Fluid and pharmacological agents for adhesion prevention after gynaecological surgery

Gaity Ahmad; Matthew Thompson; Kyungmin Kim; Priya Agarwal; Fiona L Mackie; Sofia Dias; Mostafa Metwally; Andrew Watson

doi:10.1002/14651858.CD001298.pub5

. 2020 Jul 17;2020(7):CD001298. doi: 10.1002/14651858.CD001298.pub5

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery

Gaity Ahmad ^1,^✉, Matthew Thompson ², Kyungmin Kim ², Priya Agarwal ², Fiona L Mackie ³, Sofia Dias ⁴, Mostafa Metwally ⁵, Andrew Watson ⁶

Editor: Cochrane Gynaecology and Fertility Group

PMCID: PMC7388178 PMID: 32683695

Abstract

Background

Adhesions are fibrin bands that are a common consequence of gynaecological surgery. They are caused by conditions that include pelvic inflammatory disease and endometriosis. Adhesions are associated with comorbidities, including pelvic pain, subfertility, and small bowel obstruction. Adhesions also increase the likelihood of further surgery, causing distress and unnecessary expenses. Strategies to prevent adhesion formation include the use of fluid (also called hydroflotation) and gel agents, which aim to prevent healing tissues from touching one another, or drugs, aimed to change an aspect of the healing process, to make adhesions less likely to form.

Objectives

To evaluate the effectiveness and safety of fluid and pharmacological agents on rates of pain, live births, and adhesion prevention in women undergoing gynaecological surgery.

Search methods

We searched: the Cochrane Gynaecology and Fertility Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, and Epistemonikos to 22 August 2019. We also checked the reference lists of relevant papers and contacted experts in the field.

Selection criteria

Randomised controlled trials investigating the use of fluid (including gel) and pharmacological agents to prevent adhesions after gynaecological surgery.

Data collection and analysis

We used standard methodological procedures recommended by Cochrane. We assessed the overall quality of the evidence using GRADE methods. Outcomes of interest were pelvic pain; live birth rates; incidence of, mean, and changes in adhesion scores at second look‐laparoscopy (SLL); clinical pregnancy, miscarriage, and ectopic pregnancy rates; quality of life at SLL; and adverse events.

Main results

We included 32 trials (3492 women), and excluded 11.

We were unable to include data from nine studies in the statistical analyses, but the findings of these studies were broadly in keeping with the findings of the meta‐analyses.

Hydroflotation agents versus no hydroflotation agents (10 RCTs)

We are uncertain whether hydroflotation agents affected pelvic pain (odds ratio (OR) 1.05, 95% confidence interval (CI) 0.52 to 2.09; one study, 226 women; very low‐quality evidence).

It is unclear whether hydroflotation agents affected live birth rates (OR 0.67, 95% CI 0.29 to 1.58; two studies, 208 women; low‐quality evidence) compared with no treatment.

Hydroflotation agents reduced the incidence of adhesions at SLL when compared with no treatment (OR 0.34, 95% CI 0.22 to 0.55, four studies, 566 women; high‐quality evidence). The evidence suggests that in women with an 84% chance of having adhesions at SLL with no treatment, using hydroflotation agents would result in 54% to 75% having adhesions.

Hydroflotation agents probably made little or no difference to mean adhesion score at SLL (standardised mean difference (SMD) ‐0.06, 95% CI ‐0.20 to 0.09; four studies, 722 women; moderate‐quality evidence).

It is unclear whether hydroflotation agents affected clinical pregnancy rate (OR 0.64, 95% CI 0.36 to 1.14; three studies, 310 women; moderate‐quality evidence) compared with no treatment. This suggests that in women with a 26% chance of clinical pregnancy with no treatment, using hydroflotation agents would result in a clinical pregnancy rate of 11% to 28%.

No studies reported any adverse events attributable to the intervention.

Gel agents versus no treatment (12 RCTs)

No studies in this comparison reported pelvic pain or live birth rate.

Gel agents reduced the incidence of adhesions at SLL compared with no treatment (OR 0.26, 95% CI 0.12 to 0.57; five studies, 147 women; high‐quality evidence). This suggests that in women with an 84% chance of having adhesions at SLL with no treatment, the use of gel agents would result in 39% to 75% having adhesions.

It is unclear whether gel agents affected mean adhesion scores at SLL (SMD ‐0.50, 95% CI ‐1.09 to 0.09; four studies, 159 women; moderate‐quality evidence), or clinical pregnancy rate (OR 0.20, 95% CI 0.02 to 2.02; one study, 30 women; low‐quality evidence).

No studies in this comparison reported on adverse events attributable to the intervention.

Gel agents versus hydroflotation agents when used as an instillant (3 RCTs)

No studies in this comparison reported pelvic pain, live birth rate or clinical pregnancy rate.

Gel agents probably reduce the incidence of adhesions at SLL when compared with hydroflotation agents (OR 0.50, 95% CI 0.31 to 0.83; three studies, 538 women; moderate‐quality evidence). This suggests that in women with a 46% chance of having adhesions at SLL with a hydroflotation agent, the use of gel agents would result in 21% to 41% having adhesions.

We are uncertain whether gel agents improved mean adhesion scores at SLL when compared with hydroflotation agents (MD ‐0.79, 95% CI ‐0.82 to ‐0.76; one study, 77 women; very low‐quality evidence).

No studies in this comparison reported on adverse events attributable to the intervention.

Steroids (any route) versus no steroids (4 RCTs)

No studies in this comparison reported pelvic pain, incidence of adhesions at SLL or mean adhesion score at SLL.

It is unclear whether steroids affected live birth rates compared with no steroids (OR 0.65, 95% CI 0.26 to 1.62; two studies, 223 women; low‐quality evidence), or clinical pregnancy rates (OR 1.01, 95% CI 0.66 to 1.55; three studies, 410 women; low‐quality evidence).

No studies in this comparison reported on adverse events attributable to the intervention.

Authors' conclusions

Gels and hydroflotation agents appear to be effective adhesion prevention agents for use during gynaecological surgery, but we found no evidence indicating that they improve fertility outcomes or pelvic pain, and further research is required in this area. It is also worth noting that for some comparisons, wide confidence intervals crossing the line of no effect meant that clinical harm as a result of interventions could not be excluded. Future studies should measure outcomes in a uniform manner, using the modified American Fertility Society score. Statistical findings should be reported in full. No studies reported any adverse events attributable to intervention.

Plain language summary

Use of fluids and pharmacological agents (medicinal drugs) to prevent the formation of adhesions (scar tissue) after surgery of the female pelvis

Review question: This Cochrane Review evaluated the use of fluid and pharmacological agents that aim to prevent adhesion formation after gynaecological surgery (we defined gels as fluid agents).

Background: Adhesions are a type of scar tissue, which can cause two normally separate surfaces within the body to stick together. Adhesions often form within the pelvis following surgery, infection, or due to endometriosis. Adhesions caused by gynaecological surgery can cause pain and reduced fertility. Women with adhesions often require further surgery. Strategies to prevent adhesion formation include the use of fluid and gel agents, which aim to prevent healing tissues from touching one another, or drugs, aimed to change an aspect of the healing process, to make adhesions less likely to form.

Study characteristics: We included 32 randomised controlled trials (3492 women). We pooled the results of 23 trials (2796 women). We were unable to pool the results from the remaining nine trials, because investigators either measured adhesions in a way that would not allow us to pool the findings with other data, or did not report important statistical information. We searched all evidence up to August 2019.

Key results:

Fluids and gels appear to be effective in reducing adhesions, but more information is needed to determine whether they affect pelvic pain or live birth rates. Large, high‐quality studies should be conducted in which investigators use the standardised way of measuring adhesions, developed by the American Fertility Society (the modified AFS score).

For the outcome of pain: one study reported uncertain results of the effect of a fluid agent (4% icodextrin, a glucose polymer) on pelvic pain. No studies reported pelvic pain outcomes with any other interventions.

For the outcome of fertility: the pooled results of two studies of fluid agents (dextran, another glucose polymer) found uncertain effects on live birth rates. The data suggest that in women with a 13% chance of giving birth with no treatment, 4% to 19% would give birth if treated with fluid agents. The pooled results of two studies of steroids found uncertain effects on live birth rates. The data suggest that in women with a 13% chance of giving birth with no treatment, 4% to 19% would give birth if treated with steroids. No studies reported live birth rate with any other interventions.

We are uncertain whether fluid agents, gel agents, or steroids affect clinical pregnancy rates compared with no treatment. No studies comparing the effect of fluid agents with gel agents reported clinical pregnancy rates.

For the outcome of adhesions at SLL: four studies found that fluid agents reduced the incidence of adhesions at second‐look laparoscopy (SLL) compared with no treatment (high‐quality evidence). This suggests that in women with an 84% chance of having adhesions at SLL with no treatment, the use of fluid agents would result in 54% to 75% having adhesions. Five studies found that gel agents reduced the incidence of adhesions at SLL compared with no treatment (high‐quality evidence). This suggests that in women with an 84% chance of having adhesions at SLL with no treatment, using gel agents would result in 39% to 75% having adhesions. Three studies found that gel agents probably reduced the incidence of adhesions at SLL compared with fluid agents (moderate‐quality evidence). This suggests that in women with a 46% chance of having adhesions at SLL with a fluid agent, using gel agents would result in 21% to 41% having adhesions.

Eight studies examined the effect of gel agents or fluid agents on mean adhesion score. We are uncertain if they have an effect when compared with no treatment, or with each other.

No studies reported the effect of steroids on adhesion incidence or mean adhesion scores at SLL.

For the outcome of adverse events: no studies reported any adverse events caused by the intervention being investigated.

Quality of the evidence: The quality of the evidence ranged from very‐low to high. The main reasons for downgrading evidence were imprecision (small sample sizes and wide confidence intervals that crossed the line of no effect), and poor reporting of methods.

Summary of findings

Background

Description of the condition

Adhesions are fibrin bands that form as the result of aberrant peritoneal healing (ASRM 2013). Normally, peritoneal damage causes an inflammatory response; this activates the coagulation cascade, and a fibrin plug is formed over the damaged mesothelium, which is then broken down to reveal regenerated peritoneum. However, in adhesion formation, fibrinolysis of the fibrin plug is decreased, and consequently, a fibrin matrix develops. Adhesions may be defined as ‘de novo', meaning they formed at a location that was previously free from adhesions, or ‘re‐formed’, which means they recurred post adhesiolysis. A variety of factors influence the extent of adhesion formation, including type of surgery performed (i.e. laparoscopic or open), haemostasis, and the presence of endometriosis and infection, particularly pelvic inflammatory disease (Diamond 2001). Although the aetiologies are different, the pathogenesis is similar.

