Fluid and Pharmacological Agents for Adhesion Prevention After Gynaecological Surgery (Review)

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review)

Ahmad G, Mackie FL, Iles DA, O’Flynn H, Dias S, Metwally M, Watson A

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2014, Issue 7 http://www.thecochranelibrary.com

HEADER...... 1 ABSTRACT ...... 1 PLAINLANGUAGESUMMARY ...... 2 SUMMARY OF FINDINGS FOR THE MAIN COMPARISON ...... 4 BACKGROUND ...... 6 OBJECTIVES ...... 7 METHODS ...... 7 RESULTS...... 9 Figure1...... 10 Figure2...... 12 Figure3...... 13 Figure4...... 14 Figure5...... 15 Figure6...... 16 Figure7...... 17 Figure8...... 18 Figure9...... 18 Figure10...... 19 ADDITIONALSUMMARYOFFINDINGS ...... 22 DISCUSSION ...... 32 AUTHORS’CONCLUSIONS ...... 33 ACKNOWLEDGEMENTS ...... 33 REFERENCES ...... 33 CHARACTERISTICSOFSTUDIES ...... 36 DATAANDANALYSES...... 83 Analysis 1.1. Comparison 1 Hydroflotation agent vs no hydroflotation agent, Outcome 1 Improvement in pelvic pain at second-looklaparoscopy...... 86 Analysis 1.2. Comparison 1 Hydroflotation agent vs no hydroflotation agent, Outcome 2 Live birth rate. . . . . 86 Analysis 1.3. Comparison 1 Hydroflotation agent vs no hydroflotation agent, Outcome 3 Improvement in adhesion score atSLL...... 87 Analysis 1.4. Comparison 1 Hydroflotation agent vs no hydroflotation agent, Outcome 4 Number of participants with worseningadhesionscore...... 88 Analysis 1.5. Comparison 1 Hydroflotation agent vs no hydroflotation agent, Outcome 5 Number of participants with adhesions at second-look laparoscopy...... 88 Analysis 1.6. Comparison 1 Hydroflotation agent vs no hydroflotation agent, Outcome 6 Mean adhesion score at second- looklaparoscopy...... 89 Analysis 1.7. Comparison 1 Hydroflotation agent vs no hydroflotation agent, Outcome 7 Clinical pregnancy rate. . 90 Analysis 1.9. Comparison 1 Hydroflotation agent vs no hydroflotation agent, Outcome 9 Ectopic pregnancy rate (per pregnancy)...... 91 Analysis 2.3. Comparison 2 Gel agent vs no treatment, Outcome 3 Number of participants with improvement in adhesion score...... 92 Analysis 2.4. Comparison 2 Gel agent vs no treatment, Outcome 4 Number of participants with worsening adhesion score...... 92 Analysis 2.5. Comparison 2 Gel agent vs no treatment, Outcome 5 Number of participants with adhesions at second-look laparoscopy...... 93 Analysis 2.6. Comparison 2 Gel agent vs no treatment, Outcome 6 Mean adhesion score at second-look laparoscopy. 93 Analysis 3.3. Comparison 3 Gel agent vs hydroflotation agent when used as an instillant, Outcome 3 Number of participants with improvement in adhesion score...... 94 Analysis 3.4. Comparison 3 Gel agent vs hydroflotation agent when used as an instillant, Outcome 4 Number of participants with worsening adhesion score...... 95

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) i Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 3.5. Comparison 3 Gel agent vs hydroﬂotation agent when used as an instillant, Outcome 5 Number of participants with adhesions at second-look laparoscopy...... 95 Analysis 3.6. Comparison 3 Gel agent vs hydroﬂotation agent when used as an instillant, Outcome 6 Mean adhesion score atsecond-looklaparoscopy...... 96 Analysis 4.2. Comparison 4 Steroid (any route) vs no steroid, Outcome 2 Live birth rate...... 96 Analysis 4.3. Comparison 4 Steroid (any route) vs no steroid, Outcome 3 Number of participants with improvement in adhesionscore...... 97 Analysis 4.4. Comparison 4 Steroid (any route) vs no steroid, Outcome 4 Number of participants with worsening adhesion score...... 97 Analysis 4.7. Comparison 4 Steroid (any route) vs no steroid, Outcome 7 Clinical pregnancy rate...... 98 Analysis 4.9. Comparison 4 Steroid (any route) vs no steroid, Outcome 9 Ectopic pregnancy rate (per pregnancy). . 98 Analysis 5.4. Comparison 5 Intraperitoneal noxytioline vs no treatment, Outcome 4 Number of participants with worsening adhesionscore...... 99 Analysis 5.7. Comparison 5 Intraperitoneal noxytioline vs no treatment, Outcome 7 Clinical pregnancy rate. . . . 100 Analysis 5.9. Comparison 5 Intraperitoneal noxytioline vs no treatment, Outcome 9 Ectopic pregnancy rate (per pregnancy)...... 100 Analysis 6.3. Comparison 6 Intraperitoneal heparin solution vs no intraperitoneal heparin, Outcome 3 Number of participants with improvement in adhesion score...... 101 Analysis 6.4. Comparison 6 Intraperitoneal heparin solution vs no intraperitoneal heparin, Outcome 4 Number of participants with worsening adhesion score...... 101 Analysis 7.3. Comparison 7 Systemic promethazine vs no promethazine, Outcome 3 Number of participants with improvementinadhesionscore...... 102 Analysis 7.4. Comparison 7 Systemic promethazine vs no promethazine, Outcome 4 Number of participants with worseningadhesionscore...... 102 APPENDICES ...... 103 WHAT’SNEW...... 109 HISTORY...... 110 CONTRIBUTIONSOFAUTHORS ...... 110 DECLARATIONSOFINTEREST ...... 110 SOURCESOFSUPPORT ...... 111 DIFFERENCES BETWEEN PROTOCOL AND REVIEW ...... 111 INDEXTERMS ...... 111

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) ii Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. [Intervention Review] Fluid and pharmacological agents for adhesion prevention after gynaecological surgery

Gaity Ahmad1, Fiona L Mackie1, David A Iles2, Helena O’Flynn3, Soﬁa Dias4, Mostafa Metwally5, Andrew Watson6

1Obstetrics & Gynaecology, Pennine Acute NHS Trust, Manchester, UK. 2Obstetrics and Gynaecology, Blackpool Victoria Hospital, Blackpool, UK. 3University Hospital of South Manchester, Manchester, UK. 4School of Social and Community Medicine, University of Bristol, Bristol, UK. 5The Jessop Wing and Royal Hallamshire Hospital, Shefﬁeld Teaching Hospitals, Shefﬁeld, UK. 6Tameside & Glossop Acute Services NHS Trust, Tameside General Hospital, Ashton-Under-Lyne, UK

Contact address: Gaity Ahmad, Obstetrics & Gynaecology, Pennine Acute NHS Trust, Manchester, UK. [email protected]. [email protected].

Editorial group: Cochrane Menstrual Disorders and Subfertility Group. Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 7, 2014. Review content assessed as up-to-date: 7 April 2014.

Citation: Ahmad G, Mackie FL, Iles DA, O’Flynn H, Dias S, Metwally M, Watson A. Fluid and pharmacological agents for adhesion prevention after gynaecological surgery. Cochrane Database of Systematic Reviews 2014, Issue 7. Art. No.: CD001298. DOI: 10.1002/14651858.CD001298.pub4.

ABSTRACT

Background

Adhesions are fibrin bands that are a common consequence of gynaecological surgery. They are caused by various conditions including pelvic inflammatory disease and endometriosis. Adhesions are associated with considerable co-morbidity, including pelvic pain, subfertility and small bowel obstruction. Patients may require further surgery-a fact that has financial implications.

Objectives

To evaluate the role of ﬂuid and pharmacological agents used as adjuvants in preventing formation of adhesions after gynaecological surgery.

Search methods

The following databases were searched up to April 2014: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and PsycINFO. Studies involving hydroﬂotation, gel and such pharmacological agents as steroids, noxytioline, heparin, promethazine, N,O-carboxymethyl chitosan and gonadotrophin- releasing hormone agonists were evaluated.

Selection criteria

Randomised controlled trials investigating the use of fluid and pharmacological agents to prevent adhesions after gynaecological surgery. Gels were defined as fluid agents.

Data collection and analysis

Three review authors independently assessed trials for eligibility, extracted data and evaluated risk of bias. Results were expressed as odds ratios (ORs), mean differences (MDs) or standard mean differences (SMDs) as appropriate, with 95% conﬁdence intervals (CIs).

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 1 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Main results Twenty-nine trials were included (3227 participants), and nine were excluded. One study examined pelvic pain and found no evidence of a difference between use of hydroflotation agents and no treatment. We found no evidence that any of the antiadhesion agents significantly affected the live birth rate. When gels were compared with no treatment or with hydroflotation agents at second-look laparoscopy (SLL), fewer participants who received a gel showed a worsening adhesion score when compared with those who received no treatment (OR 0.16, 95% CI 0.04 to 0.57, P value 0.005, two studies, 58 women, I2 = 0%, moderate-quality evidence) and with those given hydroflotation agents (OR 0.28, 95% CI 0.12 to 0.66, P value 0.003, two studies, 342 women, I2 = 0%, high-quality evidence). Participants who received steroids were less likely to have a worsening adhesion score (OR 0.27, 95% CI 0.12 to 0.58, P value 0.0008, two studies, 182 women, I2 = 0%, low-quality evidence). Participants were less likely to have adhesions at SLL if they received a hydroflotation agent or gel than if they received no treatment (OR 0.34, 95% CI 0.22 to 0.55, P value < 0.00001, four studies, 566 participants, I2 = 0%, high-quality evidence; OR 0.25, 95% CI 0.11 to 0.56, P value 0.0006, four studies, 134 women, I2 = 0%, high-quality evidence, respectively). When gels were compared with hydroflotation agents, participants who received a gel were less likely to have adhesions at SLL than those who received a hydroflotation agent (OR 0.36, 95% CI 0.19 to 0.67, P value 0.001, two studies, 342 women, I2 = 0%, high-quality evidence). No studies evaluated quality of life. In all studies apart from one, investigators stated that they were going to assess serious adverse outcomes associated with treatment agents, and no adverse effects were reported. Results suggest that for a woman with a 77% risk of developing adhesions without treatment, the risk of developing adhesions after use of a gel would be between 26% and 65%. For a woman with an 83% risk of worsening of adhesions after no treatment at initial surgery, the chance when a gel is used would be between 16% and 73%. Similarly, for hydroflotation fluids for a woman with an 84% chance of developing adhesions with no treatment, the risk of developing adhesions when hydroflotation fluid is used would be between 53% and 73%. Several of the included studies could not be included in a meta-analysis: The findings of these studies broadly agreed with the findings of the meta-analyses. The quality of the evidence, which was assessed using the GRADE approach, ranged from low to high. The main reasons for downgrading of evidence included imprecision (small sample sizes and wide confidence intervals) and poor reporting of study methods. Authors’ conclusions Gels and hydroflotation agents appear to be effective adhesion prevention agents for use during gynaecological surgery, but no evidence indicates that they improve fertility outcomes or pelvic pain, and further research is required in this area. Future studies should measure outcomes in a uniform manner, using the modified American Fertility Society (mAFS) score. Statistical findings should be reported in full.

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 systematic review evaluated all fluid and pharmacological agents that aim to prevent adhesion formation after gynaecological surgery (gels were defined as fluid agents). Background: Adhesions are defined as internal scar tissue that may form as part of the body’s healing process after surgery. They can also be caused by pelvic infection and endometriosis. Adhesions join together tissues and organs that are not normally connected. They are common after gynaecological surgery and can cause pelvic pain, infertility and bowel obstruction. Women with adhesions may need further surgery, which is more difficult and can lead to additional complications. The fluid agents are placed inside the pelvic cavity (which contains all female reproductive organs) during surgery and physically prevent raw, healing tissues from touching. These fluids can be broken down into hydroflotation agents or gels; hydroflotation agents are fluids placed in large volumes (usually around a litre); gels are directly applied to the internal surgical site. Pharmacological agents act by changing part of the healing process. Study characteristics: We included 29 randomised controlled trials in the review (3227 participants). Of these, results of 18 trials were pooled (2740 participants). Results from the remaining 11 trials could not be used in the meta-analysis because investigators did not use a way of measuring adhesions that would allow findings to be pooled with other data, or because important statistical information was not reported. We searched all evidence up to April 2014.

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 2 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Key results: Only one study evaluated pelvic pain and provided no evidence that the adhesion prevention agent made a difference. No evidence suggests that any of the investigated agents affected live birth rate. Regarding adhesions, participants given a fluid agent during surgery were less likely to form adhesions than participants who did not receive a fluid agent. When fluids and gels were compared with each other, gels appeared to perform better than fluids. No pharmacological agents showed good evidence of causing a significant effect on adhesions. No studies looked at differences in quality of life. All studies apart from one stated that investigators were going to assess serious adverse outcomes associated with the agents, and no adverse effects were reported. For gels, results suggest that for a woman with a 77% risk of developing adhesions without treatment, the risk of developing adhesions after a gel is used would be between 26% and 65%. For a woman with an 83% risk of worsening of adhesions after no treatment at initial surgery, the chance when a gel is used would be between 16% and 73%. Similarly, for hydroflotation fluids in a woman with an 84% chance of developing adhesions with no treatment, the risk of developing adhesions when hydroflotation fluid is used would be between 53% and 73%. Fluids and gels appear to be effective in reducing adhesions, but more information is needed to determine whether this affects pelvic pain, live birth rate, quality of life and long-term complications such as bowel obstruction. Further large, high-quality studies should be conducted in which investigators use the standard way of measuring adhesions as developed by the American Fertility Society (the modified AFS score). Quality of the evidence: The quality of the evidence ranged from low to high. The main reasons for downgrading of evidence were imprecision (small sample sizes and wide confidence intervals) and poor reporting of study methods.

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 3 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. oyih 04TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The a 2014 prevention © adhesion Copyright for agents pharmacological and Fluid SUMMARYOFFINDINGSFORTHEMAINCOMPARISON [Explanation]

Hydroflotation agents vs no hydroflotation agents for adhesion prevention after gynaecological surgery

Patient or population: women after gynaecological surgery Settings: postsurgical Intervention: hydroflotation agents vs no hydroflotation agents

Outcomes Illustrative comparative risks* (95% CI) Relative effect No. of participants Quality of the evidence Comments (95% CI) (studies) (GRADE)

Assumed risk Corresponding risk

No hydroflotation agents Hydroflotation agents trgneooia ugr (Review) surgery gynaecological fter

h ie os Ltd. Sons, & Wiley ohn Improvement in pelvic 806 per 1000 730 per 1000 OR 0.65 286 ⊕⊕⊕ pain in participants with (606-826) (0.37-1.14) (1 study) moderate1 a primary diagnosis of pelvic pain, at second- look laparoscopy

Live birth rate 140 per 1000 98 per 1000 OR 0.67 208 ⊕⊕⊕ (45-205) (0.29-1.58) (2 studies) moderate1

Improvement in adhe- 437 per 1000 496 per 1000 OR 1.27 665 ⊕⊕⊕ sion score (380-614) (0.79-2.05) (4 studies) moderate1,2

Number of participants 308 per 1000 111 per 1000 OR 0.28 53 ⊕⊕⊕ with worsening adhesion (30-350) (0.07-1.21) (1 study) moderate1,3 score

Number of participants 836 per 1000 635 per 1000 OR 0.34 566 ⊕⊕⊕⊕ with adhesions at sec- (529-738) (0.22-0.55) (4 studies) high ond-look laparoscopy 4 oyih 04TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The a 2014 prevention © adhesion Copyright for agents pharmacological and Fluid

Mean adhesion score The mean adhesion 722 ⊕⊕⊕⊕ SMD -0.06 (-0.2 to 0.09) at second-look la- score at second-look la- (4 studies) high 4 paroscopy paroscopy in the intervention groups was 0.06 standard deviations lower (0.2 lower-0.09 higher)

Clinical pregnancy rate 234 per 1000 163 per 1000 OR 0.64 310 ⊕⊕⊕ (99-258) (0.36-1.14) (3 studies) moderate1

*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. trgneooia ugr (Review) surgery gynaecological fter h ie os Ltd. Sons, & Wiley ohn 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.

1Wide 95% CI. 2Moderate heterogeneity. 3Small number of events. 4Scale: mean of the ‘ ‘ mean adhesion score’’ used. A lower mean ‘ ‘ mean adhesion score’’ represents an improvement in adhesion disease. A variety of adhesion scoring systems were used (e.g. Hulka, mAFS or system developed by authors for purpose of study); therefore for comparison, standardised mean difference was calculated. 5 BACKGROUND to relevant surfaces using a specific instrument. SprayGel (Con- fluent Surgical Inc., Waltham, MA, USA) is formed by two PEG- containing liquid precursors, which create a cross-linked gel when Description of the condition combined. Intercoat (FzioMed, San Luis Obispo, CA, USA) is an Oxiplex/AP viscoelastic gel composed of polyethylene oxide Adhesions are fibrin bands that form as the result of aberrant (PEO), which is very similar to PEG but has a different molecular peritoneal healing (Cheong 2001). Normally, peritoneal damage weight, and carboxymethylcellulose. causes an inflammatory response; this activates the coagulation cas- Steroids have been used to prevent adhesions and can be adminis- cade, and a fibrin plug is formed over the damaged mesothelium, tered in a number of ways, including systemically before, during which is then broken down to reveal regenerated peritoneum. and after surgery; intraperitoneally during surgery; and via hy- However, in adhesion formation, fibrinolysis of the fibrin plug is drotubation postoperatively. Other pharmacological agents used decreased and, consequently, a fibrin matrix develops. Adhesions to prevent adhesions include noxytioline, an antibacterial agent; may be defined as ‘de novo,’ meaning that they have formed at a promethazine, an antihistamine; and reteplase, a thrombolytic location that was previously free from adhesions, or ‘re-formed,’ drug, all of which are instilled intraperitoneally; as well as hep- which describes adhesions that recur post adhesiolysis. A variety of arin, an anticoagulant used for intraoperative irrigation. A nasal factors influence the extent of adhesion formation, including type gonadotrophin-releasing hormone agonist (GnRHa) has also been of surgery performed (i.e. laparoscopic or open), haemostasis and used preoperatively and postoperatively. the presence of endometriosis and infection, particularly pelvic inflammatory disease (Diamond 2001). Although the aetiologies are different, the basic pathogenesis is similar. How the intervention might work Hyaluronic acid is a major component of many body tissues and Description of the intervention fluids, where it provides physically supportive and mechanically protective roles (Johns 2001). PEG is a polymer; when the two Adhesion prevention agents can be divided into three types: fluid, PEG-containing liquids are sprayed simultaneously, they form a pharmacological and barrier. This review will examine fluid and cross-linked gel. Gels are thought to decrease adhesion formation pharmacological agents. A separate review evaluates barrier agents. mainly by preventing denuded tissues from touching. Fluid agents include both hydroflotation products and gels. Exam- Steroids and antihistamines (e.g. promethazine) act as im- ples of hydroflotation devices are 4% icodextrin solution (Adept, munomodulating agents and were used in the belief that they pro- Baxter, Berkshire, UK), an iso-osmolar and non-viscous high mote fibrinolysis during healing, without hindering the healing molecular weight glucose polymer, and 32% dextran (Hyskon process. GnRHa may work by decreasing oestrogen-related growth Pharmacia, Uppsala, Sweden), a polysaccharide-containing solu- factors and promoting fibroblasts. Fluid agents such as icodex- tion that is no longer approved for use as an antiadhesion agent. trin and dextran work through the act of hydroflotation, whereby Both agents can be used as intraperitoneal irrigants and/or instil- the fluid separates raw opposing surfaces until the healing process lants. has been completed. Fluid agents are believed to remain in the Derivatives of hyaluronic acid form the basis of a number of antiad- peritoneal cavity for several days, which is considered a sufficient hesion gels. Hyaluronic acid is a linear polysaccharide with repeat- length of time, given that adhesions form within eight days of ing disaccharide units composed of sodium D-glucuronate and N- surgery (Diamond 2001; Hosie 2001). acetyl-D-glucosamine. SepraSpray (Genzyme Corporation, Cam- bridge, MA, USA) contains hyaluronic acid in addition to carboxymethylcellulose powder and is applied to relevant tissues with Why it is important to do this review the use of a preloaded delivery device. SepraCoat (Genzyme Cor- poration) is a dilute hyaluronic acid solution that is applied be- Adhesiolysis is the only available treatment for adhesions, although fore and after surgery. Hyalobarrier gel (Nordic Pharma, Read- controversy regarding its efficacy is ongoing (Hammoud 2004). ing, UK) contains auto-cross-linked hyaluronic acid. Intergel (Gy- The focus of adhesion management is now prevention. Intraperi- necare, Lifecore Biomedical, Chaska, MN, USA) contains ferrous toneal adhesions are associated with considerable co-morbidity hyaluronic acid, although it has been withdrawn from the market. and have large economic and public health repercussions. They are N,O-carboxymethyl chitosan is a derivative of chitin and is simi- the most common complication of gynaecological surgery, form- lar in structure to hyaluronic acid and carboxymethylcellulose. It ing in 50% to 100% of women (diZerega 1994). Women present is formed when the gel and solution components are combined. with the secondary effects of adhesions including dyspareunia, Polyethylene glycol (PEG)-based gels are also available. CoSeal subfertility, bowel obstruction and chronic pelvic pain, although (Baxter) is formed by mixing a powder and a liquid intraopera- the latter has a controversial association with adhesions, as no cor- tively, both of which contain PEG and are then applied as a gel relation with extent of adhesions and severity of pain is apparent.

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 6 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Nevertheless, these consequences can greatly decrease a woman’s 1. Hydroflotation agent versus no hydroflotation agent. well-being and require further surgery. Subsequent surgery in 2. Gel agent versus no treatment. women with adhesions is more difficult, often takes longer and is 3. Gel agent versus hydroflotation agent when used as an associated with a higher complication rate. It is estimated that in instillant. the first year after lower abdominal surgery, the cost of adhesion- 4. Steroid (including systemic, intraperitoneal, preoperative related readmissions in the UK is £24.2 million, which increases to and postoperative) versus no steroid (or placebo). £95.2 million over the subsequent nine years (Wilson 2002). The 5. Intraperitoneal noxytioline versus no noxytioline (or Surgical and Clinical Adhesions Research (SCAR) study found placebo). that 5% (n = 245) of readmissions 10 years after open gynaecolog- 6. Intraperitoneal heparin versus no heparin (or placebo). ical surgery were due to adhesions (Lower 2000; Lower 2004). An 7. Systemic promethazine versus no promethazine (or English study estimated that the National Health Service (NHS) placebo). could save £700,000 per year if an antiadhesion agent that reduced 8. GnRHa versus no GnRHa (or placebo). adhesions by 25% and cost £110 was used or, at worst, that this 9. Reteplase plasminogen activator versus no reteplase approach would be cost-neutral (Cheong 2011). plasminogen activator (or placebo). 10. N,O-carboxymethyl chitosan versus no N,O-carboxymethyl chitosan (or placebo).

OBJECTIVES Types of outcome measures To evaluate the role of ﬂuid and pharmacological agents used as We decided to alter outcomes slightly from the previous version adjuvants in preventing formation of adhesions after gynaecolog- of the review, so that the primary outcomes focus on what is most ical surgery. important to the participants rather than on adhesion formation, which has little correlation with symptoms experienced. A variety of adhesion assessment measures were included as secondary out- METHODS comes to enable maximum study inclusion.

Criteria for considering studies for this review Primary outcomes 1. Pelvic pain (improvement/worsening/no change in pain at second-look laparoscopy (SLL)), independent of the method used to Types of studies assess pelvic pain. Published and unpublished randomised controlled trials (RCTs) 2. Live birth rate, as defined by the individual study. investigating the use of fluid and pharmacological agents to prevent adhesion formation after gynaecological surgery were eligible for inclusion. Non-randomised trials and those considered to be at Secondary outcomes high risk of bias for sequence generation or allocation concealment 3. Improvement in adhesion score at SLL, recorded on whichever were excluded. Studies using a cross-over design were excluded. scale the study authors used, but with preference given to the modified American Fertility Society (mAFS) score. Types of participants 4. Worsening in adhesion score at SLL, recorded on whichever Female participants in any age group who underwent pelvic scale the study authors used, but with preference given to the surgery (by laparoscopy or laparotomy). Studies investigating ad- mAFS score. hesion prevention in non-gynaecological specialities were not in- 5. Adhesions at SLL. cluded. 6. Mean adhesion score at SLL per participant, recorded on whichever scale the study authors used, but with preference given to the mAFS score. Types of interventions 7. Clinical pregnancy rate as defined by the individual study. Interventions were grouped together for meta-analysis according 8. Miscarriage rate, defined as loss of pregnancy before 24 weeks’ to physical state and main mechanism of action: hydroflotation gestation. agents (including dextran, 4% icodextrin solution), gel agents (in- 9. Ectopic pregnancy rate. cluding SepraSpray, SepraCoat, Hyalobarrier gel, Intergel, CoSeal, 10. Improvement in quality of life (QoL) at SLL, recorded on SprayGel and Intercoat) and pharmacological agents. The follow- whichever scale the study authors used, but with preference given ing comparisons were made. to Short Form (SF)-36.

