence in this review, which ranged from very low to moderate quality (see Figure 2; Table 1; Table 2). We downgraded the quality of evidence mainly due to risk of bias, imprecision, and inconsistency.

The major limitation of this review is the small number of identified studies, preventing us from giving robust conclusions. Another limitation is the high risk of performance and selection biases because the main outcomes are subjective and are patient‐ or operator‐reported, and blinding to the allocated intervention was not possible, especially when the media studied were gas versus liquid. Therefore, this might have influenced the results of individual studies.

Potential biases in the review process

We ran a thorough search of databases using comprehensive strategies with the help of the Information Specialist in the CGF Group, to ensure inclusion of all eligible studies. We handsearched references of included studies as well as similar systematic reviews on the same intervention. We could not construct funnel plots to detect publication bias because each comparison included fewer than 10 studies.

We tried to contact all authors of included and excluded studies, as well as authors of trial registrations, to confirm eligibility, but most authors did not respond to our emails.

Agreements and disagreements with other studies or reviews

We identified two previous systematic reviews that compared only saline to carbon dioxide (Cooper 2011; Craciunas 2013). We intended to include any RCT comparing any two or more distension media, to make the review more comprehensive and to draw conclusions on the best distension medium in outpatient hysteroscopy.

This review found insufficient evidence that saline might be associated with the same pain scores as carbon dioxide, in keeping with the results of Cooper 2011, but not with the findings of Craciunas 2013, which concluded that pain scores were lower with the use of saline. Both reviews, however, included quasi‐randomised trials that were excluded from this review to prevent selection bias. Nevertheless, the results of this review are consistent with those of both reviews that saline is associated with fewer side effects (shoulder‐tip pain and vasovagal reaction).

Authors' conclusions

Implications for practice.

Evidence is insufficient to conclude that there are differences between different distension media used for uterine distension in outpatient hysteroscopy in terms of patient tolerability, operator satisfaction, and duration of the procedure. However, saline was superior to carbon dioxide in producing fewer adverse events (shoulder‐tip pain and vasovagal reaction).

Implications for research.

More high‐quality well‐designed RCTs comparing gaseous and liquid distension media or liquid media at different temperatures are needed. These studies should standardise ‐ or include in a powered subgroup analysis ‐ the patient's menopausal state (reproductive age versus post menopause), parity (nullipara versus multipara), indication of hysteroscopy, size of the hysteroscope, hysteroscopic approach, and operator experience, with avoidance of any surgical manoeuvres in the same setting. Also, future studies should consider performing cost‐effectiveness analyses in comparing different media.

What's new

Date	Event	Description
1 December 2021	Amended	Correcting textual errors

History

Protocol first published: Issue 3, 2007
Review first published: Issue 11, 2021

Date	Event	Description
21 August 2009	Amended	Authorship changed
10 November 2008	Amended	Converted to new review format

Appendices

Appendix 1. Cochrane Gynaecology and Fertility Group specialised register search strategy

Searched 28 April 2021

ProCite platform

Keywords CONTAINS "hysteroscopic "or "hysteroscopy" or "hysteroscopy pain" or "hysteroscopy, techniques" or "hysterosonography" or "hysterscope" or "endoscopy"
AND
Keywords CONTAINS "uterine distension" or "distension" or "distention fluid volume" or "distention medium" or"CO2" or" carbon dioxide" or "carbon dioxide distention" or "gas" or "gasless "or "saline" or "saline contrast "or "saline contrast hysterosonography" or "saline infusion sonography" or "saline salpingosonography" or Title CONTAINS "uterine distension" or "distension" or "distention fluid volume" or "distention medium" or"CO2" or "carbon dioxide" or "carbon dioxide distention" or "gas" or "gasless "or "saline" or "saline contrast "or "saline contrast hysterosonography" or "saline infusion sonography" or "saline salpingosonography"
(131 records)

Appendix 2. CENTRAL via the Cochrane Register of Studies Online (CRSO) search strategy

Searched 28 April 2021

Web platform

#1 MESH DESCRIPTOR Hysteroscopy EXPLODE ALL TREES 398

#2 Hysteroscop*:TI,AB,KY 1572

#3 #1 OR #2 1572

#4 ((distension adj5 medi*)):TI,AB,KY 81

#5 ((uter* adj5 disten*)):TI,AB,KY 36

#6 ((gas adj5 medi*)):TI,AB,KY 140

#7 ((liquid adj5 medi*)):TI,AB,KY 347

#8 MESH DESCRIPTOR Carbon Dioxide EXPLODE ALL TREES 2792

#9 (Carbon Dioxide):TI,AB,KY 7914

#10 CO2:TI,AB,KY 4373

#11 MESH DESCRIPTOR Sodium Chloride EXPLODE ALL TREES 2493

#12 (Sodium Chloride):TI,AB,KY 8204

#13 saline:TI,AB,KY 34174

#14 #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 47767

#15 #3 AND #14 239

Appendix 3. MEDLINE search strategy

Searched from 1946 to 28 April 2021

Ovid platform

1 Hysteroscopy/ (4960)
2 uterine endoscop$.tw. (5)
3 (uteroscop$ or hysteroscop$).tw. (7227)
4 uterus/ and endoscopy/ (356)
5 or/1‐4 (8362)
6 (distension adj5 medi$).tw. (317)
7 (uter$ adj5 disten$).tw. (458)
8 (gas adj5 medi$).tw. (2960)
9 (liquid adj5 medi$).tw. (13442)
10 Carbon Dioxide/ (89324)
11 Carbon Dioxide.ti,ab,sh. (117819)
12 CO2.tw. (99098)
13 Sodium Chloride/ (59024)
14 Sodium Chloride.ti,ab,sh. (71130)
15 saline.tw. (181789)
16 or/6‐15 (429794)
17 5 and 16 (763)
18 randomized controlled trial.pt. (527900)
19 controlled clinical trial.pt. (94130)
20 randomized.ab. (517559)
21 placebo.tw. (223231)
22 clinical trials as topic.sh. (195611)
23 randomly.ab. (355970)
24 trial.ti. (238733)
25 (crossover or cross‐over or cross over).tw. (88784)
26 or/18‐25 (1394239)
27 exp animals/ not humans.sh. (4817213)
28 26 not 27 (1282327)
29 17 and 28 (134)