Description of the intervention

Adhesion prevention agents can be divided into three types: fluid, pharmacological, and barrier. This review examines fluid and pharmacological agents. A separate review evaluates barrier agents (Ahmad 2020).

Fluid agents include both hydroflotation products and gels. Examples of hydroflotation devices are 4% icodextrin solution (Adept, Baxter, Berkshire, UK), an iso‐osmolar and non‐viscous high molecular weight glucose polymer; and 32% dextran (Hyskon Pharmacia, Uppsala, Sweden), a polysaccharide‐containing solution that is no longer approved for use as an anti‐adhesion agent. Both agents can be used as intraperitoneal irrigants or instillants.

Derivatives of hyaluronic acid form the basis of a number of anti‐adhesion gels. Hyaluronic acid is a linear polysaccharide with repeating disaccharide units, composed of sodium D‐glucuronate and N‐acetyl‐D‐glucosamine. SepraSpray (Genzyme Corporation, Cambridge, MA, USA) contains hyaluronic acid in addition to carboxymethylcellulose powder, and is applied to relevant tissues using a preloaded delivery device. SepraCoat (Genzyme Corporation) is a dilute hyaluronic acid solution that is applied before and after surgery. Hyalobarrier gel (Nordic Pharma, Reading, UK) and HyaRegen gel (BioRegen Biomedical CO., Ltd.) contain cross‐linked hyaluronic acid. Intergel (Gynecare, Lifecore Biomedical, Chaska, MN, USA) contains ferrous hyaluronic acid, although it has been withdrawn from the market. N,O‐carboxymethyl chitosan is a derivative of chitin, and is similar in structure to hyaluronic acid and carboxymethylcellulose. It is formed when the gel and solution components are combined. Polyethylene glycol (PEG)‐based gels are also available. CoSeal (Baxter) is formed by mixing a powder and a liquid intraoperatively, both of which contain PEG, which is then applied as a gel to relevant surfaces, using a specific instrument. SprayGel (Confluent Surgical Inc., Waltham, MA, USA) is formed by two PEG‐containing liquid precursors, which create a cross‐linked gel when combined. Intercoat (FzioMed, San Luis Obispo, CA, USA) is a viscoelastic gel composed of polyethylene oxide (PEO), which is very similar to PEG, but has a different molecular weight, and carboxymethylcellulose.

Steroids have been used to prevent adhesions and can be administered in a number of ways, including systemically before, during, and after surgery; intraperitoneally during surgery; and via hydrotubation postoperatively. Other pharmacological agents used to prevent adhesions include: noxytioline, an antibacterial agent; promethazine, an antihistamine; and reteplase, a thrombolytic drug, all of which are instilled intraperitoneally; as well as heparin, an anticoagulant used for intraoperative irrigation. A nasal gonadotrophin‐releasing hormone agonist (GnRHa) has also been used preoperatively and postoperatively.

How the intervention might work

Hyaluronic acid is a major component of many body tissues and fluids, where it provides physically supportive and mechanically protective roles (Johns 2001). PEG is a polymer; when the two PEG‐containing liquids are sprayed simultaneously, they form a cross‐linked gel. Gels are thought to decrease adhesion formation mainly by preventing denuded tissues from touching.

Steroids and antihistamines (e.g. promethazine) act as immunomodulating agents, and were used in the belief that they promoted fibrinolysis during healing, without hindering the healing process. GnRHa may work by decreasing oestrogen‐related growth factors, and promoting fibroblasts. Fluid agents, such as icodextrin and dextran, work through the act of hydroflotation, whereby the fluid separates raw opposing surfaces until the healing process has been completed. Fluid agents are believed to remain in the peritoneal cavity for up to 4 days, compared with crystalloids such as normal saline and Hartmann's solution which are effectively fully reabsorbed within 24 hours.This prolonged period before reabsorption is thought to give added protection against the formation of adhesions, which form within eight days of surgery (Diamond 2001; Hosie 2001).

Why it is important to do this review

Adhesiolysis is the only available treatment for adhesions, although its long‐term efficacy is unclear (Van Den Beukel 2017). In many cases, the focus of adhesion management is now on prevention of adhesions during the initial surgery (De Wilde 2012). Intraperitoneal adhesions are associated with considerable comorbidities, and have large economic and public health repercussions. They are the most common complication of gynaecological surgery, forming in 25% to 92% of women (Okabayashi 2014). Women present with secondary effects of adhesions, including dyspareunia, subfertility, bowel obstruction, and chronic pelvic pain, although the latter has a controversial association with adhesions, as no correlation between the extent of adhesions and severity of pain is apparent. Nevertheless, these consequences can greatly decrease a woman’s well‐being, and require further surgery. Subsequent surgery in women with adhesions is more difficult, often takes longer, and is associated with a higher complication rate. It is estimated that in the first year after lower abdominal surgery, the cost of adhesion‐related readmissions in the UK is £24.2 million, which increases to £95.2 million over the subsequent nine years (Wilson 2002). The Surgical and Clinical Adhesions Research (SCAR) study found that 5% (n = 245) of readmissions, 10 years after open gynaecological surgery, were due to adhesions (Lower 2000; Lower 2004). An English study estimated that the National Health Service (NHS) could save £700,000 per year if an anti‐adhesion agent that reduced adhesions by 25% and cost £110 was used; at worst, this approach would be cost‐neutral (Cheong 2011).

Objectives

To evaluate the effectiveness and safety of fluid and pharmacological agents on rates of pain, live births, and adhesion prevention in women undergoing gynaecological surgery.

Methods

Criteria for considering studies for this review

Types of studies

Published and unpublished randomised controlled trials (RCTs) investigating the use of fluid and pharmacological agents to prevent adhesion formation after gynaecological surgery were eligible for inclusion. We defined gels as fluid agents.

We excluded non‐randomised trials and studies using a cross‐over design.

Types of participants

Females, in any age group, who underwent gynaecological surgery (by laparoscopy or laparotomy).

We excluded studies investigating adhesion prevention in non‐gynaecological specialities.

Types of interventions

We grouped interventions for meta‐analysis according to physical state and main mechanism of action: hydroflotation agents (including dextran, 4% icodextrin solution), gel agents (including hyaluronic acid‐based gels, polyethylene‐glycol‐based gels, and polyethylene oxide and carboxymethylcellulose‐based gels), and pharmacological agents. We included the following comparisons.

Hydroflotation agent versus no hydroflotation agent (or placebo)
Gel agent versus no treatment (or placebo)
Gel agent versus hydroflotation agent used as an instillant
Steroid (including systemic, intraperitoneal, preoperative and postoperative) versus no steroid (or placebo)
Intraperitoneal noxytioline versus no noxytioline (or placebo)
Intraperitoneal heparin versus no heparin (or placebo)
Systemic promethazine versus no promethazine (or placebo)
GnRHa versus no GnRHa (or placebo)
Reteplase plasminogen activator versus no reteplase plasminogen activator (or placebo)
N,O‐carboxymethyl chitosan versus no N,O‐carboxymethyl chitosan (or placebo)

We made the decision to group hydroflotation agents and gel agents during the development of the 2014 update to this review (Ahmad 2014). To ease comparison between this update and the previous update we retained these groupings.

Types of outcome measures

Primary outcomes

1. Pelvic pain (improvement, worsening, no change in pain at second‐look laparoscopy (SLL)), independent of the method used to assess pelvic pain

2. Live birth rate, as defined by the individual study

Secondary outcomes

3. Incidence of adhesions at SLL

4. Mean adhesion score at SLL per participant, recorded on whichever scale the study authors used, but with preference given to the mAFS score

5. Clinical pregnancy rate as defined by the individual study

6. Improvement in adhesion score at SLL, recorded on whichever scale the study authors used, but with preference given to the modified American Fertility Society (mAFS) score

7. Worsening of adhesion score at SLL, recorded on whichever scale the study authors used, but with preference given to the mAFS score

8. Miscarriage rate, defined as loss of pregnancy before 24 weeks' gestation

9. Ectopic pregnancy rate

10. Improvement in quality of life (QoL) at SLL, recorded on whichever scale the study authors used, but with preference given to Short Form (SF)‐36

11. Adverse outcomes, local and systemic, thought to be due to the anti‐adhesion agent, in studies stating this as one of their outcomes, as opposed to observation

We included articles independent of the adhesion scoring method used. We included articles that met the inclusion criteria but did not report any of the outcomes of interest in this review in the qualitative analysis.

Search methods for identification of studies

This is an update of the review by Ahmad and colleagues (Ahmad 2014). The Cochrane Gynaecology and Fertility (CGF) Information Specialist designed the search strategy. We applied no language restrictions. See the Review Group website for additional details on the make‐up of the Specialised Register.

Electronic searches

We searched these electronic databases:

The Cochrane Gynaecology and Fertility Specialised Register, PROCITE platform, searched 22 August 2019 (Appendix 1)
CENTRAL, OVID platform, searched Issue 7 July, on 22 August 2019 (Appendix 2)
MEDLINE, OVID platform, searched from 1946 to 22 August 2019 (Appendix 3)
Embase, OVID platform, searched from 1980 to 22 August 2019 (Appendix 4)
PsycINFO, OVID platform, searched from 1806 to 22 August 2019 (Appendix 5)
International Clinical Trials Registry Platform (ICTRP), Web platform, searched 22 August 2019 (Appendix 6)
Clinicaltrials.gov, Web platform, searched 22 August 2019 (Appendix 7).

Searching other resources

We handsearched grey literature in August 2019, specifically, abstracts presented at meetings of the British Society of Gynaecological Endoscopy, the European Society of Gynaecological Endoscopy, the American Association of Gynecological Laparoscopists, and the British Fertility Society. We also searched the reference lists of included studies and communicated with experts in the field.