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 7 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 11. Adverse outcomes, local and systemic, thought to be due to the Data extraction and management antiadhesion agent, in studies stating this as one of their outcomes, Two review authors (FM, DI) independently extracted the data. as opposed to observation. Data were transcribed onto a Microsoft Word data collection form Articles were included independent of the adhesion scoring designed for this review before they were entered into RevMan. method used. Articles that met the inclusion criteria but did not The statistical package Metaview of RevMan 5.1, provided by The report any of the outcomes considered within this review were Cochrane Collaboration, was used to analyse and synthesise data. included within the qualitative analysis. Study authors were contacted for further information as required. If no reply was received and the information was related to bias, this was denoted as unclear; if the information required was statistical Search methods for identification of studies and prevented inclusion in the meta-analysis, the study was not included in that outcome analysis, although it was still considered This is an update of the review by Metwally et al. published in an “included study.” Disagreements were resolved by consensus 2006. The Menstrual Disorders and Subfertility Group (MDSG) by GA and AW. Specialised Register of Controlled Trials, the Cochrane Central Register of Controlled Trials (CENTRAL) and citation indexes were searched using a search strategy designed by the MDSG Trials Assessment of risk of bias in included studies Search Co-ordinator. No restriction on language was applied. See The risk of bias of all studies deemed eligible was assessed indepen- the Review Group module for additional details on the make-up dently by two review authors (FM, DI). These included allocation of the Specialised Register. (random sequence generation and allocation concealment); blinding of participants, personnel and outcome assessors; incomplete Electronic searches outcome data; selective reporting and other biases. Disagreements Electronic databases were searched using Ovid software: MED- regarding interpretation of data were settled by consensus by GA LINE (1950 to April 2014), MDSG database (inception to April and AW. The quality of trials was assessed as recommended by the 2014), EMBASE (1980 to April 2014), CENTRAL (inception to risk of bias tool in the Cochrane Handbook for Systematic Reviews April 2014), PsycINFO (1806 to April 2014) and the Cumulative of Interventions (Higgins 2011) and was entered into the risk of Index to Nursing and Allied Health Literature (CINAHL) (1982 bias table. to April 2014). The clinical trials databases International Clini- cal Trials Registry Platform (ICTRP) and clinicaltrials.gov were Measures of treatment effect searched from inception to February 2013. The odds ratio (OR) was used for dichotomous data (e.g. number See Appendix 1; Appendix 2; Appendix 3; Appendix 4; Appendix of women with worsening adhesion score). The standardised mean 5; Appendix 6; Appendix 7; and Appendix 8, difference (SMD) was used for continuous measures that used different scales (e.g. mean adhesion score at SLL). When the same Searching other resources scale was used, the mean difference (MD) on this specific scale Grey literature was handsearched, specifically, abstracts presented was used. We presented 95% confidence intervals (CIs) for all at meetings of the British Society of Gynaecological Endoscopy, outcomes. the European Society of Gynaecological Endoscopy, the American Association of Gynecological Laparoscopists and the British Fer- Unit of analysis issues tility Society. Reference lists of included studies were also searched. The included primary studies were analysed per woman. Studies that used an internal control were excluded and have been listed as such. Data collection and analysis

Dealing with missing data Selection of studies Investigators were contacted to request missing data. If data were Three review authors (GA, FM, DI) independently performed an insufficient for inclusion of the study in a particular analysis, it initial screen of titles and abstracts to assess trials for suitability of was not included. inclusion in accordance with the eligibility criteria. FM and DI independently examined the full-text articles and abstracts to con- firm eligibility. If necessary, investigators were contacted to obtain Assessment of heterogeneity further information. Discrepancies were settled by consensus by The Chi2 test was performed and the I2 statistic calculated to GA and AW. determine significant heterogeneity. An I2 measurement > 30%

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 8 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. was considered moderate heterogeneity, > 50% substantial hetero- sus re-formed adhesions would have been performed if sufﬁcient geneity and > 70% high heterogeneity. data were available.

Assessment of reporting biases Sensitivity analysis Sensitivity analysis was performed to determine whether the results In consideration of the difficulty of detecting and correcting pub- were robust to decisions made regarding eligibility of the studies lication bias and other reporting bias, we aimed to minimise the and analysis. If a study was considered to have a high risk of bias, impact by ensuring that a robust and comprehensive search was or an apparent outlier was identified, the reason for the significant performed. We planned to create a funnel plot to assess the risk heterogeneity was investigated, as to whether this was believed of reporting bias if 10 or more studies were included in a meta- to be clinical or methodological, and analysis was conducted to analysis. evaluate whether inclusion of the study significantly affected the results. Results of the sensitivity analysis are reported in the Risk Data synthesis of bias in included studies subsection of the results section. Statistical analysis was performed in accordance with guidelines developed by The Cochrane Collaboration. Data from the primary studies were combined in RevMan using the fixed-effect model. An increase in OR or SMD or MD was indicated to the right RESULTS of the central line of the forest plot; a decrease was indicated to the left of the central line. Whether this favoured treatment or no treatment depended on the outcome analysed, but the axes were Description of studies labelled accordingly.

Results of the search Subgroup analysis and investigation of heterogeneity Forty-four studies were identified as potentially eligible for inclu- When significant heterogeneity was identified, the cause was ex- sion. Twenty-nine studies were included. For a summary of each plored, and a sensitivity analysis was performed using the random- included study, see the section Characteristics of included studies. effects model. This was highlighted in the results section, and any Reasons for study exclusion are detailed in the Characteristics of variation in the direction of effect was noted. A subanalysis com- excluded studies section. For details of the screening and selection paring the effects of antiadhesion agents on de novo adhesions ver- process, see Figure 1.

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 9 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Figure 1. Study ﬂow diagram.

studies could not be entered was that complete statistical data were Included studies not published, for example, Thornton 1998 and Rosenberg 1984 did not report standard deviations (SDs) or standard errors of the Study design and setting mean (SEMs), and although Fossum 2011 reported the outcomes Of the 29 included studies, 19 were conducted at multiple centres we were examining, results were displayed on a graph without ac- and 10 at a single centre. Nine were conducted in the USA, six tual numbers stated at any point in the text. DiZerega 2007 was in Europe, two in the USA/Europe, two in the Netherlands, three not entered into the meta-analysis, as investigators reported only in Australia, one in Sweden, two in Italy and one in Germany/ the effect that the antiadhesion agent had on AFS endometriosis Canada/Netherlands/Antilles; three studies did not state their lo- score, and as the results were presented per adnexa, not per par- cation. ticipant. Thus 20 trials were involved in the meta-analysis. Results of nine of the included trials could not be entered into the Fifteen studies stated that they received commercial funding. meta-analysis because the data were not reported in an appropriate Participants format. In some cases, the study authors used different ways of A wide variety was noted in the number of participants in each assessing adhesions, such as reporting only individual sections of study, with participant numbers ranging from 10 to 203 in the the mAFS, as in Hellebrekers 2009 and Diamond 2003, or the intervention group and from 10 to 199 in the control group. All adhesion area (cm2), as in Coddington 2009. Another reason why

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 10 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. participants were women undergoing a gynaecological procedure Lundorff 2001; Mais 2006; Mettler 2004; Pellicano 2003; Ten who had had a second-look laparoscopy. Reasons for surgery in- Broek 2012). cluded pelvic inflammatory disease (PID), endometriosis, adhe- Of 29 studies, seven examined the mean adhesion score at SLL sions, fibroids, pelvic pain, pelvic mass, endometrioid cysts and per participant (Adhesion SG 1983; Brown 2007; Larsson 1985; infertility assessment and treatment (e.g. tubal surgery). Lundorff 2001; Mais 2006; Ten Broek 2012; Trew 2011). Interventions Of 29 studies, five examined the clinical pregnancy rate. All par- The numbers of studies entered into the meta-analysis for each ticipants in these studies were actively seeking pregnancy during comparison are as follows. the study time period (Adhesion SG 1983; Jansen 1985; Larsson 1. Seven studies compared hydroflotation agents versus no 1985; Querleu 1989; Rock 1984). hydroflotation agents. A distinction was made between None of the 29 studies examined the miscarriage rate. hydroflotation agents (e.g. dextran, 4% icodextrin, SepraCoat) Of 29 studies, four examined the ectopic pregnancy rate (Jansen designed as antiadhesion agents and liquids such as saline, which 1985; Larsson 1985; Querleu 1989; Rock 1984). was often used as a control and is not considered a None of the 29 studies examined QoL. hydroflotation agent in this review. Of 29 studies, 28 examined adverse outcomes. Rosenberg 1984 2. Five studies compared gel agents versus no gel agents. was the only study that did not examine adverse outcomes. 3. Two studies compared hydroflotation agents versus gel agents. 4. Four studies compared steroids versus no steroids. Excluded studies 5. One study compared noxytioline versus no noxytioline. Nine studies were excluded. Johns 2003 used an internal control. 6. One study compared heparin versus no heparin. Diamond 2011 and Tulandi 1991 used internal controls, which 7. One study compared promethazine versus no was not explicitly stated in the abstract. Two studies were interim promethazine. reports (Mettler 2003(a); Mettler 2003(b)) and the final report No studies that evaluated GnRHa, reteplase plasminogen activator was included. One trial was not randomised (Tsuji 2005), and or N,O-carboxymethyl chitosan could be included in the meta- one study did not state that it was randomised (Pellicano 2005), analysis. although it appeared to include the same study group as was used Outcomes in Pellicano 2003. This was not explicitly stated in the methods, Two studies did not assess adhesions (Rose 1991; Sites 1997). nor was the fact that the study was randomised. Thus Pellicano DiZerega 2007 and Lundorff 2005 presented the results per ad- 2005 was excluded. One study was excluded because it was quasi- nexa. randomised (Swolin 1967). Tulandi 1985 reported the effect of the Primary outcomes agent on blood indices, not on adhesions. This study was included One of 29 studies examined pelvic pain (Brown 2007). in the original review but has been excluded because investigators Three of 29 studies examined live birth rate (Jansen 1985; Larsson used an external control. 1985; Rock 1984). Secondary outcomes Of 29 studies, 11 examined improvement in adhesion score at SLL Studies awaiting classification (Adhesion SG 1983; Brown 2007; diZerega 2002; Jansen 1985; Three studies sit in the awaiting classification section (Hudecek Jansen 1988; Jansen 1990; Johns 2001; Larsson 1985; Lundorff 2012; Litta 2013; Tchartchian 2009) pending publication of suf- 2001; Mettler 2004; Young 2005). ficient data to allow their inclusion. Of 29 studies, nine examined the number of participants with worsening adhesion score at SLL (diZerega 2002; Jansen 1985; Risk of bias in included studies Jansen 1988; Jansen 1990; Johns 2001; Lundorff 2001; Mettler The risk of bias for each included study can be seen in the 2004; Querleu 1989; Young 2005). Characteristics of included studies section. Figure 2 presents a Of 29 studies, 10 examined adhesions at SLL (Adhesion SG summary of risk of bias of all included studies. Figure 3 depicts 1983; Diamond 1998; diZerega 2002; Jansen 1985; Johns 2001; the proportions of studies within each judgement for each risk of bias element.

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 11 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 12 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Figure 3. Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.

Allocation blinded reviewer to assess videos or diagrams obtained through Sequence generation the second-look laparoscopy (Diamond 1998; Diamond 2003; No studies were at high risk of sequence generation bias. Seventeen diZerega 2002; DiZerega 2007; Fossum 2011; Hellebrekers 2009; studies adequately explained an appropriate method of sequence Jansen 1985; Jansen 1988; Johns 2001; Larsson 1985; Lundorff generation and were thus deemed at low risk. Twelve studies de- 2001; Mais 2006; Trew 2011; Young 2005). scribed the methods of random sequence generation inadequately and were at unclear risk. Allocation concealment Incomplete outcome data No studies were at high risk of allocation concealment bias. Eleven Two studies (Rosenberg 1984; Thornton 1998) were considered studies were at low risk of allocation concealment bias, as the au- at high risk of attrition bias, as neither study reported SDs or thors described an acceptable method of allocation concealment. SEMs. Twenty-two studies were at low risk for attrition bias. Five Eighteen studies did not provide sufﬁcient information on alloca- studies did not provide sufﬁcient information to reveal attrition tion to permit a judgement. bias; consequently the risk of attrition bias was unclear.

Blinding Six studies did not provide sufficient information on blinding to Selective reporting permit a judgement. Three studies blinded only the participant One study (Mettler 2008) was at high risk for reporting bias. The (Coddington 2009; Mettler 2008; Rose 1991). Five studies were authors of the study decided “in hindsight” to change the primary double-blinded (i.e. both participant and operating surgeon were outcome scoring method from the total mAFS score, as stated blinded) (Brown 2007; Mettler 2004; Pellicano 2003; Querleu in the original protocol, to the mAFS of the posterior uterus, as 1989; Rosenberg 1984). Ten Broek 2012 stated that the study was discussed during data analysis. Consequently, a sensitivity analysis single-blinded (participant), although the surgeon performing the was conducted and found that excluding Mettler 2008 made no initial surgery was unaware of allocation until the end of the initial difference to the direction of treatment effect. Thus the study procedure after the adhesions were scored, and the second-look la- was excluded from analysis. Twenty-five studies were at low risk paroscopy surgeon was blinded. The remaining 14 studies blinded for reporting bias, and three studies did not provide sufficient the participant and the operating surgeon and used an independent information to allow judgement on reporting bias risk.

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 13 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Other potential sources of bias prevention after gynaecological surgery; Summary of findings 6 Intraperitoneal heparin solution vs no intraperitoneal heparin Two studies were identified as having other sources of bias that for adhesion prevention after gynaecological surgery; Summary were unclear (Jansen 1988; Ten Broek 2012). A potential source of findings 7 Systemic promethazine vs no promethazine for of bias in Jansen 1988 was that the practice of adding hydrocor- adhesion prevention after gynaecological surgery tisone sodium succinate to the irrigation solution was stopped after 46 participants had received it because a possible detrimental effect was reported in an earlier study. These 46 participants were 1. Hydroflotation agents versus no treatment 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 unex- Primary outcomes pectedly required a separate fee for both laparoscopic procedures in each patient”; this study was still included. No potential sources of bias were identified in the other 27 included studies. 1.1 Pelvic pain One study (Brown 2007) examined the effect of a hydroflotation agent (4% icodextrin) on pelvic pain and found no evidence of Effects of interventions a difference compared with saline (OR 0.65, 95% CI 0.37 to See: Summary of findings for the main comparison 1.14, P value 0.13, one study, 286 participants, moderate-quality Hydroflotation agents vs no hydroflotation agents for adhesion evidence). See Analysis 1.1. prevention after gynaecological surgery; Summary of findings 2 Gel agents vs no treatment for adhesion prevention after gynaecological surgery; Summary of findings 3 Gel agents 1.2 Live birth rate compared with hydroflotation agents when used as an instillant No evidence of a difference between groups was seen (OR 0.67, for adhesion prevention after gynaecological surgery; Summary 95% CI 0.29 to 1.58, P value 0.36, two studies, 208 participants, of findings 4 Steroids (any route) vs no steroids for adhesion I2 = 0%, moderate-quality evidence) (Jansen 1985: dextran vs prevention after gynaecological surgery; Summary of findings Hartmann’s; Larsson 1985: dextran vs saline). See Analysis 1.2 and 5 Intraperitoneal noxytioline vs no treatment for adhesion Figure 4.

Figure 4. Forest plot of comparison: 1 Hydroﬂotation agent vs no hydroﬂotation agent, outcome: 1.2 Live birth rate.

I2 = 38%, moderate heterogeneity, moderate-quality evidence) Secondary outcomes (Adhesion SG 1983: dextran vs saline; Brown 2007: 4% icodextrin vs saline; diZerega 2002: 4% icodextrin vs saline; Jansen 1985: dextran vs Hartmann’s). Heterogeneity was reduced to I2 = 0% 1.3 Improvement in adhesion score at SLL when Jansen 1985 was removed, which consequently meant that No evidence of a difference between groups was seen (OR 1.27, a signiﬁcant difference between groups was seen (OR 1.47, 95% 95% CI 0.79 to 2.05, P value 0.32, four studies, 665 participants, CI 1.03 to 2.10, P value 0.03, three studies, 546 participants);

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 14 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. however a cause for the heterogeneity was not elucidated, and thus outcome was poorly defined in Jansen 1985, this study was re- the study remained in the meta-analysis. The only difference that moved from the analysis; this did not affect the results, as they we could discern was the use of Hartmann’s as a control as opposed remained not statistically significant. See Analysis 1.4. to saline by Jansen 1985; however, the review authors believed this difference to be unlikely to cause significant heterogeneity, as the solutions are so similar in composition. See Analysis 1.3. 1.5 Adhesions at SLL Meta-analysis demonstrated a significant difference in adhesions at SLL, with participants less likely to have adhesions at SLL if 1.4 Worsening in adhesion score at SLL they received a hydroflotation agent (OR 0.34, 95% CI 0.22 to No evidence of a difference between groups was seen (OR 0.28, 0.55, P value < 0.00001, four studies, 566 participants, I2 = 0%, 95% CI 0.07 to 1.21, P value 0.09, one study, 53 participants, high-quality evidence) (Adhesion SG 1983: dextran vs saline; moderate-quality evidence) (diZerega 2002: 4% icodextrin vs Diamond 1998: SepraCoat vs phosphate-buffered saline (PBS); saline). With the addition of Jansen 1985, heterogeneity was high diZerega 2002: 4% icodextrin vs saline; Jansen 1985: dextran vs in the analysis of worsening adhesion score (I2 = 79%). As this Hartmann’s). See Analysis 1.5 and Figure 5.

Figure 5. Forest plot of comparison: 1 Hydroﬂotation agent vs no hydroﬂotation agent, outcome: 1.5 Number of participants with adhesions at second-look laparoscopy.

1.6 Mean adhesion score at SLL per participant 1.9 Ectopic pregnancy rate No evidence of a difference between groups was seen (OR -0.06, No evidence of a difference between groups was seen (OR 0.35, 95% CI -0.20 to 0.09, P value 0.44, four studies, 722 participants, 95% CI 0.06 to 1.85, P value 0.21, two studies, 50 participants, 2 I = 0%, high-quality evidence) (Adhesion SG 1983: dextran vs I2 = 5%) (Jansen 1985: dextran vs Hartmann’s; Larsson 1985: saline; Brown 2007: 4% icodextrin vs saline; Larsson 1985: dextran dextran vs saline). See Analysis 1.9. vs saline; Trew 2011: 4% icodextrin vs saline). See Analysis 1.6.

1.10 Quality of life 1.7 Clinical pregnancy rate This was not assessed by any study. No evidence of a difference between groups was seen (OR 0.64, 95% CI 0.36 to 1.14, P value 0.13, three studies, 310 participants, 1.11 Adverse outcomes I2 = 0%, moderate-quality evidence) (Adhesion SG 1983: dextran No adverse outcomes were reported. vs saline; Jansen 1985: dextran vs Hartmann’s; Larsson 1985: dextran vs saline). See Analysis 1.7. 2. Gel agents versus no treatment

1.8 Miscarriage rate This was not assessed by any study. Primary outcomes

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 15 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 2.1 Pelvic pain 2.4 Worsening in adhesion score at SLL This was not assessed by any study. A signiﬁcant difference was seen, with fewer participants who had received a gel showing worsening in adhesion score at SLL compared with those who received no treatment (OR 0.16, 95% CI 2.2 Live birth rate 0.04 to 0.57, P value 0.005, two studies, 58 participants, I2 = 0%, This was not assessed by any study. moderate-quality evidence) (Mettler 2004: SprayGel vs no treatment; Young 2005: Oxiplex/AP gel vs no treatment). See Analysis 2.4. Secondary outcomes

2.3 Improvement in adhesion score at SLL 2.5 Adhesions at SLL No evidence of a difference between groups was seen (OR 3.78, Participants who received a gel were signiﬁcantly less likely to have 95% CI 0.61 to 23.32, P value 0.15, two studies, 58 participants, adhesions at SLL compared with those who received no adhesion I2 = 0%, moderate-quality evidence) (Mettler 2004: SprayGel vs prevention agent (OR 0.25, 95% CI 0.11 to 0.56, P value 0.0006, no treatment; Young 2005: Oxiplex/AP gel vs no treatment). The four studies, 134 participants, I2 = 0%, high-quality evidence) 95% CI is very wide though, which was believed to be related (Mais 2006: Hyalobarrier vs no treatment; Mettler 2004: SprayGel to the small number of participants that could be included in vs no treatment; Pellicano 2003: auto-cross-linked hyaluronic acid this analysis. Irrespective, the result remains not signiﬁcant. See gel vs no treatment; Ten Broek 2012: SepraSpray vs no treatment). Analysis 2.3. See Analysis 2.5 and Figure 6.

Figure 6. Forest plot of comparison: 2 Gel agent vs no treatment, outcome: 2.5 Number of participants with adhesions at second-look laparoscopy.

2.6 Mean adhesion score at SLL per participant No evidence of a difference between groups was seen (SMD -0.13, 95% CI -0.65 to 0.39, P value 0.63, two studies, 58 participants, I2 = 0%, moderate-quality evidence) (Mais 2006: Hyalobarrier vs no treatment; Ten Broek 2012: SepraSpray vs no treatment). See Analysis 2.6 and Figure 7.

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 16 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Figure 7. Forest plot of comparison: 2 Gel agent vs no treatment, outcome: 2.6 Mean adhesion score at second-look laparoscopy.

2.7 Clinical pregnancy rate 3. Gel agents versus hydroﬂotation agents when used This was not assessed by any study. as an instillant

2.8 Miscarriage rate Primary outcomes This was not assessed by any study.

3.1 Pelvic pain 2.9 Ectopic pregnancy rate This was not assessed by any study. This was not assessed by any study. 3.2 Live birth rate 2.10 Quality of life This was not assessed by any study. Secondary outcomes This was not assessed by any study.

3.3 Improvement in adhesion score at SLL 2.11 Adverse outcomes No evidence of a difference between groups was seen (OR 1.55, No adverse outcomes were reported. 95% CI 0.82 to 2.92, P value 0.17, two studies, 342 partici- Data that could not be included in a meta-analysis but were con- pants, I2 = 0%, moderate-quality evidence) (both Johns 2001 and sidered in the review are outlined here. Mettler 2008 (hydrogel vs Lundorff 2001 examined Intergel vs saline). See Analysis 3.3. saline), Rosenberg 1984 (dextran vs saline) and Thornton 1998 Fossum 2011 (Sepraspray vs no SepraSpray) found no significant (0.5% ferric hyaluronate vs saline) found that participants who difference in adhesion scores between participants who received did not receive the antiadhesion agent had a significantly worse an antiadhesion agent and those who did not. These data could adhesion score at SLL than participants who had received the anti- not be included in the meta-analysis. adhesion agent. Diamond 2003 (N,O-carboxymethyl chitosan vs saline) found no significant difference in adhesion scores between participants who received an antiadhesion agent and those who did 3.4 Worsening in adhesion score at SLL not. Lundorff 2005 (Oxiplex/AP gel) found a significant differ- Participants who received a gel (Intergel) were less likely to have a ence in adhesions at SLL, with adnexae that had not been treated worsening adhesion score at SLL compared with participants who with Oxiplex/AP gel having significantly worse adhesions at SLL received saline (OR 0.28, 95% CI 0.12 to 0.66, P value 0.003, two than adnexae that had been treated. See Analysis 2.2; Analysis 2.7; studies, 342 participants, I2 = 0%, high-quality evidence) (Johns and Analysis 2.8. 2001; Lundorff 2001). See Figure 8.

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 17 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Figure 8. Forest plot of comparison: 3 Gel agent vs hydroﬂotation agent when used as an instillant, outcome: 3.4 Number of participants with worsening adhesion score.

3.5 Adhesions at SLL Participants who received a gel (Intergel) were signiﬁcantly less likely to have adhesions at SLL (OR 0.36, 95% CI 0.19 to 0.67, P value 0.001, two studies, 342 participants, I2 = 0%, high-quality evidence) (Johns 2001; Lundorff 2001) compared with participants who had received no gel but were given a hydroﬂotation agent (saline) as an instillant. See Figure 9.

Figure 9. Forest plot of comparison: 3 Gel agent vs hydroﬂotation agent when used as an instillant, outcome: 3.5 Number of participants with adhesions at second-look laparoscopy.

3.6 Mean adhesion score at SLL per participant 3.9 Ectopic pregnancy rate Lundorff 2001 reported a lower adhesion score at SLL in par- This was not assessed by any study. ticipants who received Intergel compared with those given saline (MD -0.79, 95% CI -0.79 to -0.79, P value < 0.00001, one study, 77 participants, moderate-quality evidence); however as the SD 3.10 Quality of life appears very precise for a study that included only 38 participants This was not assessed by any study. in each arm, the study authors advise caution in interpreting these results. 3.11 Adverse outcomes 3.7 Clinical pregnancy rate No adverse outcomes were reported. This was not assessed by any study. 4. Steroids (including systemic, intraperitoneal, 3.8 Miscarriage rate preoperative and postoperative) versus no steroids (or placebo) This was not assessed by any study.