Appendix 4. Embase search strategy

Searched from 1980 to 28 April 2021

Ovid platform

1 Hysteroscopy/ (12593)
2 Hysteroscop$.tw. (12280)
3 uterine endoscop$.tw. (5)
4 uteroscop$.tw. (26)
5 uterus/ and endoscopy/ (866)
6 or/1‐5 (15868)
7 (distension adj5 medi$).tw. (497)
8 (uter$ adj5 disten$).tw. (593)
9 (gas adj5 medi$).tw. (3499)
10 (liquid adj5 medi$).tw. (14681)
11 Carbon Dioxide/ (98426)
12 Carbon Dioxide.ti,ab,sh. (120404)
13 CO2.tw. (126422)
14 Sodium Chloride/ (189808)
15 Sodium Chloride.ti,ab,sh. (197537)
16 saline.tw. (241739)
17 or/7‐16 (531536)
18 6 and 17 (1310)
19 Clinical Trial/ (1008632)
20 Randomized Controlled Trial/ (660188)
21 exp randomization/ (91668)
22 Single Blind Procedure/ (42807)
23 Double Blind Procedure/ (183060)
24 Crossover Procedure/ (67276)
25 Placebo/ (356331)
26 Randomi?ed controlled trial$.tw. (258625)
27 Rct.tw. (41879)
28 random allocation.tw. (2199)
29 randomly allocated.tw. (38657)
30 allocated randomly.tw. (2674)
31 (allocated adj2 random).tw. (846)
32 Single blind$.tw. (26794)
33 Double blind$.tw. (215105)
34 ((treble or triple) adj blind$).tw. (1332)
35 placebo$.tw. (322679)
36 prospective study/ (684352)
37 or/19‐36 (2367519)
38 case study/ (78652)
39 case report.tw. (439738)
40 abstract report/ or letter/ (1174799)
41 or/38‐40 (1681332)
42 37 not 41 (2308726)
43 18 and 42 (327)

Appendix 5. CINAHL search strategy

Searched from 1961 to 7 January 2020 (Output from the 28 April 2021 search was included in the CENTRAL search results)

Ebsco platform

#	Query	Result
S29	S16 AND S28	52
S28	S17 OR S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25 OR S26 OR S27	1,372,202
S27	TX allocat* random*	11,307
S26	(MH "Quantitative Studies")	24,111
S25	(MH "Placebos")	11,559
S24	TX placebo*	60,519
S23	TX random* allocat*	11,307
S22	(MH "Random Assignment")	56,782
S21	TX randomi* control* trial*	180,883
S20	TX ( (singl* n1 blind*) or (singl* n1 mask*) ) or TX ( (doubl* n1 blind*) or (doubl* n1 mask*) ) or TX ( (tripl* n1 blind*) or (tripl* n1 mask*) ) or TX ( (trebl* n1 blind*) or (trebl* n1 mask*) )	1,044,575
S19	TX clinic* n1 trial*	256,154
S18	PT Clinical trial	86,321
S17	(MH "Clinical Trials+")	271,763
S16	S4 AND S15	157
S15	S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14	59,176
S14	TX saline	17,939
S13	TX Sodium Chloride	7,246
S12	(MM "Sodium Chloride")	1,360
S11	TX CO2	3,651
S10	TX Carbon Dioxide	9,488
S9	(MM "Carbon Dioxide")	2,484
S8	TX liquid N5 medi*	638
S7	TX gas	26,419
S6	TX (uter* N5 disten*)	53
S5	TX(distension N5 medi*)	54
S4	S1 OR S2 OR S3	2,289
S3	TX uteroscop* or hysteroscop*	2,277
S2	TX uter* N2 endoscop*	17
S1	(MM "Hysteroscopy")	969

Appendix 6. Epistemonikos and Google Scholar search strategies

Web platform

Searched 28 April 2021 using the following words:

"hysteroscopy" "media" "saline" "carbon dioxide"

No additional studies were identified.

Appendix 7. Database of Abstracts of Reviews of Effects (DARE) search strategy

Web platform

Searched 28 April 2021

1 Hysteroscop*

2 distension medi*

3 (1) AND (2): 5 results

Appendix 8. LILACS search strategy

Virtual Health Library Regional Portal (VHL) Web platform

Searched 28 April 2021

hysteroscop* OR histeroscop* AND distension OR distensión AND (instance:"regional") AND ( db:("LILACS"))

335 hits

Filter: "Hysteroscopy": 187 hits

Appendix 9. OpenGrey search strategy

Web platform

Searched 28 April 2021

Hysteroscop* (0)

Distension medi* (0)

Hysteroscopic AND Hysteroscopy (1)

Appendix 10. Web of Science search strategy

Web platform

Searched 28 April 2021

hysteroscop* AND distension medi* (129)

Data and analyses

Comparison 1. Saline vs carbon dioxide.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Tolerability of the procedure ‐ Pain during the procedure	9	1705	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.07 [‐0.17, 0.02]
1.2 Tolerability of the procedure ‐ Procedures abandoned due to intense pain	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only
1.3 Tolerability of the procedure ‐ Need for analgesia	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only
1.4 Adverse events and complications	6		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only
1.4.1 Vasovagal reaction	6	1076	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.53 [0.32, 0.86]
1.4.2 Shoulder‐tip pain	4	623	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.28 [0.14, 0.54]
1.4.3 Endometrial bleeding	2	349	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.83 [0.25, 2.75]
1.5 Quality of hysteroscopic view ‐ Clarity of the view on a scale	2		Std. Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.6 Quality of hysteroscopic view ‐ Procedures with unsatisfactory view	5	1082	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.51 [0.32, 0.82]
1.7 Duration of the procedure	4		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 2. Warm saline vs room temperature saline.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Tolerability of the procedure ‐ Pain during the procedure	3	241	Mean Difference (IV, Fixed, 95% CI)	‐1.14 [‐1.55, ‐0.73]
2.2 Tolerability of the procedure ‐ Procedures abandoned due to intense pain	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only
2.3 Tolerability of the procedure ‐ Need for analgesia	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only
2.4 Duration of the procedure	3	241	Mean Difference (IV, Fixed, 95% CI)	13.17 [‐12.96, 39.29]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Almeida 2008.