Data collection and analysis

Selection of studies

Three review authors (KK, MT, PA) independently performed an initial screen of titles and abstracts to assess reports for suitability of inclusion in accordance with the eligibility criteria. GA, KK, MT, and PA independently examined the full‐text articles and abstracts to confirm eligibility. If necessary, we contacted investigators to obtain further information. We settled discrepancies by consensus between GA, KK, and MT.

Data extraction and management

Three review authors (KK, MT, PA) independently extracted the data. Data were transcribed onto a Microsoft Word data collection form designed for this review, before they entered them into Review Manager 5. We used the statistical package included in Review Manager 5, provided by Cochrane, to analyse and synthesise the data. We contacted study authors for further information as required. If we did not receive a reply, and the information was related to bias, we denoted this as unclear; if the information required was statistical, and the information lacking prevented inclusion in the meta‐analysis, we did not include the study in that outcome analysis, although it was still considered an 'included study'. GA, KK, and MT resolved disagreements by consensus.

Assessment of risk of bias in included studies

Two review authors (KK, MT) independently assessed the risk of bias of all studies deemed eligible. The 'Risk of bias' domains included allocation (random sequence generation and allocation concealment); blinding of women, personnel, and outcome assessors; incomplete outcome data; selective reporting, and other biases. We settled disagreements regarding interpretation of data by consensus between GA, KK, and MT. We assessed the quality of trials with the 'Risk of bias' tool, recommended in the Cochrane Handbook for Systematic Reviews of Interventions and entered our assessment into the 'Risk of bias' tables (Higgins 2011).

Measures of treatment effect

We used an odds ratio (OR) for dichotomous data (e.g. number of women with worsening adhesion score). We used a standardised mean difference (SMD) for continuous measures that used different scales (e.g. mean adhesion score at SLL). When the same scale was used, we used a mean difference (MD) for this specific scale. We presented 95% confidence intervals (CIs) for all outcomes.

Unit of analysis issues

The included primary studies were analysed per woman. We excluded studies that used an internal control, and listed them as such.

Dealing with missing data

We contacted Investigators to request missing data. If data were insufficient to include the study in a particular analysis, we did not include it.

Assessment of heterogeneity

We used the Chi² test and the I² statistic to determine significant heterogeneity. We considered an I² measurement > 30% to be moderate heterogeneity, > 50% substantial heterogeneity, and > 70% high heterogeneity.

Assessment of reporting biases

In consideration of the difficulty of detecting and correcting publication bias and other reporting bias, we aimed to minimise the impact by ensuring that we performed a robust and comprehensive search. We planned to create a funnel plot to assess the risk of reporting bias if we included 10 or more studies in a meta‐analysis.

Data synthesis

We performed statistical analysis in accordance with guidelines developed by Cochrane. We combined data from the primary studies in Review Manager 5, using the fixed‐effect model. An increase in OR or SMD or MD was indicated if it fell to the right of the central line of the forest plot; a decrease was indicated if it fell to the left of the central line. Whether this favoured treatment or control depended on the outcome analysed, but we labelled the axes accordingly.

Subgroup analysis and investigation of heterogeneity

When we identified significant heterogeneity, we explored the cause, and performed a sensitivity analysis using the random‐effects model. We highlighted this in the results section, and noted any variation in the direction of effect. We would have performed a subgroup analysis comparing the effects of antiadhesion agents on de novo adhesions versus re‐formed adhesions, if sufficient data were available.

Sensitivity analysis

We performed a sensitivity analysis to determine whether the results were robust to decisions made regarding eligibility of the studies and analysis. If we considered that a study had a high risk of bias, or we identified an apparent outlier, we investigated the reason for the significant heterogeneity, whether this was believed to be clinical or methodological, and we conducted an analysis to evaluate whether including the study significantly affected the results. We reported results of the sensitivity analysis in the Risk of bias in included studies subsection of the results section.

Overall quality of the body of evidence and 'Summary of findings' table

We prepared 'Summary of findings' tables using GRADEpro GDT software and Cochrane methods (GRADEpro GDT; Higgins 2011) for the following comparisons; hydroflotation agents versus no hydroflotation agents (or placebo); gel agents versus no gel agents (or placebo); gel agents versus hydroflotation agents used as instillants; and steroids (any route) versus no steroids (or placebo), all for adhesion prevention after gynaecological surgery. These tables evaluate the overall quality of the body of evidence for the main review outcomes (pelvic pain, live birth rate, incidence of adhesions at SLL, mean adhesion score at SLL, clinical pregnancy rate, and adverse events) using GRADE criteria (study limitations (i.e. risk of bias), consistency of effect, imprecision, indirectness, and publication bias). We justified our judgements about the quality of the evidence quality (high, moderate, low, or very low), and documented and incorporated them into the reporting of results for each outcome.

Results

Description of studies

Results of the search

We identified 44 studies as potentially eligible for inclusion. We included 32 studies. For a summary of each included study, see the section Characteristics of included studies. Reasons for study exclusion are detailed in the Characteristics of excluded studies section. For details of the screening and selection process, see Figure 1.

Included studies

Study design and setting

Of the 32 included studies, 20 were conducted at multiple centres, and 12 at a single centre. Nine were conducted in the USA, seven in Europe, three in Australia, one in the USA and Europe, two in the Netherlands, two in Italy, one in Sweden, one in the UK, one in Germany, one in China, and one in Germany, Canada, and the Netherlands Antilles; three studies did not state their location.

We were unable to include the results from nine of the included trials in any statistical analyses. In some cases, the study authors used different ways of assessing adhesions, such as reporting only individual sections of the modified American Fertility Society endometriosis scale (mAFS) (Hellebrekers 2009; Diamond 2003); the adhesion area (cm²), as in Coddington 2009, or change in adhesion score at SLL as in Mettler 2008.

We could not include Lundorff 2005 in the statistical analyses, as investigators reported the effect of the anti‐adhesion agent per adnexa, not per participant.

Relevant outcome data from Rosenberg 1984 and Thornton 1998 were only displayed in the form of graphs, without any written numerical values. We read the results off the graphs, and presented them in additional tables, but did not include them in the statistical analyses. Caution is needed when interpreting affected data sets, as the exact numerical values are unknown.

Rose 1991 and Sites 1997 did not report any data regarding any of our outcomes of interest, so could not be included in any statistical analysis.

Thus, we included 23 trials in the statistical analyses presented below.

Eighteen studies stated that they received commercial funding.

Participants

There was a wide variety in the number of women in each study, with participant numbers ranging from 9 to 203 in the intervention group, and from 6 to 199 in the control group. All participants were women undergoing a gynaecological procedure, who had a second‐look laparoscopy (SLL). Reasons for surgery included pelvic inflammatory disease (PID), endometriosis, adhesions, fibroids, pelvic pain, pelvic mass, endometrioid cysts, and infertility assessment and treatment (e.g. tubal surgery).

Interventions

The numbers of studies entered into any statistical analysis for each comparison are as follows.

Seven studies compared hydroflotation agents versus placebo (Brown 2007; Buttram 1983; Diamond 1998; diZerega 2002; Jansen 1985; Larsson 1985; Trew 2011). We made a distinction between hydroflotation agents (e.g. dextran, 4% icodextrin, 0.4% hyaluronic acid) designed as anti‐adhesion agents; and liquids, such as saline, which was often used as a control, and was not considered a hydroflotation agent in this review.
Nine studies compared gel agents versus no gel agents (Cheong 2017; Fossum 2011; Mais 2006; Mettler 2004; Pellicano 2003; Tchartchian 2014; Ten Broek 2012; Trew 2017; Young 2005) .
Three studies compared gel agents versus hydroflotation agents (Johns 2001; Liu 2015; Lundorff 2001).
Four studies compared steroids versus no steroids (or placebo) (Jansen 1985; Jansen 1990; Querleu 1989; Rock 1984) .
One study compared noxytioline versus no noxytioline (Querleu 1989).
One study compared heparin versus placebo (Jansen 1988).
One study compared promethazine versus no promethazine (Jansen 1990).

Coddington 2009 investigated gonadotrophin‐releasing hormone agonist (GnRH) analogues versus placebo; however, we did not include it in a statistical analysis as it only reported adhesion area, which was not one of our outcomes of interest.

Hellebrekers 2009 investigated plasminogen activator versus placebo; however, we did not include it in any statistical analyses, as it only reported individual sections of the mAFS.

Diamond 2003 investigated the use of N,O‐carboxymethyl chitosan versus placebo; however this study reported only individual sections of the mAFS and incidence as proportion of sites affected rather than true incidence, thus we did not include it in any statistical analyses..

Outcomes

Three studies did not assess adhesions (Cheong 2017; Rose 1991; Sites 1997). Lundorff 2005 presented the results per adnexa.

Primary outcomes

One of the 32 studies examined pelvic pain (Brown 2007).

Three of the 32 studies examined live birth rate (Jansen 1985; Larsson 1985; Rock 1984).

Secondary outcomes

Of the 32 studies, 13 examined the incidence of adhesions at SLL (Buttram 1983; Diamond 1998; diZerega 2002; Jansen 1985; Johns 2001; Liu 2015; Lundorff 2001; Mais 2006; Mettler 2004; Pellicano 2003; Tchartchian 2014; Ten Broek 2012; Thornton 1998).

Of the 32 studies, nine examined the mean adhesion score at SLL per woman (Brown 2007; Buttram 1983; Larsson 1985; Lundorff 2001; Mais 2006; Ten Broek 2012; Thornton 1998; Trew 2011; Trew 2017).

Of the 32 studies, six examined the clinical pregnancy rate. All of the women in these studies were actively seeking pregnancy during the study time period (Buttram 1983; Cheong 2017; Jansen 1985; Larsson 1985; Querleu 1989; Rock 1984).

Of the 32 studies, 12 examined improvement in adhesion score at SLL (Brown 2007; Buttram 1983; diZerega 2002; Jansen 1985; Jansen 1988; Jansen 1990; Johns 2001; Larsson 1985; Lundorff 2001; Mettler 2004; Trew 2017; Young 2005).

Of the 32 studies, nine examined the number of women with a worse adhesion score at SLL (diZerega 2002; Jansen 1985; Jansen 1988; Jansen 1990; Johns 2001; Lundorff 2001; Mettler 2004; Querleu 1989; Young 2005).

None of the 32 studies examined the miscarriage rate.

Of the 32 studies, four examined the ectopic pregnancy rate (Jansen 1985; Larsson 1985; Querleu 1989; Rock 1984).