4.1 Pelvic pain This was not assessed by any study.

4.2 Live birth rate No signiﬁcant difference was seen (OR 0.65, 95% CI 0.26 to 1.62, P value 0.35, two studies, 223 participants, I2 = 0%) (Jansen 1985: intraperitoneal hydrocortisone, IV dexamethasone and PO prednisolone vs no steroids; Rock 1984: intraperitoneal hydrocortisone vs saline). See Figure 10.

Figure 10. Forest plot of comparison: 4 Steroid (any route) vs no steroid, outcome: 4.2 Live birth rate.

IV dexamethasone and PO prednisolone vs no steroids; Querleu Secondary outcomes 1989: IM dexamethasone vs no steroids). See Analysis 4.4.

4.3 Improvement in adhesion score at SLL 4.5 Adhesions at SLL A signiﬁcant difference was demonstrated by the only study that measured this outcome (OR 4.83, 95% CI 1.71 to 13.65, P value This was not assessed by any study. 0.003, one study, 75 participants, low-quality evidence) (Jansen 1990: IV dexamethasone and PO prednisolone vs no steroids). The data from this study are taken from the previous version of 4.6 Mean adhesion score at SLL per participant this review; data are unpublished and were supplied by the study This was not assessed by any study. author along with little information about the characteristics of the study. Thus caution is urged in interpreting this result. See Analysis 4.3. 4.7 Clinical pregnancy rate No evidence of a difference between groups was seen (OR 1.01, 4.4 Worsening in adhesion score at SLL 95% CI 0.66 to 1.55, P value 0.96, three studies, 410 participants, Fewer participants who received steroids showed worsening in I2 = 0%, moderate-quality evidence) (Jansen 1985: intraperitoneal adhesion score compared with participants who did not receive hydrocortisone, IV dexamethasone and PO prednisolone vs no steroids (OR 0.27, 95% CI 0.12 to 0.58, P value 0.0008, two stud- steroids; Querleu 1989: IM dexamethasone vs no steroids; Rock ies, 187 participants, I2 = 0%, low-quality evidence) (Jansen 1990: 1984: intraperitoneal hydrocortisone vs saline). See Analysis 4.7.

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 19 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 4.8 Miscarriage rate 5.5 Adhesions at SLL This was not assessed by any study. This was not assessed by any study.

4.9 Ectopic pregnancy rate 5.6 Mean adhesion score at SLL per participant No evidence of a difference between groups was seen (OR 0.67, This was not assessed by any study. 95% CI 0.08 to 5.70, P value 0.71, three studies, 83 participants, I2 = 60%, substantial heterogeneity, moderate-quality evidence) (Jansen 1985: intraperitoneal hydrocortisone, IV dexamethasone 5.7 Clinical pregnancy rate and PO prednisolone vs no steroids; Querleu 1989: IM dexam- No evidence of a difference was seen between participants who ethasone vs no steroids; Rock 1984: intraperitoneal hydrocorti- received intraperitoneal noxytioline and those who did not (OR sone vs saline). See Analysis 4.9. 0.66, 95% CI 0.30 to 1.47, P value 0.31, one study, 126 participants, moderate-quality evidence) (Querleu 1989). See Analysis 4.10 Quality of life 5.7. This was not assessed by any study. 5.8 Miscarriage rate 4.11 Adverse outcomes This was not assessed by any study. No adverse outcomes were reported.

5.9 Ectopic pregnancy rate 5. Intraperitoneal noxytioline versus no noxytioline No evidence of a difference was seen between participants who (or placebo) received intraperitoneal noxytioline and those who did not (OR Noxytioline was examined by only one study: Querleu 1989. 4.91, 95% CI 0.45 to 53.27, P value 0.19, one study, 33 participants, low-quality evidence) (Querleu 1989). See Analysis 5.9.

Primary outcomes 5.10 Quality of life This was not assessed by any study. 5.1 Pelvic pain This was not assessed by any study. 5.11 Adverse outcomes No adverse outcomes were reported. 5.2 Live birth rate This was not assessed by any study. 6. Intraperitoneal heparin versus no heparin (or placebo) Secondary outcomes Heparin was examined by only one study: Jansen 1988.

5.3 Improvement in adhesion score at SLL Primary outcomes This was not assessed by any study.

6.1 Pelvic pain 5.4 Worsening in adhesion score at SLL This was not assessed by any study. No evidence of a difference was seen between participants who received intraperitoneal noxytioline and those who did not (OR 0.55, 95% CI 0.17 to 1.76, P value 0.32, one study, 87 partic- 6.2 Live birth rate ipants, moderate-quality evidence) (Querleu 1989). See Analysis 5.4. This was not assessed by any study.

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 20 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Secondary outcomes Primary outcomes

6.3 Improvement in adhesion score at SLL 7.1 Pelvic pain No evidence of a difference was seen between participants who This was not assessed by any study. received intraperitoneal heparin and those who did not (OR 0.87, 95% CI 0.32 to 2.35, P value 0.78, one study, 63 participants, low-quality evidence) (Jansen 1988). See Analysis 6.3. 7.2 Live birth rate This was not assessed by any study.

6.4 Worsening in adhesion score at SLL Secondary outcomes No evidence of a difference was seen between participants who received intraperitoneal heparin and those who did not (OR 1.27, 95% CI 0.56 to 2.91, P value 0.57, one study, 92 participants, low-quality evidence) (Jansen 1988). See Analysis 6.4. 7.3 Improvement in adhesion score at SLL No signiﬁcant difference was seen between participants who received promethazine and those who did not (OR 0.56, 95% CI 6.5 Adhesions at SLL 0.22 to 1.43, P value 0.22, one study, 75 participants, low-quality evidence) (Jansen 1990). This was not assessed by any study.

7.4 Worsening in adhesion score at SLL 6.6 Mean adhesion score at SLL per participant No evidence of a difference was seen between participants who This was not assessed by any study. received promethazine and those who did not (OR 0.59, 95% CI 0.25 to 1.42, P value 0.24, one study, 93 participants, low-quality evidence) (Jansen 1990). See Analysis 7.4. 6.7 Clinical pregnancy rate This was not assessed by any study. 7.5 Adhesions at SLL This was not assessed by any study. 6.8 Miscarriage rate This was not assessed by any study. 7.6 Mean adhesion score at SLL per participant This was not assessed by any study. 6.9 Ectopic pregnancy rate

This was not assessed by any study. 7.7 Clinical pregnancy rate This was not assessed by any study. 6.10 Quality of life This was not assessed by any study. 7.8 Miscarriage rate This was not assessed by any study.

6.11 Adverse outcomes No adverse outcomes were reported. 7.9 Ectopic pregnancy rate This was not assessed by any study.

7. Systemic promethazine versus no promethazine (or placebo) 7.10 Quality of life Promethazine was examined by only one study: Jansen 1990. This was not assessed by any study.

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 21 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 7.11 Adverse outcomes This was not assessed by any study that could be used in the No adverse outcomes were reported. meta-analysis. Fossum 2011 (SepraSpray vs no SepraSpray) and Hellebrekers 2009 (reteplase vs saline) found no evidence of a difference in adhesion scores between participants who received 8. GnRHa versus no GnRHa (or placebo) an antiadhesion agent and those who did not. See Analysis 9.1. This was not assessed by any study eligible for inclusion in the meta-analysis. Coddington 2009 (GnRHa vs no GnRHa) found 10. N,O-carboxymethyl chitosan versus no N,O- no evidence of a difference in adhesion scores between participants carboxymethyl chitosan (or placebo) who received an antiadhesion agent and those who did not. Data This was not assessed by any study that could be used in the meta- from this study could not be included in the meta-analysis. See analysis. Analysis 8.1. The only included study that did not examine adverse outcomes was Rosenberg 1984. None of the included studies reported any adverse effects that the study authors believed to be due to antiad- 9. Reteplase plasminogen activator versus no hesion agents; however new evidence has come to light since the reteplase plasminogen activator (or placebo) publication of these studies that led to the withdrawal of Intergel.

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 22 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. oyih 04TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The a 2014 prevention © adhesion Copyright for agents pharmacological and Fluid ADDITIONALSUMMARYOFFINDINGS [Explanation]

Gel agents vs no treatment for adhesion prevention after gynaecological surgery

Patient or population: women after gynaecological surgery Settings: postsurgical Intervention: gel agents vs no treatment

Outcomes Illustrative comparative risks* (95% CI) Relative effect No. of participants Quality of the evidence Comments (95% CI) (studies) (GRADE)

Assumed risk Corresponding risk

No treatment Gel agents trgneooia ugr (Review) surgery gynaecological fter

h ie os Ltd. Sons, & Wiley ohn Number of participants 43 per 1000 147 per 1000 OR 3.78 58 ⊕⊕⊕ with improvement in ad- (27-515) (0.61-23.32) (2 studies) moderate1 hesion score

Number of participants 826 per 1000 432 per 1000 OR 0.16 58 ⊕⊕⊕ with worsening adhesion (160-730) (0.04-0.57) (2 studies) moderate2 score

Number of participants 766 per 1000 450 per 1000 OR 0.25 134 ⊕⊕⊕⊕ with adhesions at sec- (264-647) (0.11-0.56) (4 studies) high ond-look laparoscopy

Mean adhesion score Mean adhesion score at 58 ⊕⊕⊕ SMD -0.13 (-0.65 to 0. at second-look la- second-look laparoscopy (2 studies) moderate3 39)4 paroscopy in the intervention groups was 0.13 standard deviations lower (0.65 lower-0.39 higher)

23 CI: Confidence interval; OR: Odds ratio. oyih 04TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The a 2014 prevention © adhesion Copyright for agents pharmacological and Fluid

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.

1Large 95% confidence interval-small number of participants able to be included in analysis. 2Low number of events. 3Small population size. 4Scale: mean of the ‘ ‘ mean adhesion score’’ used. A lower mean ‘ ‘ mean adhesion score’’ represents an improvement in the adhesion disease. A variety of adhesion scoring systems were used (e.g. Hulka, mAFS, system developed by trial authors for purpose of study); therefore for comparison standardised mean difference was calculated. xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx trgneooia ugr (Review) surgery gynaecological fter h ie os Ltd. Sons, & Wiley ohn 24 oyih 04TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The a 2014 prevention © adhesion Copyright for agents pharmacological and Fluid

Gel agents compared with hydroflotation agents when used as an instillant for adhesion prevention after gynaecological surgery

Patient or population: women after gynaecological surgery Settings: postsurgical Intervention: gel agents Comparison: hydroflotation agents when used as an instillant

Outcomes Illustrative comparative risks* (95% CI) Relative effect No. of participants Quality of the evidence Comments (95% CI) (studies) (GRADE)

Assumed risk Corresponding risk

Hydroflotation agents Gel agents when used as an instil- trgneooia ugr (Review) surgery gynaecological fter h ie os Ltd. Sons, & Wiley ohn lant

Number of participants 110 per 1000 161 per 1000 OR 1.55 342 ⊕⊕⊕ with improvement in ad- (92-265) (0.82-2.92) (2 studies) moderate1 hesion score

Number of participants 139 per 1000 43 per 1000 OR 0.28 342 ⊕⊕⊕⊕ with worsening adhesion (19-96) (0.12-0.66) (2 studies) high score

Number of participants 225 per 1000 95 per 1000 OR 0.36 342 ⊕⊕⊕⊕ with adhesions at sec- (52-163) (0.19-0.67) (2 studies) high ond-look laparoscopy

Mean adhesion score Mean adhesion score at 77 ⊕⊕⊕ 3 at second-look la- second-look laparoscopy (1 study) moderate2 paroscopy in the intervention groups was 0.79 lower (0.79-0.79 lower) 25 oyih 04TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The a 2014 prevention © adhesion Copyright for agents pharmacological and Fluid

1Wide 95% CI. 2Study authors advise caution in interpreting result; SD appears very precise for study with only 38 participants in each arm. 3Scale: mean of the ‘ ‘ mean adhesion score’’ used. A lower mean ‘ ‘ mean adhesion score’’ represents an improvement in the adhesion disease. A variety of adhesion scoring systems were used (e.g. Hulka, mAFS, system developed by authors for purpose of study);

trgneooia ugr (Review) surgery gynaecological fter therefore for comparison, standardised mean difference was calculated. h ie os Ltd. Sons, & Wiley ohn 26 oyih 04TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The a 2014 prevention © adhesion Copyright for agents pharmacological and Fluid

Steroids (any route) vs no steroids for adhesion prevention after gynaecological surgery

Patient or population: women after gynaecological surgery Settings: postsurgical Intervention: steroids (any route) vs no steroids

Outcomes Illustrative comparative risks* (95% CI) Relative effect No. of participants Quality of the evidence Comments (95% CI) (studies) (GRADE)

Assumed risk Corresponding risk

No steroids Steroids (any route)

Live birth rate 112 per 1000 76 per 1000 OR 0.65 223 ⊕⊕⊕ trgneooia ugr (Review) surgery gynaecological fter 2 h ie os Ltd. Sons, & Wiley ohn (32-170) (0.26-1.62) (2 studies) moderate

Number of participants 462 per 1000 805 per 1000 OR 4.83 75 ⊕⊕ 4 with improvement in ad- (594-921) (1.71-13.65) (1 study) low1 hesion score

Number of participants 343 per 1000 124 per 1000 OR 0.27 176 ⊕⊕ 4 with worsening adhesion (59-233) (0.12-0.58) (2 studies) low1,2 score

Clinical pregnancy rate 297 per 1000 299 per 1000 OR 1.01 410 ⊕⊕⊕ (218-396) (0.66-1.55) (3 studies) moderate1,2

Ectopic rate (per preg- 195 per 1000 140 per 1000 OR 0.67 83 ⊕⊕⊕ nancy) (19-580) (0.08-5.7) (3 studies) moderate3

1Unpublished data from study author. Little information about characteristics of study; therefore caution in interpreting this result is urged. 2Wide 95% CI. 3Substantial heterogeneity. 4Modified American Fertility Society endometriosis scoring scale used by Jansen 1990 and Querleu 1989. A lower mean ‘ ‘ mean adhesion score’’ represents improvement in adhesion disease. xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx trgneooia ugr (Review) surgery gynaecological fter h ie os Ltd. Sons, & Wiley ohn 28 oyih 04TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The a 2014 prevention © adhesion Copyright for agents pharmacological and Fluid

Intraperitoneal noxytioline vs no treatment for adhesion prevention after gynaecological surgery

Patient or population: women after gynaecological surgery Settings: postsurgical Intervention: intraperitoneal noxytioline vs no treatment

Outcomes Illustrative comparative risks* (95% CI) Relative effect No. of participants Quality of the evidence Comments (95% CI) (studies) (GRADE)

Assumed risk Corresponding risk

No treatment Intraperitoneal noxytioline trgneooia ugr (Review) surgery gynaecological fter 2 h ie os Ltd. Sons, & Wiley ohn Number of participants 205 per 1000 124 per 1000 OR 0.55 87 ⊕⊕⊕ with worsening adhesion (42-312) (0.17-1.76) (1 study) moderate1 score

Clinical pregnancy rate 302 per 1000 222 per 1000 OR 0.66 126 ⊕⊕⊕ (115-388) (0.3-1.47) (1 study) moderate1

Ectopic pregnancy rate 53 per 1000 214 per 1000 OR 4.91 33 ⊕⊕ (per pregnancy) (24-747) (0.45-53.27) (1 study) low1

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. 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.

1Wide confidence intervals-small numbers of participants and events. 2Modified American Fertility Society endometriosis scoring scale used by Querleu 1989. A lower mean ‘ ‘ mean adhesion score’’

29 represents improvement in adhesion disease. oyih 04TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The a 2014 prevention © adhesion Copyright for agents pharmacological and Fluid

Intraperitoneal heparin solution vs no intraperitoneal heparin for adhesion prevention after gynaecological surgery

Patient or population: women after gynaecological surgery Settings: postsurgical Intervention: intraperitoneal heparin solution vs no intraperitoneal heparin

Outcomes Illustrative comparative risks* (95% CI) Relative effect No. of participants Quality of the evidence Comments (95% CI) (studies) (GRADE)

Assumed risk Corresponding risk

No intraperitoneal hep- Intraperitoneal heparin arin solution

trgneooia ugr (Review) surgery gynaecological fter 3

h ie os Ltd. Sons, & Wiley ohn Number of participants 571 per 1000 537 per 1000 OR 0.87 63 ⊕⊕ with improvement in ad- (299-758) (0.32-2.35) (1 study) low1,2 hesion score

Number of participants 396 per 1000 454 per 1000 OR 1.27 92 ⊕⊕ 3 with worsening adhesion (268-656) (0.56-2.91) (1 study) low1,2 score

1Hydrocortisone added to irrigation solution for first 46 patients. Stopped after report of possible detrimental side effect in an earlier study. 2Wide 95% CI. 3Modified American Fertility Society endometriosis scoring scale used by Jansen 1988. A lower mean ‘ ‘ mean adhesion score’’ represents improvement in adhesion disease. 30 oyih 04TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The a 2014 prevention © adhesion Copyright for agents pharmacological and Fluid

Systemic promethazine vs no promethazine for adhesion prevention after gynaecological surgery

Patient or population: women after gynaecological surgery Settings: postsurgical Intervention: systemic promethazine vs no promethazine

Outcomes Illustrative comparative risks* (95% CI) Relative effect No. of participants Quality of the evidence Comments (95% CI) (studies) (GRADE)

Assumed risk Corresponding risk

No promethazine Systemic promethazine

Number of participants 692 per 1000 558 per 1000 OR 0.56 75 ⊕⊕ 3 trgneooia ugr (Review) surgery gynaecological fter 1,2 h ie os Ltd. Sons, & Wiley ohn with improvement in ad- (331-763) (0.22-1.43) (1 study) low hesion score

Number of participants 391 per 1000 275 per 1000 OR 0.59 93 ⊕⊕ 3 with worsening adhesion (138-477) (0.25-1.42) (1 study) low1,2 score

1Data obtained from review article and study author. Many characteristics unclear. 2Wide 95% CI. 3Modified American Fertility Society endometriosis scoring scale used by Jansen 1990. A lower mean ‘ ‘ mean adhesion score’’ represents improvement in adhesion disease. 31 DISCUSSION Five studies recorded live birth rate, although these were mainly the earlier studies, conducted in 1984, 1985 and 2003. Summary of main results A gap in knowledge has been noted regarding the effects that antiadhesion agents have on quality of life, as no studies were Pelvic pain as an outcome was reported by one study evaluating found that examined this. a hydroflotation agent that reported no evidence of an effect. No Studies included in this review were performed in Europe, Aus- evidence suggested that any agent significantly affected live birth tralia, USA, Canada and Columbia. These results are thought to rate. Hydroflotation agents and gel agents (including those con- be applicable to developed countries. taining hyaluronic acid, PEG and PEO) compared with no treatment significantly reduced the likelihood of adhesions at second- look laparoscopy. Gel agents compared with no treatment also Quality of the evidence lowered the mean adhesion score and led to fewer participants with a worse adhesion score. When gel and hydroflotation agents were The quality of the evidence was assessed using the GRADE ap- compared, participants receiving a gel were less likely to have adhe- proach. Quality ranged from low to high. The main reasons for sions present and had a lower mean adhesion score. Noxytioline, downgrading of evidence were imprecision (small sample sizes and heparin and promethazine were found to have no significant effect wide confidence intervals) and poor reporting of study methods. on adhesion formation, apart from steroids, which were found to Only one of the included studies was considered to have a high decrease the likelihood of worsening in adhesion score (compared risk of bias (Mettler 2008) regarding both performance and de- with no treatment or placebo). No evidence was found of a higher tection bias. Pilot studies were included, and although eight stud- rate of clinical pregnancy, miscarriage or ectopic pregnancy for any ies performed a power calculation, most studies were not statisti- of the interventions. According to one study, steroids improved cally powered to detect differences between treatments, although the adhesion score, but no other agents improved the adhesion this fact would not have affected internal validity. The results of score. Quality of life outcomes were not reported. The fluid and a number of studies could not be included because of the way pharmacological agents examined in this review appeared to be researchers assessed adhesions. Study authors were contacted for safe; investigators in all included studies apart from one stated that complete results so they could be included in the meta-analyses, they were going to assess serious adverse outcomes that may be but from most, no reply was received. Despite the fact that the due to these agents, and none were reported. Several studies could American Fertility Society developed a scoring system and advised not be included in the meta-analysis but were included within the that it be used in trials, this was not the case, and the SMD had review; the findings of these studies were broadly consistent with to be used or, as mentioned, results could not be used. The review the findings of our meta-analyses. authors are not aware of one measurement shown to have more bearing on clinical outcomes than another. The different methods of reporting adhesions also led to a variety of similar secondary Overall completeness and applicability of outcomes investigated regarding measurement of adhesions to al- evidence low maximum study inclusion. Additionally, and unfortunately, several studies could not be included in the meta-analysis because Adhesion formation is a complex process that is affected by many statistical data were reported incompletely, thus limiting our meta- factors. The ongoing pathological process, the magnitude of sur- analysis. Additionally, the wide variety of methods used to mea- gical insult, infection and haemostasis after surgery may influence sure adhesions meant that some studies could not be included in the formation of adhesions after surgery. The studies used in this the meta-analysis. review included heterogeneous participants with diverse gynaeco- Jansen 1990 was included in the previous version, and the same logical pathology who were undergoing both minimal access pro- data have been used in this review. Results were obtained from the cedures and open surgery. In addition, some studies looked at ad- study author, but little information was available on the character- hesion prophylaxis as a primary prevention of de novo adhesions istics of the study; therefore these results should also be interpreted after surgery, whilst others looked at secondary prevention after with caution. surgical adhesiolysis to prevent re-formation. Unfortunately a subanalysis comparing the effects of antiadhesion agents on de novo adhesions versus re-formed adhesions could not be conducted, as Potential biases in the review process too few studies discriminated between the different types of adhesions. The review authors made every effort to identify all studies that Only one study explored pelvic pain. It is important to note that should be considered for inclusion. Since the time of the previous although a causal relationship has been established between ad- review, the necessary detail required for inclusion in Cochrane re- hesions and infertility (or bowel obstruction), the correlation be- views has increased substantially. Although the previously included tween adhesions and pelvic pain is uncertain (Hammoud 2004). studies were all reassessed for bias, some information was required

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 32 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. from the study authors themselves. We attempted to contact them AUTHORS’ CONCLUSIONS but to no avail. Implications for practice Overall, hydroflotation and gel agents appear beneficial in reducing adhesion formation after gynaecological surgery, compared Agreements and disagreements with other with no treatment. However, a large gap in evidence has been studies or reviews identified regarding actual effects on clinical outcomes, which are A systematic review with meta-analysis of the efficacy of auto-cross- more important to patients than the extent of their adhesions. linked hyaluronan gel for adhesion prevention in laparoscopy and hysteroscopy was identified. It concluded that the gel pre- Implications for research vented both intraperitoneal adhesions after laparoscopic myomec- Studies evaluating antiadhesion agents should report outcomes in tomy and intrauterine adhesions after hysteroscopic surgery (Mais a uniform way, using the mAFS. The statistics should be reported 2012). A Cochrane review analysing adhesion prevention after in full, as is good practice. The effects that adhesion prevention non-gynaecological abdominal surgery (Kumar 2009) included a agents and adhesions themselves have on pelvic pain, live birth rate single study (Tang 2006) looking at fluid and pharmacological and quality of life should be explored in greater detail. Knowledge agents. In this study, participants underwent surgery in which the regarding the effects that different adhesion prevention strategies gastrointestinal tract was opened. An unacceptably higher rate of have on various patient subgroups (e.g. patients with and without postoperative complications was reported for participants receiv- active endometriosis or PID) and differences noted between de ing 0.5% ferric hyaluronate gel. Recruitment was suspended and novo and re-formed adhesions is also required. The longer-term efficacy was not assessed. Both the Society of Obstetricians and effects regarding outcomes such as small bowel obstruction should Gynaecologists of Canada and the American Society of Repro- be evaluated. ductive Medicine Practice Committee have published documents stating that evidence of efficacy for fluid or pharmacological agents was insufficient (ASRM 2008; Robertson 2010). The Anti-Adhe- sions in Gynaecology Expert Panel for the European Society for ACKNOWLEDGEMENTS Gynaecological Endoscopy has published guidelines to encour- age the adoption of adhesion reduction strategies, advising con- The review authors would like to thank Richard Lilford and Patrick sideration of agents with data supporting safety and efficacy (De Vanderkerchove, who were co-authors of the original review. We Wilde 2012). The same panel published a consensus position that also acknowledge Marian Showell and Helen Nagels for assistance is consistent with the conclusion of our review that evidence for provided with this review. In addition, the review authors thank Dr pharmacological agents is lacking, with gels and 4% icodextrin Jansen for information and data previously supplied with respect showing efficacy in reducing adhesions (De Wilde 2007). to the included study of Jansen 1985.

