fluid and pharmacological agents for adhesion prevention ... · [intervention review] fluid and...
TRANSCRIPT
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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 Library2014, Issue 7
http://www.thecochranelibrary.com
Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
http://www.thecochranelibrary.com
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T A B L E O F C O N T E N T S
1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .
6BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Figure 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Figure 9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Figure 10. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
22ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . .
32DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
36CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
83DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Hydroflotation agent vs no hydroflotation agent, Outcome 1 Improvement in pelvic pain at
second-look laparoscopy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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
at SLL. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Analysis 1.4. Comparison 1 Hydroflotation agent vs no hydroflotation agent, Outcome 4 Number of participants with
worsening adhesion score. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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-
look laparoscopy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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
iFluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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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
at second-look laparoscopy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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
adhesion score. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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
adhesion score. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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
improvement in adhesion score. . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Analysis 7.4. Comparison 7 Systemic promethazine vs no promethazine, Outcome 4 Number of participants with
worsening adhesion score. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
103APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
109WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
110HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
110CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
110DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
111SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
111DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .
111INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iiFluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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[Intervention Review]
Fluid and pharmacological agents for adhesion preventionafter 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].
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.
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
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, sub-
fertility 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).
1Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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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.
P L A I N L A N G U A G E S U M M A R Y
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.
2Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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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.
3Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [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
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed risk Corresponding risk
No hydroflotation agents Hydroflotation agents
Improvement in pelvic
pain in participants with
a primary diagnosis of
pelvic pain, at second-
look laparoscopy
806 per 1000 730 per 1000
(606-826)
OR 0.65
(0.37-1.14)
286
(1 study)
⊕⊕⊕©
moderate1
Live birth rate 140 per 1000 98 per 1000
(45-205)
OR 0.67
(0.29-1.58)
208
(2 studies)
⊕⊕⊕©
moderate1
Improvement in adhe-
sion score
437 per 1000 496 per 1000
(380-614)
OR 1.27
(0.79-2.05)
665
(4 studies)
⊕⊕⊕©
moderate1,2
Number of participants
withworseningadhesion
score
308 per 1000 111 per 1000
(30-350)
OR 0.28
(0.07-1.21)
53
(1 study)
⊕⊕⊕©
moderate1,3
Number of participants
with adhesions at sec-
ond-look laparoscopy
836 per 1000 635 per 1000
(529-738)
OR 0.34
(0.22-0.55)
566
(4 studies)
⊕⊕⊕⊕
high
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Mean adhesion score
at second-look la-
paroscopy
The mean adhesion
score at second-look la-
paroscopy in the interven-
tion groups was
0.06 standard deviations
lower
(0.2 lower-0.09 higher)
722
(4 studies)
⊕⊕⊕⊕
high
SMD -0.06 (-0.2 to 0.09)4
Clinical pregnancy rate 234 per 1000 163 per 1000
(99-258)
OR 0.64
(0.36-1.14)
310
(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.
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.
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B A C K G R O U N D
Description of the condition
Adhesions are fibrin bands that form as the result of aberrant
peritoneal healing (Cheong 2001). Normally, peritoneal damage
causes an inflammatory response; this activates the coagulation cas-
cade, and a fibrin plug is formed over the damaged mesothelium,
which is then broken down to reveal regenerated peritoneum.
However, in adhesion formation, fibrinolysis of the fibrin plug is
decreased and, consequently, a fibrin matrix develops. Adhesions
may be defined as ‘de novo,’ meaning that they have formed at a
location that was previously free from adhesions, or ‘re-formed,’
which describes adhesions that recur post adhesiolysis. A variety of
factors influence the extent of adhesion formation, including type
of surgery performed (i.e. laparoscopic or open), haemostasis and
the presence of endometriosis and infection, particularly pelvic
inflammatory disease (Diamond 2001). Although the aetiologies
are different, the basic pathogenesis is similar.
Description of the intervention
Adhesion prevention agents can be divided into three types: fluid,
pharmacological and barrier. This review will examine fluid and
pharmacological agents. A separate review evaluates barrier agents.
Fluid agents include both hydroflotation products and gels. Exam-
ples of hydroflotation devices are 4% icodextrin solution (Adept,
Baxter, Berkshire, UK), an iso-osmolar and non-viscous high
molecular weight glucose polymer, and 32% dextran (Hyskon
Pharmacia, Uppsala, Sweden), a polysaccharide-containing solu-
tion that is no longer approved for use as an antiadhesion agent.
Both agents can be used as intraperitoneal irrigants and/or instil-
lants.