None of the 32 studies examined quality of life (QoL).

Of the 32 studies, 30 examined adverse outcomes. Cheong 2017 and Rosenberg 1984 were the only studies that did not examine adverse outcomes.

Excluded studies

We excluded 10 studies. Abu‐Elhasan 2014 used the same fluid agent for both the control and intervention group. Johns 2003 used an internal control. Diamond 2011 and Tulandi 1991 used internal controls, which was not explicitly stated in the abstract. One trial was not randomised (Tsuji 2005). One study did not state that it was randomised (Pellicano 2005), although it appeared to include the same study group as was used in Pellicano 2003. This was not explicitly stated in the methods, nor was the fact that the study was randomised, thus we excluded Pellicano 2005. One study was quasi‐randomised (Swolin 1967). One study assessed adhesions at caesarean section, so did not meet our review's inclusion criteria (Imai 2003). Tulandi 1985 was included in the original review, however it has been excluded as it does not report fertility or adhesion outcomes.

DiZerega 2007 was included in the previous update of the review (Ahmad 2014) however at this update it was noted that this study reported composite data from two previous studies already included in the review (Lundorff 2005 and Young 2005). DiZerega 2007 did not recruit any new participants, therefore it could not be considered at true RCT and as it presented composite data its results could not be wholly attributed to either Lundorff 2005 or Young 2005. As DiZerega 2007 reported results per adnexa rather than per participant, data it presented were not incorporated in any statistical analysis, meaning its exclusion does not affect our conclusions.

Studies awaiting classification

Three studies are awaiting classification, pending publication of sufficient data to allow their inclusion (Hudecek 2012; Litta 2013; Robertson 2018).

Risk of bias in included studies

The risk of bias for each included study can be seen in the Characteristics of included studies section. Figure 2 presents a summary of risk of bias of all included studies. Figure 3 depicts the proportions of studies within each judgement for each 'Risk of bias' element.

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

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

Allocation

Sequence generation

We did not assess any studies at high risk of sequence generation bias.

Twenty studies adequately explained an appropriate method of sequence generation; thus, we deemed them at low risk (Brown 2007; Cheong 2017; Diamond 1998; diZerega 2002; Hellebrekers 2009; Jansen 1985; Jansen 1988; Johns 2001; Larsson 1985; Liu 2015; Lundorff 2001; Lundorff 2005; Mais 2006; Mettler 2004; Mettler 2008; Pellicano 2003; Rock 1984; Rose 1991; Sites 1997; Tchartchian 2014).

Twelve studies described the methods of random sequence generation inadequately; we deemed them at unclear risk (Buttram 1983; Coddington 2009; Diamond 2003; Fossum 2011; Jansen 1990; Querleu 1989; Rosenberg 1984; Ten Broek 2012; Thornton 1998; Trew 2011; Trew 2017; Young 2005).

Allocation concealment

We did not assess any studies at high risk of allocation concealment bias.

We assessed 15 studies at low risk of allocation concealment bias, as the authors described an acceptable method of allocation concealment (Cheong 2017; Diamond 1998; diZerega 2002; Johns 2001; Liu 2015; Lundorff 2001; Mais 2006; Mettler 2004; Mettler 2008; Rosenberg 1984; Tchartchian 2014; Ten Broek 2012; Trew 2011; Trew 2017; Young 2005).

Seventeen studies did not provide sufficient information on allocation to permit a judgement, so we considered them at unclear risk (Brown 2007; Buttram 1983; Coddington 2009; Diamond 2003; Fossum 2011; Hellebrekers 2009; Jansen 1985; Jansen 1988; Jansen 1990; Larsson 1985; Lundorff 2005; Pellicano 2003; Querleu 1989; Rock 1984; Rose 1991; Sites 1997; Thornton 1998).

Blinding

We rated two studies at low risk for performance bias, as both the women and initial surgical team were blinded to the treatment allocation (Pellicano 2003; Trew 2011). We rated the remaining studies as unclear risk of bias. In six studies, while the women were blinded to treatment allocation, it was not practical to blind the initial surgical teams, due to the differences between the interventions being compared (Cheong 2017; Liu 2015; Mettler 2008; Rosenberg 1984; Tchartchian 2014; Ten Broek 2012). In 10 studies, the blinding of the women was not clearly stated, and the initial surgical teams were not blinded, due to the differences between the interventions (Brown 2007; diZerega 2002; Hellebrekers 2009; Jansen 1985; Jansen 1988; Jansen 1990; Lundorff 2001; Mais 2006; Rosenberg 1984; Young 2005). In the remaining studies, there was insufficient information to assess risk of performance bias; therefore, we rated them as unclear risk of bias.

We rated 20 studies at low risk for detection bias, as all outcome assessors were unaware of allocation at the time of assessment (Cheong 2017; Coddington 2009; Diamond 1998; diZerega 2002; Fossum 2011; Hellebrekers 2009; Jansen 1985; Jansen 1988; Johns 2001; Liu 2015; Lundorff 2001; Lundorff 2005; Mais 2006; Rose 1991; Rosenberg 1984; Tchartchian 2014; Ten Broek 2012; Trew 2011; Trew 2017; Young 2005). We rated one study at high risk for detection bias, as the surgeons assessing the adhesions were not blinded to the treatment allocation (Mettler 2008). The remaining studies provided insufficient information to assess risk of detection bias; therefore, we rated them as unclear risk of bias.

Incomplete outcome data

We assessed three studies at high risk of attrition bias (Brown 2007; Rosenberg 1984; Thornton 1998).

Forty‐seven women in Brown 2007 (N = 402) withdrew from the study prior to its completion; 18 of these due to 'major protocol violations', without any further information; therefore, we considered this study at high risk of attrition bias.

One participant in the control group in Thornton 1998 was excluded from efficacy analyses as they had a large number of adhesions at baseline, which all reformed. The explanation for this was to make the two study groups more comparable; however, the trial authors stated there were no statistically significant differences between the two groups at baseline, so there seems to be no clear reason for this exclusion; therefore, we considered this study at high risk of attrition bias.

Two women in Rosenberg 1984 withdrew prior to SLL; no explanation was provided; therefore, we considered this study at high risk of attrition bias.

We considered 22 studies to be at low risk for attrition bias (Coddington 2009; Diamond 1998; Diamond 2003; diZerega 2002; Fossum 2011; Hellebrekers 2009; Jansen 1985; Jansen 1988; Johns 2001; Larsson 1985; Lundorff 2005; Mettler 2004; Mettler 2008; Pellicano 2003; Querleu 1989; Rock 1984; Rose 1991; Sites 1997; Ten Broek 2012; Trew 2011; Trew 2017; Young 2005).

Seven studies did not provide sufficient information to reveal attrition bias; consequently, we rated the risk of attrition bias as unclear (Buttram 1983; Cheong 2017; Jansen 1990; Liu 2015; Lundorff 2001; Mais 2006; Tchartchian 2014).

Selective reporting

We assessed one study at high risk for reporting bias (Mettler 2008). The trial authors decided 'in hindsight' to change the primary outcome scoring method from the total mAFS score, as stated in the original review protocol, to the mAFS of the posterior uterus, as discussed during data analysis. Consequently, we conducted a sensitivity analysis and found that excluding Mettler 2008 made no difference to the direction of treatment effect.

We obtained study protocols or found trial register entries for five studies (Cheong 2017; Fossum 2011; Liu 2015; Tchartchian 2014; Trew 2017). These studies reported all planned outcomes; therefore, we considered them at low risk of reporting bias.

We considered the remaining 26 studies as unclear risk of reporting bias, as we were unable to identify any study protocols or trial registries for comparison.

Other potential sources of bias

We rated five studies at high risk of other potential source of bias (Fossum 2011; Lundorff 2001; Rosenberg 1984; Tchartchian 2014; Thornton 1998).

Fossum 2011, Rosenberg 1984 and Thornton 1998 all reported important outcomes in graphical format only, without providing key numerical results such as standard deviations (SD), standard error of the mean (SEM), confidence intervals (CI), and P values. We imputed data from these studies, based on the available data, however, the imputed data are not likely to be entirely accurate.

The study groups used in the study by Tchartchian 2014 had multiple statistically significant differences at baseline; therefore, we considered it at high risk of other sources of bias.

Lundorff 2001 reported standard deviations of 0.01 for the mean adhesion score. These standard deviations appear highly likely to be inaccurate, considering the size of the sample involved. We thought that standard errors may have been mistakenly reported as standard deviations; therefore, we imputed data based upon this assumption, however, it is highly likely that these results are inaccurate.

We assessed two studies as having other sources of bias that were unclear (Jansen 1988; Ten Broek 2012). A potential source of bias in Jansen 1988 was that the practice of adding hydrocortisone sodium succinate to the irrigation solution was stopped after 46 women had received it, because a possible detrimental effect was reported in an earlier study. These 46 women were still included in the analysis. The study by Ten Broek 2012 was "prematurely ended due to financial and organizational reasons. During the conduct of the study, the clinical trial insurance unexpectedly required a separate fee for both laparoscopic procedures in each patient"; we still included this study.

We did not identify any potential sources of bias in the other 25 included studies.

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4

Summary of findings 1. Hydroflotation agents versus no hydroflotation agents (or placebo) for adhesion prevention after gynaecological surgery.

Hydroflotation agents versusno hydroflotation agents (or placebo)
Patient or population: women undergoing gynaecological surgery Settings: hospital Intervention: hydroflotation agents Control: no hydroflotation agents (or placebo)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	No hydroflotation agents (or placebo)	Hydroflotation agents
Pelvic pain	806 per 1000	814 per 1000 (684 to 897)	OR 1.05  (0.52 to 2.09)	226 (1 study)	⊕⊝⊝⊝ Very low^a,b
Live birth rate	129 per 1000	90 per 1000 (41 to 189)	OR 0.67  (0.29 to 1.58)	208 (2 studies)	⊕⊕⊝⊝ Low^b
Incidence of adhesions at second‐look laparoscopy	842 per 1000	645 per 1000 (540 to 746)	OR 0.34  (0.22 to 0.55)	566 (4 studies)	⊕⊕⊕⊕ High
Mean adhesion score at second‐look laparoscopy	The mean adhesion score at second‐look laparoscopy ranged across the control groups from 2.19 to 8.42	The mean adhesion score at second‐look laparoscopy in the intervention groups was 0.06 standard deviations lower (0.2 lower to 0.09 higher)		722 (4 studies)	⊕⊕⊕⊝ Moderate^a	SMD ‐0.06 (‐0.2 to 0.09)^c
Clinical pregnancy rate	256 per 1000	180 per 1000 (110 to 281)	OR 0.64  (0.36 to 1.14)	310 (3 studies)	⊕⊕⊕⊝ Moderate^d
Adverse events	No studies reported any adverse events attributable to the intervention
The basis for the assumed risk* is the median control group risk across studies. The corresponding risk (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; OR: odds ratio; SMD: standardised mean difference; mAFS: modified American Fertility Society
GRADE Working Group grades of evidence. High quality. Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality. Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality. Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality. We are very uncertain about the estimate.