Study characteristics
Methods	Design: randomised controlled trial Country: Brazil Setting: single centre, service of hysteroscopy, Integrated Health Center Amaury de Medeiros, University of Pernambuco Timing: between May and December 2006 Source of funding: not reported Conflict of interest: not reported Power calculation: yes
Participants	Number randomised: 184 Number analysed: 184 Number excluded: none Inclusion criteria: women over 18 years of age, referred to undergo diagnostic hysteroscopy for various indications Exclusion criteria: acute pelvic inflammatory disease, pregnancy, uterine perforation in the last 30 days, active uterine bleeding, using hormone‐based vaginal cream Age: mean in carbon dioxide group 45.0 years vs mean in saline group 46.7 years Parity: mean in carbon dioxide group 3.23 vs mean in saline group 3.95
Interventions	Study group: saline solution (n = 91) warmed at 36°C, vaginoscopic approach Control group: carbon dioxide (n = 93), traditional approach Hysteroscope: 2.7‐mm hysteroscope and 3.7‐mm cannula (Endoview, Bingen, Germany)
Outcomes	Pain during procedure on VAS Adverse events and complications Duration of the procedure in minutes
Notes	Trial registration: no We attempted to contact the corresponding author for further details on methods and outcomes, but we got no response
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "as participants eram alocadas em cada grupo por randomização por meio da geração de uma seqüência de números aleatórios no aplicativo de domínio público Epi‐ Info 6.04" English translation: "participants were allocated in each group by randomization by generating a sequence of random numbers in the public domain application Epi‐Info 6.04"
Allocation concealment (selection bias)	Low risk	Quote: "endo a técnica alocada mascarada por envelopes opacos e lacrados, somente abertos após a seleção da participante" English translation: "allocated technique was masked by opaque and sealed envelopes, which were opened only after participant selection"
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding was not possible in this type of intervention, which might induce performance bias
Blinding of outcome assessment (detection bias) All outcomes	High risk	Blinding was not possible in this type of intervention, and as outcomes were either patient‐assessed or operator‐assessed, we judged risk of detection bias as high
Incomplete outcome data (attrition bias) All outcomes	Low risk	Data were reported for all randomised women
Selective reporting (reporting bias)	Low risk	Protocol was not available. However, all primary outcomes of interest were mentioned, including complications, and all outcomes mentioned in methods section were fully reported in the results
Other bias	Low risk	We found no other sources of bias

Diniz 2009.

Study characteristics
Methods	Design: randomised controlled trial Country: Brazil Setting: single centre, Hospital of State Public Servant "Francisco Morato Oliveira", Institute of Medical Assistance to the State Public Servant, São Paulo Timing: between April 2005 and October 2006 Source of funding: not reported Conflict of interest: not reported Power calculation: yes
Participants	Number randomised: 117 Number analysed: 117 Number excluded: none Inclusion criteria: women over 18 years of age, undergoing hysteroscopy regardless of the indication for the procedure Exclusion criteria: pregnancy, cervicitis, genital bleeding, acute pelvic inflammatory disease Age: mean in carbon dioxide group 50.9 years vs mean in saline group 53.2 years Parity: numbers nulliparous were 2 in carbon dioxide group and 4 in saline group; medians of multiparity were 2.37 in carbon dioxide group and 3.00 in saline group
Interventions	Study group: saline solution (n = 59) at room temperature, vaginoscopic approach Control group: carbon dioxide (n = 58), traditional approach Hysteroscope: optical 2.9‐mm 30° with 2 sheaths for streaming, making a total of 5‐mm oval profile (hysteroscope: Bettocchi, Karl Storz, Germany), was used in the study group; in the control group, an optical 4‐mm 30° with a circular diagnostic sheath of 5 mm from the same manufacturer was used
Outcomes	Pain during procedure on VAS Quality of hysteroscopic view (satisfactory vs unsatisfactory)
Notes	Trial registration: no We attempted to contact the corresponding author for further details on methods and outcomes, but we got no response
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	It was mentioned that allocation was random, but method of randomisation was unclear
Allocation concealment (selection bias)	Unclear risk	Not mentioned
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding was not possible in this type of intervention, which might induce performance bias
Blinding of outcome assessment (detection bias) All outcomes	High risk	Blinding was not possible in this type of intervention, and as outcomes were either patient‐assessed or operator‐assessed, we judged risk of detection bias as high
Incomplete outcome data (attrition bias) All outcomes	Low risk	Data were reported for all randomised women
Selective reporting (reporting bias)	Unclear risk	Protocol was not available. All outcomes mentioned in methods section were fully reported in the results. Complications and adverse effects were not reported, and it is unclear whether they were assessed and not reported or were not assessed at all
Other bias	Low risk	We did not find other sources of bias

Evangelista 2011.