Derivatives of hyaluronic acid form the basis of a number of antiad-
hesion gels. Hyaluronic acid is a linear polysaccharide with repeat-
ing disaccharide units composed of sodium D-glucuronate and N-acetyl-D-glucosamine. SepraSpray (Genzyme Corporation, Cam-
bridge, MA, USA) contains hyaluronic acid in addition to car-
boxymethylcellulose powder and is applied to relevant tissues with
the use of a preloaded delivery device. SepraCoat (Genzyme Cor-
poration) is a dilute hyaluronic acid solution that is applied be-
fore and after surgery. Hyalobarrier gel (Nordic Pharma, Read-
ing, UK) contains auto-cross-linked hyaluronic acid. Intergel (Gy-
necare, Lifecore Biomedical, Chaska, MN, USA) contains ferrous
hyaluronic acid, although it has been withdrawn from the market.
N,O-carboxymethyl chitosan is a derivative of chitin and is simi-lar in structure to hyaluronic acid and carboxymethylcellulose. It
is formed when the gel and solution components are combined.
Polyethylene glycol (PEG)-based gels are also available. CoSeal
(Baxter) is formed by mixing a powder and a liquid intraopera-
tively, both of which contain PEG and are then applied as a gel
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
combined. Intercoat (FzioMed, San Luis Obispo, CA, USA) is
an Oxiplex/AP viscoelastic gel composed of polyethylene oxide
(PEO), which is very similar to PEG but has a different molecular
weight, and carboxymethylcellulose.
Steroids have been used to prevent adhesions and can be adminis-
tered in a number of ways, including systemically before, during
and after surgery; intraperitoneally during surgery; and via hy-
drotubation postoperatively. Other pharmacological agents used
to prevent adhesions include noxytioline, an antibacterial agent;
promethazine, an antihistamine; and reteplase, a thrombolytic
drug, all of which are instilled intraperitoneally; as well as hep-
arin, an anticoagulant used for intraoperative irrigation. A nasal
gonadotrophin-releasing hormone agonist (GnRHa) has also been
used preoperatively and postoperatively.
How the intervention might work
Hyaluronic acid is a major component of many body tissues and
fluids, where it provides physically supportive and mechanically
protective roles (Johns 2001). PEG is a polymer; when the two
PEG-containing liquids are sprayed simultaneously, they form a
cross-linked gel. Gels are thought to decrease adhesion formation
mainly by preventing denuded tissues from touching.
Steroids and antihistamines (e.g. promethazine) act as im-
munomodulating agents and were used in the belief that they pro-
mote fibrinolysis during healing, without hindering the healing
process. GnRHa may work by decreasing oestrogen-related growth
factors and promoting fibroblasts. Fluid agents such as icodex-
trin and dextran work through the act of hydroflotation, whereby
the fluid separates raw opposing surfaces until the healing process
has been completed. Fluid agents are believed to remain in the
peritoneal cavity for several days, which is considered a sufficient
length of time, given that adhesions form within eight days of
surgery (Diamond 2001; Hosie 2001).
Why it is important to do this review
Adhesiolysis is the only available treatment for adhesions, although
controversy regarding its efficacy is ongoing (Hammoud 2004).
The focus of adhesion management is now prevention. Intraperi-
toneal adhesions are associated with considerable co-morbidity
and have large economic and public health repercussions. They are
the most common complication of gynaecological surgery, form-
ing in 50% to 100% of women (diZerega 1994). Women present
with the secondary effects of adhesions including dyspareunia,
subfertility, bowel obstruction and chronic pelvic pain, although
the latter has a controversial association with adhesions, as no cor-
relation with extent of adhesions and severity of pain is apparent.
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Nevertheless, these consequences can greatly decrease a woman’s
well-being and require further surgery. Subsequent surgery in
women with adhesions is more difficult, often takes longer and is
associated with a higher complication rate. It is estimated that in
the first year after lower abdominal surgery, the cost of adhesion-
related readmissions in the UK is £24.2 million, which increases to
£95.2 million over the subsequent nine years (Wilson 2002). The
Surgical and Clinical Adhesions Research (SCAR) study found
that 5% (n = 245) of readmissions 10 years after open gynaecolog-
ical surgery were due to adhesions (Lower 2000; Lower 2004). An
English study estimated that the National Health Service (NHS)
could save £700,000 per year if an antiadhesion agent that reduced
adhesions by 25% and cost £110 was used or, at worst, that this
approach would be cost-neutral (Cheong 2011).