REFERENCES

References to studies included in this review icodextrin in a pivotal adhesion reduction trial in the USA. Fertility and Sterility 2005;84(Suppl 1):S160. Adhesion SG 1983 {published data only} Coddington 2009 {published data only} Adhesion Study Group (Buttram V, Malinak R, Cleary R, Coddington C, Grow D, Ahmed M, Toner J, Cook E, Cohen S, Cowan B, Daniell J, Maxon W, DeCherney A, Diamond M. Gonadotropin-releasing hormone agonist Haseltine F, Haney A, March C, Soules M). Reduction of pretreatment did not decrease postoperative adhesion postoperative pelvic adhesions with intraperitoneal 32% formation after abdominal myomectomy in a randomized dextran 70: a prospective, randomized clinical trial. Fertility control trial. Fertility and Sterility 2009;91:1909–13. and Sterility 1983;40:612–9. Diamond 1998 {published data only} Brown 2007 {published data only} Diamond MP. Reduction of de novo postsurgical adhesions ∗ Brown CB, Luciano AA, Martin D, Peers E, Scrimgeour by intraoperative pre coating with Sepracoat (HAL-C) A, diZerega GS. Adept (icodextrin 4% solution) reduces solution: a prospective, randomized, blinded, placebo- adhesions after laparoscopic surgery for adhesiolysis: a controlled multicenter study. The Sepracoat Adhesion double-blind, randomised, controlled study. Fertility and Study Group. Fertility and Sterility 1998;69(6):1067–74. Sterility 2007;88(5):1413–26. Peers EM, Brown CB, Adept Adhesion SG. American Diamond 2003 {published data only} Fertility Society score as a measure of effectiveness of 4% Diamon MP, Luciano A, Johns A, Dunn R, Young P,

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 33 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Bieber E. Reduction of postoperative adhesions by N,O- Lundorff 2001 {published data only} carboxymethylchitosan: a pilot study. Fertility and Sterility Lundorff P, Geldorp H, Tronstad SE, Lalos O, Larsson B, 2003;80(3):631–6. Johns DB, diZerega G. Reduction of postsurgical adhesions with ferric hyaluronate gel: a European study. Human diZerega 2002 {published data only} Reproduction 2001;16(9):1982–8. ∗ diZerega GS, Verco SJ, Young P, Kettel M, Kobak W, Martin D, et al.A randomized, controlled pilot study of the Lundorff 2005 {published data only} safety and efficacy of 4% icodextrin solution in the reduction Lundorff P, Donnez J, Korell M, Audebert AJM, Block K, of adhesions following laparoscopic gynaecological surgery. diZerega GS. 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Fertility and Mettler 2004 {published data only} ∗ Sterility 2011;96:487–91. Mettler L, Audebert A, Lehmann-Willenbrock E, Schive-Peterhansi K, Jacobs V. A randomized prospective, Hellebrekers 2009 {published data only} controlled, multicenter clinical trial of a sprayable, site Hellebrekers BWJ, Trimbos-Kemper TCM, Boesten L, specific adhesion barrier system in patients undergoing Jansen FW, Kolkman W, Trimbos JB, et al.Preoperative myomectomy. Fertility and Sterility 2004;82(2):398–404. predictors of postsurgical adhesion formation and the prevention of adhesions with plasminogen activator (PAPA- Mettler 2008 {published data only} study): results of a clinical pilot study. Fertility and Sterility Mettler L, Hucke J, Bojahr B, Tinneberg HR, Leyland 2009;91(4):1204–14. N, Avelar R. A safety and efficacy study of a resorbable hydrogel for reduction of post-operative adhesions following Jansen 1985 {published data only} myomectomy. Human Reproduction 2008;23(5):1093–100. Jansen RPS. 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Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 34 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Rosenberg 1984 {published data only} Mettler 2003(a) {published data only} Rosenberg SM, Board JA. High-molecular weight dextran Mettler L, Audebert A, Lehmann-Willenbrock E, Schive in human infertility surgery. American Journal of Obstetrics K, Jacobs VR. Prospective clinical trial of SprayGel as a & Gynaecology 1984;148:380–5. barrier to adhesion formation: an interim analysis. Journal 2003; Sites 1997 {published data only} of American Association of Gynecologic Laparoscopists Sites CK, Jensen BA, Glock JL, Blackman JA, Badger 10(3):339–44. GJ, Joh JV, Brumsted JR. Transvaginal ultrasonographic Mettler 2003(b) {published data only} assessment of Hyskon and lactated Ringer’s solution Mettler. Pelvic adhesions: laparoscopic approach. Annals of instillation after laparoscopy. 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Effect of intraperitoneal 32% dextran 70 on 2015–27. blood coagulation and serum electrolytes. Journal of Reproductive Medicine 1985;30:431–4. Young 2005 {published data only} Young P, Johns A, Templeman C, Witz C, Webster B, Tulandi 1991 {published data only} Ferland R, et al.Reduction of postoperative adhesions for Tulandi T. Effects of fibrin sealant on tubal anastomosis and laparoscopic gynaecological surgery with Oxiplex/AP gel: a adhesion formation. Fertility and Sterility 1991;56:136–8. pilot study. Fertility and Sterility 2005;84(5):1450–6. References to studies awaiting assessment References to studies excluded from this review Hudecek 2012 {published data only} Diamond 2011 {published data only} Hudecek R, Ivanova Z, Smerdova M, Pankova S, Diamond MP, Korell M, Martinez S, Kurman E, Kamar M, Krajcovicova R. Effect of GnRH analogues pre-treatment Adhexil Adhesion Study Group. A prospective, controlled, on myomectomy outcomes in reproductive age women. randomized, multicenter,exploratory pilot study evaluating Ceska Gynekol 2009;77(2):109–17. the safety and potential trends in efficacy of Adhexil. Fertility and Sterility 2011;95:1086–90. Litta 2013 {published data only} Litta P, Pluchino N, Freschi L, Borgato S, Angioni S. Imai 2003 {published data only} Evaluation of adhesions after laparoscopic myomectomy Imai A, Sugiyama T, Furui A, Takahashi S, Tamaya using the Harmonic Ace and the auto-crosslinked T. Gonadotrophin-releasing hormones agonist therapy hyaluronan gel vs Ringer’s lactate solution. Clinical and increases peritoneal fibrinolytic activity and prevents Experimental Obstetrics and Gynecology 2013;2:210–4. adhesion formation after myomectomy. Journal of Obstetrics and Gynecology 2003;23(6):660–63. Tchartchian 2009 {published data only} Tchartchian G, Dittert B, De Wilde RL. Evaluation of Johns 2003 {published data only} SprayShield in a center: randomized controlled study in Johns DA, Ferland R, Dunn R. Initial feasibility study of women undergoing myomectomy. Gynecological Surgery a sprayable hydrogel adhesion barrier system in patients 2009;Suppl 6:S72. undergoing laparoscopic ovarian surgery. Journal of the American Association of Gynecologic Laparoscopists 2003;10 Additional references (3):334–8.

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 35 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. ASRM 2008 Kumar 2009 Practice Committee of American Society for Reproductive Kumar S, Wong PF,Leaper DJ. Intra-peritoneal prophylactic Medicine in collaboration with Society of Reproductive agents for preventing adhesions and adhesive intestinal Surgeons. Pathogenesis, consequences, and control of obstruction after non-gynaecological abdominal surgery. peritoneal adhesions in gynecologic surgery. Fertility and Cochrane Database of Systematic Reviews 2009. Sterility 2008 Nov;90(5 Suppl):S144–9. Cheong 2001 Lower 2000 Cheong YC, Laird SM, Li TC, Shelton JB, Ledger WL, Lower AM, Hawthorn RJ, Ellis H, O’Brien F, Buchan Cooke ID. Peritoneal healing and adhesions formation/ S, Crowe AM. The impact of adhesions on hospital reformation. Human Reproduction Update 2001;7:566–76. readmissions over ten years after 8849 open gynaecological operations: an assessment from the Surgical and Clinical Cheong 2011 Adhesions Research Study. BJOG 2000;107:855–62. Cheong Y, Sadek K, Watson A, Metwally M, Li TC. Adhesion reduction agents in gynaecological procedures: Lower 2004 can NHS afford it?. Journal of Obstetrics and Gynaecology Lower AM, Hawthorn RJ, Clark D, Boyd JH, Finlayson 2011;31:631–5. AR, Knight AD, et al.Adhesion-related readmissions De Wilde 2007 following gynaecological laparoscopy or laparotomy in De Wilde RL, Trew G. Postoperative abdominal adhesions Scotland: an epidemiological study of 24 046 patients. and their prevention in gynaecological surgery. Expert Human Reproduction 2004;19:1877–85. consensus position. Part 2-steps to reduce adhesions. Gynaecological Surgery 2007;4(4):243–53. Mais 2012 De Wilde 2012 Mais V, Cirronis MG, Peiretti M, Ferrucci G, Cossu E, De Wilde RL, Brölmann H, Koninckx PR, Lundorff Melis GB. Efﬁcacy of auto-crosslinked hyaluronan gel P, Lower AM, Wattiez A, et al.The Anti-Adhesions for adhesion prevention in laparoscopy and hysteroscopy: in Gynecology Expert Panel (ANGEL). Prevention of a systematic review and meta-analysis of randomized adhesions in gynaecological surgery: the 2012 European controlled trials.. European Journal of Obstetric and ﬁeld guideline. Gynecological Surgery 2012;9(4):365–8. Gynaecological Reproductive Biology 2012 January;160(1): 1–5. Diamond 2001 Diamond MP, Freeman ML. Clinical implications of Robertson 2010 postsurgical adhesions. Human Reproduction Update 2001; Robertson D, Lefebvre G, Leyland N, Wolfman W, 7:567–76. Allaire C, Awadalla A, et al.Society of Obstetricians diZerega 1994 and Gynaecologists of Canada. SOGC clinical practice diZerega G. Contemporary adhesion prevention. Fertility guidelines: adhesion prevention in gynaecological surgery. and Sterility 1994;61:219–35. International Journal of Gynaecology and Obstetrics 2010;111 Hammoud 2004 (2):193–7. Hammoud A, Gago LA, Diamond MP. Adhesions in patients with chronic pelvic pain: a role for adhesiolysis?. Tang 2006 Fertility and Sterility 2004;82:1483–91. Tang CL, Jayne DG, Seow-Choen F, Ng YY, Eu KW, Mustapha N. A randomized controlled trial of 0.5% ferric Higgins 2011 hyaluronate gel (Intergel) in the prevention of adhesions Higgins JPT, Green S (editors). Cochrane Handbook for following abdominal surgery. Annals of Surgery 2006r;243 Systematic Reviews of Interventions Version 5.1.0 [updated (4):449–55. March 2011]. The Cochrane Collaboration, 2011. www.cochrane–handbook.org. Wilson 2002 Hosie 2001 Wilson MS, Menzies D, Knight AD, Crowe AM. Hosie K, Gilbert JA, Kerr D, et al.Fluid dynamics in man of Demonstrating the clinical and cost effectiveness of adhesion an intraperitoneal drug delivery solution: 4% icodextrin. reduction strategies. Colorectal Disease 2002;4:355–60. Drug Delivery 2001;8:9–12. ∗ Indicates the major publication for the study

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 36 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. CHARACTERISTICSOFSTUDIES

Characteristics of included studies [ordered by study ID]

Adhesion SG 1983

Methods Truly randomised trial (method not stated) Time of randomisation: not stated Double-blind Location: multi-centre-9 centres in the USA (Houston, Indianapolis, Worcester, Bethesda, Nashville, New Haven, Durham, Los Angeles and Seattle) Timing and duration: not stated

Participants Infertility patients undergoing open pelvic surgery (macrosurgery 53, loupe magnifica- tion 32, microsurgery 17) Condition: pelvic inflammatory disease with distal tubal disease (42), endometriosis (14) , pelvic adhesions (46) Surgery performed: adhesiolysis, tubal surgery Preexisting adhesions: all participants Age: 18-35 years (mean not stated) Duration infertility: not stated Infertility workup: 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: 8-12 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 participants randomly assigned: 277 Number of participants undergoing second-look laparoscopy evaluation: 245

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 1. Method of diagnosis: not stated 2. Duration follow-up: 8-12 weeks Adhesions at second-look laparoscopy 1. Improvement 2. Change in score OTHER OUTCOMES Adhesions at second-look laparoscopy 1. Present, absent; according to anatomical site Appearance of tube Tubal patency rate

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 37 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Adhesion SG 1983 (Continued)

Postoperative infection rate

Notes Adhesion scoring system used Hulka system based on extent of adhesions (scored from 1-4) over ﬁmbriae and ovaries (range 0-16) 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 Unclear risk Insufﬁcient information to permit judge- bias) ment. “Patients were randomly assigned to either treatment”

Allocation concealment (selection bias) Unclear risk Insufﬁcient information to permit judgement.

Blinding of participants and personnel Unclear risk Insufﬁcient information to permit judge- (performance bias) ment. “Blinded” All outcomes

Blinding of outcome assessment (detection Unclear risk Insufﬁcient information to permit judge- bias) ment. “Blinded” All outcomes

Incomplete outcome data (attrition bias) Unclear risk Exclusion criteria for randomisation; num- All outcomes ber of participants randomly assigned not stated. All participants who underwent treatment were accounted for

Selective reporting (reporting bias) Low risk Data were presented in full and as stated in the methods section regarding outcomes

Other bias Low risk No others

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-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 Preexisting adhesions: not all participants 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: 4-8 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 Adept vs Ringer’s lactated saline > 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 1. Number of participants with improvement in adhesion score OTHER OUTCOMES Adhesions at second-look laparoscopy 1. Number of adhesion sites 2. Mean AFS score reduction 3. Number of participants free of de novo adhesions 4. “Clinical success”-study authors’ deﬁnition: reduction of 3 or 30% of number of sites lysed 5. Change in AFS score category 6. Adhesion extent, severity Many subanalyses based on primary diagnosis

Notes mAFS score Funded by Innovata Ltd, Vectura Group

Risk of bias

Bias Authors’ judgement Support for judgement

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 39 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Brown 2007 (Continued)

Random sequence generation (selection Low risk “Treatment was randomised by computer- bias) generated randomisation on a 1:1 basis”

Allocation concealment (selection bias) Unclear risk Allocation concealment not commented upon

Blinding of participants and personnel Low risk “Patient number[s] were allocated to treat- (performance bias) ment group before labelling of the blinded All outcomes study treatment bags. The study solutions were presented in identical 1 litre infusion bags, and each bag had an outer wrap that contained the study code and patient number on an identiﬁcation label”

Blinding of outcome assessment (detection Unclear risk “The ﬁrst three patients’ videos recorded bias) by each investigator were assessed by a sin- All outcomes gle, independent, masked reviewer. If these videos were deemed acceptable, then one in every ﬁve subsequent videos was reviewed. ” An independent blinded reviewer was not used for all videos, nor is it stated whether the reviewer was blinded

Incomplete outcome data (attrition bias) Low risk “449 patients were randomised and re- All outcomes ceived treatment with Adept or LRS. A total of 29 patients were withdrawn from the study; nine of those were because of pregnancy or resolution of their pain after ﬁrst surgery (ﬁve in the Adept group and four in the LRS group). A further 12 patients (six in each treatment group) declined second surgery; one patient (LRS) withdrew because of a SAE (bowel perforation, unrelated to study device); and four patients (two in each group) were lost to follow-up. In addition one Adept patient moved away from the centre before second surgery, and one patient in the LRS group requested a hysterectomy Overall 6.6% of patients in Adept group were withdrawn compared with 6.3% in the LRS group. Therefore 420 patients completed the trial. Of this group, 18 patients had major protocol violations, leav- ing 402 patients in the PP population”

Selective reporting (reporting bias) Low risk No reporting issues identiﬁed

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 40 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Brown 2007 (Continued)

Other bias Low risk

Coddington 2009

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 participants randomly assigned 2 participants excluded from analysis because of severe pelvic adhesive disease and no myoma requiring treatment Second-look laparoscopy 2-10 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 Unclear risk Insufﬁcient information to allow judge- bias) ment

Allocation concealment (selection bias) Unclear risk Insufﬁcient information to allow judgement

Blinding of participants and personnel Unclear risk Insufﬁcient information to allow judge- (performance bias) ment All outcomes

Blinding of outcome assessment (detection Low risk “The same senior surgeon performed all bias) adhesion scoring and was blinded to the All outcomes treatment group of the patients. All procedures were videotaped and measurements

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 41 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Coddington 2009 (Continued)

conﬁrmed by an external reviewer”

Incomplete outcome data (attrition bias) Low risk No outcome data missing All outcomes

Selective reporting (reporting bias) Low risk No reporting issues identiﬁed

Other bias Low risk

Diamond 1998

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 participants randomly assigned: 277 Number of participants undergoing second-look laparoscopy evaluation: 245

Interventions SepraCoat vs PBS 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 1. Adhesions present at second-look laparoscopy 2. Mean adhesion score OTHER OUTCOMES 1. Mean extent of adhesion score 2. Mean incidence of de novo adhesions at second-look laparoscopy 3. 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 Low risk “Before their initial procedure, patients at bias) each centre were assigned randomly accord-

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 42 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Diamond 1998 (Continued)

ing to a computer-generated list”

Allocation concealment (selection bias) Low risk “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 Low risk “Patients were assigned a number that cor- (performance bias) responded to an identically numbered set All outcomes of 2500ml bottles of blinded solution”

Blinding of outcome assessment (detection Low risk “A videotape recording of the ab- bias) dominopelvic cavity was made at this time All outcomes [of second-look laparoscopy]; the video was reviewed later by a blinded, independent reviewer”

Incomplete outcome data (attrition bias) Low risk No missing outcome data All outcomes

Selective reporting (reporting bias) Low risk Data were presented in full and as stated in the methods section regarding outcomes

Other bias Low risk Sponsored by Genzyme Corporation

Diamond 2003

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 Preexisting adhesions: not all participants 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: 2-10 weeks postoperative Blinding at second-look laparoscopy: yes, independent blinded reviewer used Exclusion criteria: pregnant, lactating, had previously undergone salpingectomy/ oophorectomy/hysterectomy, had a known cancer, active PID, received hormonal therapy within 1 month of initial surgery

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 43 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Diamond 2003 (Continued)

Interventions NOCC vs instillant of Ringer’s lactated saline > 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 1. Number of adhesion sites 2. Extent of adhesions 3. Severity of adhesions 4. Total new surface area of adhesions Duration surgery

Notes mAFS score used, data presented in such a way as to not allow inclusion of results regarding adhesions at SLL Funded by Chitogenetics

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk States: was randomised “just before clo- bias) sure” but method not described

Allocation concealment (selection bias) Unclear risk Allocation concealment not commented on

Blinding of participants and personnel Low risk “Reviewer-blinded” (performance bias) All outcomes

Blinding of outcome assessment (detection Low risk “Each surgical procedure was videotaped in bias) its entirety. After editing to remove applica- All outcomes tion of the test or study agent, the video of each procedure was reviewed by an evalua- tor who was blinded to group assignment. The reviewer applied the same scoring system as the surgeons”

Incomplete outcome data (attrition bias) Low risk “All but 1 woman in the NOCC group un- All outcomes derwent 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”

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 44 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Diamond 2003 (Continued)

Selective reporting (reporting bias) Low risk No reporting issues identiﬁed, although total adhesion score not used

Other bias Low risk Funded by Chitogenetics. Signiﬁcant baseline differences between control and treatment groups-co-variate analysis used diZerega 2002

Methods True randomisation (randomisation list) Pilot study; therefore no power calculation was performed Multi-centre: 5 centres in USA Blinding: assessor blind

Interventions Icodextrin 4% vs Ringer’s lactated saline Timing second-look laparoscopy: 6-12 months

Outcomes Analysed in review Adhesions present, improvement or deterioration in adhesion scores at second-look laparoscopy Duration follow-up: 6-12 months Other outcomes: change in adhesion score at second-look laparoscopy No data on pregnancy rates

Notes Adhesion scoring system used Modiﬁed American Fertility Society endometriosis scoring system

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “Each patient was assigned the next avail- bias) able study number which was pre-allocated to treatment according to a randomization list”

Allocation concealment (selection bias) Low risk Sealed treatment codes provided to centres by the supplier of the investigational prod-

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 45 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. diZerega 2002 (Continued)

uct

Blinding of participants and personnel Low risk Open label (assessor blinded) (performance bias) All outcomes

Blinding of outcome assessment (detection Low risk Third party-blinded videotape review of bias) adhesions at initial and second surgeries All outcomes

Incomplete outcome data (attrition bias) Low risk 4 withdrawn because of major protocol vi- All outcomes olation after initial surgery. 1 participant did not return for second surgery. 4 further protocol violators withdrawn (1 because study device was not being used cor- rectly, 3 because of adhesions at more than 50% of sites. 53 of 62 included in per-protocol analysis

Selective reporting (reporting bias) Low risk No reporting issues identiﬁed

Other bias Low risk

DiZerega 2007

Methods Randomised trial, although method of randomisation not stated Time of randomisation: not stated Double-blind. Independent blinded reviewer scored videos of surgery Power calculation: no Location: multi-centre-Europe and USA Timing and duration: not stated

Participants Females 18 years of age and older undergoing laparoscopic gynaecological surgery only, who had gross visual evidence of endometriosis at ﬁrst-look laparoscopy (n = 37) Indication for surgery: endometriosis Surgery performed: laparoscopy Preexisting adhesions: not all participants Number analysed: 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: 6-12 weeks postoperative Blinding at second-look laparoscopy: yes, independent blinded reviewer used Exclusion criteria: AFS stage IV or only endometriomas seen at surgery

Interventions Oxiplex/AP gel vs surgery only

Outcomes No outcomes analysed in review (mainly looking at endometriosis score) OTHER OUTCOMES Adhesions at second-look laparoscopy 1. Change in adhesion score at SLL per adnexa

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 46 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. DiZerega 2007 (Continued)

Subanalysis based on presence of red lesions

Notes mAFS score used, but scored per adnexa, not per participant; thus results could not be included in meta-analysis Other parts of study published in Lundorff 2005 and Young 2005 Funded by FzioMed Inc

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk States: was randomised, method not stated bias)

Allocation concealment (selection bias) Unclear risk Allocation concealment method not stated

Blinding of participants and personnel Unclear risk Not stated (performance bias) All outcomes

Blinding of outcome assessment (detection Low risk “Videos of both procedures were scored bias) by a reviewer masked to treatment assign- All outcomes ment”

Incomplete outcome data (attrition bias) Unclear risk Number of participants/adnexae analysed All outcomes not stated, only number randomly assigned

Selective reporting (reporting bias) Low risk No reporting issues identiﬁed

Other bias Low risk Sponsored by FzioMed

Fossum 2011

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: 4-12 weeks after initial surgery

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 47 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Fossum 2011 (Continued)

Interventions SepraSpray Adhesion Barrier Power delivered by specially designed laparoscopic delivery instrument or 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 (modiﬁed AFS score) Adverse effects

Notes Funded by Genzyme

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No comment on randomisation method bias)

Allocation concealment (selection bias) Unclear risk No comment on allocation concealment

Blinding of participants and personnel Unclear risk Insufﬁcient information to provide judge- (performance bias) ment All outcomes

Blinding of outcome assessment (detection Low risk Blinded videotaped assessment of mAFS bias) All outcomes

Incomplete outcome data (attrition bias) Low risk No issues identiﬁed All outcomes

Selective reporting (reporting bias) Low risk No issues identiﬁed

Other bias Low risk

Hellebrekers 2009

Methods Truly randomised trial (computer-generated schema) Time of randomisation: at scheduling of surgery Blinding: single-blind Power calculation: no ITT: no Location: sIngle centre-Leiden University Medical Centre Timing and duration: not stated

Participants Participants 18 years of age or older who were candidates for open abdominal myomectomy with tubes and ovaries present bilaterally. All participants were menstruating regu- larly, none had received hormonal treatment for at least 2 months before surgery. Good general health with no signiﬁcant systemic conditions (n = 26) Indication for surgery: clinical indications for myomectomy not stated

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 48 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Hellebrekers 2009 (Continued)

Number undergoing second-look laparoscopy: 25 Timing second-look laparoscopy: 8th postoperative day Exclusion criteria: pregnancy, haematological disorder or coagulopathy, cancer therapy, unavailable for study duration, ongoing pelvic infection, participation in other clinical investigations, diabetes mellitus

Interventions 300 mL Ringer’s lactate with 1 mg reteplase vs 300 mL Ringer’s lactate alone Instillation of agent after completion of myomectomy

Outcomes Scoring of adhesions: 1. Incidence-number of adhesions adherent to uterus or surrounding tissues 2. Severity-deﬁned as adhesion tenacity score (0-3) 3. Extent-area covered by adhesions in cm2 Adverse effects: Deﬁned as undesirable physical, psychological or behavioural effects experienced by participant

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Computer-generated randomisation bias)

Allocation concealment (selection bias) Unclear risk No comments regarding allocation concealment-insufﬁcient information to allow judgement

Blinding of participants and personnel Low risk “Same two gynaecologists performed the (performance bias) second-look laparoscopy and were blinded All outcomes to the randomisation during both surgical procedures”