Gel agents versusno gel agents (or placebo)
Patient or population: women undergoing gynaecological surgery Settings: hospital Intervention: gel agents Control: no gel agents (or placebo)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	No gel agents (or placebo)	Gel agents
Pelvic pain	Not reported by any studies in this comparison
Live birth rate	Not reported by any studies in this comparison
Incidence of adhesions at second‐look laparoscopy	842 per 1000	581 per 1000 (391 to 752)	OR 0.26  (0.12 to 0.57)	147 (5 studies)	⊕⊕⊕⊕ High
Mean adhesion score at second‐look laparoscopy	The mean adhesion score at second‐look laparoscopy ranged across the control groups from 2.19 to 8.42	Mean adhesion score at second‐look laparoscopy in the intervention groups was 0.50standard deviations lower (1.09 lower to 0.09 higher)		159 (4 studies)	⊕⊕⊕⊝ Moderate^a	SMD ‐0.50 (‐1.09 to 0.09)^b
Clinical pregnancy rate	256 per 1000	64 per 1000 (6 to 410)	OR 0.20 (0.02 to 2.02)	30 (1 study)	⊕⊕⊝⊝ Low^c
Adverse events	No studies reported any adverse events attributable to the intervention
The basis for the assumed risk* is the median control group risk across studies. The corresponding risk (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; OR: odds ratio; SMD: standardised mean difference; mAFS: modified American Fertility Society
GRADE Working Group grades of evidence. High quality. Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality. Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality. Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality. We are very uncertain about the estimate.

Gel agents versus hydroflotation agents used as instillants
Patient or population: women during gynaecological surgery Settings: hospital Intervention: gel agents Comparison: hydroflotation agents used as instillants
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Hydroflotation agents used as instillants	Gel agents
Pelvic pain	Not reported by any study in this comparison
Live birth rate	Not reported by any study in this comparison
Incidence of adhesions at second‐look laparoscopy	457 per 1000	297 per 1000 (207 to 412)	OR 0.50  (0.31 to 0.83)	538 (3 studies)	⊕⊕⊕⊝ Moderate^a
Mean adhesion score at second‐look laparoscopy	The mean adhesion score at second‐look laparoscopy in the hydroflotation group was 1.25	Mean adhesion score at second‐look laparoscopy in the intervention group was 0.79 lower (0.82 to 0.76 lower)		77 (1 study)	⊕⊝⊝⊝ Very low^b,c	^d
Clinical pregnancy rate	Not reported by any study in this comparison
Adverse events	No studies reported any adverse events attributable to the interventions
The basis for the assumed risk* is the median hydroflotation group risk across studies. The corresponding risk (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; OR: odds ratio; MD: mean difference; mAFS: modified American Fertility Society
GRADE Working Group grades of evidence. High quality. Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality. Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality. Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality. We are very uncertain about the estimate.

Steroids (any route) versusno steroids (or placebo)
Patient or population: women after gynaecological surgery Settings: postsurgical Intervention: steroids (any route) Control: no steroids (or placebo)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	No steroids (or placebo)	Steroids (any route)
Pelvic pain	Not reported by any study in this comparison
Live birth rate	129 per 1000	88 per 1000 (38 to 194)	OR 0.65  (0.26‐1.62)	223 (2 studies)	⊕⊕⊝⊝ Low^a
Incidence of adhesions at second‐look laparoscopy	Not reported by any study in this comparison
Mean adhesion score at second‐look laparoscopy	Not reported by any study in this comparison
Clinical pregnancy rate	256 per 1000	258 per 1000 (185 to 348)	OR 1.01  (0.66 to 1.55)	410 (3 studies)	⊕⊕⊝⊝ Low^a,b
Adverse events	No studies reported any adverse events attributable to the intervention
The basis for the assumed risk* is the median control group risk across studies. The corresponding risk (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; OR: odds ratio
GRADE Working Group grades of evidence. High quality. Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality. Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality. Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality. We are very uncertain about the estimate.


Imputed mean change in adhesion score at SLL
Study	Mean change in adhesion score in hydroflotation agent group	SD	Number of participants	Mean change in adhesion score in placebo group	SD	Number of participants
Rosenberg 1984	‐2.72	4.1	23	2.14	6.64	21


Proportion of sites with adhesions at SLL
Study	Proportion in gel agent group	SD	Number of participants	Proportion in placebo group	SD	Number of participants
Thornton 1998	0.364	0.280	13	0.629	0.168	10


Imputed mean adhesion score at SLL
Study	Mean adhesion score at SLL in gel agent group	SD in gel agent group	Mean adhesion score at SLL in placebo group	SD in placebo group
Thornton 1998	1.78	0.80	6.06	1.67


Change in mean adnexal adhesion score at SLL
Study	Change in mean adnexal adhesion score in gel agent group	Number of participants/adnexa	Change in mean adnexal adhesion score in no gel agent group	Number of participants/adnexa
Lundorff 2005	‐2.8	25/45	7.0	24/41


Area of adhesions (cm²)
Study	Area of adhesions at first surgery in GnRH analogue group	Area of adhesions at SLL in GnRH analogue group	Number of participants	Area of adhesions at first surgery in placebo group	Area of adhesions at SLL in placebo group	Number of participants
Coddington 2009	0.4 (0.1)	10.7 (2.2)	10	0.4 (0.1)	9.2 (3.8)	8


Incidence of adhesions at SLL
Study	Mean incidence score in plasminogen activator group	SD	Number of participants	Mean incidence score in placebo group	SD	Number of participants
Hellebrekers 2009	1.8	2.2	11	1.5	1.7	14


Change in adhesion extent
Study	Change in adhesion extent in N,O‐carboxymethyl chitosan group	Number of participants	Change in adhesion extent in placebo group	Number of participants
Diamond 2003	‐0.1	16	‐0.06	17

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Pelvic pain at SLL	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.2 Live birth rate	2	208	Odds Ratio (M‐H, Fixed, 95% CI)	1.48 [0.63, 3.47]
1.3 Incidence of adhesions at SLL	4	566	Odds Ratio (M‐H, Fixed, 95% CI)	0.34 [0.22, 0.55]
1.4 Mean adhesion score at SLL	4	722	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.06 [‐0.20, 0.09]
1.5 Clinical pregnancy rate	3	310	Odds Ratio (M‐H, Fixed, 95% CI)	1.56 [0.88, 2.77]
1.6 Number of participants with improved adhesion score at SLL	4	665	Odds Ratio (M‐H, Random, 95% CI)	0.79 [0.49, 1.27]
1.7 Number of participants with worse adhesion score at SLL	1	53	Odds Ratio (M‐H, Fixed, 95% CI)	0.28 [0.07, 1.21]
1.8 Ectopic pregnancy rate (per pregnancy)	2	50	Odds Ratio (M‐H, Fixed, 95% CI)	0.35 [0.06, 1.85]
1.9 Imputed mean change in adhesion score at SLL	1		Other data	No numeric data

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Incidence of adhesions at SLL	3	538	Odds Ratio (M‐H, Fixed, 95% CI)	0.50 [0.31, 0.83]
3.2 Mean adhesion score at SLL	1	77	Mean Difference (IV, Fixed, 95% CI)	‐0.79 [‐0.82, ‐0.76]
3.3 Number of participants with improved adhesion score at SLL	2	342	Odds Ratio (M‐H, Fixed, 95% CI)	0.64 [0.34, 1.22]
3.4 Number of participants with worse adhesion score at SLL	2	342	Odds Ratio (M‐H, Fixed, 95% CI)	0.28 [0.12, 0.66]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Live birth rate	2	223	Odds Ratio (M‐H, Fixed, 95% CI)	1.54 [0.62, 3.84]
4.2 Clinical pregnancy rate	3	410	Odds Ratio (M‐H, Fixed, 95% CI)	0.99 [0.64, 1.51]
4.3 Number of participants with improved adhesion score at SLL	1	75	Odds Ratio (M‐H, Fixed, 95% CI)	0.21 [0.07, 0.58]
4.4 Number of participants with worse adhesion score at SLL	2	182	Odds Ratio (M‐H, Random, 95% CI)	0.27 [0.12, 0.58]
4.5 Ectopic pregnancy rate (per pregnancy)	3	83	Odds Ratio (M‐H, Random, 95% CI)	0.67 [0.08, 5.70]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Clinical pregnancy rate	1	126	Odds Ratio (M‐H, Fixed, 95% CI)	1.51 [0.68, 3.37]
5.2 Number of participants with worse adhesion score at SLL	1	87	Odds Ratio (M‐H, Fixed, 95% CI)	0.55 [0.17, 1.76]
5.3 Ectopic pregnancy rate (per pregnancy)	1	33	Odds Ratio (M‐H, Fixed, 95% CI)	4.91 [0.45, 53.27]


Change in adhesion severity
Study	Change in adhesion severity in N,O‐carboxymethyl chitosan group	Number of participants	Change in adhesion severity in placebo group	Number of participants
Diamond 2003	0.11	16	‐0.06	17

Date	Event	Description
25 June 2020	New citation required but conclusions have not changed	The addition of four new studies and exclusion of one study did not lead to a change in the conclusions of this review.
25 June 2020	New search has been performed	The review has been updated; four new studies have been incorporated (Cheong 2017; Liu 2015; Tchartchian 2014; Trew 2017). One study which was previously included (DiZerega 2007) has been excluded.