O B J E C T I V E S
To evaluate the role of fluid and pharmacological agents used as
adjuvants in preventing formation of adhesions after gynaecolog-
ical surgery.
M E T H O D S
Criteria for considering studies for this review
Types of studies
Published and unpublished randomised controlled trials (RCTs)
investigating the use of fluid and pharmacological agents to prevent
adhesion formation after gynaecological surgery were eligible for
inclusion. Non-randomised trials and those considered to be at
high risk of bias for sequence generation or allocation concealment
were excluded. Studies using a cross-over design were excluded.
Types of participants
Female participants in any age group who underwent pelvic
surgery (by laparoscopy or laparotomy). Studies investigating ad-
hesion prevention in non-gynaecological specialities were not in-
cluded.
Types of interventions
Interventions were grouped together for meta-analysis according
to physical state and main mechanism of action: hydroflotation
agents (including dextran, 4% icodextrin solution), gel agents (in-
cluding SepraSpray, SepraCoat, Hyalobarrier gel, Intergel, CoSeal,
SprayGel and Intercoat) and pharmacological agents. The follow-
ing comparisons were made.
1. Hydroflotation agent versus no hydroflotation agent.
2. Gel agent versus no treatment.
3. Gel agent versus hydroflotation agent when used as an
instillant.
4. Steroid (including systemic, intraperitoneal, preoperative
and postoperative) versus no steroid (or placebo).
5. Intraperitoneal noxytioline versus no noxytioline (or
placebo).
6. Intraperitoneal heparin versus no heparin (or placebo).
7. Systemic promethazine versus no promethazine (or
placebo).
8. GnRHa versus no GnRHa (or placebo).
9. Reteplase plasminogen activator versus no reteplase
plasminogen activator (or placebo).
10. N,O-carboxymethyl chitosan versus no N,O-carboxymethylchitosan (or placebo).
Types of outcome measures
We decided to alter outcomes slightly from the previous version
of the review, so that the primary outcomes focus on what is most
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-
comes to enable maximum study inclusion.
Primary outcomes
1. Pelvic pain (improvement/worsening/no change in pain at sec-
ond-look laparoscopy (SLL)), independent of the method used to
assess pelvic pain.
2. Live birth rate, as defined by the individual study.
Secondary outcomes
3. Improvement in adhesion score at SLL, recorded on whichever
scale the study authors used, but with preference given to the
modified American Fertility Society (mAFS) score.
4. Worsening in adhesion score at SLL, recorded on whichever
scale the study authors used, but with preference given to the
mAFS score.
5. Adhesions at SLL.
6. Mean adhesion score at SLL per participant, recorded on
whichever scale the study authors used, but with preference given
to the mAFS score.
7. Clinical pregnancy rate as defined by the individual study.
8. Miscarriage rate, defined as loss of pregnancy before 24 weeks’
gestation.
9. Ectopic pregnancy rate.
10. Improvement in quality of life (QoL) at SLL, recorded on
whichever scale the study authors used, but with preference given
to Short Form (SF)-36.
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11. Adverse outcomes, local and systemic, thought to be due to the
antiadhesion agent, in studies stating this as one of their outcomes,
as opposed to observation.
Articles were included independent of the adhesion scoring
method used. Articles that met the inclusion criteria but did not
report any of the outcomes considered within this review were
included within the qualitative analysis.
Search methods for identification of studies
This is an update of the review by Metwally et al. published in
2006. The Menstrual Disorders and Subfertility Group (MDSG)
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
Search Co-ordinator. No restriction on language was applied. See
the Review Group module for additional details on the make-up
of the Specialised Register.
Electronic searches
Electronic databases were searched using Ovid software: MED-
LINE (1950 to April 2014), MDSG database (inception to April
2014), EMBASE (1980 to April 2014), CENTRAL (inception to
April 2014), PsycINFO (1806 to April 2014) and the Cumulative
Index to Nursing and Allied Health Literature (CINAHL) (1982
to April 2014). The clinical trials databases International Clini-
cal Trials Registry Platform (ICTRP) and clinicaltrials.gov were
searched from inception to February 2013.
See Appendix 1; Appendix 2; Appendix 3; Appendix 4; Appendix
5; Appendix 6; Appendix 7; and Appendix 8,
Searching other resources
Grey literature was handsearched, specifically, abstracts presented
at meetings of the British Society of Gynaecological Endoscopy,
the European Society of Gynaecological Endoscopy, the American
Association of Gynecological Laparoscopists and the British Fer-
tility Society. Reference lists of included studies were also searched.