Blinding of outcome assessment (detection Low risk “The surgeon calculated adhesion scores bias) immediately after surgery. Photographs All outcomes were taken during myomectomy and videotapes were recorded during ESL. A single independent and blinded observer reviewed the photographs and videotapes and made new adhesion scores. These adhesion scores were then compared with the scores from the CRFs made by the two surgeons to ensure consistency of adhesion scoring”

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 49 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Hellebrekers 2009 (Continued)

Incomplete outcome data (attrition bias) Low risk 1 participant refused consent for second- All outcomes look laparoscopy. No other missing outcome data

Selective reporting (reporting bias) Low risk No reporting issues identiﬁed

Other bias Low risk

Jansen 1985

Methods Truly randomised (random number generated) Time of randomisation: not stated Factorial design Power calculation: yes Location: Sydney, Australia Timing and duration: Feb 1982-Nov 1983

Participants Adult females older than 18 years of age scheduled for pelvic 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 21-40); 32 years for control group (range 18- 50) Number eligible: 62 Number undergoing second0look laparoscopy: 53 Infertility patients undergoing open pelvic 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) Preexisting adhesions: 119 participants Mean age: 30 years (range 21-39) Duration infertility: not stated Infertility workup: not stated Number eligible: 170 Number randomly assigned: 168 Number undergoing SLL: 164

Interventions 1. Dextran vs Hartmann’s solution Route of administration: intraperitoneal Dosage/volume: dextran 100-200 mL; Hartmann’s 100 mL or more 2. Steroids vs no treatment Route of administration: intraperitoneal + also systemic (iv and oral) if preexisting adhesions or endometriosis Dosage/volume: intraperitoneal: 500 mg hydrocortisone in 100-200 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

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 50 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Jansen 1985 (Continued)

Timing SLL: 12-21 days Blinding at SLL: yes

Outcomes Analysed in review Pregnancy Method of diagnosis: not stated Duration follow-up: 1-18 months Live birth Miscarriage rate Ectopic rate Adhesions at second-look laparoscopy 1. Present; absent 2. Improvement; deterioration Other outcomes Adhesions at second-look laparoscopy 1. Change in score

Notes Adhesion scoring system used Modiﬁed American Fertility Society endometriosis scoring system (range 0-27) Results expressed as medians with 95% conﬁdence limits

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “Randomization sequences were generated bias) by a random number-generation program, and assignment of adjuncts was carried out strictly in the pre-determined sequence. Two separate randomisations 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 Unclear risk “Although completely effective blinding in (performance bias) the allocation of the adjuncts was not prac- All outcomes ticable (owing to the viscous nature of the dextran solution and the need to admin- ister systemic corticosteroids to some patients), information on allocation and use of adjuncts was not recorded in the operation notes and was not readily available at the time of post-operative laparoscopy”

Blinding of outcome assessment (detection Low risk “Qualiﬁcation of adhesions was carried out bias) from operation diagrams at a later date, All outcomes without knowledge of the patient’s identity

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 51 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Jansen 1985 (Continued)

or the use of an adjunct”

Incomplete outcome data (attrition bias) Low risk All participants accounted for, no missing All outcomes outcome data

Selective reporting (reporting bias) Low risk Data were presented in full and as stated in the methods section regarding outcomes

Other bias Low risk None detected

Jansen 1988

Methods Truly randomised trial (random numbers generated) Time of randomisation: not stated Power calculation done Location: Sydney, Australia Timing and duration: Nov 1983-Oct 1984

Participants Infertility patients undergoing open pelvic microsurgery Condition: pelvic adhesions; endometriosis; tubal disease; uterine abnormalities Surgery performed: adhesiolysis or treatment for endometriosis (52); tubal anastomosis or uterine surgery (40) Preexisting adhesions: 63 participants Mean age: 28 years (range 21-42) Duration infertility: not stated Infertility workup: 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 vs Ringer’s solution Route of administration: intraperitoneal preoperative pelvic irrigation Dosage/volume: Ringer’s solution containing 5000 IU heparin/L Other adjuvants: 52 participants with preexisting adhesions or endometriosis received systemic steroids intraoperatively and postoperatively. The ﬁrst 46 participants in the study received intraperitoneal steroids Prophylactic antibiotics: yes

Outcomes Analysed in review Adhesions at second-look laparoscopy 1. Improvement; no change; deterioration 2. Change in score Other outcomes Blood transfusion requirements Wound healing

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 52 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Jansen 1988 (Continued)

Notes Adhesion scoring system used Modiﬁed American Fertility Society endometriosis scoring system (range 0-27) Data for adhesions at SL (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 Low risk “Strictly in a pre-determined random se- bias) quence”

Allocation concealment (selection bias) Unclear risk Insufﬁcient information available to permit judgement

Blinding of participants and personnel Low risk “Although completely effective blinding in (performance bias) heparin use was not practicable, owing to its All outcomes 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”

Blinding of outcome assessment (detection Low risk “Improvement scores were derived later, bias) without knowledge of the identity of the All outcomes patient, or the use of heparin”

Incomplete outcome data (attrition bias) Low risk No missing outcome data All outcomes

Selective reporting (reporting bias) Low risk Data were presented in full and as stated in the methods section regarding outcomes

Other bias Unclear risk The practice of adding hydrocortisone sodium succinate to the irrigation solution was stopped after 46 participants had received it because of a possible detrimental effect reported in an earlier study

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 Infertility patients undergoing open pelvic microsurgery Condition: pelvic adhesions and/or endometriosis Surgery performed: adhesiolysis; excision of endometriosis Preexisting adhesions: 75 participants Age: not stated Duration infertility: not stated Infertility workup: 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 vs no treatment Route of administration: systemic (po and im) Dosage/volume: 50 mg po 6 hours preoperatively and 50 mg im intraoperatively 2. Postoperative steroids vs no treatment Route of administration: systemic (po) Dosage/volume: postoperative prednisone 25 mg po bd for 4 days, then 25 mg daily until SLL Other adjuvants: All participants 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 1. Improvement; no change; deterioration Other outcomes: adhesions at second-look laparoscopy 1. Change in score

Notes Adhesion scoring system used Modiﬁed American Fertility Society endometriosis scoring system (range 0-27) 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 Unclear risk States: was randomised, but method not bias) stated

Allocation concealment (selection bias) Unclear risk Not stated

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 54 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Jansen 1990 (Continued)

Blinding of participants and personnel Unclear risk Not stated (performance bias) All outcomes

Blinding of outcome assessment (detection Unclear risk Not stated bias) All outcomes

Incomplete outcome data (attrition bias) Unclear risk Not stated All outcomes

Selective reporting (reporting bias) Unclear risk Not stated

Other bias Unclear risk Insufﬁcient information to make any judgement

Johns 2001

Methods Truly randomised, third party-blinded study (randomisation schedule) Multi-centre: 16 centres in the USA and Europe Power calculation: no

Participants Truly randomised, third party-blinded study (randomisation schedule) Multi-centre: 16 centres in the USA and Europe Power calculation: no

Interventions Intergel vs Ringer’s lactate Volume: 300 mL Ringer’s lactate or Intergel instilled at the end of the procedure Antibiotics: no Second-look laparoscopy: 6-12 weeks after primary procedure

Outcomes Analysed in review 1. Adhesions present at second-look laparoscopy 2. Improvement in adhesion score (AFS) 3. Deterioration in adhesion score (AFS) Other outcomes 1. Shift in mAFS adhesion score 2. Per cent reduction in mAFS score 3. Severity and extent of adhesions (median and standard deviation) Pregnancy rates: no

Notes Adhesion scoring system used 1. AFS adhesion score 2. mAFS adhesion score Funded by Lifecore Biomedical Inc

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 55 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Johns 2001 (Continued)

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “At the time of initial surgical procedure, bias) 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 enroll the participant was made

Blinding of participants and personnel Low risk Two methods: “In the ﬁrst method, the (performance bias) study device or control solution was ad- All outcomes ministered into the peritoneal cavity by a surgical assistant (third party) after the surgeon had completed the primary surgical procedure and had left the operating area. The surgeon then conducted the second look laparoscopy. In the second method, the surgeon conducting the initial surgery instilled the study material, and the second look laparoscopy was carried out by a different surgeon”

Blinding of outcome assessment (detection Low risk Blinded independent review of adhesion bias) data as a quality assurance check All outcomes

Incomplete outcome data (attrition bias) Low risk 281 randomly assigned participants receiv- All outcomes ing treatment-a total of 265 completed the study. “Of the 16 patient[s] who did not return for laparoscopy, 9 patients discontin- ued for reasons unrelated to treatment. Al- though treatment-related discontinuation could not be ruled out in the other seven patients, a similar number were present in the treatment (n=4) and control (n=3) groups”

Selective reporting (reporting bias) Low risk No reporting issues identiﬁed

Other bias Low risk

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 Infertility patients undergoing open pelvic microsurgery Condition: tubal and/or peritoneal adhesions Surgery performed: adhesiolysis; tubal surgery (cases without adhesions excluded) Preexisting adhesions: all participants Mean age: 31 years (range 21-39) Duration infertility: not stated Infertility workup: semen analysis, postcoital test, conﬁrmation of ovulation (not spec- iﬁed) and laparoscopy; some also had hysterosalpingogram and/or sperm-mucus pene- tration test Number randomly assigned: 109 4 exclusions (lost to follow-up) Number analysed: 105 Timing second-look laparoscopy: 4-10 weeks postoperative Blinding at second-look laparoscopy: not stated

Interventions Dextran vs saline Route of administration: intraperitoneal Dosage/volume: dextran 250 mL; 0.9% saline 250 mL Prophylactic antibiotics: yes

Outcomes Analysed in review Pregnancy rate 1. Method of diagnosis: not stated 2. Duration follow-up: 12-36 months Full-term pregnancy rate Miscarriage rate Ectopic rate Adhesions at SLL 1. Change in score (ovaries, tubes, ﬁmbriae) Other outcomes Adhesions at SLL 1. Change in score according to anatomical site (total, pouch of Douglas, pelvic sidewall, colon, small bowel, anterior abdominal wall) 2. Change in score according to etiology of adhesions Tubal patency Laboratory tests

Notes Adhesion scoring system used Own scoring system based on extent of adhesions (scored from 1-4) over tubes, ﬁmbriae and ovaries (range 4-24) 0 = none 1 = minimal

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 57 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Larsson 1985 (Continued)

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 Low risk “Random selection sequence” bias)

Allocation concealment (selection bias) Unclear risk Insufﬁcient information to permit judgement

Blinding of participants and personnel Low risk States: was “double-blinded,” although no (performance bias) further information given All outcomes

Blinding of outcome assessment (detection Unclear risk States: was “double-blinded,” although no bias) further information given. No mention of All outcomes an independent reviewer or blinding during assessment

Incomplete outcome data (attrition bias) Low risk No missing outcome data All outcomes

Selective reporting (reporting bias) Low risk Data were presented in full and as stated in the methods section regarding outcomes

Other bias Low risk

Lundorff 2001

Methods Randomised trial (computer-generated schedule) Third party-blind Multi-centre: 5 European centres Time of randomisation: at the time of the procedure Power calculation: no

Participants 14 females 42 years of age undergoing laparotomy were included; participants with systemic disease or inﬂammatory pelvic condition or receiving any other form of adhesion prevention agent were excluded 77 participants were analysed, not clear how many participants were randomly assigned Not clear whether intention-to-treat analysis was used

Interventions Intergel vs lactated Ringer’s Route of administration: intraperitoneal Dosage/volume: 300 mL of Intergel or Ringer’s lactate Prophylactic antibiotics: no

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 58 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Lundorff 2001 (Continued)

Second-look laparoscopy performed 6-12 weeks after initial procedure

Outcomes Analysed in review 1. Presence of adhesions at second look 2. Improvement or deterioration in adhesion scores at second look 3. Change in mean adhesion score Other outcomes 1. Severity and extent of adhesions 2. mAFS score categorised by surgical procedure Pregnancy rates: no

Notes Adhesion scoring system used mAFS Funded by Lifecore Biomedical Inc

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Low risk Study device or control solution was maintained in a sealed carton until decision to enroll the participant was made

Blinding of outcome assessment (detection Low risk Third party-blinded review of videotaped bias) second laparoscopy to determine outcome All outcomes data

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 59 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Lundorff 2001 (Continued)

Incomplete outcome data (attrition bias) Unclear risk 77 participants completed study. No com- All outcomes ment on total number randomly assigned

Selective reporting (reporting bias) Low risk No reporting issues identiﬁed

Other bias Low risk

Lundorff 2005

Methods Truly randomised trial Time of randomisation: during initial surgery Double-blind: videoed and blinded reviewer scored adhesions Power calculation: no ITT: no Location: multi-centre (4)-Europe Timing and duration: not stated

Participants Females 18-46 years of age and older undergoing laparoscopic peritoneal cavity surgery (n = 49) Surgery performed: laparoscopy and adhesiolysis Preexisting adhesions: not all participants Number randomly assigned: 14 Timing second-look laparoscopy: 6-10 weeks postoperative Blinding at second-look laparoscopy: yes Exclusion criteria: participant had diabetes, hepatic or renal disorders, pelvic/abdominal infection, history of malignancy within 5 years of study; had received systemic corticosteroids within 30 days of surgery; pregnant; converted to open surgery; exposure to irrigation ﬂuids other than RLS or saline solution; use of any other antiadhesion agents during surgery, use of topical haemostatic agents left in the body; elective or accidental enterotomy; no evidence of adnexal disease or endometriosis at ﬁrst-look laparoscopy

Interventions Oxiplex/AP gel vs surgery only

Outcomes Safety outcomes OTHER OUTCOMES Adhesions at second-look laparoscopy 1. Change in adhesion score: numerical and categorical 2. Shift analysis Subanalyses based on stage of endometriosis

Notes mAFS used Scored per adnexa, not per participant; thus the results could not be included in the meta-analysis, although appears not to have used an internal control Funded by FzioMed Inc

Risk of bias

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 60 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Lundorff 2005 (Continued)

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “Randomisation schedule” was used bias)

Allocation concealment (selection bias) Unclear risk Not stated

Blinding of participants and personnel Unclear risk Not stated (performance bias) All outcomes

Blinding of outcome assessment (detection Unclear risk “The entire procedure was recorded on bias) videotape...blinded reviews to the video- All outcomes tapes were performed to quantify adhesion scores”

Incomplete outcome data (attrition bias) Low risk All 86 adnexae that were enrolled were anal- All outcomes ysed

Selective reporting (reporting bias) Low risk No selective reporting issues identiﬁed

Other bias Low risk Funded in part by FzioMed Inc

Mais 2006

Methods Truly randomised trial (computer-generated sequence, sealed envelopes) Time of randomisation: intraoperatively Double-blind: Reviewer was blinded Power calculation: no ITT: yes Location: Italy, multi-centre-4 (Cagliari, Florence, Padova, Turin) Timing and duration: March 2002-March 2004; 2 years

Participants Females with both tubes and ovaries undergoing laparoscopic myomectomy for 1-3 subserous/intramural myomas Indication for surgery: pelvic pain and infertility (93), infertility investigation (214), endometriosis (243) Age: 22-42 years Number randomly assigned: 52 Number undergoing second-look laparoscopy: 43 (9 lost to follow-up) Timing second-look laparoscopy: 12-14 weeks postoperative Blinding at second-look laparoscopy: yes Exclusion criteria: postmenopausal, pregnancy, largest myoma < 20 mm or > 50 mm; history of diabetes, hepatic disorders, renal disorders, severe cardiopathies, malignancies; previous administration of antiadhesion agents; presence of pelvic/abdominal infection; oral steroids, immunosuppressives, cytostatic treatment, coagulation disorder, insufﬁ- cient intraoperative haemostasis

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 61 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Mais 2006 (Continued)

Interventions Hyalobarrier vs no treatment Ringer’s lactated saline used as irrigant, then Hyalobarrier applied at end of operation in those randomly assigned to the treatment group for all uterine incisions and suture material

Outcomes Analysed in review Adhesions at second-look laparoscopy 1. Mean adhesion score at ﬁrst-look and second-look laparoscopy 2. Number of participants with adhesions at SLL OTHER OUTCOMES Adhesions at SLL 1. Subanalyses of uterine adhesions only

Notes Operative Laparoscopy Study Group scoring system used

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “Computer generated 1:1 random alloca- bias) tion sequence”

Allocation concealment (selection bias) Low risk “Concealed in numbered sealed envelopes until interventions assigned”

Blinding of participants and personnel Low risk OLSG scoring at initial surgery was per- (performance bias) formed before assignment All outcomes

Blinding of outcome assessment (detection Low risk “The surgeon performing the second look bias) laparoscopy was unaware of the assign- All outcomes ment of the patients to the different study groups”

Incomplete outcome data (attrition bias) Unclear risk “Of 52 patients, ﬁve in Hyalobarrier gel All outcomes group and four in control group...declined to undergo second-look laparoscopy...for personal reasons”

Selective reporting (reporting bias) Low risk No reporting issues identiﬁed

Other bias Low risk

Methods Truly randomised trial (computer-generated). Blinding: yes Time of randomisation: not stated Multi-centre-Germany and France

Participants 64 participants with a mean age of 34.9 years undergoing laparoscopy or laparotomy for treatment of ﬁbroids Exclusion criteria: 1. Participants younger than 18 years of age 2. Cannot adequately communicate in German or English 3. Unwilling to undergo second-look laparoscopy Number of participants randomly assigned: 64 Number of participants undergoing second-look laparoscopy: 62.5% return rate for second look

Interventions SprayGel vs no treatment

Outcomes Analysed in review Presence or absence of adhesions at second-look laparoscopy Other outcomes 1. Change in severity of adhesions at second-look laparoscopy

Notes Adhesion scoring system used Mean adhesion tenacity score

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “Computer-generated randomization bias) schema”

Allocation concealment (selection bias) Low risk “Until the completion of the surgical resection procedure, at which time a preprinted, sealed envelope was opened”

Blinding of participants and personnel Unclear risk Insufﬁcient information to permit judge- (performance bias) ment All outcomes

Blinding of outcome assessment (detection Low risk “The surgeon was blinded to the random- bias) ization”; no mention is made of an inde- All outcomes pendent/blinded reviewer at SLL

Incomplete outcome data (attrition bias) Low risk No missing outcome data All outcomes

Selective reporting (reporting bias) Low risk Data were presented in full and as stated in the methods section regarding outcomes

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 63 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Mettler 2004 (Continued)

Other bias Low risk Funded by Conﬂuent Surgical

Mettler 2008

Methods Truly randomised trial (sequentially numbered sealed envelopes) Time of randomisation: intraoperatively Single-blind: participant Power calculation: yes ITT: yes Location: multi-centre-6 centres (Germany, Canada, Netherlands, Antilles) Timing and duration: July 2003-Jan 2005; 1 year 7 months

Participants Females 18 years of age and older undergoing myomectomy by laparoscopy or laparotomy Number randomly assigned: 72 Number undergoing second-look laparoscopy: 58 (13 lost to follow-up, 1 excluded intraoperatively) Timing second-look laparoscopy: 6-8 weeks postoperative Blinding at second-look laparoscopy: yes Exclusion criteria: uterine incision not > 2 cm or on posterior surface, pelvic inﬂammatory disease, malignancy, pregnancy, immune-compromised condition, use of corticosteroids intraoperatively/postoperatively

Interventions Hyalogel vs Ringer’s lactated saline Hyalogel applied before closure to uterine sutures and surgically treated areas. 300-500 mL RLS instilled at end if in RLS group

Outcomes Analysed in review Adhesions at second-look laparoscopy 1. Number of participants with adhesions at SLL 2. Mean adhesion score at SLL OTHER OUTCOMES Adhesions at second-look laparoscopy 1. Mean AFS score change Subanalyses based on whether laparoscopy/laparotomy, no/previous abdominal surgery, removal of 1/multiple myomas

Notes mAFS score used at 15 sites but during study to restrict to posterior uterus score Funded by Angiotech Pharmaceuticals

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Treatment assignments had been randomly bias) generated from a list of sequential numbers before ﬁrst participant was enrolled

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 64 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Mettler 2008 (Continued)

Allocation concealment (selection bias) Low risk Sealed envelope technique

Blinding of participants and personnel High risk Single-blind study: “While study person- (performance bias) nel were aware of the treatment assignation, All outcomes study patients were not told which treatment they had received until after they ter- minated the study”

Blinding of outcome assessment (detection High risk Participants returned for second-look la- bias) paroscopy at 6-8 weeks-study personnel ap- All outcomes pear not to have been blinded at this outcome assessment

Incomplete outcome data (attrition bias) Low risk “Ten hydrogel and 3 control patients All outcomes withdrew or were withdrawn from the study prior to attending the second look surgery;most of them (9 hydrogel, 2 control) withdrew consent to undergo the second procedure. As a result data was available for 58 patients (38 hydrogel, 20 control) i.e. 81.7% of those who were randomised and received the study intervention”

Selective reporting (reporting bias) High risk mAFS score was to have been calculated by averaging the scores from participants at each of 15 sites treated for adhesions according to the original study protocol. mAFS score at posterior uterus used “In hindsight it became apparent that use of this score would have biased interpretation of the results...for hydrogel subjects, the composite score would have been calculated as the average of the individual mAFS scores from the 2 or 3 sites treated with hydrogel; whereas, for control subjects the composite score would have been calculated as the average of all 15 sites....it became apparent that the posterior uterus was the one anatomical site at which all patients were at risk for adhesion formation... in keeping with these ﬁndings it was determined that the mAFS score at the posterior uterus was the outcome best suited to serve as the primary measure of performance”

Other bias Low risk

Methods Truly randomised trial (computer-generated central randomisation) Double-blinded (known by correspondence with study author) Power calculation: no Intention-to-treat analysis: yes Single-centre-Italy

Participants Infertile participants undergoing laparoscopic myomectomy 36 participants randomly assigned and analysed Inclusion criteria: 1. History of infertility or recurrent miscarriages 2. Lack of pedunculation of the main myoma 3. Presence of not more than 4 myomas 4. Absence of submucosal fibroids as screened by hysteroscopy 5. No calcification of the main myoma 6. Absence of abnormal cervical smear 7. Negative urine pregnancy test Exclusion criteria: 1. Participants who did not fulfil the inclusion criteria Mean age: 26.8 years Both groups demographically similar at the start of the study Number of participants randomly assigned: 36 Number of participants analysed after second-look laparoscopy: 36

Interventions Auto-cross-linked hyaluronic acid gel, 5 mL, vs no treatment Time of application: at the end of the procedure Second-look laparoscopy: 60-90 days after the primary procedure

Outcomes Analysed in review Presence of adhesions at second-look laparoscopy Other outcomes Incidence of adhesions with regards to the site of the primary myoma Pregnancy rates: no

Notes Scoring system not used, only rate of presence or absence of adhesions

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Computer-generated random list bias)

Allocation concealment (selection bias) Unclear risk No reference to allocation concealment in article

Blinding of participants and personnel Low risk No reference to blinding in article, al- (performance bias) though study author contacted and con- All outcomes ﬁrmed double-blinding

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 66 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Pellicano 2003 (Continued)

Blinding of outcome assessment (detection Unclear risk Insufﬁcent information to permit judge- bias) ment All outcomes

Incomplete outcome data (attrition bias) Low risk 36 participants enrolled; all evaluated by All outcomes second-look laparoscopy

Selective reporting (reporting bias) Low risk No reporting issues identiﬁed

Other bias Low risk

Querleu 1989

Methods Truly randomised trial Double-blinded (known by correspondence with study author) Power calculation: no Intention-to-treat analysis: yes Randomised trial: method not stated Time of randomisation: evening before surgery Factorial design Power calculation done Location: multi-centre-5 centres in France (Clermond-Ferrand, Montpellier, Paris, Roubaix and Lyon) and 1 centre in the Netherlands (Nijmegen) Timing and duration: 1984 Sponsored by Laboratories Chanterau, France

Participants Infertility patients undergoing open pelvic microsurgery Condition: distal tubal obstruction and/or pelvic adhesions (active PID, endometriosis, proximal tubal obstruction cases excluded) Surgery performed: tubal surgery; adhesiolysis (19) Preexisting adhesions: analysis done according to preexisting adhesion status, but number not stated Age: not stated Duration infertility: not stated Infertility workup: not stated Number randomly assigned: 131 5 lost to follow-up Number analysed: 126 Number undergoing second-look laparoscopy: 88 Timing second-look laparoscopy: 3-6 months postoperative Blinding at second-look laparoscopy: not stated

Interventions Auto-cross-linked hyaluronic acid gel, 5 mL, vs no treatment Time of application: end of the procedure Second-look laparoscopy performed: 60-90 days after primary procedure 1. Steroids vs no steroids Route of administration: systemic (im) Dosage/volume: dexamethasone 2 mg day before surgery, 8 mg day of surgery and day

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 67 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Querleu 1989 (Continued)

after, 2 mg on 5 following days 2. Noxytioline vs no treatment Route of administration: intraperitoneal Dosage/volume: noxytioline (Noxyﬂex) 5 mg diluted in 250 mL normal saline instilled in the pelvis via a removable drain Other adjuvants: perioperative pelvic irrigation with heparinised (5000 IU/L) normal saline Prophylactic antibiotics: yes (doxycycline)