Study characteristics
Methods	Design: randomised controlled trial Country: Brazil Setting: single centre, hysteroscopy outpatient clinic at Fernandes Figueira Institute, Rio de Janeiro Timing: second half of 2008 Source of funding: not reported Conflict of interest: not reported Power calculation: yes
Participants	Number randomised: 67 Number analysed: 64 Number excluded: 3 women due to cervical stenosis (2 in warm saline group and 1 in control group) Inclusion criteria: women referred to undergo diagnostic hysteroscopy for any indication Exclusion criteria: pregnancy, uterine perforation that occurred less than 1 month previously, profuse uterine bleeding, acute pelvic inflammatory disease, uncompensated clinical conditions such as diabetes mellitus and arterial hypertension Age: mean in warm saline group 41.5 years vs mean in room temperature saline group 44.1 years Parity: mean in warm saline group 2.17 deliveries vs mean in room temperature saline group 1.80 deliveries
Interventions	Study group: saline solution (n = 34) warmed at 37.5°C, vaginoscopic approach Control group: saline solution (n = 30) at room temperature, vaginoscopic approach Hysteroscope: Bettochi system with 2.9‐mm diameter for both groups
Outcomes	Pain during procedure on VAS Duration of the procedure in minutes Adverse events and complications
Notes	Trial registration: no
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "patients were allocated to 1 of 2 groups... The randomization was computer‐generated"
Allocation concealment (selection bias)	Low risk	Quote: "the numbers were placed in opaque envelopes that were sealed and numbered. These were opened only at the time of the examination"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The study was single‐blinded (patient ‐ blinded)
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcomes were either patient‐reported or objective
Incomplete outcome data (attrition bias) All outcomes	Low risk	Three women were excluded after randomisation (2 in study group and 1 in control group)
Selective reporting (reporting bias)	Low risk	Protocol was not available. However, all primary outcomes of interest were mentioned including complications, and all outcomes mentioned in methods section were fully reported in the results
Other bias	Low risk	We did not find other sources of bias

Garbin 2000.

Study characteristics
Methods	Design: random study Country: France Setting: single centre, Department of Obstetrics and Gynaecology, University of Strasbourg, Schiltigheim Timing: between November 1999 and March 2000 Source of funding: not reported Conflict of interest: not reported Power calculation: no
Participants	Number randomised: 120 Number analysed: 120 Number excluded: none Inclusion criteria: women undergoing office hysteroscopy Exclusion criteria: active genital bleeding Age: not mentioned Parity: not mentioned
Interventions	Study group: saline solution (n = 60), traditional approach Control group: carbon dioxide (n = 60), traditional approach Hysteroscope: rigid panoramic hysteroscope, external sheet 3.9 mm
Outcomes	Pain during procedure on VAS Quality of hysteroscopic view on a 5‐point scale
Notes	Trial registration: no This was published as a conference abstract. We contacted study authors, who gave us the needed information
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "in this monocentric random‐study..." Comment: unclear method of randomisation
Allocation concealment (selection bias)	Unclear risk	Pre‐filled sealed envelope, but we are not sure whether the envelopes were numbered and opaque
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding was not possible in this type of intervention, which might induce performance bias
Blinding of outcome assessment (detection bias) All outcomes	High risk	Blinding was not possible in this type of intervention, and as outcomes were either patient‐assessed or operator‐assessed, we judged risk of detection bias as high
Incomplete outcome data (attrition bias) All outcomes	Low risk	After contacting the study author, we learned that the procedure was not performed in 6 women (3 in each group) due to failure to pass through the cervix. However, these women were included in the analysis of outcomes
Selective reporting (reporting bias)	Low risk	Protocol was not available. All outcomes mentioned in methods section were fully reported in the results, and study author confirmed that no other outcomes were assessed
Other bias	Low risk	We did not find other sources of bias

Isaat 2017.

Study characteristics
Methods	Design: randomised controlled trial Country: Poland Setting: single centre, Department of Obstetrics, Women’s Diseases and Oncogynecology, Central Clinical Hospital of Ministry of Interior, Warsaw Timing: between 01 January and 01 July 2015 Source of funding: not reported Conflict of interest: not reported Power calculation: no
Participants	Number randomised: 103 Number analysed: 100 Number excluded: 3 due to failure to pass the cervical os (1 in study group and 2 in control group) Inclusion criteria: all women over 18 years of age, referred for hysteroscopy for diagnosis of abnormal endometrium on ultrasound, endometrial polyps, and uterine bleeding Exclusion criteria: women with possible pregnancy, lower genital tract infection, gestational trophoblastic disease, presence of endocervical polyps visualised on a speculum examination, endometrial polyps measuring more than 30 mm, asthma, acute porphyria, hepatitis, renal failure, lactation, and hypersensitivity to one of the agents or its elements Age: median age in warm saline group was 43 years vs 46.5 years in room temperature saline group Parity: number of nullipara in warm saline group was 24 vs 21 in room temperature saline group
Interventions	Study group: saline solution warmed at 36°C (n = 50), vaginoscopic approach Control group: saline solution at room temperature (n = 50), vaginoscopic approach Hysteroscope: 3.2‐mm Versascope hysteroscope
Outcomes	Pain during procedure on VAS Need for analgesia Duration of the procedure in seconds Adverse events and complications
Notes	Trial registration: yes (ISRCTN56764412) We attempted to contact the corresponding author for further details on methods and outcomes, but we got no response
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "randomization ... was generated automatically in an allocation ratio of 1:1"
Allocation concealment (selection bias)	Low risk	Quote: "the randomization envelopes were opaque and were kept in an outpatient hysteroscopy room in a closed study box"
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not mentioned
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not mentioned
Incomplete outcome data (attrition bias) All outcomes	Low risk	3 patients were excluded after randomisation due to failure of the hysteroscope to pass the cervical os (1 in study group and 2 in control group)
Selective reporting (reporting bias)	Low risk	All pre‐specified outcomes in the protocol were reported.
Other bias	Low risk	We did not find other sources of bias

Mazzon 2014.