Data collection and analysis
Selection of studies
Three review authors (GA, FM, DI) independently performed an
initial screen of titles and abstracts to assess trials for suitability of
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
further information. Discrepancies were settled by consensus by
GA and AW.
Data extraction and management
Two review authors (FM, DI) independently extracted the data.
Data were transcribed onto a Microsoft Word data collection form
designed for this review before they were entered into RevMan.
The statistical package Metaview of RevMan 5.1, provided by The
Cochrane Collaboration, was used to analyse and synthesise data.
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
and prevented inclusion in the meta-analysis, the study was not
included in that outcome analysis, although it was still considered
an “included study.” Disagreements were resolved by consensus
by GA and AW.
Assessment of risk of bias in included studies
The risk of bias of all studies deemed eligible was assessed indepen-
dently by two review authors (FM, DI). These included allocation
(random sequence generation and allocation concealment); blind-
ing of participants, personnel and outcome assessors; incomplete
outcome data; selective reporting and other biases. Disagreements
regarding interpretation of data were settled by consensus by GA
and AW. The quality of trials was assessed as recommended by the
risk of bias tool in the Cochrane Handbook for Systematic Reviewsof Interventions (Higgins 2011) and was entered into the risk ofbias table.
Measures of treatment effect
The odds ratio (OR) was used for dichotomous data (e.g. number
of women with worsening adhesion score). The standardised mean
difference (SMD) was used for continuous measures that used
different scales (e.g. mean adhesion score at SLL). When the same
scale was used, the mean difference (MD) on this specific scale
was used. We presented 95% confidence intervals (CIs) for all
outcomes.
Unit of analysis issues
The included primary studies were analysed per woman. Studies
that used an internal control were excluded and have been listed
as such.
Dealing with missing data
Investigators were contacted to request missing data. If data were
insufficient for inclusion of the study in a particular analysis, it
was not included.
Assessment of heterogeneity
The Chi2 test was performed and the I2 statistic calculated to
determine significant heterogeneity. An I2 measurement > 30%
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was considered moderate heterogeneity, > 50% substantial hetero-
geneity and > 70% high heterogeneity.
Assessment of reporting biases
In consideration of the difficulty of detecting and correcting pub-
lication bias and other reporting bias, we aimed to minimise the
impact by ensuring that a robust and comprehensive search was
performed. We planned to create a funnel plot to assess the risk
of reporting bias if 10 or more studies were included in a meta-
analysis.
Data synthesis
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
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
labelled accordingly.
Subgroup analysis and investigation of heterogeneity
When significant heterogeneity was identified, the cause was ex-
plored, and a sensitivity analysis was performed using the random-
effects model. This was highlighted in the results section, and any
variation in the direction of effect was noted. A subanalysis com-
paring the effects of antiadhesion agents on de novo adhesions ver-
sus re-formed adhesions would have been performed if sufficient
data were available.
Sensitivity analysis
Sensitivity analysis was performed to determine whether the results
were robust to decisions made regarding eligibility of the studies
and analysis. If a study was considered to have a high risk of bias,
or an apparent outlier was identified, the reason for the significant
heterogeneity was investigated, as to whether this was believed
to be clinical or methodological, and analysis was conducted to
evaluate whether inclusion of the study significantly affected the
results. Results of the sensitivity analysis are reported in the Risk
of bias in included studies subsection of the results section.
R E S U L T S
Description of studies
Results of the search
Forty-four studies were identified as potentially eligible for inclu-
sion. Twenty-nine studies were included. For a summary of each
included study, see the section Characteristics of included studies.
Reasons for study exclusion are detailed in the Characteristics of
excluded studies section. For details of the screening and selection
process, see Figure 1.
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Figure 1. Study flow diagram.
Included studies
Study design and setting
Of the 29 included studies, 19 were conducted at multiple centres
and 10 at a single centre. Nine were conducted in the USA, six
in Europe, two in the USA/Europe, two in the Netherlands, three
in Australia, one in Sweden, two in Italy and one in Germany/
Canada/Netherlands/Antilles; three studies did not state their lo-
cation.
Results of nine of the included trials could not be entered into the
meta-analysis because the data were not reported in an appropriate
format. In some cases, the study authors used different ways of
assessing adhesions, such as reporting only individual sections of
the mAFS, as in Hellebrekers 2009 and Diamond 2003, or the
adhesion area (cm2), as in Coddington 2009. Another reason why
studies could not be entered was that complete statistical data were
not published, for example, Thornton 1998 and Rosenberg 1984
did not report standard deviations (SDs) or standard errors of the
mean (SEMs), and although Fossum 2011 reported the outcomes
we were examining, results were displayed on a graph without ac-
tual numbers stated at any point in the text. DiZerega 2007 was
not entered into the meta-analysis, as investigators reported only
the effect that the antiadhesion agent had on AFS endometriosis
score, and as the results were presented per adnexa, not per par-
ticipant. Thus 20 trials were involved in the meta-analysis.