Date	Event	Description
8 April 2014	New citation required and conclusions have changed	This review has been updated; the following new studies have been incorporated (Brown 2007; Coddington 2009; Diamond 2003; DiZerega 2007a; Fossum 2011; Hellebrekers 2009; Lundorff 2005; Mais 2006; Mettler 2008; Rose 1991; Sites 1997; Ten Broek 2012; Thornton 1998; Trew 2011; Young 2005). The conclusions were changed.
7 November 2008	Amended	Converted to new review format.
13 January 2006	New citation required and conclusions have changed	Substantive amendment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Incidence of adhesions at SLL	5	147	Odds Ratio (M‐H, Fixed, 95% CI)	0.26 [0.12, 0.57]
2.2 Mean adhesion score at SLL	4	159	Mean Difference (IV, Fixed, 95% CI)	‐0.50 [‐1.09, 0.09]
2.3 Clinical pregnancy rate	1	30	Odds Ratio (M‐H, Fixed, 95% CI)	0.20 [0.02, 2.02]
2.4 Number of participants with improved adhesion score at SLL	2	58	Odds Ratio (M‐H, Fixed, 95% CI)	0.26 [0.04, 1.63]
2.5 Number of participants with worse adhesion score at SLL	2	58	Odds Ratio (M‐H, Fixed, 95% CI)	0.16 [0.04, 0.57]
2.6 Proportion of sites with adhesions at SLL	1		Other data	No numeric data
2.7 Mean change in adhesion score at SLL	2	134	Mean Difference (IV, Fixed, 95% CI)	‐1.60 [‐2.27, ‐0.92]
2.8 Change in mean adnexal adhesion score at SLL	1		Other data	No numeric data
2.9 Imputed mean adhesion score at SLL	1		Other data	No numeric data
2.10 Imputed number of sites with adhesions at SLL	1		Other data	No numeric data


Imputed number of sites with adhesions at SLL
Study	Number of sites with adhesions in gel agent group	Total number of sites in gel agent group	Number of sites with adhesions in placebo group	Total number of sites in placebo group
Thornton 1998	67	189	99	157

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Number of participants with improved adhesion score at SLL	1	63	Odds Ratio (M‐H, Fixed, 95% CI)	1.16 [0.43, 3.14]
6.2 Number of participants with worse adhesion score at SLL	1	92	Odds Ratio (M‐H, Fixed, 95% CI)	1.27 [0.56, 2.91]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Number of participants with improved adhesion score at SLL	1	75	Odds Ratio (M‐H, Fixed, 95% CI)	1.80 [0.70, 4.63]
7.2 Number of participants with worse adhesion score at SLL	1	93	Odds Ratio (M‐H, Fixed, 95% CI)	0.59 [0.25, 1.42]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 Change in adhesion extent	1		Other data	No numeric data
10.2 Change in adhesion severity	1		Other data	No numeric data

*Study characteristics*
Methods	Truly randomised trial (computer‐generated random numbers) Time of randomisation: day of surgery Double‐blind Power calculation: no ITT: yes Location: multi‐centre—16 centres, not stated where Timing and duration: July 2001 to March 2004; 2 years 8 months
Participants	Females 18 years of age and older undergoing laparoscopic gynaecological surgery only (N = 402) Indications for surgery: pelvic pain and infertility (93), infertility investigation (214), endometriosis (243) Surgery performed: laparoscopy and adhesiolysis Pre‐existing adhesions: not all women Number randomly assigned: 449 Number undergoing second‐look laparoscopy: 402 (29 withdrew, 13 declined SLL, 2 excluded intraoperatively, 18 major protocol violations) Timing second‐look laparoscopy: 4 to 8 weeks postoperative Blinding at second‐look laparoscopy: yes Exclusion criteria: < 3 adhesions lysed, systemic steroids, antineoplastic agents, radiation, pregnancy, active pelvic infection, cancer, allergy to Adept, additional non‐O+G procedures performed
Interventions	4% icodextrin versus Ringer's lactate > 100 mL every 30 minutes, no limit on amount used for irrigation. 1000 mL instilled at end
Outcomes	Analysed in review Pelvic pain Adhesions at second‐look laparoscopy Number of women with improvement in adhesion score Other outcomes Adhesions at second‐look laparoscopy Number of adhesion sites Mean AFS score reduction Number of women free of de novo adhesions "Clinical success"—study authors' definition: reduction of 3 or 30% of number of sites lysed Change in AFS score category Adhesion extent, severity Many sub‐analyses based on primary diagnosis
Notes	mAFS score Funded by Innovata Ltd, Vectura Group
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Treatment was randomised by computer‐generated randomisation on a 1:1 basis"
Allocation concealment (selection bias)	Unclear risk	no comments on allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Initial surgeons were blinded. Not clearly stated whether women were blinded.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not clearly stated whether the reviewer of the second‐look laparoscopy was blinded.
Incomplete outcome data (attrition bias) All outcomes	High risk	449 women were initially recruited and randomised. 29 withdrew from the studies with reasons given for their withdrawal. However, an additional 18 women had major protocol violations and therefore, were excluded from any efficacy analyses. No clear explanation of these violations was provided. Due to this lack of information and high rate of attrition (47 women, more than 10%), this is considered to be at high risk of attrition bias
Selective reporting (reporting bias)	Unclear risk	Data presented in full for all outcomes specified, however no study protocol or trial registry identified for comparison
Other bias	Low risk

*Study characteristics*
Methods	Truly randomised trial (method not stated) Time of randomisation: not stated Double‐blind Location: multi‐centre—9 centres in the USA (Duke, Yale, Baylor, USC, Vanderbilt, Washington, Indiana, Navy, and Masachussets) Timing and duration: not stated
Participants	Infertile women undergoing open gynaecological surgery (macrosurgery 53, loupe magnification 32, microsurgery 17) Condition: pelvic inflammatory disease with distal tubal disease (42), endometriosis (14), pelvic adhesions (46) Surgery performed: adhesiolysis, tubal surgery Pre‐existing adhesions: all women Age: 18 to 35 years (mean not stated) Duration infertility: not stated Infertility work‐up: semen analysis, postcoital test, and confirmation of ovulation (method not stated). Any abnormality was corrected before surgery Number randomly assigned: ? (no exclusions stated) Number undergoing treatment: 102 Number undergoing second‐look laparoscopy: 91 (11 conceived before laparoscopy) Timing second‐look laparoscopy: 8 to 12 weeks postoperative Blinding at second‐look laparoscopy: not explicitly stated Females 18 years of age and older undergoing laparotomy for gynaecological surgery Exclusion criteria: pregnancy, cancer, PID Number of women randomly assigned: 102
Interventions	Dextran versus normal saline Route of administration: intraperitoneal Dosage/volume: dextran 250 mL; saline 250 mL Prophylactic antibiotics: yes
Outcomes	Analysed in review Pregnancy rate Method of diagnosis: not stated Duration follow‐up: 8 to 12 weeks Adhesions at second‐look laparoscopy Improvement Change in score Other outcomes` Adhesions at second‐look laparoscopy Present, absent; according to anatomical site Appearance of tube Tubal patency rate Postoperative infection rate
Notes	Adhesion scoring system used Hulka system based on extent of adhesions (scored from 1 to 4) over fimbriae and ovaries (range 0 to 16) 1 = whole organ seen 2 = > 50% seen 3 = < 50% seen 4 = totally obscured
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement. "Patients were randomly assigned to either treatment"
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Insufficient information to permit judgement. "Blinded"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement. "Blinded"
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Exclusion criteria for randomisation; number of women randomly assigned not stated. All women who underwent treatment were accounted for.
Selective reporting (reporting bias)	Unclear risk	Data presented in full for all outcomes specified, however, no study protocol or trial registry identified for comparison
Other bias	Low risk	No others

PERMALINK

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery

Gaity Ahmad

Matthew Thompson

Kyungmin Kim

Priya Agarwal

Fiona L Mackie

Sofia Dias

Mostafa Metwally

Andrew Watson

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Overall quality of the body of evidence and 'Summary of findings' table

Results

Description of studies

Results of the search

1.

Included studies

Study design and setting

Participants

Interventions

Outcomes

Primary outcomes

Secondary outcomes

Excluded studies

Studies awaiting classification

Risk of bias in included studies

2.

3.

Allocation

Sequence generation

Allocation concealment

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Summary of findings 1. Hydroflotation agents versus no hydroflotation agents (or placebo) for adhesion prevention after gynaecological surgery.

Summary of findings 2. Gel agents versus no gel agents (or placebo) for adhesion prevention after gynaecological surgery.

Summary of findings 3. Gel agents versus hydroflotation agents used as instillants for adhesion prevention after gynaecological surgery.

Summary of findings 4. Steroids (any route) versus no steroids (or placebo) for adhesion prevention after gynaecological surgery.

1. Hydroflotation agents versus no hydroflotation agents (or placebo)

Primary outcomes

*Study characteristics*
Methods	Unit of randomisation: women Method of randomisation: computer‐generated random numbers in concealed envelopes Time of randomisation: randomised intraoperatively Blinding: women blinded. Assessors at follow‐up blinded.
Participants	Women aged between 18 and 38 years, undergoing gynaecological laparoscopy with possible peri‐ovarian adhesions Exclusion criteria: presence of, or history of malignancy, women on medications affecting ovulation, women with known conditions resulting in anovulation N = 30 15 randomised to intervention and 15 to control Dropouts: None stated. Flow diagram states 17 women randomised to intervention group, however, all other text states 15. Age: mean age 32.7 in intervention group, 31.5 in control Baseline characteristics: states no significant differences Indication for surgery: not clearly stated. States undergoing laparoscopy for gynaecological pathology. Pre‐existing adhesions: all women had peri‐ovarian adhesions and underwent adhesiolysis. Aetiology of pre‐existing adhesions: not stated Microsurgery: principles of microsurgery were followed Additional surgical procedures: not clearly stated, but all women underwent surgery for some form of gynaecological pathology Location: Southampton, UK Timing: December 2011 to January 2014
Interventions	Cross‐linked hyaluronic acid versus no treatment Other adjuvants used: none stated Second‐look laparoscopy not performed
Outcomes	Pregnancy outcomes: Ovarian function Clinical pregnancy rate at 2 years
Notes	Funding provided by Nordic Pharma No power calculation performed ISRCTN Number: ISRCTN1833588
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated random numbers. The randomisation code was broken at the end of follow‐up period
Allocation concealment (selection bias)	Low risk	Consent was obtained prior to baseline assessment. Concealed, opaque, unlabelled envelopes were opened only after it had been determined that the woman met the intraoperative criteria
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	women were blinded to the allocation treatment, but the primary surgeon was not blinded; women who wished to know their treatment group were informed at the end of follow‐up period.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The assessor who administered the questionnaires and recruited the women was the research nurse who did not have prior knowledge of what type of surgery the women underwent. The assessor during follow‐up was blinded to treatment.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	2 women randomised to Hyalobarrier were lost to follow‐up and were not accounted for; low initial sample number (43 screened, 32 randomised)
Selective reporting (reporting bias)	Low risk	All outcomes stated in clinical trial registry are reported per doi: org/10.1186/ISRCTN18335881
Other bias	Unclear risk	80% of women in intervention group had mild adhesions initially, versus 46.7% in control group. Paper states no difference in severity between the two groups, however, no statistical analysis was provided.