Outcomes Analysed in review Pregnancy 1. Method of diagnosis: not speciﬁed 2. Duration follow-up: 36 months Ectopic pregnancy rate Adhesions at second-look laparoscopy 1. Improvement; deterioration or no change 2. Change in score Other outcomes Adhesions at second-look laparoscopy 1. Change in score according to initial score 2. Change in score according to grade of adhesions 3. Change in score in subgroup of pure adhesiolysis 4. Grade of adhesions 5. Per cent of ovarian surface free of adhesions 6. Fimbrial status 7. Mobility of the tube

Notes Adhesion scoring system used Modiﬁed American Fertility Society endometriosis scoring system (range 0-84) Adhesions graded as ﬁlmy, vascular or dense Power calculation envisaged participation of 10 centres, entering 32 participants each Only 4 centres reached this number; 2 more centres entered fewer participants Pregnancy rates also presented in a cumulative conception curve using life-table analysis for steroid and no-treatment groups

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Not stated bias)

Allocation concealment (selection bias) Unclear risk Not stated

Blinding of participants and personnel Low risk Was double-blinded according to the study (performance bias) author All outcomes

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 68 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Querleu 1989 (Continued)

Blinding of outcome assessment (detection Unclear risk Insufﬁcent information to permit judge- bias) ment All outcomes

Incomplete outcome data (attrition bias) Low risk All participants accounted for All outcomes

Selective reporting (reporting bias) Low risk No reporting issues identiﬁed

Other bias Low risk Did not recruit enough participants to power study as intended

Rock 1984

Methods Randomised trial (method not stated) Time of randomisation: evening before surgery Factorial design Power calculation done Location: multi-centre-5 centres in France (Clermond-Ferrand, Montpellier, Paris, Roubaix and Lyon) and 1 centre in the Netherlands (Nijmegen) Timing and duration: 1984 Sponsored by Laboratories Chanterau, France Truly randomised (pack of cards) Time of randomisation: not stated Sequential analysis Location: multi-centre-4 centres in the USA (Norfolk, Durham, 2 units in New York), 1 in the Netherlands (Amsterdam) and 1 in Colombia (Bogota) Timing and duration: Jan 1978-Dec 1981

Participants Infertility patients undergoing open pelvic microsurgery Condition: bilateral distal tubal obstruction (unilateral if only 1 residual tube) Surgery performed: tubal surgery Preexisting adhesions: not stated Age: < 36 years (mean 28) Mean duration infertility: 10.7 years (range 1-18) Infertility workup: semen analysis, PCT, documentation of ovulation (method not stated), HSG and laparoscopy (90% of participants) Number randomly assigned: ? (no exclusions stated) Number analysed: 120

Interventions Steroids vs Ringer‘s lactated solution Route of administration: postoperative hydrotubation on the ﬁrst 3 postoperative days and on day of discharge Dosage/volume: 50 mL Ringer‘s lactate with or without 150 mg hydrocortisone Prophylactic antibiotics: yes

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 69 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Rock 1984 (Continued)

Outcomes Analysed in review Pregnancy rate (total and live births) 1. Method of diagnosis: not stated 2. Duration follow-up: > 2 years Miscarriage rate Ectopic rate Other outcomes-infection rates and complications after hydrotubation

Notes 3-Way trial comparing postoperative hydrotubation with or without steroids or no hydrotubation; also included in review on postoperative procedures following tubal surgery

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “A card drawn from a previously ran- bias) domised deck”

Allocation concealment (selection bias) Unclear risk Insufﬁcent information to permit judgement

Blinding of participants and personnel Unclear risk Insufﬁcent information to permit judge- (performance bias) ment All outcomes

Blinding of outcome assessment (detection Unclear risk Insufﬁcent information to permit judge- bias) ment All outcomes

Incomplete outcome data (attrition bias) Low risk No missing outcome data All outcomes

Selective reporting (reporting bias) Low risk Data were presented in full and as stated in the methods section regarding outcomes

Other bias Low risk None

Rose 1991

Methods Truly randomised trial: random number table Time of randomisation: not stated Blinding: participant blind (sIngle-blind) Power calculation: not done ITT: no Location: Milton S Hershey Medical Center, Pennsylvania state Timing and duration: not stated

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 70 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Rose 1991 (Continued)

Participants All participants of the ﬁrst study scheduled for elective laparoscopic surgery offered option of participating Intervention used if any additional surgery performed during laparoscopy. If intervention not used, participant used as control Number of participants: 24 No exclusion criteria stated

Interventions Abdominal instillation of 2000 mL lactated Ringer’s solution, or 200 mL high molecular weight dextran, or no intervention, if surgery in addition to laparoscopy not performed

Outcomes Weight (compared with morning before surgery and morning of surgery) 1. Returning home from surgery 2. Bedtime on day of surgery 3. 4 times a day on 2 days after day of surgery 4. Morning on days 3-6 after surgery

Notes Adhesions not assessed in this paper

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “The assignment was randomised using a bias) random number table”

Allocation concealment (selection bias) Unclear risk Not enough information to allow judgement

Blinding of participants and personnel Unclear risk Not enough information to allow judge- (performance bias) ment All outcomes

Blinding of outcome assessment (detection Low risk “Patients were not informed of what sub- bias) stance had been added to their abdominal All outcomes cavities”

Incomplete outcome data (attrition bias) Low risk No issues identiﬁed All outcomes

Selective reporting (reporting bias) Low risk No issues identiﬁed

Other bias Low risk

Methods Truly randomised trial (method not stated) Time of randomisation Double-blinded-participant and primary surgeon (conducting initial surgery and second-look laparoscopy) Power calculation: no ITT: no Location: single-centre-Medical College of Virginia Reproductive and Infertility Service Timing and duration: 1 Aug 1981-31 July 1982; 1 year

Participants Participants scheduled to undergo major abdominal infertility surgical procedures (n = 46) Number undergoing second-look laparoscopy: 44 (2 participants randomly assigned but did not undergo second-look laparoscopy-no reason stated in published data) Timing second-look laparoscopy: 6 weeks Blinding at second-look laparoscopy: yes Exclusion criteria: none stated

Interventions 32% high molecular weight dextran 70 vs Ringer’s lactate crystalloid solution Instilled into peritoneal cavity before closure after major abdominal surgery

Outcomes American Fertility Society “Classiﬁcation of endometriosis” score-adhesions component of score at second-look laparoscopy Change in score from initial surgery to second-look laparoscopy

Notes Standard deviations not reported

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No comment in published text on genera- bias) tion of sequence

Allocation concealment (selection bias) Low risk “Randomized code assigned by institution’s research pharmacist..two hundred millil- itres of either 32% dextran 70 or Ringer’s lactate labelled with only the patient’s name and substance code delivered to operation room”

Blinding of participants and personnel Low risk “Primary surgeon left the table and the test (performance bias) substance was instilled into the peritoneal All outcomes cavity by the ﬁrst assistant”

Blinding of outcome assessment (detection Low risk “All patients were scheduled for follow up bias) laparoscopy by the original surgeon...adhe- All outcomes sion scores were reassigned”

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 72 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Rosenberg 1984 (Continued)

Incomplete outcome data (attrition bias) High risk No SDs or SEMs given All outcomes

Selective reporting (reporting bias) Unclear risk “46 patients were enrolled in the study and 44 completed the initial phase with a second look laparoscopy” No comment about 2 participants who were randomly assigned but did not undergo second-look surgery No additional outcomes measured. Adverse effects not examined. Standard deviations not reported

Other bias Low risk

Sites 1997

Methods Truly randomised trial: random number table Time of randomisation: not stated Blinding: not stated Power calculation: not done ITT: NA Location: single centre in Vermont Timing and duration: not stated

Participants Participants undergoing laparoscopy for lysis of adhesions, neosalpingostomy, laser va- porisation of endometriosis, ovarian cystectomy or oophorectomy (n = 13) No exclusion criteria stated

Interventions Intra-abdominal instillation of dextran 70 250 mL, lactated Ringer’s solution 250 mL or no ﬂuid following primary surgery

Outcomes Volume of ﬂuid on transvaginal ultrasound scan at 1 hour, 3 hours, 6 hours, 24 hours, 96 hours and 168 hours

Notes Adhesions not assessed

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Random number table bias)

Allocation concealment (selection bias) Unclear risk Not enough information to provide judgement

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 73 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Sites 1997 (Continued)

Blinding of participants and personnel Unclear risk Not enough information to provide judge- (performance bias) ment All outcomes

Blinding of outcome assessment (detection Unclear risk Not enough information to provide judge- bias) ment All outcomes

Incomplete outcome data (attrition bias) Low risk No issues identiﬁed All outcomes

Selective reporting (reporting bias) Low risk No issues identiﬁed

Other bias Low risk

Ten Broek 2012

Methods Truly randomised trial (shufﬂed, sealed envelopes) Time of randomisation: intraoperatively-just before barrier application Single-blinded-participant Power calculation: yes ITT: no Location: single centre-Netherlands Timing and duration: Sep 2002-March 2004; 1 year 7 months

Participants Females 18 years of age and older undergoing laparoscopic gynaecological surgery for benign gynaecological conditions (n = 16) Number undergoing second-look laparoscopy: 15 (1 was excluded at ﬁrst-look laparoscopy) Timing second-look laparoscopy: 4-8 weeks postoperative Blinding at second-look laparoscopy: yes Exclusion criteria: pregnancy, lactating, malignancy, endometriosis stage IV, if complete adhesiolysis not possible

Interventions SepraSpray vs no treatment SepraSpray applied to all sites of surgical injury with potential for adhesion formation

Outcomes Analysed in review Adhesions at second-look laparoscopy 1. Number of participants with adhesion at SLL 2. Mean adhesion score at SLL

Notes Prematurely ended for ﬁnancial and organisational reasons Supported by Conﬂuent Surgery Inc. Adhesions scored by Local Adhesion Barrier Scoring System, based on mAFS score

Risk of bias

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 74 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Ten Broek 2012 (Continued)

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “Patients were randomly assigned-via shuf- bias) ﬂed sealed envelopes-to treatment”

Allocation concealment (selection bias) Low risk “Sealed envelopes”

Blinding of participants and personnel Low risk “Single-blinded (patient)” (performance bias) All outcomes

Blinding of outcome assessment (detection Low risk No mention of an independent/blinded re- bias) viewer, but surgeons unaware of randomi- All outcomes sation until end of initial surgery, and surgeons were blinded at SLL

Incomplete outcome data (attrition bias) Low risk No missing outcome data All outcomes

Selective reporting (reporting bias) Low risk Data were presented in full and as stated in the methods section regarding outcomes

Other bias Unclear risk PEG donated by Conﬂuent. “The study was prematurely ended due to ﬁnancial and organizational reasons. During the conduct of the study, the clinical trial insurance un- expectedly required a separate fee for both laparoscopic procedures in each patient” Was only a pilot study

Thornton 1998

Methods Truly randomised trial (concealed envelope). Randomised as to whether left or right ovary treated Time of randomisation: at initial procedure Double-blind Power calculation: no, feasibility study ITT: yes Location: multi-centre (2)-USA Timing and duration: not stated

Participants Females 24-41 years of age undergoing peritoneal cavity surgery via laparotomy Indication for surgery: not stated Number randomly assigned: 23 Timing second-look laparoscopy: 4-12 weeks postoperative Blinding at second-look laparoscopy: not stated Exclusion criteria: diabetes; haemochromatosis; hepatic, renal, autoimmune, lymphatic, haematological or coagulation disorders; active pelvic infection; inﬂammation or ma-

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 75 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Thornton 1998 (Continued)

lignancy; frozen pelvis or hydrosalpinges; exposure to irrigation ﬂuids other than RLS or saline solution; use of any other antiadhesion agents during surgery; use of topical haemostatic agents left in the body; use of catgut or non-resorbable sutures on the ovaries or immediately adjacent structures; use of gasless laparoscopy, elective or accidental enterotomy; additional non-O+G procedures performed; endometriosis stage IV at time of surgery; ﬁndings that prevented/precluded SLL

Interventions 0.5% ferric hyaluronate adhesion prevention gel vs RLS

Outcomes Adverse effects OTHER OUTCOMES Adhesions at second-look laparoscopy 1. Presence of adhesions 2. Number of adhesions 3. Extent of adhesions 4. Severity of adhesions

Notes mAFS used No actual ﬁgures of SEM and SD given; thus results could not be included in meta- analysis Funded by Conﬂuent Surgical Inc

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk “Randomisation schedule” bias)

Allocation concealment (selection bias) Unclear risk Not stated

Blinding of participants and personnel Unclear risk Not stated (performance bias) All outcomes

Blinding of outcome assessment (detection Unclear risk Not stated bias) All outcomes

Incomplete outcome data (attrition bias) High risk No SDs or SEMs given All outcomes

Selective reporting (reporting bias) Unclear risk No selective reporting issues noted

Other bias Low risk

Methods Truly randomised trial (telephone-generated) Time of randomisation: 24 hours before surgery Double-blind. Independent blinded video reviewer Power calculation: yes ITT: yes Location: multi-centre-25 centres in Europe Timing and duration: Sep 2003-Aug 2005; 1 year 11 months

Participants Females 18 years of age and older undergoing laparoscopic gynaecological surgery only Indication for surgery: myoma or endometriotic cysts Number randomly assigned: 498 Number undergoing second-look laparoscopy: 330 Timing second-look laparoscopy: 4-16 weeks postoperative Blinding at SLL: yes Exclusion criteria: endometriosis stage 3-4, AFS score moderate or severe, pregnancy, systemic corticosteroids, antineoplastic drugs/radiation, GnRHa, active pelvic/abdominal infection, known allergy to starch polymer, prior surgery for endometriotic cysts, > 4 myomas, largest myoma < 2 or > 8 cm in diameter, cancer, re-formed adhesions not counted, drain, pedunculated cysts, use of glue/other antiadhesion agent

Interventions Adept vs Ringer’s lactated saline > 100 mL every 30 minutes, no limit on amount used for irrigation. 1000 mL instilled at end

Outcomes Analysed in review Adhesions at second-look laparoscopy 1. Mean adhesion score OTHER OUTCOMES Adhesions at second-look laparoscopy 1. Number of adhesions 2. 1 or more de novo adhesions at SLL 3. Number of de novo adhesions at SLL 4. Mean AFS score reduction 5. Number of participants free of de novo adhesions Many subanalyses based on sites of adhesions

Notes mAFS score. Looked only at de novo adhesions, not re-formed Funded by Innovata Ltd, Vectura Group

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk “Treatment was randomised through a 24- bias) h central randomization telephone system”

Allocation concealment (selection bias) Low risk “Double-blinding was possible as both ﬂu- ids are clear and odourless solutions with similar viscosities and were packaged iden-

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 77 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Trew 2011 (Continued)

tically”

Blinding of participants and personnel Low risk “Double-blinding was possible as both ﬂu- (performance bias) ids are clear and odourless solutions with All outcomes similar viscosities and were packaged identically”

Blinding of outcome assessment (detection Low risk “The surgery was video recorded according bias) to a detailed protocol to enable all assess- All outcomes ments to be made through an independent and blinded review of video recordings... reviewers were blinded to the study treatment assignment, subject confidential information and investigator site identifiers. ..first and second procedures were scored independently”

Incomplete outcome data (attrition bias) Low risk No missing outcome data All outcomes

Selective reporting (reporting bias) Low risk Data were presented in full and as stated in the methods section regarding outcomes

Other bias Low risk Funded by Innovata Ltd, Vectura Group

Young 2005

Methods Truly randomised trial (central ofﬁce-generated) Time of randomisation: intraoperatively Double-blind. Independent blinded video reviewer Power calculation: yes, but study authors state not powered as pilot study ITT: yes Location: multi-centre (6)-locations not stated Timing and duration: not stated

Participants Females 18 years of age and older undergoing laparoscopic gynaecological surgery on at least 1 adnexa Indication for surgery: adnexal pathology (e.g. adhesions, endometrioma, endometriosis, dermoid cyst, tubal occlusion) Number randomly assigned: 28 Number undergoing second-look laparoscopy: 27 Timing second-look laparoscopy: 6-10 weeks postoperative Blinding at SLL: yes Exclusion criteria

Interventions Oxiplex/AP gel vs no treatment < 30 mL Oxiplex gel applied to areas where surgeon thought adhesions may occur

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 78 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Young 2005 (Continued)

Outcomes Analysed in review Adhesions at second-look laparoscopy 1. Number of participants with improvement in adhesion score 2. Number of participants with worsening adhesion score OTHER OUTCOMES Adhesions at second-look laparoscopy 1. Mean AFS score per adnexa at ﬁrst look and SLL 2. Change in adhesion score Many results, then reported as per adnexa

Notes mAFS score Funded by FzioMed Ltd

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No comment on method of sequence gen- bias) eration

Allocation concealment (selection bias) Low risk “After a standard surgical treatment was completed and before closing, the investigator contacted a central ofﬁce for subject group assignment”

Blinding of participants and personnel Low risk “Selection of group assignment was ran- (performance bias) dom and not available to the investigator All outcomes until all inclusion and exclusion criteria were met, including those determined by surgery”

Blinding of outcome assessment (detection Low risk “All surgeries were recorded and the video- bias) tapes were forwarded to a single masked re- All outcomes viewer to assess”

Incomplete outcome data (attrition bias) Low risk All 28 participants randomly assigned were All outcomes evaluated by second-look laparoscopy. No issues identiﬁed

Selective reporting (reporting bias) Low risk No reporting issues identiﬁed

Other bias Low risk Data reported in terms of adnexae rather than individual participants

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 79 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Diamond 2011 Randomised controlled trial comparing Adhexil vs no treatment but using an internal control for 16 participants undergoing laparoscopy with known bilateral ovarian disease Reason for exclusion: used internal control and thus could not be included in analyses

Imai 2003 Adhesions were assessed at caesarean section; not as thorough as at second-look laparoscopy

Johns 2003 Used an internal control and thus could not be included in analyses

Mettler 2003(a) This is an interim analysis; the completed study (Mettler 2004) has been included

Mettler 2003(b) This is an interim analysis; the completed study (Mettler 2004) has been included

Pellicano 2005 Study evaluating the clinical pregnancy rate when auto-cross-linked hyaluronic acid gel was compared with no treatment in 36 participants Reason for exclusion: not randomised controlled trial

Swolin 1967 Quasi-randomised trial of steroids vs non-steroids Reason for exclusion: quasi-randomised trial (case record numbers)

Tsuji 2005 Prospective study of 63 participants undergoing myomectomy comparing Sepraﬁlm, Dextran 40, Beriplast and no treatment Reason for exclusion: not a randomised controlled trial

Tulandi 1985 Randomised controlled trials of 22 participants comparing 32% dextran vs normal saline Reason for exclusion: evaluates blood indices, not adhesions

Tulandi 1991 Randomised controlled trial of 12 participants comparing ﬁbrin sealant vs no treatment Reason for exclusion: internal control

Characteristics of studies awaiting assessment [ordered by study ID]

Hudecek 2012

Methods Info from abstract (article in Czech) Truly randomised trial (method not stated) Time of randomisation: not stated Blinding: not stated Power calculation: no Intention-to-treat (ITT): yes Location: multi-centre (16 centres)-not stated where Timing and duration: July 2001-March 2004; 2 years 8 months

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 80 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Hudecek 2012 (Continued)

Participants Females 18 years of age and older undergoing laparoscopic/laparotomic myomectomy (n = 212) Indication for surgery: symptomatic ﬁbroids Preexisting adhesions: not stated Number randomly assigned: 178 Number undergoing second-look laparoscopy: not stated Timing second-look laparoscopy: not stated Blinding at second-look laparoscopy: not stated Exclusion criteria: not stated

Interventions Pretreatment with gonadotrophin-releasing hormone agonist (GnRHa) before myomectomy vs no GnRHa

Outcomes Intraoperative blood loss, duration of surgery, length of hospital stay, preoperative and postoperative complications, ﬁnal result by second-look laparoscopy (SLL), including adhesions

Notes Need to obtain translation of article so it can be included in next review update

Litta 2013

Methods Randomised: not stated Blinding: not stated Power calculation: not stated Intention-to-treat (ITT): not stated Location: Italy Second-look laparoscopy: 45-60 days Timing and duration of study: not stated

Participants Women 23-42 years of age undergoing laparoscopic myomectomy using the Harmonic Ace to improve fertility

Interventions Cross-linked hyaluronic acid applied to myometrial scar vs Ringer’s lactate

Outcomes Incidence of adhesions, site-speciﬁc

Notes Only in abstract form at present time

Tchartchian 2009

Methods Truly randomised trial in 2:1 ratio (method not stated) Time of randomisation (not stated) Blinding: single-blinded Power calculation: no Intention-to-treat (ITT): no Location: single centre-Germany Timing and duration of study: not stated

Participants Females 18 years of age and older (n = 15) Surgery performed: laparoscopic myomectomy Number randomly assigned: not stated

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 81 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Tchartchian 2009 (Continued)

Number undergoing second-look laparoscopy (SLL): not stated Timing of SLL: 8-12 weeks Blinding at SLL: scored by independent blinded surgeon via video Exclusion criteria: not stated

Interventions SprayShield vs no treatment

Outcomes American Fertility Society (AFS) used; area in mm of uterus covered by adhesions scored

Notes Published abstract only, no full-text article found No actual results published

Abbreviations: AFS: American Fertility Society. GnRHa: Gonadotrophin-releasing hormone agonist. ITT: Intention-to-treat. LRS: Lactated Ringer’s saline. mAFS: Modiﬁed American Fertility Society. NOCC: N,O-carboxymethyl chitosan. PBS: Phosphate-buffered saline. PEG: Polyethylene glycol. PID: Pelvic inﬂammatory disease. PP: Per-protocol. SAE: Serious adverse event. SD: Standard deviation. SEM: Standard error of the mean. SLL: Second-look laparoscopy.

Comparison 1. Hydroﬂotation agent vs no hydroﬂotation agent

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Improvement in pelvic pain at 1 Odds Ratio (M-H, Fixed, 95% CI) Subtotals only second-look laparoscopy 2 Live birth rate 2 208 Odds Ratio (M-H, Fixed, 95% CI) 0.67 [0.29, 1.58] 3 Improvement in adhesion score 4 665 Odds Ratio (M-H, Random, 95% CI) 1.27 [0.79, 2.05] at SLL 4 Number of participants with 1 53 Odds Ratio (M-H, Fixed, 95% CI) 0.28 [0.07, 1.21] worsening adhesion score 5 Number of participants with 4 566 Odds Ratio (M-H, Fixed, 95% CI) 0.34 [0.22, 0.55] adhesions at second-look laparoscopy 6 Mean adhesion score at 4 722 Std. Mean Difference (IV, Random, 95% CI) -0.06 [-0.20, 0.09] second-look laparoscopy 7 Clinical pregnancy rate 3 310 Odds Ratio (M-H, Fixed, 95% CI) 0.64 [0.36, 1.14] 9 Ectopic pregnancy rate (per 2 50 Odds Ratio (M-H, Fixed, 95% CI) 0.35 [0.06, 1.85] pregnancy)

Comparison 2. Gel agent vs no treatment

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Proportion of sites with Other data No numeric data adhesions at SLL 2 Mean change from baseline Other data No numeric data adhesion score at SLL 3 Number of participants with 2 58 Odds Ratio (M-H, Fixed, 95% CI) 3.78 [0.61, 23.32] improvement in adhesion score 4 Number of participants with 2 58 Odds Ratio (M-H, Fixed, 95% CI) 0.16 [0.04, 0.57] worsening adhesion score 5 Number of participants with 4 134 Odds Ratio (M-H, Fixed, 95% CI) 0.25 [0.11, 0.56] adhesions at second-look laparoscopy 6 Mean adhesion score at 2 58 Std. Mean Difference (IV, Fixed, 95% CI) -0.13 [-0.65, 0.39] second-look laparoscopy 7 Decrease in mean adnexal Other data No numeric data adhesion score 8 Recurrence of adhesions at SLL Other data No numeric data

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 83 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Comparison 3. Gel agent vs hydroﬂotation agent when used as an instillant

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

3 Number of participants with 2 342 Odds Ratio (M-H, Fixed, 95% CI) 1.55 [0.82, 2.92] improvement in adhesion score 4 Number of participants with 2 342 Odds Ratio (M-H, Fixed, 95% CI) 0.28 [0.12, 0.66] worsening adhesion score 5 Number of participants with 2 342 Odds Ratio (M-H, Fixed, 95% CI) 0.36 [0.19, 0.67] adhesions at second-look laparoscopy 6 Mean adhesion score at 1 77 Mean Difference (IV, Fixed, 95% CI) -0.79 [-0.79, -0.79] second-look laparoscopy

Comparison 4. Steroid (any route) vs no steroid

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

2 Live birth rate 2 223 Odds Ratio (M-H, Fixed, 95% CI) 0.65 [0.26, 1.62] 3 Number of participants with 1 75 Odds Ratio (M-H, Fixed, 95% CI) 4.83 [1.71, 13.65] improvement in adhesion score 4 Number of participants with 2 182 Odds Ratio (M-H, Random, 95% CI) 0.27 [0.12, 0.58] worsening adhesion score 7 Clinical pregnancy rate 3 410 Odds Ratio (M-H, Fixed, 95% CI) 1.01 [0.66, 1.55] 9 Ectopic pregnancy rate (per 3 83 Odds Ratio (M-H, Random, 95% CI) 0.67 [0.08, 5.70] pregnancy)

Comparison 5. Intraperitoneal noxytioline vs no treatment

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

4 Number of participants with 1 87 Odds Ratio (M-H, Fixed, 95% CI) 0.55 [0.17, 1.76] worsening adhesion score 7 Clinical pregnancy rate 1 126 Odds Ratio (M-H, Fixed, 95% CI) 0.66 [0.30, 1.47] 9 Ectopic pregnancy rate (per 1 33 Odds Ratio (M-H, Fixed, 95% CI) 4.91 [0.45, 53.27] pregnancy)

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 84 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Comparison 6. Intraperitoneal heparin solution vs no intraperitoneal heparin

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

3 Number of participants with 1 63 Odds Ratio (M-H, Fixed, 95% CI) 0.87 [0.32, 2.35] improvement in adhesion score 4 Number of participants with 1 92 Odds Ratio (M-H, Fixed, 95% CI) 1.27 [0.56, 2.91] worsening adhesion score

Comparison 7. Systemic promethazine vs no promethazine

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

3 Number of participants with 1 75 Odds Ratio (M-H, Fixed, 95% CI) 0.56 [0.22, 1.43] improvement in adhesion score 4 Number of participants with 1 93 Odds Ratio (M-H, Fixed, 95% CI) 0.59 [0.25, 1.42] worsening adhesion score

Comparison 8. GnRH analogue vs no treatment/ placebo

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Area of adhesions (cm2) Other data No numeric data

Comparison 9. Plasminogen activator vs control

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Incidence of adhesions at SLL Other data No numeric data (score)

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 85 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 1.1. Comparison 1 Hydroﬂotation agent vs no hydroﬂotation agent, Outcome 1 Improvement in pelvic pain at second-look laparoscopy.