Fifteen studies stated that they received commercial funding.
Participants
A wide variety was noted in the number of participants in each
study, with participant numbers ranging from 10 to 203 in the
intervention group and from 10 to 199 in the control group. All
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participants were women undergoing a gynaecological procedure
who had had a second-look laparoscopy. Reasons for surgery in-
cluded pelvic inflammatory disease (PID), endometriosis, adhe-
sions, fibroids, pelvic pain, pelvic mass, endometrioid cysts and
infertility assessment and treatment (e.g. tubal surgery).
Interventions
The numbers of studies entered into the meta-analysis for each
comparison are as follows.
1. Seven studies compared hydroflotation agents versus no
hydroflotation agents. A distinction was made between
hydroflotation agents (e.g. dextran, 4% icodextrin, SepraCoat)
designed as antiadhesion agents and liquids such as saline, which
was often used as a control and is not considered a
hydroflotation agent in this review.
2. Five studies compared gel agents versus no gel agents.
3. Two studies compared hydroflotation agents versus gel
agents.
4. Four studies compared steroids versus no steroids.
5. One study compared noxytioline versus no noxytioline.
6. One study compared heparin versus no heparin.
7. One study compared promethazine versus no
promethazine.
No studies that evaluated GnRHa, reteplase plasminogen activator
or N,O-carboxymethyl chitosan could be included in the meta-analysis.
Outcomes
Two studies did not assess adhesions (Rose 1991; Sites 1997).
DiZerega 2007 and Lundorff 2005 presented the results per ad-
nexa.
Primary outcomes
One of 29 studies examined pelvic pain (Brown 2007).
Three of 29 studies examined live birth rate (Jansen 1985; Larsson
1985; Rock 1984).
Secondary outcomes
Of 29 studies, 11 examined improvement in adhesion score at SLL
(Adhesion SG 1983; Brown 2007; diZerega 2002; Jansen 1985;
Jansen 1988; Jansen 1990; Johns 2001; Larsson 1985; Lundorff
2001; Mettler 2004; Young 2005).
Of 29 studies, nine examined the number of participants with
worsening adhesion score at SLL (diZerega 2002; Jansen 1985;
Jansen 1988; Jansen 1990; Johns 2001; Lundorff 2001; Mettler
2004; Querleu 1989; Young 2005).
Of 29 studies, 10 examined adhesions at SLL (Adhesion SG
1983; Diamond 1998; diZerega 2002; Jansen 1985; Johns 2001;
Lundorff 2001; Mais 2006; Mettler 2004; Pellicano 2003; Ten
Broek 2012).
Of 29 studies, seven examined the mean adhesion score at SLL
per participant (Adhesion SG 1983; Brown 2007; Larsson 1985;
Lundorff 2001; Mais 2006; Ten Broek 2012; Trew 2011).
Of 29 studies, five examined the clinical pregnancy rate. All par-
ticipants in these studies were actively seeking pregnancy during
the study time period (Adhesion SG 1983; Jansen 1985; Larsson
1985; Querleu 1989; Rock 1984).
None of the 29 studies examined the miscarriage rate.
Of 29 studies, four examined the ectopic pregnancy rate (Jansen
1985; Larsson 1985; Querleu 1989; Rock 1984).
None of the 29 studies examined QoL.
Of 29 studies, 28 examined adverse outcomes. Rosenberg 1984
was the only study that did not examine adverse outcomes.
Excluded studies
Nine studies were excluded. Johns 2003 used an internal control.
Diamond 2011 and Tulandi 1991 used internal controls, which
was not explicitly stated in the abstract. Two studies were interim
reports (Mettler 2003(a); Mettler 2003(b)) and the final report
was included. One trial was not randomised (Tsuji 2005), and
one study did not state that it was randomised (Pellicano 2005),
although it appeared to include the same study group as was used
in Pellicano 2003. This was not explicitly stated in the methods,
nor was the fact that the study was randomised. Thus Pellicano
2005 was excluded. One study was excluded because it was quasi-
randomised (Swolin 1967). Tulandi 1985 reported the effect of the
agent on blood indices, not on adhesions. This study was included
in the original review but has been excluded because investigators
used an external control.