Study characteristics
Methods	Design: randomised controlled trial Country: Italy Setting: single centre, Arbor Vitae Center for Endoscopic Gynecology (Clinica Nuova Villa Claudia, Rome, Italy) Timing: between June 2013 and January 2014 Source of funding: not mentioned Conflict of interest: one study author received non‐financial support from Karl STORZ Endoscopy GmbH STORZ, Tuttlingen, Germany. Other study authors declared no conflicts of interest Power calculation: yes
Participants	Number randomised: 414 Number analysed: 392 Number excluded: 22 (had endometrial biopsy) Inclusion criteria: Italian‐speaking patients undergoing diagnostic hysteroscopy. Indications for hysteroscopy were abnormal uterine bleeding, infertility, recurrent miscarriage, fibroids, polyps, uterine malformation, and endometrial thickening Exclusion criteria: ongoing pregnancy, cervical carcinoma, pelvic inflammatory disease, previous cervical surgery, previous diagnostic hysteroscopy. During the procedure, women were excluded in cases of excessive bleeding or if endometrial biopsy was taken Age: mean in carbon dioxide group 43.83 years vs mean in saline group 44.03 years Parity: percentage of nulliparous was 59.89% in carbon dioxide group and 61.02% in saline group; percentages of multiparous were 40.01% and 38.97%, respectively
Interventions	Study group: saline solution (n = 195), vaginoscopic approach Control group: carbon dioxide (n = 197), vaginoscopic approach Hysteroscope: rigid telescope with a diameter of 4 mm and a 30° fore‐oblique covered with a single‐flow examination sheath with diameter of 5.1 mm (Hamou II; Karl Storz) for both groups
Outcomes	Pain during procedure on VAS Quality of hysteroscopic view (satisfactory vs unsatisfactory) Duration of the procedure in seconds Adverse events and complications
Notes	Trial registration: yes (NCT01873391)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “randomization was performed by a statistical consultant using computer‐generated numbers”
Allocation concealment (selection bias)	Low risk	Quote: “the distension medium was assigned before starting the diagnostic procedure by opening a sealed, opaque envelope containing the group allotment”
Blinding of participants and personnel (performance bias) All outcomes	High risk	Although study authors mentioned, "Patients were not allowed to follow the procedure on a monitor", blinding was not possible in this type of intervention for neither patients nor operators, which might induce performance bias
Blinding of outcome assessment (detection bias) All outcomes	High risk	Blinding was not possible in this type of intervention, and as outcomes were either patient‐assessed or operator‐assessed, we judged risk of detection bias as high
Incomplete outcome data (attrition bias) All outcomes	Low risk	Although there were randomised participants who were excluded from analysis due to the need for endometrial biopsy, this was unlikely to cause bias, as the number of excluded participants was nearly similar in both groups (10 in carbon dioxide group vs 12 in saline group)
Selective reporting (reporting bias)	Low risk	All outcomes mentioned in the protocol were reported in the publication
Other bias	Low risk	Financial support from the hysteroscopy manufacturer received by one study author was unlikely to have had an influence, as the same hysteroscope was used in both groups

Paschopoulos 2004.

Study characteristics
Methods	Design: randomised controlled trial Country: Greece Setting: single centre, Department of Obstetrics and Gynecology of the Ioannina University School of Medicine Timing: between April 2001 and November 2003 Source of funding: not mentioned Conflict of interest: not mentioned Power calculation: no
Participants	Number randomised: 79 Number analysed: 74 Number excluded: 5 (4 in carbon dioxide group and 1 in saline group due to inability to perform hysteroscopy) Inclusion criteria: women admitted to undergo total abdominal hysterectomy Exclusion criteria: suspicion of endometrial cancer Age: mean in carbon dioxide group 52.3 years vs mean in saline group 53.5 years Parity: mean in carbon dioxide group 2.05 vs mean in saline group 1.97
Interventions	Study group: saline solution (n = 35), vaginoscopic approach Control group: carbon dioxide (n = 39), vaginoscopic approach Hysteroscope: Bettochi hysteroscope (Karl Storz, Tuttlingen, Germany) with a diagnostic sheath with diameter 2.8 mm and lances with an inclination of 30° was used
Outcomes	Pain during the procedure on a 4‐point scale Proportion of procedures abandoned due to intense pain Adverse events and complications
Notes	Trial registration: no
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “all women were asked to choose between two identical, sealed envelopes. One of the envelopes contained the indication 1, which corresponded to CO2, and the other the indication 2, which corresponded to normal saline” Comment: this was based on chance process, and there was a 50% chance for every patient on either indication
Allocation concealment (selection bias)	Low risk	It was mentioned that allocations were kept in sealed envelopes
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding was not possible in this type of intervention, which might induce performance bias
Blinding of outcome assessment (detection bias) All outcomes	High risk	Blinding was not possible in this type of intervention, and as outcomes were either patient‐assessed or operator‐assessed, we judged risk of detection bias as high
Incomplete outcome data (attrition bias) All outcomes	High risk	5 randomised patients were excluded due to inability to perform hysteroscopy, and they were unequally distributed in both groups: 4 in carbon dioxide group (2 of whom are considered complications) and 1 in saline group
Selective reporting (reporting bias)	Low risk	Protocol was not available. However, all primary outcomes of interest were mentioned including complications, and all outcomes mentioned in methods section were fully reported in the results
Other bias	Low risk	We did not find other sources of bias

Pellicano 2003.

Study characteristics
Methods	Design: randomised controlled trial Country: Italy Setting: multi‐centre, hysteroscopy units in 2 university hospitals and at a private centre Timing: between March 2000 and December 2000 Source of funding: not mentioned Conflict of interest: not mentioned Power calculation: yes
Participants	Number randomised: 189 Number analysed: 189 Number excluded: none Inclusion criteria: infertile women undergoing outpatient hysteroscopy. Indications for hysteroscopy were abnormal uterine bleeding, increased endometrial thickness at ultrasound, suspicion of endometrial polyp or myoma, endocervical polyp, and repeated spontaneous abortion Exclusion criteria: not mentioned Age and Parity: not reported in numbers, but it was mentioned that there was no difference between groups in terms of age and parity
Interventions	Study group: saline solution (n = 97), vaginoscopic approach Control group: carbon dioxide (n = 92), vaginoscopic approach Hysteroscope: compact continuous‐flow 5‐mm hysteroscope (Wolf, Germany)
Outcomes	Pain during procedure on VAS Proportion of procedures abandoned due to intense pain Need for analgesia Quality of hysteroscopic view (satisfactory vs unsatisfactory) Duration of the procedure in minutes Adverse events and complications
Notes	Trial registration: no We contacted the corresponding author for additional clarification regarding methods and outcome data (failure rate and procedures needed to be stopped due to poor vision), but we received no response
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "patients were prospectively randomised and divided into two groups according to a computer‐generated random assignment"
Allocation concealment (selection bias)	Unclear risk	Not mentioned
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding was not possible in this type of intervention, which might induce performance bias
Blinding of outcome assessment (detection bias) All outcomes	High risk	Blinding was not possible in this type of intervention, and as outcomes were either patient‐assessed or operator‐assessed, we judged risk of detection bias as high
Incomplete outcome data (attrition bias) All outcomes	Low risk	All randomised women were included in the analysis, and there were no losses to follow‐up
Selective reporting (reporting bias)	Low risk	Protocol was not available. However, all primary outcomes of interest were mentioned, including complications, and all outcomes mentioned in methods section were fully reported in the results
Other bias	High risk	Standard deviations of the means of the outcome 'pain during the procedure' were noticed to be unusually low. We tried to contact study authors for clarification, but we got no reply

Pluchino 2010.