*Study characteristics*
Methods	Truly randomised trial: no comment regarding method of randomisation Time of randomisation: no comment about timing of randomisation Blinding: single‐blind trial Power calculation: no power calculation ITT: no Location: sIngle centre. Location not stated Timing and duration: not stated
Participants	Women of reproductive age undergoing surgery for symptomatic uterine leiomyomata 20 women randomly assigned 2 women excluded from analysis because of severe pelvic adhesive disease and no myoma requiring treatment Second‐look laparoscopy 2 to 10 weeks after initial surgery Blinding at second‐look laparoscopy: yes
Interventions	3 months' preoperative treatment with GnRHa therapy (Lupron 3.75 mg monthly depot injection) or placebo (saline) Surgery within 4 weeks of last injection
Outcomes	Second‐look adhesion area (cm²) defined as surface of uterine visceral peritoneum covered with adhesions Ratio of adhesion area (cm²) to total myometrial, incision length in cm (total length of all incisions made through uterine visceral peritoneum)
Notes	Received funding from TAP Pharmaceuticals
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to allow judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to allow judgement
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Insufficient information to allow judgement
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "The same senior surgeon performed all adhesion scoring and was blinded to the treatment group of the women. All procedures were videotaped and measurements confirmed by an external reviewer"
Incomplete outcome data (attrition bias) All outcomes	Low risk	No outcome data missing
Selective reporting (reporting bias)	Unclear risk	Data presented in full for all outcomes specified, however, no study protocol or trial registry identified for comparison
Other bias	Low risk

*Study characteristics*
Methods	True randomisation (randomisation list) Time of randomisation: preoperative Multi‐centre study: 23 centres in USA Power calculation: no Double‐blinding: yes
Participants	Females 18 years of age and older undergoing laparotomy for gynaecological surgery Exclusion criteria: pregnancy, cancer, PID Number of women randomly assigned: 277 Number of women undergoing second‐look laparoscopy evaluation: 245
Interventions	0.4% hyaluronic acid versus phosphate‐buffered saline as irrigant, not instillant Route of administration: intraperitoneal Dosage/volume: maximum of 1 L of SepraCoat or placebo Second‐look laparoscopy: average of 40 days later
Outcomes	Analysed in review Adhesions present at second‐look laparoscopy Mean adhesion score Other outcomes Mean extent of adhesion score Mean incidence of de novo adhesions at second‐look laparoscopy Mean extent of adhesion score at second‐look laparoscopy. Pregnancy rates: no
Notes	Adhesion scoring system used: own system 0 = no adhesions 1 = up to 25% 2 = 26%‐50% 3 = more than 50%
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Before their initial procedure, patients at each centre were assigned randomly according to a computer‐generated list"
Allocation concealment (selection bias)	Low risk	Quote: "The surgeons who performed the initial procedures, the surgeons who performed the second‐look laparoscopies, and the independent reviewer were blinded to randomisation"
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Initial surgeons were blinded to the solution being used in each woman. Not clearly stated whether women were blinded to allocation.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "A videotape recording of the abdominopelvic cavity was made at this time [of second‐look laparoscopy]; the video was reviewed later by a blinded, independent reviewer"
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data
Selective reporting (reporting bias)	Unclear risk	Data presented in full for all outcomes specified, however no study protocol or trial registry identified for comparison
Other bias	Low risk	Sponsored by Genzyme Corporation

*Study characteristics*
Methods	Randomised trial, although method of randomisation not stated Time of randomisation: during surgery Double‐blind. independent blinded reviewer scored videos of surgery, in addition to the surgeon who performed the procedure Power calculation: no, pilot study Location: multi‐centre (4)—USA Timing and duration: not stated
Participants	Females 18 years of age and older undergoing laparoscopic gynaecological surgery only (N = 34) Indication for surgery: pelvic pain, infertility, pelvic mass, uterine fibroids, endometriosis Surgery performed: laparoscopy Pre‐existing adhesions: not all women Number analysed: 32 (videotape not made in 1 case, 1 did not undergo SLL because of a reaction that was subsequently attributed to existing rheumatoid arthritis) Timing second‐look laparoscopy: 2 to 10 weeks postoperative Blinding at second‐look laparoscopy: yes, independent blinded reviewer used Exclusion criteria: pregnant, lactating, had previously undergone salpingectomy, oophorectomy, or hysterectomy, had a known cancer, active PID, received hormonal therapy within 1 month of initial surgery
Interventions	N,O‐carboxymethyl chitosan versus instillant of Ringer's lactate > 100 mL every 30 minutes, no limit on amount used for irrigation. 1000 mL instilled at end
Outcomes	Analysed in review Adverse effects Other outcomes Adhesions at second‐look laparoscopy Number of adhesion sites Extent of adhesions Severity of adhesions Total new surface area of adhesions Duration surgery
Notes	mAFS score used, data presented in a way that did not allow us to include results regarding adhesions at SLL Funded by Chitogenetics
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	States: was randomised "just before closure" but method not described
Allocation concealment (selection bias)	Unclear risk	no comments on allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not clearly stated whether women or initial surgeons were blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Each surgical procedure was videotaped in its entirety. After editing to remove application of the test or study agent, the video of each procedure was reviewed by an evaluator who was blinded to group assignment. The reviewer applied the same scoring system as the surgeons"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "All but 1 woman in the NOCC group underwent SLL; this patient developed a reaction that was subsequently attributed to her pre‐existing rheumatoid arthritis. A videotape was not made for one participant in the control group and thus, was not available for blinded review"
Selective reporting (reporting bias)	Unclear risk	Data presented in full for all outcomes specified, however, no study protocol or trial registry identified for comparison
Other bias	Low risk	Funded by Chitogenetics. Significant baseline differences between control and treatment groups—co‐variate analysis used

*Study characteristics*
Methods	Truly randomised trial: not stated Time of randomisation: at conclusion of initial surgery before closure Blinding: assessor blinded Power calculation: not used ITT: no Location: multi‐centre trial in USA Timing and duration: not stated
Participants	Inclusion criteria: non‐pregnant women between 18 and 49 years of age scheduled to undergo laparoscopic myomectomy for resection of at least 1 uterine fibroid (N = 41) Exclusion criteria: intraoperatively if infection or abscess identified, if entry into endometrial cavity or bowel lumen noted, if adhesiolysis involving bowel wall performed, or if concurrent, non‐gynaecological procedure was performed Number undergoing second‐look laparoscopy: 38 Timing second‐look laparoscopy: 4 to 12 weeks after initial surgery
Interventions	Hyaluronic acid and carboxymethylcellulose versus no treatment
Outcomes	Presence or absence of adhesions, extent and severity at 14 intra‐abdominal and pelvic sites at initial surgery and second‐look laparoscopy (mAFS score) Adverse effects
Notes	Funded by Genzyme Clinicaltrials.gov register number: NCT00624390
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No comment on randomisation method
Allocation concealment (selection bias)	Unclear risk	No comment on allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Insufficient information to provide judgement
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Surgeries videotaped and reviewed by blinded investigator
Incomplete outcome data (attrition bias) All outcomes	Low risk	No issues identified
Selective reporting (reporting bias)	Low risk	All outcomes specified in trial registry reported ‐ NCT00624390
Other bias	High risk	Data were only displayed in graphs, with no indication of SD, SE, CI or P value

*Study characteristics*
Methods	Truly randomised (random number generated) Time of randomisation: not stated Factorial design Power calculation: yes Location: Sydney, Australia Timing and duration: Feb 1982 to Nov 1983
Participants	Females older than 18 years of age scheduled for gynaecological laparoscopic surgery for pelvic pain and infertility Condition: pelvic adhesions, endometriosis Surgery performed: adhesiolysis and tubal, adnexal surgery Mean age: 31 years for study group (range 21 to 40); 32 years for control group (range 18 to 50) Number eligible: 62 Number undergoing second‐look laparoscopy: 53 Infertile women undergoing open gynaecological microsurgery Condition: peritubal adhesions (76), endometriosis (27), midtubal occlusion (61) Surgery performed: salpingolysis on its own (92) or with tubal reanastomosis (20); endometriosis surgery (11); tubal reanastomosis (41) Pre‐existing adhesions: 119 women Mean age: 30 years (range 21 to 39) Duration infertility: not stated Infertility work‐up: not stated Number eligible: 170 Number randomly assigned: 168 Number undergoing SLL: 164
Interventions	1. Dextran versus Hartmann's solution Route of administration: intraperitoneal Dosage/volume: dextran 100‐200 mL; Hartmann's 100 mL or more 2. Steroids versus no treatment Route of administration: intraperitoneal + systemic (IV and oral) if pre‐existing adhesions or endometriosis Dosage/volume: intraperitoneal: 500 mg hydrocortisone in 100 mL to 200 mL of dextran or Hartmann's; systemic: 8 mg of IV dexamethasone at time of surgery and 30 mg oral prednisolone daily until second‐look laparoscopy (SLL) Other adjuvants: perioperative pelvic irrigation with heparinised (5000 IU/L) Ringer's Prophylactic antibiotics: yes Timing SLL: 12 to 21 days Blinding at SLL: yes
Outcomes	Analysed in review Pregnancy Method of diagnosis: not stated Duration follow‐up: 1 to 18 months Live birth Miscarriage rate Ectopic rate Adhesions at second‐look laparoscopy Present; absent Improvement; deterioration Other outcomes Adhesions at second‐look laparoscopy Change in score
Notes	Adhesion scoring system used Modified American Fertility Society endometriosis scoring system (range 0 to 27) Results expressed as medians with 95% confidence limits
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization sequences were generated by a random number‐generation program, and assignment of adjuncts was carried out strictly in the pre‐determined sequence. Two separate randomizations were carried out independently"—1 for dextran or no dextran, and 1 for steroids or no steroids
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "Although completely effective blinding in the allocation of the adjuncts was not practicable (owing to the viscous nature of the dextran solution and the need to administer systemic corticosteroids to some women), information on allocation and use of adjuncts was not recorded in the operation notes, and was not readily available at the time of postoperative laparoscopy". Inital surgeons not blinded to allocation and unclear whether women were blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Qualification of adhesions was carried out from operation diagrams at a later date, without knowledge of the patient's identity or the use of an adjunct"
Incomplete outcome data (attrition bias) All outcomes	Low risk	All women accounted for, no missing outcome data
Selective reporting (reporting bias)	Unclear risk	Data presented in full for all outcomes specified, however, no study protocol or trial registry identified for comparison
Other bias	Low risk	None detected