Studies awaiting classification
Three studies sit in the awaiting classification section (Hudecek
2012; Litta 2013; Tchartchian 2009) pending publication of suf-
ficient data to allow their inclusion.
Risk of bias in included studies
The risk of bias for each included study can be seen in the
Characteristics of included studies section. Figure 2 presents a
summary of risk of bias of all included studies. Figure 3 depicts
the proportions of studies within each judgement for each risk of
bias element.
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Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included
study.
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Figure 3. Risk of bias graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.
Allocation
Sequence generation
No studies were at high risk of sequence generation bias. Seventeen
studies adequately explained an appropriate method of sequence
generation and were thus deemed at low risk. Twelve studies de-
scribed the methods of random sequence generation inadequately
and were at unclear risk.
Allocation concealment
No studies were at high risk of allocation concealment bias. Eleven
studies were at low risk of allocation concealment bias, as the au-
thors described an acceptable method of allocation concealment.
Eighteen studies did not provide sufficient information on alloca-
tion to permit a judgement.
Blinding
Six studies did not provide sufficient information on blinding to
permit a judgement. Three studies blinded only the participant
(Coddington 2009; Mettler 2008; Rose 1991). Five studies were
double-blinded (i.e. both participant and operating surgeon were
blinded) (Brown 2007; Mettler 2004; Pellicano 2003; Querleu
1989; Rosenberg 1984). Ten Broek 2012 stated that the study was
single-blinded (participant), although the surgeon performing the
initial surgery was unaware of allocation until the end of the initial
procedure after the adhesions were scored, and the second-look la-
paroscopy surgeon was blinded. The remaining 14 studies blinded
the participant and the operating surgeon and used an independent
blinded reviewer to assess videos or diagrams obtained through
the second-look laparoscopy (Diamond 1998; Diamond 2003;
diZerega 2002; DiZerega 2007; Fossum 2011; Hellebrekers 2009;
Jansen 1985; Jansen 1988; Johns 2001; Larsson 1985; Lundorff
2001; Mais 2006; Trew 2011; Young 2005).
Incomplete outcome data
Two studies (Rosenberg 1984; Thornton 1998) were considered
at high risk of attrition bias, as neither study reported SDs or
SEMs. Twenty-two studies were at low risk for attrition bias. Five
studies did not provide sufficient information to reveal attrition
bias; consequently the risk of attrition bias was unclear.
Selective reporting
One study (Mettler 2008) was at high risk for reporting bias. The
authors of the study decided “in hindsight” to change the primary
outcome scoring method from the total mAFS score, as stated
in the original protocol, to the mAFS of the posterior uterus, as
discussed during data analysis. Consequently, a sensitivity analysis
was conducted and found that excluding Mettler 2008 made no
difference to the direction of treatment effect. Thus the study
was excluded from analysis. Twenty-five studies were at low risk
for reporting bias, and three studies did not provide sufficient
information to allow judgement on reporting bias risk.
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Other potential sources of bias
Two studies were identified as having other sources of bias that
were unclear (Jansen 1988; Ten Broek 2012). A potential source
of bias in Jansen 1988 was that the practice of adding hydrocor-
tisone sodium succinate to the irrigation solution was stopped af-
ter 46 participants had received it because a possible detrimental
effect was reported in an earlier study. These 46 participants were
still included in the analysis. The study by Ten Broek 2012 was
“prematurely ended due to financial and organizational reasons.
During the conduct of the study, the clinical trial insurance unex-
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.
Effects of interventions
See: Summary of findings for the main comparison
Hydroflotation agents vs no hydroflotation agents for adhesion
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
compared with hydroflotation agents when used as an instillant
for adhesion prevention after gynaecological surgery; Summary
of findings 4 Steroids (any route) vs no steroids for adhesion
prevention after gynaecological surgery; Summary of findings
5 Intraperitoneal noxytioline vs no treatment for adhesion
prevention after gynaecological surgery; Summary of findings
6 Intraperitoneal heparin solution vs no intraperitoneal heparin
for adhesion prevention after gynaecological surgery; Summary
of findings 7 Systemic promethazine vs no promethazine for
adhesion prevention after gynaecological surgery
1. Hydroflotation agents versus no treatment
Primary outcomes
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
a difference compared with saline (OR 0.65, 95% CI 0.37 to
1.14, P value 0.13, one study, 286 participants, moderate-quality
evidence). See Analysis 1.1.
1.2 Live birth rate
No evidence of a difference between groups was seen (OR 0.67,
95% CI 0.29 to 1.58, P value 0.36, two studies, 208 participants,
I2 = 0%, moderate-quality evidence) (Jansen 1985: dextran vs
Hartmann’s; Larsson 1985: dextran vs saline). See Analysis 1.2 and
Figure 4.