Study characteristics
Methods	Design: randomised controlled trial Country: Italy Setting: multi‐centre, University medical centres in Pisa and Cagliari Timing: between November 2006 and June 2008 Source of funding: not mentioned Conflict of interest: study authors declared no conflicts of interest Power calculation: yes
Participants	Number randomised: 184 Number analysed: 165 Number excluded: 19 were excluded after receiving the intervention when an additional surgical procedure was performed Inclusion criteria: the only indication for performing a diagnostic hysteroscopy was primary infertility Exclusion criteria: women with acute infection, active bleeding, viable pregnancy, or previous hysteroscopy were excluded. Additional exclusion criteria included a history of cervical or pelvic surgery and a diagnosis of chronic pelvic pain or endometriosis Age: mean in carbon dioxide O₂ group 33.6 years vs mean in saline group 33.3 years Parity: not mentioned
Interventions	Participants were divided according to the diameter of the hysteroscopy into 2 groups, then were further divided into 2 groups according to the distension media, and finally they were divided again into 2 groups according to the experience of the operator Study group: saline solution (n = 92), vaginoscopic approach Control group: carbon dioxide (n = 92), vaginoscopic approach Hysteroscope: the conventional hysteroscopy set (Karl Storz GmbH & Co. KG, Tuttlingen, Germany) included a rigid optic (rod lens, 4.0 mm; 30° oblique vision) with a 5.0‐mm single‐flow sheath. The mini‐hysteroscopy set (Karl Storz GmbH) included a rigid optic (rod lens, 2.9 mm; 30° for oblique vision) with a 3.5‐mm single‐flow sheath
Outcomes	Pain during procedure on VAS Proportion of procedures abandoned due to intense pain Need for analgesia Adverse events and complications
Notes	Trial registration: no We attempted to contact the corresponding author for further details on methods and outcomes, but we got no response
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "randomization was based on a computer‐generated randomization table"
Allocation concealment (selection bias)	Unclear risk	Not mentioned
Blinding of participants and personnel (performance bias) All outcomes	High risk	"The patient, who was blinded to group assignment...." as mentioned by study authors. However, blinding to distension media is not possible, and it may be that the patient was blinded to the experience of the operator and to the diameter of the hysteroscope
Blinding of outcome assessment (detection bias) All outcomes	High risk	Blinding was not possible in this type of intervention, and as outcomes were either patient‐assessed or operator‐assessed, we judged risk of detection bias as high
Incomplete outcome data (attrition bias) All outcomes	Low risk	Although 19 women were excluded from analysis after they were randomised and had received the intervention, the distribution of excluded women in each group was similar (9 in saline group vs 10 in carbon dioxide group). In addition, the remaining number of women in each group met the lower limit in power calculation, and the reason for exclusion was reasonable (additional surgical procedures performed)
Selective reporting (reporting bias)	Low risk	Our primary outcomes were mentioned in the reported results. Although 2 secondary outcomes (quality of visualisation and duration of the procedure) were not reported in detail, we rated this domain as low risk
Other bias	High risk	Standard deviations of the means of the outcome 'pain during the procedure' were noted to be unusually low. We tried to contact study authors for clarification, but we got no reply

Raimondo 2010.

Study characteristics
Methods	Design: randomised controlled trial Country: Italy Setting: multi‐centre, number or locations not mentioned Timing: between February 2007 and May 2007 Source of funding: not mentioned Conflict of interest: all study authors declared no conflicts of interest Power calculation: yes
Participants	Number randomised: 264 Number analysed: 264 Number excluded: none Inclusion criteria: evaluation of abnormal uterine bleeding, suspected mullerian anomalies, assessment of uncertain or abnormal findings on imaging studies, infertility, increased endometrial thickness, assessment of the endometrium in women taking tamoxifen, cytological endometrial hyperplasia Exclusion criteria: cervical carcinoma, menstruation or excessive bleeding at the time of hysteroscopy, pelvic inflammatory disease, pregnancy Age: mean in carbon dioxide group 46.3 years vs mean in saline group 46.16 years Parity: percentage of nulliparous 24.3% in carbon dioxide group and 22.7% in saline group
Interventions	Study group: saline solution (n = 132), vaginoscopic approach Control group: carbon dioxide (n = 132), vaginoscopic approach Hysteroscope: in group A (carbon dioxide), a forward‐oblique 30° telescope, 4‐mm diameter, 24‐cm length, covered with a single‐flow examination sheath of 5.1‐mm diameter (Hamou I; Karl Storz) was used. In group B (normal saline solution), a forward‐oblique 30° telescope, 2.9‐mm diameter, 30‐cm length (Karl Storz) with a 5.1‐mm diameter continuous‐flow sheath (Bettocchi, Karl Storz) was used
Outcomes	Pain during procedure on VAS Quality of hysteroscopic view on VAS Adverse events and complications Duration of the procedure in seconds
Notes	Trial registration: no We attempted to contact the corresponding author for further details on methods and outcomes, but we got no response
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomization was achieved [...] containing computer‐generated block randomization numbers"
Allocation concealment (selection bias)	Low risk	"Randomization was achieved using sealed, opaque envelopes..."
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding was not possible in this type of intervention, which might induce performance bias
Blinding of outcome assessment (detection bias) All outcomes	High risk	Blinding was not possible in this type of intervention, and as outcomes were either patient‐assessed or operator‐assessed, we judged risk of detection bias as high
Incomplete outcome data (attrition bias) All outcomes	Low risk	No losses to follow‐up or exclusions from analysis after randomisation
Selective reporting (reporting bias)	Low risk	Protocol was not available. However, all primary outcomes of interest were mentioned, including complications, and all outcomes mentioned in methods section were fully reported in the results
Other bias	Low risk	We did not find other sources of bias

Shankar 2004.