*Study characteristics*
Methods	Truly randomised trial (random numbers generated) Time of randomisation: not stated Power calculation done Location: Sydney, Australia Timing and duration: Nov 1983 to Oct 1984
Participants	Infertile women undergoing open gynaecological microsurgery Condition: pelvic adhesions; endometriosis; tubal disease; uterine abnormalities Surgery performed: adhesiolysis or treatment for endometriosis (52); tubal anastomosis or uterine surgery (40) Pre‐existing adhesions: 63 women Mean age: 28 years (range 21 to 42) Duration infertility: not stated Infertility work‐up: not stated Number eligible: 102 Number undergoing second‐look laparoscopy: 92 Timing second‐look laparoscopy: 12 days postoperative Blinding at second‐look laparoscopy: yes
Interventions	Heparin containing Ringer's lactate versus Ringer's lactate Route of administration: intraperitoneal preoperative pelvic irrigation Dosage/volume: Ringer's solution containing 5000 IU heparin/L Other adjuvants: 52 women with pre‐existing adhesions or endometriosis received systemic steroids intraoperatively and postoperatively. The first 46 women in the study received intraperitoneal steroids Prophylactic antibiotics: yes
Outcomes	Analysed in review Adhesions at second‐look laparoscopy Improvement; no change; deterioration Change in score Other outcomes Blood transfusion requirements Wound healing
Notes	Adhesion scoring system used Modified American Fertility Society endometriosis scoring system (range 0 to 27) Data for adhesions at SLL (improvement; no change; deterioration) derived from scatter plot Some study information supplied in correspondence from study authors
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Strictly in a pre‐determined random sequence"
Allocation concealment (selection bias)	Unclear risk	Insufficient information available to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "Although completely effective blinding in heparin use was not practicable, owing to its obvious anticoagulant effect during the operation, information on its allocation was not recorded in the operation notes and was not available at the time of postoperative laparoscopy". Initial surgeons not completely blinded to allocation and unclear whether women were blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Improvement scores were derived later, without knowledge of the identity of the patient, or the use of heparin"
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data
Selective reporting (reporting bias)	Unclear risk	Data presented in full for all outcomes specified, however, no study protocol or trial registry identified for comparison
Other bias	Unclear risk	The practice of adding hydrocortisone sodium succinate to the irrigation solution was stopped after 46 women had received it, because of a possible detrimental effect reported in an earlier study

*Study characteristics*
Methods	Truly randomised trial (random number sequence) Timing of randomisation: not stated Factorial design Power calculation: yes Location: Sydney, Australia Timing and duration: not stated
Participants	Infertile women undergoing open gynaecological microsurgery Condition: pelvic adhesions, endometriosis, or both Surgery performed: adhesiolysis; excision of endometriosis Pre‐existing adhesions: 75 women Age: not stated Duration infertility: not stated Infertility work‐up: not stated Number randomly assigned: 95 (no exclusions stated) Number analysed: 93 for comparison 1; 95 for comparison 2 Timing second‐look laparoscopy: 10 or 12 days postoperative Blinding at second‐look laparoscopy: not stated
Interventions	1. Promethazine versus no treatment Route of administration: systemic (oral and IM) Dosage/volume: 50 mg oral 6 hours preoperatively and 50 mg IM intraoperatively 2. Postoperative steroids versus no treatment Route of administration: systemic (oral) Dosage/volume: postoperative prednisone 25 mg oral twice a day for 4 days, then 25 mg daily until SLL Other adjuvants: all women received systemic preoperative (50 mg prednisone 8 hours preoperatively) and intraoperative (24 mg dexamethasone IV) steroids Prophylactic antibiotics: yes
Outcomes	Analysed in review Adhesions at second‐look laparoscopy Improvement; no change; deterioration Other outcomes: adhesions at second‐look laparoscopy Change in score
Notes	Adhesion scoring system used Modified American Fertility Society endometriosis scoring system (range 0 to 27) Data obtained from review article and investigator himself Some study information supplied in correspondence from study authors
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stated that study was randomised, but method not stated
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not stated
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not stated
Selective reporting (reporting bias)	Unclear risk	Data presented in full for all outcomes specified, however, no study protocol or trial registry identified for comparison
Other bias	Low risk

*Study characteristics*
Methods	Truly randomised, third party–blinded study (randomisation schedule) Multi‐centre: 16 centres in the USA and Europe Power calculation: no
Participants	Women aged 18 to 46 years, undergoing peritoneal cavity surgery by laparotomy Intention‐to‐treat: no Exclusion criteria: diabetes, haemochromatosis, hepatic disorders, renal disorders, lymphatic disorders, haematological disorders, autoimmune disorders, coagulation disorders, patients with pelvic or abdominal infection, patients receiveing cancer therapy, postoperative hydrotubation, anticoagulants, fibrin glue or other thrombogenic agents at initial surgery. N = 265 131 randomised to gel and 134 to Ringer's lactate Dropouts: 16 patients did not return for SLL. Age: mean age not stated Baseline characteristics: No significant differences in severity or extent of adhesions at baseline Indication for surgery: variety of indications Pre‐existing adhesions: present in the majority of women Aetiology of pre‐existing adhesions: not clearly stated Microsurgery: no Additional surgical procedures: not clearly stated Timing: not clearly stated
Interventions	0.5% ferric hyaluronate gel versus Ringer's lactate Volume: 300 mL Ringer's lactate or Intergel instilled at the end of the procedure Antibiotics: no Second‐look laparoscopy: 6 to 12 weeks after primary procedure
Outcomes	Analysed in review Adhesions present at second‐look laparoscopy Improvement in adhesion score (AFS) Deterioration in adhesion score (AFS) Other outcomes Shift in mAFS adhesion score Per cent reduction in mAFS score Severity and extent of adhesions (median and standard deviation) Pregnancy rates: no
Notes	Adhesion scoring system used AFS adhesion score mAFS adhesion score Funded by Lifecore Biomedical Inc
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "At the time of initial surgical procedure, patients were assigned the next available study number corresponding to study device or control solution as determined by the randomization schedule"
Allocation concealment (selection bias)	Low risk	Study device or control solution was maintained in a sealed carton until decision to enrol the participant was made
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Initial surgical team not blinded to allocation. Not clearly stated whether women blinded to allocation.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinded independent review of adhesion data as a quality assurance check
Incomplete outcome data (attrition bias) All outcomes	Low risk	281 randomly assigned women receiving treatment—a total of 265 completed the study. Quote: "Of the 16 patient[s] who did not return for laparoscopy, 9 women discontinued for reasons unrelated to treatment. Although treatment‐related discontinuation could not be ruled out in the other seven women, a similar number were present in the treatment (N = 4) and control (N = 3) groups"
Selective reporting (reporting bias)	Unclear risk	Data presented in full for all outcomes specified, however, no study protocol or trial registry identified for comparison
Other bias	Low risk

*Study characteristics*
Methods	Truly randomised trial (random number generated) Time of randomisation: at end of surgery Double‐blind Location: multi‐centre—5 centres in Sweden (Huddinge, Umea, Stockholm, Skovde, and Molndal) Timing and duration: not stated
Participants	Infertile women undergoing open gynaecological microsurgery Condition: tubal or peritoneal adhesions, or both Surgery performed: adhesiolysis; tubal surgery (cases without adhesions excluded) Pre‐existing adhesions: all women Mean age: 31 years (range 21 to 39) Duration infertility: not stated Infertility work‐up: semen analysis, postcoital test, confirmation of ovulation (not specified), and laparoscopy; some also had hysterosalpingogram, sperm‐mucus penetration test, or both Number randomly assigned: 109 4 exclusions (lost to follow‐up) Number analysed: 105 Timing second‐look laparoscopy: 4 to 10 weeks postoperative Blinding at second‐look laparoscopy: not stated
Interventions	Dextran versus saline Route of administration: intraperitoneal Dosage/volume: dextran 250 mL; 0.9% saline 250 mL Prophylactic antibiotics: yes
Outcomes	Analysed in review Pregnancy rate Method of diagnosis: not stated Duration follow‐up: 12 to 36 months Full‐term pregnancy rate Miscarriage rate Ectopic rate Adhesions at SLL Change in score (ovaries, tubes, fimbriae) Other outcomes Adhesions at SLL Change in score according to anatomical site (total, pouch of Douglas, pelvic sidewall, colon, small bowel, anterior abdominal wall) Change in score according to aetiology of adhesions Tubal patency Laboratory tests
Notes	Adhesion scoring system used Own scoring system based on extent of adhesions (scored from 1 to 4) over tubes, fimbriae, and ovaries (range 4 to 24) 0 = none 1 = minimal 2 = mild (1 or 2 simple thin strands less than 1 cm in width) 3 = moderate (more than 2 adhesions of type 2 or at least 1 solid adhesion) 4 = severe (more than type 3)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "random selection sequence"
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Stated study was double‐blinded, but no clear details regarding blinding provided.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: was "double‐blinded," although no further information given. No mention of an independent reviewer or blinding during assessment
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data
Selective reporting (reporting bias)	Unclear risk	Data presented in full for all outcomes specified, however, no study protocol or trial registry identified for comparison
Other bias	Low risk