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery

Comparison: 1 Hydroﬂotation agent vs no hydroﬂotation agent

Outcome: 1 Improvement in pelvic pain at second-look laparoscopy

Studyorsubgroup Adept RLS OddsRatio Weight OddsRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Brown 2007 111/152 108/134 0.65 [ 0.37, 1.14 ] Subtotal (95% CI) 0 0 0.0 [ 0.0, 0.0 ] Total events: 111 (Adept), 108 (RLS) Heterogeneity: not applicable Test for overall effect: Z = 0.0 (P < 0.00001) Test for subgroup differences: Not applicable

0.5 0.7 1 1.5 2 Favours RLS Favours Adept

Analysis 1.2. Comparison 1 Hydroﬂotation agent vs no hydroﬂotation agent, Outcome 2 Live birth rate.

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery

Comparison: 1 Hydroﬂotation agent vs no hydroﬂotation agent

Outcome: 2 Live birth rate

Studyorsubgroup Hydroﬂotation Control OddsRatio Weight Odds Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Jansen 1985 (1) 4/50 8/53 54.4 % 0.49 [ 0.14, 1.74 ]

Larsson 1985 6/51 7/54 45.6 % 0.90 [ 0.28, 2.87 ] Total (95% CI) 101 107 100.0 % 0.67 [ 0.29, 1.58 ] Total events: 10 (Hydroﬂotation), 15 (Control) Heterogeneity: Chi2 = 0.47, df = 1 (P = 0.49); I2 =0.0% Test for overall effect: Z = 0.91 (P = 0.36) Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10 Favours control Favours hydroﬂotation

(1) Some data for this study supplied by study authors

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 86 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 1.3. Comparison 1 Hydroﬂotation agent vs no hydroﬂotation agent, Outcome 3 Improvement in adhesion score at SLL.

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery

Comparison: 1 Hydroﬂotation agent vs no hydroﬂotation agent

Outcome: 3 Improvement in adhesion score at SLL

Studyorsubgroup Hydroﬂotation Control OddsRatio Weight Odds Ratio M- M- H,Random,95% H,Random,95% n/N n/N CI CI Adhesion SG 1983 38/51 27/40 19.3 % 1.41 [ 0.56, 3.51 ]

Brown 2007 87/203 70/199 44.8 % 1.38 [ 0.92, 2.07 ]

diZerega 2002 10/27 4/26 10.9 % 3.24 [ 0.86, 12.12 ]

Jansen 1985 (1) 35/59 41/60 25.0 % 0.68 [ 0.32, 1.43 ] Total (95% CI) 340 325 100.0 % 1.27 [ 0.79, 2.05 ] Total events: 170 (Hydroﬂotation), 142 (Control) Heterogeneity: Tau2 = 0.09; Chi2 = 4.84, df = 3 (P = 0.18); I2 =38% Test for overall effect: Z = 0.99 (P = 0.32) Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10 Favours control Favours hydroﬂotation

(1) Some data for this study supplied by study authors

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 87 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 1.4. Comparison 1 Hydroﬂotation agent vs no hydroﬂotation agent, Outcome 4 Number of participants with worsening adhesion score.

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery

Comparison: 1 Hydroﬂotation agent vs no hydroﬂotation agent

Outcome: 4 Number of participants with worsening adhesion score

Studyorsubgroup Hydroﬂotation Control OddsRatio Weight Odds Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI diZerega 2002 3/27 8/26 100.0 % 0.28 [ 0.07, 1.21 ] Total (95% CI) 27 26 100.0 % 0.28 [ 0.07, 1.21 ] Total events: 3 (Hydroﬂotation), 8 (Control) Heterogeneity: not applicable Test for overall effect: Z = 1.70 (P = 0.089) Test for subgroup differences: Not applicable

0.05 0.2 1 5 20 Favours hydroﬂotation Favours control

Analysis 1.5. Comparison 1 Hydroﬂotation agent vs no hydroﬂotation agent, Outcome 5 Number of participants with adhesions at second-look laparoscopy.

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery

Comparison: 1 Hydroﬂotation agent vs no hydroﬂotation agent

Outcome: 5 Number of participants with adhesions at second-look laparoscopy

Studyorsubgroup Hydroﬂotation Control OddsRatio Weight Odds Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Adhesion SG 1983 13/55 24/47 31.7 % 0.30 [ 0.13, 0.69 ]

Diamond 1998 119/137 103/108 24.2 % 0.32 [ 0.12, 0.89 ]

diZerega 2002 18/27 21/26 11.4 % 0.48 [ 0.13, 1.68 ]

Jansen 1985 (1) 56/78 77/88 32.7 % 0.36 [ 0.16, 0.81 ] Total (95% CI) 297 269 100.0 % 0.34 [ 0.22, 0.55 ] Total events: 206 (Hydroﬂotation), 225 (Control) Heterogeneity: Chi2 = 0.41, df = 3 (P = 0.94); I2 =0.0% Test for overall effect: Z = 4.44 (P < 0.00001) Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10 Favours hydroﬂotation Favours control

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 88 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. (1) Some data for this study supplied by study authors

Analysis 1.6. Comparison 1 Hydroﬂotation agent vs no hydroﬂotation agent, Outcome 6 Mean adhesion score at second-look laparoscopy.

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery

Comparison: 1 Hydroﬂotation agent vs no hydroﬂotation agent

Outcome: 6 Mean adhesion score at second-look laparoscopy

Std. Std. Mean Mean Studyorsubgroup Hydroﬂotation Control Difference Weight Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Adhesion SG 1983 51 3.63 (5.78) 40 4.83 (5.75) 12.4 % -0.21 [ -0.62, 0.21 ]

Brown 2007 102 5.9 (8.8) 112 7.2 (9.1) 29.6 % -0.14 [ -0.41, 0.12 ]

Larsson 1985 51 6.92 (5.68) 54 6.07 (5.58) 14.6 % 0.15 [ -0.23, 0.53 ]

Trew 2011 159 8.13 (12.37) 153 8.42 (11.8) 43.4 % -0.02 [ -0.25, 0.20 ] Total (95% CI) 363 359 100.0 % -0.06 [ -0.20, 0.09 ] Heterogeneity: Tau2 = 0.0; Chi2 = 2.11, df = 3 (P = 0.55); I2 =0.0% Test for overall effect: Z = 0.76 (P = 0.44) Test for subgroup differences: Not applicable

-0.5 -0.25 0 0.25 0.5 Favours hydroﬂotation Favours control

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 89 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 1.7. Comparison 1 Hydroﬂotation agent vs no hydroﬂotation agent, Outcome 7 Clinical pregnancy rate.

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery

Comparison: 1 Hydroﬂotation agent vs no hydroﬂotation agent

Outcome: 7 Clinical pregnancy rate

Studyorsubgroup Hydroﬂotation Control OddsRatio Weight Odds Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Adhesion SG 1983 4/55 7/47 24.0 % 0.45 [ 0.12, 1.64 ]

Jansen 1985 (1) 9/50 11/53 30.1 % 0.84 [ 0.31, 2.23 ]

Larsson 1985 12/51 18/54 45.9 % 0.62 [ 0.26, 1.45 ] Total (95% CI) 156 154 100.0 % 0.64 [ 0.36, 1.14 ] Total events: 25 (Hydroﬂotation), 36 (Control) Heterogeneity: Chi2 = 0.59, df = 2 (P = 0.75); I2 =0.0% Test for overall effect: Z = 1.51 (P = 0.13) Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10 Favours control Favours hydroﬂotation

(1) Some data for this study supplied by study authors

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 90 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 1.9. Comparison 1 Hydroﬂotation agent vs no hydroﬂotation agent, Outcome 9 Ectopic pregnancy rate (per pregnancy).

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery

Comparison: 1 Hydroﬂotation agent vs no hydroﬂotation agent

Outcome: 9 Ectopic pregnancy rate (per pregnancy)

Studyorsubgroup Hydroﬂotation Control OddsRatio Weight Odds Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Jansen 1985 (1) 1/9 1/11 15.4 % 1.25 [ 0.07, 23.26 ]

Larsson 1985 1/12 6/18 84.6 % 0.18 [ 0.02, 1.76 ] Total (95% CI) 21 29 100.0 % 0.35 [ 0.06, 1.85 ] Total events: 2 (Hydroﬂotation), 7 (Control) Heterogeneity: Chi2 = 1.05, df = 1 (P = 0.31); I2 =5% Test for overall effect: Z = 1.24 (P = 0.21) Test for subgroup differences: Not applicable

0.02 0.1 1 10 50 Favours hydroﬂotation Favours control

(1) Some data for this study supplied by study authors

Analysis 2.1. Comparison 2 Gel agent vs no treatment, Outcome 1 Proportion of sites with adhesions at SLL. Proportion of sites with adhesions at SLL

Study Proportion in SD number of partici- Proportion in SD number of participants study group pants control group

Thornton 1998 0.364 0.280 13 0.629 0.168 10

Analysis 2.2. Comparison 2 Gel agent vs no treatment, Outcome 2 Mean change from baseline adhesion score at SLL. Mean change from baseline adhesion score at SLL

Study Mean change in SD number of partici- Mean change in SD number of participants hydrogel group pants control group

Mettler 2008 0.8 -2.0 48 2.6 -2.2 23

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 91 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 2.3. Comparison 2 Gel agent vs no treatment, Outcome 3 Number of participants with improvement in adhesion score.

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery Comparison: 2 Gel agent vs no treatment Outcome: 3 Number of participants with improvement in adhesion score

Studyorsubgroup Gel Control OddsRatio Weight OddsRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Mettler 2004 2/18 1/13 70.5 % 1.50 [ 0.12, 18.54 ]

Young 2005 5/17 0/10 29.5 % 9.24 [ 0.46, 187.28 ] Total (95% CI) 35 23 100.0 % 3.78 [ 0.61, 23.32 ] Total events: 7 (Gel), 1 (Control) Heterogeneity: Chi2 = 0.86, df = 1 (P = 0.35); I2 =0.0% Test for overall effect: Z = 1.43 (P = 0.15) Test for subgroup differences: Not applicable

0.005 0.1 1 10 200 Favours control Favours gel

Analysis 2.4. Comparison 2 Gel agent vs no treatment, Outcome 4 Number of participants with worsening adhesion score.

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery Comparison: 2 Gel agent vs no treatment Outcome: 4 Number of participants with worsening adhesion score

Studyorsubgroup Gel Control OddsRatio Weight OddsRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Mettler 2004 9/18 11/13 49.5 % 0.18 [ 0.03, 1.06 ]

Young 2005 6/17 8/10 50.5 % 0.14 [ 0.02, 0.86 ] Total (95% CI) 35 23 100.0 % 0.16 [ 0.04, 0.57 ] Total events: 15 (Gel), 19 (Control) Heterogeneity: Chi2 = 0.05, df = 1 (P = 0.83); I2 =0.0% Test for overall effect: Z = 2.83 (P = 0.0047) Test for subgroup differences: Not applicable

0.05 0.2 1 5 20 Favours gel Favours control

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 92 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 2.5. Comparison 2 Gel agent vs no treatment, Outcome 5 Number of participants with adhesions at second-look laparoscopy.

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery Comparison: 2 Gel agent vs no treatment Outcome: 5 Number of participants with adhesions at second-look laparoscopy

Studyorsubgroup Gel Control OddsRatio Weight OddsRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Mais 2006 8/21 13/22 30.8 % 0.43 [ 0.13, 1.45 ]

Mettler 2004 15/22 16/18 22.0 % 0.27 [ 0.05, 1.50 ]

Pellicano 2003 5/18 14/18 39.7 % 0.11 [ 0.02, 0.50 ]

Ten Broek 2012 7/9 6/6 7.5 % 0.23 [ 0.01, 5.73 ] Total (95% CI) 70 64 100.0 % 0.25 [ 0.11, 0.56 ] Total events: 35 (Gel), 49 (Control) Heterogeneity: Chi2 = 1.87, df = 3 (P = 0.60); I2 =0.0% Test for overall effect: Z = 3.41 (P = 0.00065) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours gel Favours control

Analysis 2.6. Comparison 2 Gel agent vs no treatment, Outcome 6 Mean adhesion score at second-look laparoscopy.

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery Comparison: 2 Gel agent vs no treatment Outcome: 6 Mean adhesion score at second-look laparoscopy

Std. Std. Mean Mean Studyorsubgroup Gel Control Difference Weight Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Mais 2006 21 2.1 (3.9) 22 2.1 (2.2) 75.7 % 0.0 [ -0.60, 0.60 ]

Ten Broek 2012 9 1.2 (1.3) 6 2.2 (2.4) 24.3 % -0.52 [ -1.58, 0.53 ] Total (95% CI) 30 28 100.0 % -0.13 [ -0.65, 0.39 ] Heterogeneity: Chi2 = 0.71, df = 1 (P = 0.40); I2 =0.0% Test for overall effect: Z = 0.48 (P = 0.63) Test for subgroup differences: Not applicable

-1 -0.5 0 0.5 1 Favours gel Favours control

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 93 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 2.7. Comparison 2 Gel agent vs no treatment, Outcome 7 Decrease in mean adnexal adhesion score. Decrease in mean adnexal adhesion score

Study Decrease in mean adnexal number of participants Decrease in mean adnexal number of particpants adhesion score in oxiplex adhesion score in control group group

Lundorff 2005 2.8 45 -7.0 41

Analysis 2.8. Comparison 2 Gel agent vs no treatment, Outcome 8 Recurrence of adhesions at SLL. Recurrence of adhesions at SLL

Study Recurrence at SLL Number of participants Recurrence at SLL con- number of participants NOCC group trol group

Diamond 2003 0.61 17 0.38 17

Analysis 3.3. Comparison 3 Gel agent vs hydroﬂotation agent when used as an instillant, Outcome 3 Number of participants with improvement in adhesion score.

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery Comparison: 3 Gel agent vs hydroﬂotation agent when used as an instillant Outcome: 3 Number of participants with improvement in adhesion score

Studyorsubgroup Gels Hydroﬂotation OddsRatio Weight Odds Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Johns 2001 18/131 12/134 66.0 % 1.62 [ 0.75, 3.51 ]

Lundorff 2001 9/38 7/39 34.0 % 1.42 [ 0.47, 4.30 ] Total (95% CI) 169 173 100.0 % 1.55 [ 0.82, 2.92 ] Total events: 27 (Gels), 19 (Hydroﬂotation) Heterogeneity: Chi2 = 0.04, df = 1 (P = 0.85); I2 =0.0% Test for overall effect: Z = 1.36 (P = 0.17) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours hydroﬂotation Favours gels

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 94 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 3.4. Comparison 3 Gel agent vs hydroﬂotation agent when used as an instillant, Outcome 4 Number of participants with worsening adhesion score.

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery Comparison: 3 Gel agent vs hydroﬂotation agent when used as an instillant Outcome: 4 Number of participants with worsening adhesion score

Studyorsubgroup Gels Hydroﬂotation OddsRatio Weight Odds Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Johns 2001 7/131 20/134 81.0 % 0.32 [ 0.13, 0.79 ]

Lundorff 2001 0/38 4/39 19.0 % 0.10 [ 0.01, 1.97 ] Total (95% CI) 169 173 100.0 % 0.28 [ 0.12, 0.66 ] Total events: 7 (Gels), 24 (Hydroﬂotation) Heterogeneity: Chi2 = 0.54, df = 1 (P = 0.46); I2 =0.0% Test for overall effect: Z = 2.93 (P = 0.0033) Test for subgroup differences: Not applicable

0.005 0.1 1 10 200 Favours gels Favours hydroﬂotation

Analysis 3.5. Comparison 3 Gel agent vs hydroﬂotation agent when used as an instillant, Outcome 5 Number of participants with adhesions at second-look laparoscopy.

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery Comparison: 3 Gel agent vs hydroﬂotation agent when used as an instillant Outcome: 5 Number of participants with adhesions at second-look laparoscopy

Studyorsubgroup Gels Hydroﬂotation OddsRatio Weight Odds Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Johns 2001 12/131 33/134 84.8 % 0.31 [ 0.15, 0.63 ]

Lundorff 2001 4/38 6/39 15.2 % 0.65 [ 0.17, 2.50 ] Total (95% CI) 169 173 100.0 % 0.36 [ 0.19, 0.67 ] Total events: 16 (Gels), 39 (Hydroﬂotation) Heterogeneity: Chi2 = 0.90, df = 1 (P = 0.34); I2 =0.0% Test for overall effect: Z = 3.20 (P = 0.0014) Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10 Favours gels Favours hydroﬂotation

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 95 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 3.6. Comparison 3 Gel agent vs hydroﬂotation agent when used as an instillant, Outcome 6 Mean adhesion score at second-look laparoscopy.

Mean Mean Studyorsubgroup Gels Hydroﬂoatation Difference Weight Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Lundorff 2001 38 0.46 (0.01) 39 1.25 (0.01) 100.0 % -0.79 [ -0.79, -0.79 ] Total (95% CI) 38 39 100.0 % -0.79 [ -0.79, -0.79 ] Heterogeneity: not applicable Test for overall effect: Z = 346.58 (P < 0.00001) Test for subgroup differences: Not applicable

-0.5 -0.25 0 0.25 0.5 Favours gels Favours hydroﬂotation

Analysis 4.2. Comparison 4 Steroid (any route) vs no steroid, Outcome 2 Live birth rate.

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery Comparison: 4 Steroid (any route) vs no steroid Outcome: 2 Live birth rate

Studyorsubgroup Steroids Control OddsRatio Weight OddsRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Jansen 1985 (1) 6/56 6/47 50.5 % 0.82 [ 0.25, 2.73 ]

Rock 1984 3/60 6/60 49.5 % 0.47 [ 0.11, 1.99 ] Total (95% CI) 116 107 100.0 % 0.65 [ 0.26, 1.62 ] Total events: 9 (Steroids), 12 (Control) Heterogeneity: Chi2 = 0.33, df = 1 (P = 0.57); I2 =0.0% Test for overall effect: Z = 0.93 (P = 0.35) Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10 Favours control Favours steroids

(1) Some data for this study supplied by study authors

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 96 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 4.3. Comparison 4 Steroid (any route) vs no steroid, Outcome 3 Number of participants with improvement in adhesion score.

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery Comparison: 4 Steroid (any route) vs no steroid Outcome: 3 Number of participants with improvement in adhesion score

Studyorsubgroup Steroids Control OddsRatio Weight OddsRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Jansen 1990 (1) 29/36 18/39 100.0 % 4.83 [ 1.71, 13.65 ] Total (95% CI) 36 39 100.0 % 4.83 [ 1.71, 13.65 ] Total events: 29 (Steroids), 18 (Control) Heterogeneity: not applicable Test for overall effect: Z = 2.97 (P = 0.0029) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours control Favours steroids

(1) Data for this study supplied by study authors

Analysis 4.4. Comparison 4 Steroid (any route) vs no steroid, Outcome 4 Number of participants with worsening adhesion score.

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery Comparison: 4 Steroid (any route) vs no steroid Outcome: 4 Number of participants with worsening adhesion score

Studyorsubgroup Steroids Control OddsRatio Weight OddsRatio M- M- H,Random,95% H,Random,95% n/N n/N CI CI Jansen 1990 (1) 8/45 23/50 67.3 % 0.25 [ 0.10, 0.65 ]

Querleu 1989 3/38 11/49 32.7 % 0.30 [ 0.08, 1.15 ] Total (95% CI) 83 99 100.0 % 0.27 [ 0.12, 0.58 ] Total events: 11 (Steroids), 34 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 0.03, df = 1 (P = 0.85); I2 =0.0% Test for overall effect: Z = 3.34 (P = 0.00084) Test for subgroup differences: Not applicable

0.001 0.01 0.1 1 10 100 1000 Favours steroids Favours control

(1) Data for this study supplied by study authors

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 97 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 4.7. Comparison 4 Steroid (any route) vs no steroid, Outcome 7 Clinical pregnancy rate.

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery Comparison: 4 Steroid (any route) vs no steroid Outcome: 7 Clinical pregnancy rate

Studyorsubgroup Steroids Control OddsRatio Weight OddsRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Jansen 1985 (1) 32/87 28/77 44.7 % 1.02 [ 0.54, 1.92 ]

Querleu 1989 19/61 18/65 28.6 % 1.18 [ 0.55, 2.54 ]

Rock 1984 12/60 14/60 26.7 % 0.82 [ 0.34, 1.96 ] Total (95% CI) 208 202 100.0 % 1.01 [ 0.66, 1.55 ] Total events: 63 (Steroids), 60 (Control) Heterogeneity: Chi2 = 0.38, df = 2 (P = 0.83); I2 =0.0% Test for overall effect: Z = 0.06 (P = 0.96) Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10 Favours control Favours steroids

(1) Some data for this study supplied by study authors

Analysis 4.9. Comparison 4 Steroid (any route) vs no steroid, Outcome 9 Ectopic pregnancy rate (per pregnancy).

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery Comparison: 4 Steroid (any route) vs no steroid Outcome: 9 Ectopic pregnancy rate (per pregnancy)

Studyorsubgroup Steroids Control OddsRatio Weight OddsRatio M- M- H,Random,95% H,Random,95% n/N n/N CI CI Jansen 1985 (1) 0/11 2/9 25.2 % 0.13 [ 0.01, 3.11 ]

Querleu 1989 1/19 3/18 33.4 % 0.28 [ 0.03, 2.96 ]

Rock 1984 6/12 3/14 41.4 % 3.67 [ 0.67, 20.19 ] Total (95% CI) 42 41 100.0 % 0.67 [ 0.08, 5.70 ] Total events: 7 (Steroids), 8 (Control) Heterogeneity: Tau2 = 2.13; Chi2 = 4.98, df = 2 (P = 0.08); I2 =60% Test for overall effect: Z = 0.37 (P = 0.71) Test for subgroup differences: Not applicable

0.001 0.01 0.1 1 10 100 1000 Favours steroids Favours control

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 98 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. (1) Some data for this study supplied by study authors

Analysis 5.4. Comparison 5 Intraperitoneal noxytioline vs no treatment, Outcome 4 Number of participants with worsening adhesion score.

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery Comparison: 5 Intraperitoneal noxytioline vs no treatment Outcome: 4 Number of participants with worsening adhesion score

Studyorsubgroup Noxytioline Control OddsRatio Weight Odds Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Querleu 1989 6/48 8/39 100.0 % 0.55 [ 0.17, 1.76 ] Total (95% CI) 48 39 100.0 % 0.55 [ 0.17, 1.76 ] Total events: 6 (Noxytioline), 8 (Control) Heterogeneity: not applicable Test for overall effect: Z = 1.00 (P = 0.32) Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10 Favours noxytioline Favours control

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 99 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 5.7. Comparison 5 Intraperitoneal noxytioline vs no treatment, Outcome 7 Clinical pregnancy rate.

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery Comparison: 5 Intraperitoneal noxytioline vs no treatment Outcome: 7 Clinical pregnancy rate

Studyorsubgroup Noxytioline Control OddsRatio Weight Odds Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Querleu 1989 14/63 19/63 100.0 % 0.66 [ 0.30, 1.47 ] Total (95% CI) 63 63 100.0 % 0.66 [ 0.30, 1.47 ] Total events: 14 (Noxytioline), 19 (Control) Heterogeneity: not applicable Test for overall effect: Z = 1.01 (P = 0.31) Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10 Favours control Favours noxytioline

Analysis 5.9. Comparison 5 Intraperitoneal noxytioline vs no treatment, Outcome 9 Ectopic pregnancy rate (per pregnancy).