Figure 4. Forest plot of comparison: 1 Hydroflotation agent vs no hydroflotation agent, outcome: 1.2 Live
birth rate.
Secondary outcomes
1.3 Improvement in adhesion score at SLL
No evidence of a difference between groups was seen (OR 1.27,
95% CI 0.79 to 2.05, P value 0.32, four studies, 665 participants,
I2 = 38%, moderate heterogeneity, moderate-quality evidence)
(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%
when Jansen 1985 was removed, which consequently meant that
a significant difference between groups was seen (OR 1.47, 95%
CI 1.03 to 2.10, P value 0.03, three studies, 546 participants);
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however a cause for the heterogeneity was not elucidated, and thus
the study remained in the meta-analysis. The only difference that
we could discern was the use of Hartmann’s as a control as opposed
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.
1.4 Worsening in adhesion score at SLL
No evidence of a difference between groups was seen (OR 0.28,
95% CI 0.07 to 1.21, P value 0.09, one study, 53 participants,
moderate-quality evidence) (diZerega 2002: 4% icodextrin vs
saline). With the addition of Jansen 1985, heterogeneity was high
in the analysis of worsening adhesion score (I2 = 79%). As this
outcome was poorly defined in Jansen 1985, this study was re-
moved from the analysis; this did not affect the results, as they
remained not statistically significant. See Analysis 1.4.
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
they received a hydroflotation agent (OR 0.34, 95% CI 0.22 to
0.55, P value < 0.00001, four studies, 566 participants, I2 = 0%,
high-quality evidence) (Adhesion SG 1983: dextran vs saline;
Diamond 1998: SepraCoat vs phosphate-buffered saline (PBS);
diZerega 2002: 4% icodextrin vs saline; Jansen 1985: dextran vs
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
No evidence of a difference between groups was seen (OR -0.06,
95% CI -0.20 to 0.09, P value 0.44, four studies, 722 participants,
I2 = 0%, high-quality evidence) (Adhesion SG 1983: dextran vs
saline; Brown 2007: 4% icodextrin vs saline; Larsson 1985: dextran
vs saline; Trew 2011: 4% icodextrin vs saline). See Analysis 1.6.
1.7 Clinical pregnancy rate
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,
I2 = 0%, moderate-quality evidence) (Adhesion SG 1983: dextran
vs saline; Jansen 1985: dextran vs Hartmann’s; Larsson 1985: dex-
tran vs saline). See Analysis 1.7.
1.8 Miscarriage rate
This was not assessed by any study.
1.9 Ectopic pregnancy rate
No evidence of a difference between groups was seen (OR 0.35,
95% CI 0.06 to 1.85, P value 0.21, two studies, 50 participants,
I2 = 5%) (Jansen 1985: dextran vs Hartmann’s; Larsson 1985:
dextran vs saline). See Analysis 1.9.
1.10 Quality of life
This was not assessed by any study.
1.11 Adverse outcomes
No adverse outcomes were reported.
2. Gel agents versus no treatment
Primary outcomes
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2.1 Pelvic pain
This was not assessed by any study.
2.2 Live birth rate
This was not assessed by any study.
Secondary outcomes
2.3 Improvement in adhesion score at SLL
No evidence of a difference between groups was seen (OR 3.78,
95% CI 0.61 to 23.32, P value 0.15, two studies, 58 participants,
I2 = 0%, moderate-quality evidence) (Mettler 2004: SprayGel vs
no treatment; Young 2005: Oxiplex/AP gel vs no treatment). The
95% CI is very wide though, which was believed to be related
to the small number of participants that could be included in
this analysis. Irrespective, the result remains not significant. See
Analysis 2.3.
2.4 Worsening in adhesion score at SLL
A significant difference was seen, with fewer participants who had
received a gel showing worsening in adhesion score at SLL com-
pared with those who received no treatment (OR 0.16, 95% CI
0.04 to 0.57, P value 0.005, two studies, 58 participants, I2 = 0%,
moderate-quality evidence) (Mettler 2004: SprayGel vs no treat-
ment; Young 2005: Oxiplex/AP gel vs no treatment). See Analysis
2.4.