Study characteristics
Methods	Design: randomised controlled trial Country: UK Setting: single centre, 1‐stop menstrual clinic and 1‐stop postmenopausal bleeding clinic at a large teaching hospital, Department of Obstetrics and Gynaecology, University of Leicester, United Kingdom Timing: between April 2000 and November 2001 Source of funding: not mentioned Conflict of interest: all study authors declared no conflicts of interest Power calculation: yes
Participants	Number randomised: 300 Number analysed: 300 Number excluded: none. In the carbon dioxide group, 17 patients underwent hysteroscopy with normal saline due to poor view with carbon dioxide Inclusion criteria: women were eligible to participate if they had an intact uterus and were referred by their general practitioner for abnormal uterine bleeding (premenopausal or postmenopausal) for which hysteroscopy was indicated. All referred patients were eligible, irrespective of age, parity, or general health status. Bleeding at the time of hysteroscopy, the presence of large fibroids, previous cone biopsy, and Manchester repair were not considered exclusion criteria Exclusion criteria: procedure was not feasible (e.g. the cervix could not be visualised, presence of severe cervical stenosis) Age: mean in carbon dioxide group 57.8 years vs mean in saline group 58.5 years Parity: unclear
Interventions	Participants were divided into 3 groups: carbon dioxide group, normal saline group, and normal saline plus lignocaine group. We included only the first 2 groups Study group: saline solution (n = 100), traditional approach Control group: carbon dioxide (n = 100), traditional approach Hysteroscope: using a 2.7‐mm rigid diagnostic hysteroscope (Wolf Lumina, Richard Wolf GMBH) with a 30° fore‐oblique lens and a 3.5‐mm single‐flow diagnostic sheath
Outcomes	Pain during procedure on VAS Quality of hysteroscopic view (satisfactory vs unsatisfactory) Adverse events and complications
Notes	Trial registration: no We attempted to contact the corresponding author for further details on methods and outcomes, but we got no response
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “randomisation tables were used to generate the randomisation sequence”
Allocation concealment (selection bias)	Low risk	Quote: “the sequence was concealed using serial sealed opaque envelopes in blocks of 15"
Blinding of participants and personnel (performance bias) All outcomes	High risk	It was mentioned that the trial was single‐blinded. However, blinding was not possible in this type of intervention, which might induce performance bias
Blinding of outcome assessment (detection bias) All outcomes	High risk	Blinding was not possible in this type of intervention, and as outcomes were either patient‐assessed or operator‐assessed, we judged risk of detection bias as high
Incomplete outcome data (attrition bias) All outcomes	Low risk	A ll randomised women were included in the analysis with no losses t o follow‐up
Selective reporting (reporting bias)	Low risk	Protocol was not available. All outcomes mentioned in methods section were fully reported in the results
Other bias	Low risk	We did not find other sources of bias

Tawfek 2019.

Study characteristics
Methods	Design: randomised trial Country: Egypt Setting: single centre, early cancer detection unit at Ain Shams Maternity Hospital Timing: from May 2017 to May 2018 Source of funding: not mentioned Conflict of interest: not mentioned Power calculation: yes
Participants	Number randomised: 82 Number analysed: 77 Number excluded: 5 patients: 2 in study group and 3 in control group (due to the need for operative intervention, intolerance to complete the procedure, or the need for cervical dilatation) Inclusion criteria: women aged 20 to 40 years with normal cervical morphology during speculum examination. Indications included abnormal uterine bleeding, assessment of the endocervical canal, uterine cavity, and tubal ostia for infertility or suspected Mullerian anomalies Exclusion criteria: pregnancy; suspected acute pelvic inflammatory disease; past history of medical disorder, especially associated with neuropathy (e.g. diabetes, chronic kidney disease; history of vaginal pruritus, discharge, dysuria, dysmenorrhoea, dyspareunia, chronic pelvic pain, presence of pain, profuse bleeding, or other symptoms at the time of the procedure; history of uterine surgery that occurred less than 1 month previously; history of previous cervical procedures; administration of general, cervical, or paracervical anaesthesia or sedatives; any usage of analgesic agents before the procedure; cervical preparation by misoprostol before procedure orally or vaginally for cervical ripening to improve the possibility of successful cervical dilation and to reduce intraoperative pain; requirement for cervical dilatation during the procedure; requirement for biopsy or any operative intervention during the procedure Age: mean in study group 33.71 years vs mean in control group 35.57 years Parity: median in study group 2 deliveries vs median in control group 2 deliveries
Interventions	Study group: warm saline solution (n = 39) at 37.5°C, vaginoscopic approach Control group: room temperature saline solution (n = 38), vaginoscopic approach Hysteroscope: a rigid hysteroscope (continuous flow, 30° forward oblique view) assembled in a 4‐mm diameter diagnostic sheath with an atraumatic tip (Karl Storz Endoscopy, Tuttlingen, Germany)
Outcomes	Pain during the procedure on VAS Duration of the procedure in minutes
Notes	Trial registration: no We attempted to contact the corresponding author for further details on methods and outcomes, but we got no response
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "cases fulfilling the inclusive research criteria were randomised to two research groups" Comment: method of randomisation was not mentioned
Allocation concealment (selection bias)	Unclear risk	Not mentioned
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not mentioned
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not mentioned
Incomplete outcome data (attrition bias) All outcomes	Low risk	Although 5 women were randomised but were excluded from analysis, the number was too small to induce bias and was matching in both groups (2 in warmed saline group vs 3 in room temperature saline group)
Selective reporting (reporting bias)	Low risk	All planned outcomes in the protocol registration were reported
Other bias	Low risk	We did not find other sources of bias

PPI: present pain intensity. 
VAS: visual analogue scale.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Brusco 2003	Quasi‐randomised trial Quote: "the midwife administered normal saline or CO₂ on a daily basis"
Campo 2005	Trial is comparing the size of the hysteroscope using room temperature saline solution in both groups
Kapur 2020	Quasi‐randomised trial Quote: "patients attending the outpatient hysteroscopy clinics...were quasi‐randomised by the hysteroscopy nurse"
Litta 2003	Quasi‐randomised trial Quote: "the nature of randomization was to alternate distension media on a weekly basis"
Nagele 1996	Quasi‐randomised trial Quote: "the nature of randomization was to alternate the distension medium between CO₂ and normal saline on a weekly basis"
Nagele 1999	Inpatient diagnostic hysteroscopy done during laparoscopy
Salazar 2019	Inpatient operative hysteroscopy
Santos 2012	Unpublished trial due to 60% protocol breaks

CO₂: carbon dioxide.