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery Comparison: 5 Intraperitoneal noxytioline vs no treatment Outcome: 9 Ectopic pregnancy rate (per pregnancy)

Studyorsubgroup Noxytioline Control OddsRatio Weight Odds Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Querleu 1989 3/14 1/19 100.0 % 4.91 [ 0.45, 53.27 ] Total (95% CI) 14 19 100.0 % 4.91 [ 0.45, 53.27 ] Total events: 3 (Noxytioline), 1 (Control) Heterogeneity: not applicable Test for overall effect: Z = 1.31 (P = 0.19) Test for subgroup differences: Not applicable

0.001 0.01 0.1 1 10 100 1000 Favours noxytioline Favours control

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 100 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 6.3. Comparison 6 Intraperitoneal heparin solution vs no intraperitoneal heparin, Outcome 3 Number of participants with improvement in adhesion score.

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery Comparison: 6 Intraperitoneal heparin solution vs no intraperitoneal heparin Outcome: 3 Number of participants with improvement in adhesion score

Studyorsubgroup Heparin Control OddsRatio Weight OddsRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Jansen 1988 (1) 15/28 20/35 100.0 % 0.87 [ 0.32, 2.35 ] Total (95% CI) 28 35 100.0 % 0.87 [ 0.32, 2.35 ] Total events: 15 (Heparin), 20 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.28 (P = 0.78) Test for subgroup differences: Not applicable

0.5 0.7 1 1.5 2 Favours control Favours heparin

(1) Data for this study supplied by study authors

Analysis 6.4. Comparison 6 Intraperitoneal heparin solution vs no intraperitoneal heparin, Outcome 4 Number of participants with worsening adhesion score.

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery Comparison: 6 Intraperitoneal heparin solution vs no intraperitoneal heparin Outcome: 4 Number of participants with worsening adhesion score

Studyorsubgroup Heparin Control OddsRatio Weight OddsRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Jansen 1988 (1) 20/44 19/48 100.0 % 1.27 [ 0.56, 2.91 ] Total (95% CI) 44 48 100.0 % 1.27 [ 0.56, 2.91 ] Total events: 20 (Heparin), 19 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.57 (P = 0.57) Test for subgroup differences: Not applicable

0.5 0.7 1 1.5 2 Favours heparin Favours control

(1) Data for this study supplied by study authors

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 101 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 7.3. Comparison 7 Systemic promethazine vs no promethazine, Outcome 3 Number of participants with improvement in adhesion score.

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery Comparison: 7 Systemic promethazine vs no promethazine Outcome: 3 Number of participants with improvement in adhesion score

Studyorsubgroup Promethazine Control OddsRatio Weight Odds Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Jansen 1990 (1) 20/36 27/39 100.0 % 0.56 [ 0.22, 1.43 ] Total (95% CI) 36 39 100.0 % 0.56 [ 0.22, 1.43 ] Total events: 20 (Promethazine), 27 (Control) Heterogeneity: not applicable Test for overall effect: Z = 1.22 (P = 0.22) Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10 Favours control Favours promethazine

(1) Data for this study supplied by study authors

Analysis 7.4. Comparison 7 Systemic promethazine vs no promethazine, Outcome 4 Number of participants with worsening adhesion score.

Review: Fluid and pharmacological agents for adhesion prevention after gynaecological surgery Comparison: 7 Systemic promethazine vs no promethazine Outcome: 4 Number of participants with worsening adhesion score

Studyorsubgroup Promethazine Control OddsRatio Weight Odds Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Jansen 1990 (1) 13/47 18/46 100.0 % 0.59 [ 0.25, 1.42 ] Total (95% CI) 47 46 100.0 % 0.59 [ 0.25, 1.42 ] Total events: 13 (Promethazine), 18 (Control) Heterogeneity: not applicable Test for overall effect: Z = 1.17 (P = 0.24) Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10 Favours promethazine Favours control

(1) Data for this study supplied by study authors

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 102 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 8.1. Comparison 8 GnRH analogue vs no treatment/ placebo, Outcome 1 Area of adhesions (cm2). Area of adhesions (cm2)

Study Area of adhe- Area number of par- Area Area of adhe- Number of par- sions of adhesions at ticipants of adhesions at sions at SLL in ticipants at ﬁrst surgery SLL GNRHa ﬁrst surgery in cotnrol group GNRHa (cm2) control group

Coddington 0.4 (0.1) 10.7 (2.2) 10 0.4 (0.1) 9.2 (3.8) 8 2009

Analysis 9.1. Comparison 9 Plasminogen activator vs control, Outcome 1 Incidence of adhesions at SLL (score). Incidence of adhesions at SLL (score)

Study Mean incidence SD Number of partici- Mean inci- SD Number of participants score in treat- pants dence score in con- ment group trol group

Hellebrekers 1.8 2.2 11 1.5 1.7 14 2009

APPENDICES

Appendix 1. MEDLINE search strategy The search has been updated to February 2013. 1 exp gynecologic surgical procedures/ or exp endometrial ablation techniques/ or exp hysterectomy/ or exp hysteroscopy/ or exp ovariectomy/ or exp salpingostomy/ or exp uterine artery embolization/ (59075) 2 (gyn$ adj3 surg$).tw. (6685) 3 exp cystoscopy/ (5810) 4 exp laparoscopy/ or exp ureteroscopy/ (62099) 5 laparoscop$.tw. (70779) 6 (hysterectom$ or cystoscop$ or hysteroscop$).tw. (33793) 7 endometrial ablation technique$.tw. (33) 8 (ovariectom$ or salpingostom$).tw. (21725) 9 (ovar$ adj2 surg$).tw. (1355) 10 (uterine artery embolization or UAE).tw. (2264) 11 (pelv$ adj5 surg$).tw. (5887) 12 (ovar$ adj5 cystect$).tw. (369) 13 endometrioma$.tw. (1282) 14 exp endometriosis/ (15375) 15 endometriosis.tw. (14167) 16 fallopian$.tw. (7315) 17 exp Tissue Adhesions/ (9668)

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 103 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 18 Adhesion$.tw. (134844) 19 myomectom$.tw. (1950) 20 (ovar$ adj2 defect$).tw. (133) 21 (ovar$ adj2 cauter$).tw. (31) 22 microsurg$.tw. (17076) 23 adhesiolysis.tw. (843) 24 electrosurg$.tw. (2435) 25 or/1-24 (343524) 26 exp heparin/ or hyaluronic acid/ (67311) 27 (heparin or hyaluron$).tw. (81117) 28 (liquid agent$ or ﬂuid agent$).tw. (54) 29 exp Steroids/ (664617) 30 steroid$.tw. (169121) 31 pharmac$ agent$.tw. (11865) 32 exp Noxythiolin/ (81) 33 Noxythiolin$.tw. (66) 34 noxytiolin$.tw. (18) 35 exp Promethazine/ (2658) 36 Promethazine$.tw. (1790) 37 exp Dextrans/ (24545) 38 Dextran$.tw. (27338) 39 Spraygel$.tw. (20) 40 isodextrin$.tw. (1) 41 sepracoat$.tw. (6) 42 intergel$.tw. (24) 43 icodextrin$.tw. (475) 44 HAL-C.tw. (7) 45 hydrogel$.tw. (11460) 46 hydrotubation.tw. (154) 47 barrier system$.tw. (325) 48 corticosteroid$.tw. (68984) 49 or/26-48 (941939) 50 25 and 49 (32527) 51 randomized controlled trial.pt. (330666) 52 controlled clinical trial.pt. (84388) 53 randomized.ab. (245867) 54 placebo.tw. (141054) 55 clinical trials as topic.sh. (160859) 56 randomly.ab. (180212) 57 trial.ti. (105833) 58 (crossover or cross-over or cross over).tw. (53807) 59 or/51-58 (809935) 60 (animals not (humans and animals)).sh. (3644312) 61 59 not 60 (747509) 62 50 and 59 (2904) 63 (2005$ or 2006$ or 2007$ or 2008$ or 2009$ or 2010$ or 2011$ or 2012$).ed. (6162178) 64 62 and 63 (1121)

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 104 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Appendix 2. Menstrual Disorders and Subfertility Group (MDSG) search strategy The search has been updated to February 2013. Keywords CONTAINS“adhesiolysis” or “adhesion” or “adhesions” or “adhesions outcome” or “adhesion prevention” or “adhesion formation” or “pelvic adhesions”or“sepracoat” or “icodextrin” or “hydrogel” or “hydrotubation” or “Sepraﬁlm” or “intergel” or “Barrier Membrane”or “hyaluronan” or “hyaluronic acid” or “hyaluronidase” or “Promethazine” or “dextran” or “SprayGel” or “adhesion barrier” or “adhesion barriers” or“post-operative adhesions”or “gynecologic surgical procedure” or “pelvic adhesions” or Title CONTAINS “adhesiolysis” or “adhesion” or “adhesions” or “adhesions outcome” or “adhesion prevention” or “adhesion formation” or “pelvic adhesions” or “sepracoat” or “icodextrin” or “hydrogel” or “hydrotubation” or “Sepraﬁlm” or “intergel” or “Barrier Membrane”or “hyaluronan” or “hyaluronic acid” or “hyaluronidase” or “Promethazine” or “dextran” or “SprayGel” or “adhesion barrier” or “adhesion barriers” or“post-operative adhesions”or “gynecologic surgical procedure” or “pelvic adhesions”

Appendix 3. EMBASE search strategy The search has been updated to February 2013. 1 liquid agent$.tw. (71) 2 ﬂuid agent$.tw. (11) 3 heparin.tw. (70679) 4 steroid$.tw. (196926) 5 Noxythiolin$.tw. (61) 6 noxytiolin$.tw. (28) 7 exp Promethazine/ (10062) 8 Promethazine$.tw. (2019) 9 Dextran$.tw. (29359) 10 Spraygel$.tw. (31) 11 isodextrin$.tw. (2) 12 sepracoat$.tw. (20) 13 intergel$.tw. (46) 14 icodextrin$.tw. (591) 15 HAL-C.tw. (8) 16 hyaluron$.tw. (24295) 17 hydrogel$.tw. (13747) 18 hydrotubation.tw. (154) 19 barrier system$.tw. (383) 20 corticosteroid$.tw. (85478) 21 pharmac$ agent$.tw. (14169) 22 exp dextran/ (20955) 23 exp noxytiolin/ (138) 24 or/1-23 (434646) 25 exp gynecologic surgery/ or exp pelvis surgery/ or exp uterine tube surgery/ or exp uterus surgery/ (116263) 26 exp endometrium ablation/ (1481) 27 exp hysterectomy/ or exp abdominal hysterectomy/ or exp vaginal hysterectomy/ or exp radical hysterectomy/ (39372) 28 exp hysteroscopy/ (6446) 29 exp ovariectomy/ (23830) 30 exp salpingoplasty/ or exp salpingostomy/ (755) 31 exp uterine artery embolization/ (1506) 32 (gyn$ adj3 surg$).tw. (8725) 33 exp cystoscopy/ (11326) 34 exp laparoscopy/ (83988) 35 laparoscop$.tw. (92550) 36 (hysterectom$ or cystoscop$ or hysteroscop$).tw. (43300) 37 endometrial ablation technique$.tw. (53) 38 (ovariectom$ or salpingostom$).tw. (22665)

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 105 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 39 (ovar$ adj2 surg$).tw. (1745) 40 (uterine artery embolization or UAE).tw. (3104) 41 (pelv$ adj5 surg$).tw. (7862) 42 (ovar$ adj5 cystect$).tw. (540) 43 endometrioma$.tw. (1667) 44 exp endometriosis/ (21188) 45 endometriosis.tw. (17788) 46 fallopian$.tw. (7875) 47 Adhesion$.tw. (156219) 48 myomectom$.tw. (2714) 49 (ovar$ adj2 defect$).tw. (154) 50 (ovar$ adj2 cauter$).tw. (35) 51 microsurg$.tw. (19902) 52 adhesiolysis.tw. (1226) 53 electrosurg$.tw. (2821) 54 or/25-53 (445158) 55 24 and 54 (16375) 56 Clinical Trial/ (866659) 57 Randomized Controlled Trial/ (323318) 58 exp randomization/ (58389) 59 Single Blind Procedure/ (15973) 60 Double Blind Procedure/ (109214) 61 Crossover Procedure/ (34073) 62 Placebo/ (199598) 63 Randomi?ed controlled trial$.tw. (75433) 64 Rct.tw. (9361) 65 random allocation.tw. (1149) 66 randomly allocated.tw. (17177) 67 allocated randomly.tw. (1808) 68 (allocated adj2 random).tw. (706) 69 Single blind$.tw. (12200) 70 Double blind$.tw. (127994) 71 ((treble or triple) adj blind$).tw. (270) 72 placebo$.tw. (175065) 73 prospective study/ (205540) 74 or/56-73 (1250836) 75 case study/ (15813) 76 case report.tw. (225398) 77 abstract report/ or letter/ (834039) 78 or/75-77 (1070692) 79 74 not 78 (1215901) 80 55 and 79 (1433) 81 (2010$ or 2011$ or 2012$).em. (2562101) 82 80 and 81 (229)

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 106 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Appendix 4. CENTRAL search strategy The search has been updated to February 2013. 1 exp gynecologic surgical procedures/ or exp endometrial ablation techniques/ or exp hysterectomy/ or exp hysteroscopy/ or exp ovariectomy/ or exp salpingostomy/ or exp uterine artery embolization/ (2979) 2 (gyn$ adj3 surg$).tw. (1251) 3 exp cystoscopy/ (183) 4 exp laparoscopy/ or exp ureteroscopy/ (3127) 5 laparoscop$.tw. (4741) 6 (hysterectom$ or cystoscop$ or hysteroscop$).tw. (2780) 7 endometrial ablation technique$.tw. (2) 8 (ovariectom$ or salpingostom$).tw. (107) 9 (ovar$ adj2 surg$).tw. (112) 10 (uterine artery embolization or UAE).tw. (244) 11 (pelv$ adj5 surg$).tw. (356) 12 (ovar$ adj5 cystect$).tw. (34) 13 endometrioma$.tw. (65) 14 exp endometriosis/ (436) 15 endometriosis.tw. (704) 16 fallopian$.tw. (223) 17 exp Tissue Adhesions/ (224) 18 Adhesion$.tw. (2125) 19 myomectom$.tw. (189) 20 (ovar$ adj2 defect$).tw. (4) 21 (ovar$ adj2 cauter$).tw. (7) 22 microsurg$.tw. (254) 23 adhesiolysis.tw. (47) 24 electrosurg$.tw. (144) 25 or/1-24 (12901) 26 exp heparin/ or hyaluronic acid/ (4046) 27 (heparin or hyaluron$).tw. (6840) 28 (liquid agent$ or ﬂuid agent$).tw. (1) 29 exp Steroids/ (33878) 30 steroid$.tw. (9513) 31 pharmac$ agent$.tw. (352) 32 exp Noxythiolin/ (6) 33 Noxythiolin$.tw. (8) 34 noxytiolin$.tw. (3) 35 exp Promethazine/ (227) 36 Promethazine$.tw. (290) 37 exp Dextrans/ (481) 38 Dextran$.tw. (857) 39 Spraygel$.tw. (9) 40 isodextrin$.tw. (0) 41 sepracoat$.tw. (2) 42 intergel$.tw. (7) 43 icodextrin$.tw. (84) 44 HAL-C.tw. (2) 45 hydrogel$.tw. (631) 46 hydrotubation.tw. (7) 47 barrier system$.tw. (8) 48 corticosteroid$.tw. (6933) 49 or/26-48 (52022)

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 107 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 50 25 and 49 (1534) 51 limit 50 to yr=“2005 -Current” (447)

Appendix 5. PSYCINFO search strategy The search has been updated to February 2013. 1 exp postsurgical complications/ (561) 2 endometrial ablation technique$.tw. (0) 3 exp hysterectomy/ or exp surgery/ or exp ovariectomy/ (36008) 4 (cystoscopy or laparoscop$).tw. (241) 5 (hysterectom$ or cystoscop$ or hysteroscop$).tw. (656) 6 (ovariectom$ or salpingostom$).tw. (2871) 7 (ovar$ adj2 surg$).tw. (25) 8 (pelv$ adj3 surg$).tw. (53) 9 (ovar$ adj3 cystect$).tw. (3) 10 endometrioma$.tw. (1) 11 endometriosis.tw. (141) 12 fallopian$.tw. (38) 13 Adhesion$.tw. (1646) 14 myomectom$.tw. (6) 15 (ovar$ adj2 defect$).tw. (2) 16 (ovar$ adj2 cauter$).tw. (0) 17 microsurg$.tw. (130) 18 adhesiolysis.tw. (12) 19 electrosurg$.tw. (9) 20 (tub$ adj2 surg$).tw. (24) 21 (infertil$ adj2 surg$).tw. (5) 22 (subfertil$ adj2 surg$).tw. (0) 23 or/1-22 (40101) 24 exp Heparin/ (101) 25 (hyaluronic acid or heparin).tw. (295) 26 (liquid agent$ or ﬂuid agent$).tw. (0) 27 steroid$.tw. (6453) 28 pharmac$ agent$.tw. (1476) 29 Noxythiolin.tw. (0) 30 noxytiolin$.tw. (0) 31 exp Promethazine/ (63) 32 Promethazine$.tw. (151) 33 Dextran$.tw. (293) 34 Spraygel$.tw. (0) 35 isodextrin$.tw. (0) 36 sepracoat$.tw. (0) 37 intergel$.tw. (1) 38 icodextrin$.tw. (0) 39 HAL-C.tw. (3) 40 hydrogel$.tw. (41) 41 hydrotubation.tw. (0) 42 barrier system$.tw. (15) 43 corticosteroid$.tw. (1943) 44 or/24-43 (10345) 45 23 and 44 (897) 46 random.tw. (35474)

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 108 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 47 control.tw. (275781) 48 double-blind.tw. (16026) 49 clinical trials/ (6112) 50 placebo/ (3227) 51 exp Treatment/ (518533) 52 or/46-51 (785951) 53 45 and 52 (632) 54 limit 53 to yr=“2005 -Current” (190) 55 (mice or rat$).tw. (646842) 56 54 not 55 (95)

Appendix 6. CINAHL search strategy Keywords CONTAIN “adhesion” or “adhesion barrier” or “adhesion barriers” or “adhesion prevention” or “adhesions” or “adhesions outcome” or “cell adhesion molecules” or “adept” or “icodextrin” or “dextran” or “sepraspray” or “sepracoat” or “hyalobarrier gel” or “intergel” or “coseal” or “spraygel” or “intercoat” or “synthetic polyethylene glycol (PEG) solutions” or “oxiplex” or “carboxymethylcellulose (CMC)” or “polyethylene oxide (PEO) composite gel” or “steroid” or “steroids” or “noxytioline” or “heparin” or “promethazine” or “reteplase plasminogen activator” or “N,O-carboxymethylchitosan” or “gonadotrophin releasing hormone agonist (GnRHa)”or title CONTAIN “adhesion” or “adhesion barrier” or “adhesion barriers” or “adhesion prevention” or “adhesions” or “adhesions outcome” or “cell adhesion molecules” or “adept” or “icodextrin” or “dextran” or “sepraspray” or “sepracoat” or “hyalobarrier gel” or “intergel” or “coseal” or “spraygel” or “intercoat” or “synthetic polyethylene glycol (PEG) solutions” or “oxiplex” or “carboxymethylcellulose (CMC)” or “polyethylene oxide (PEO) composite gel” or “steroid” or “steroids” or “noxytioline” or “heparin” or “promethazine” or “reteplase plasminogen activator” or “N,O-carboxymethylchitosan” or “gonadotrophin releasing hormone agonist (GnRHa)”

Appendix 7. ICTRP search strategy Keywords CONTAINS“adhesiolysis” or “adhesion” or “adhesions” or “adhesions outcome” or “adhesion prevention” or “adhesion formation” or “pelvic adhesions”or“sepracoat” or “icodextrin” or “hydrogel” or “hydrotubation” or “Sepraﬁlm” or “intergel” or “Barrier Membrane”or “hyaluronan” or “hyaluronic acid” or “hyaluronidase” or “Promethazine” or “dextran” or “SprayGel” or “adhesion barrier” or “adhesion barriers” or“post-operative adhesions”or “gynecologic surgical procedure” or “pelvic adhesions” or Title CONTAINS “adhesiolysis” or “adhesion” or “adhesions” or “adhesions outcome” or “adhesion prevention” or “adhesion formation” or “pelvic adhesions” or “sepracoat” or “icodextrin” or “hydrogel” or “hydrotubation” or “Sepraﬁlm” or “intergel” or “Barrier Membrane”or “hyaluronan” or “hyaluronic acid” or “hyaluronidase” or “Promethazine” or “dextran” or “SprayGel” or “adhesion barrier” or “adhesion barriers” or“post-operative adhesions”or “gynecologic surgical procedure” or “pelvic adhesions”

Appendix 8. clinicaltrials.gov search strategy Keywords CONTAINS“adhesiolysis” or “adhesion” or “adhesions” or “adhesions outcome” or “adhesion prevention” or “adhesion formation” or “pelvic adhesions”or“sepracoat” or “icodextrin” or “hydrogel” or “hydrotubation” or “Sepraﬁlm” or “intergel” or “Barrier Membrane”or “hyaluronan” or “hyaluronic acid” or “hyaluronidase” or “Promethazine” or “dextran” or “SprayGel” or “adhesion barrier” or “adhesion barriers” or“post-operative adhesions”or “gynecologic surgical procedure” or “pelvic adhesions” or Title CONTAINS “adhesiolysis” or “adhesion” or “adhesions” or “adhesions outcome” or “adhesion prevention” or “adhesion formation” or “pelvic adhesions” or “sepracoat” or “icodextrin” or “hydrogel” or “hydrotubation” or “Sepraﬁlm” or “intergel” or “Barrier Membrane”or “hyaluronan” or “hyaluronic acid” or “hyaluronidase” or “Promethazine” or “dextran” or “SprayGel” or “adhesion barrier” or “adhesion barriers” or“post-operative adhesions”or “gynecologic surgical procedure” or “pelvic adhesions”

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 109 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. WHAT’S NEW Last assessed as up-to-date: 7 April 2014.

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 2007; Fossum 2011; Hellebrekers 2009; Lundorff 2005; Mais 2006; Mettler 2008; Rose 1991; Sites 1997; Ten Broek 2012; Thornton 1998; Trew 2011; Young 2005) and new conclusions provided.

8 April 2014 New search has been performed This review has been updated.

HISTORY Protocol ﬁrst published: Issue 1, 1998 Review ﬁrst published: Issue 4, 1998

Date Event Description

7 November 2008 Amended Converted to new review format.

13 January 2006 New citation required and conclusions have changed Substantive amendment

CONTRIBUTIONSOFAUTHORS GA: main review author; designed the review, screened the search results, organised retrieval of the RCTs, screened them against the inclusion criteria, interpreted the results, settled discrepancies and supervised FM and DI throughout the process. FM: co-review author; screened search results, organised retrieval of RCTs in the updated review, screened them against the inclusion criteria, extracted data from RCTs, wrote to study authors when required, managed the data, interpreted the results and wrote most of the draft manuscript. DI: co-review author; screened search results, screened them against the inclusion criteria, extracted data from RCTs and helped draft the discussion and the plain language summary. HO: co-review author; helped with collection and analysis of data and with answering queries after the peer review. SD: co-review author; helped with statistical analysis and interpretation of data. MEM: main author of previous version of the review. AW: senior co-author and contact review author for the original review; helped design the review, supervised all steps undertaken to conduct the review and settled differences of opinion between GA, FM and DI regarding inclusion of studies. Supervised and helped draft the discussion and the conclusion.

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review) 110 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. DECLARATIONSOFINTEREST AW has received lecture fees from Gynecare and Shire. Gynecare is the manufacturer of Intergel. The same review author has received consultancy fees from NL Laboratories, the manufacturer of Adept.

SOURCES OF SUPPORT

Internal sources • No sources of support supplied

External sources • Yorkshire Regional Health Authority Research & Development Unit, UK.

DIFFERENCESBETWEENPROTOCOLANDREVIEW We decided to alter the outcomes slightly from the previous version of the review, so that the primary outcomes focus on what is most important to patients, rather than on adhesion formation, which has little correlation with symptoms experienced. A subanalysis comparing the effects of antiadhesion agents on de novo adhesions versus re-formed adhesions was planned, although it was not performed because of lack of data.

INDEX TERMS

Medical Subject Headings (MeSH) Anticoagulants [∗therapeutic use]; Glucocorticoids [∗therapeutic use]; Gynecologic Surgical Procedures [∗adverse effects]; Infertility, Female [prevention & control]; Plasma Substitutes [∗therapeutic use]; Randomized Controlled Trials as Topic; Rehydration Solutions [∗therapeutic use]; Tissue Adhesions [prevention & control]

MeSH check words Female; Humans