Characteristics of studies awaiting classification [ordered by study ID]

Guida 2003.

Methods
Participants	Postmenopausal women on tamoxifen treatment with abnormal endometrial bleeding and endometrial thickening on ultrasound
Interventions	Diagnostic hysteroscopy with carbon dioxide or saline as distension medium
Outcomes	Quality of vision of uterine cavity, procedure time, complications, patient discomfort, satisfaction rate
Notes	This was a conference abstract with insufficient information. We attempted to contact study authors to confirm eligibility of the study and to obtain more information, but we did not get a response

ISRCTN62284430.

Methods	Randomised controlled trial
Participants
Interventions	Randomised controlled trial 1. Normal saline, 37°C, 150 mmHg 2. Normal saline, room temperature, 100mmHg 3. Normal saline, room temperature, 200 mmHg 4. Saline, room temperature, 150 mmHg
Outcomes
Notes	This study was mentioned as completed on 15 July 2004. No email was found to contact the study author

Tagliaferri 2019.

Methods	Design: randomised controlled trial Country: Italy Setting: multi‐centre, Department of Obstetrics and Gynaecology, Policlinico Abano Terme (Centre A); Department of Obstetrics and Gynaecology, Università Cattolica del Sacro Cuore in Rome (Centre B); Department of Obstetrics and Gynaecology, Ente Ecclesiastico Ospedale Generale Regionale “F. Miulli” in Acquaviva delle Fonti (Centre C) Timing: between November 2016 and April 2017 Source of funding: no Conflict of interest: all study authors declared no conflicts of interest Power calculation: yes
Participants	Number randomised: 2008 Number excluded: 26 (18 cases of severe cervical stenosis, 8 cases of severe vasovagal symptoms) Inclusion criteria: enrolled for outpatient diagnostic hysteroscopy Exclusion criteria: procedure was not feasible (e.g. the cervix could not be visualised, presence of severe cervical stenosis) Age: not mentioned Parity: not mentioned
Interventions	Gas medium: carbon dioxide (n = 995), vaginoscopic approach for introduction of the hysteroscope Liquid medium: normal saline (n = 987), vaginoscopic approach for introduction of the hysteroscope Hysterscope: both groups were further subdivided into 2 other groups (Fig. 1). In particular, 485 patients in the carbon dioxide group and 455 patients in the saline group underwent the procedure with the conventional hysteroscopy set composed of a rigid optic (rod lens, 4.0 mm; 30° oblique vision) and a 5‐mm single‐flow sheath (Karl Storz, Tuttlingen, Germany); 510 patients in the carbon dioxide group and 532 patients in the saline group underwent the procedure with the mini‐hysteroscopy set including a rigid optic (rod lens, 2.9 mm; 30° for oblique vision) and a 3.5‐mm single‐flow sheath (Karl Storz, Tuttlingen, Germany)
Outcomes	Pain during procedure on VAS Duration of the procedure Complications and adverse events
Notes	This study will remain in awaiting classification due to unresolved questions regarding study data and methods

Tandon 2004.

Methods	Randomised controlled trial
Participants
Interventions	This is a pilot study comparing discomfort levels in 2 groups of patients undergoing hysteroscopy In one group, hysteroscopy will be performed in the clinic using room temperature saline to distend the uterine cavity (the existing method in use) In the second group, saline warmed to body temperature will be used
Outcomes	Discomfort levels are assessed in the 2 groups using pain scores
Notes	A full text was not found, and the abstract could not be retrieved No email could be found to contact the study author

VAS: visual analogue scale.

Differences between protocol and review

Since the protocol was published in 2007, numerous methodological advances have been made. The review now reflects current methods according to Cochrane guidance.

• The objective of the review was changed to include the comparison of warm versus room temperature saline as distension media for outpatient hysteroscopy. The protocol was planned to compare only liquid versus gaseous media.

• The outcome 'quality of hysteroscopic view' was considered as a secondary outcome in the full review, instead of as a primary outcome as in the protocol, as three primary outcomes were planned in the protocol.

• The outcome operative and postoperative complications in the protocol was further clarified in the full review as including shoulder‐tip pain, vagal symptoms (nausea, vomiting, dizziness, and fainting attack), bleeding from the endometrium, and infection.

Contributions of authors

Karim S. Abdallah (KSA) screened abstracts and full texts, wrote to study authors, extracted and managed data, interpreted results, and wrote the manuscript of the review.

Moustafa A. Gadalla (MAG) screened full texts, extracted data, interpreted results, and amended the review text.

Maria Breijer (MB) screened abstracts and full texts and amended the review text.

Ben W.J. Mol (BWJM) helped in designing the review, supervised all steps of the review process, gave clinical and methodological advice, resolved disagreements, and amended the review text.

Sources of support

Internal sources

• None, Other

External sources

• None, Other

Declarations of interest

Karim S. Abdallah (KSA): reports funding of the research scholarship at Monash University by the Missions Department of the Egyptian Ministry of Higher Education.

Moustafa A. Gadalla (MAG): none.

Maria Breijer (MB): none.

Ben W.J. Mol (BWJM): is supported by an NHMRC Investigator grant (GNT1176437); reports consultancy for ObsEva, Merck, Merck KGaA, iGenomix, and Guerbet; and reports research support from Merck and Guerbet.

Edited (no change to conclusions)