2.5 Adhesions at SLL
Participants who received a gel were significantly less likely to have
adhesions at SLL compared with those who received no adhesion
prevention agent (OR 0.25, 95% CI 0.11 to 0.56, P value 0.0006,
four studies, 134 participants, I2 = 0%, high-quality evidence)
(Mais 2006: Hyalobarrier vs no treatment; Mettler 2004: SprayGel
vs no treatment; Pellicano 2003: auto-cross-linked hyaluronic acid
gel vs no treatment; Ten Broek 2012: SepraSpray vs no treatment).
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.
16Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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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
This was not assessed by any study.
2.8 Miscarriage rate
This was not assessed by any study.
2.9 Ectopic pregnancy rate
This was not assessed by any study.
2.10 Quality of life
This was not assessed by any study.
2.11 Adverse outcomes
No adverse outcomes were reported.
Data that could not be included in a meta-analysis but were con-
sidered in the review are outlined here. Mettler 2008 (hydrogel vs
saline), Rosenberg 1984 (dextran vs saline) and Thornton 1998
(0.5% ferric hyaluronate vs saline) found that participants who
did not receive the antiadhesion agent had a significantly worse
adhesion score at SLL than participants who had received the anti-
adhesion agent. Diamond 2003 (N,O-carboxymethyl chitosan vssaline) found no significant difference in adhesion scores between
participants who received an antiadhesion agent and those who did
not. Lundorff 2005 (Oxiplex/AP gel) found a significant differ-
ence in adhesions at SLL, with adnexae that had not been treated
with Oxiplex/AP gel having significantly worse adhesions at SLL
than adnexae that had been treated. See Analysis 2.2; Analysis 2.7;
and Analysis 2.8.
3. Gel agents versus hydroflotation agents when used
as an instillant
Primary outcomes
3.1 Pelvic pain
This was not assessed by any study.
3.2 Live birth rate
This was not assessed by any study.
Secondary outcomes
3.3 Improvement in adhesion score at SLL
No evidence of a difference between groups was seen (OR 1.55,
95% CI 0.82 to 2.92, P value 0.17, two studies, 342 partici-
pants, I2 = 0%, moderate-quality evidence) (both Johns 2001 and
Lundorff 2001 examined Intergel vs saline). See Analysis 3.3.
Fossum 2011 (Sepraspray vs no SepraSpray) found no significant
difference in adhesion scores between participants who received
an antiadhesion agent and those who did not. These data could
not be included in the meta-analysis.
3.4 Worsening in adhesion score at SLL
Participants who received a gel (Intergel) were less likely to have a
worsening adhesion score at SLL compared with participants who
received saline (OR 0.28, 95% CI 0.12 to 0.66, P value 0.003, two
studies, 342 participants, I2 = 0%, high-quality evidence) (Johns
2001; Lundorff 2001). See Figure 8.
17Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review)
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 partici-
pants 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
Lundorff 2001 reported a lower adhesion score at SLL in par-
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
appears very precise for a study that included only 38 participants
in each arm, the study authors advise caution in interpreting these
results.
3.7 Clinical pregnancy rate
This was not assessed by any study.
3.8 Miscarriage rate
This was not assessed by any study.
3.9 Ectopic pregnancy rate
This was not assessed by any study.
3.10 Quality of life
This was not assessed by any study.
3.11 Adverse outcomes
No adverse outcomes were reported.
4. Steroids (including systemic, intraperitoneal,
preoperative and postoperative) versus no steroids
(or placebo)
18Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
-
Primary outcomes
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 hydrocor-
tisone vs saline). See Figure 10.
Figure 10. Forest plot of comparison: 4 Steroid (any route) vs no steroid, outcome: 4.2 Live birth rate.
Secondary outcomes
4.3 Improvement in adhesion score 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
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
this review; data are unpublished and were supplied by the study
author along with little information about the characteristics of
the study. Thus caution is urged in interpreting this result. See
Analysis 4.3.
4.4 Worsening in adhesion score at SLL
Fewer participants who received steroids showed worsening in
adhesion score compared with participants who did not receive
steroids (OR 0.27, 95% CI 0.12 to 0.58, P value 0.0008, two stud-
ies, 187 participants, I2 = 0%, low-quality evidence) (Jansen 1990:
IV dexamethasone and PO prednisolone vs no steroids; Querleu
1989: IM dexamethasone vs no steroids). See Analysis 4.4.
4.5 Adhesions at SLL
This was not assessed by any study.
4.6 Mean adhesion score at SLL per participant
This was not assessed by any study.
4.7 Clinical pregnancy rate
No evidence of a difference between groups was seen (OR 1.01,
95% CI 0.66 to 1.55, P value 0.96, three studies, 410 participants,
I2 = 0%, moderate-quality evidence) (Jansen 1985: intraperitoneal
hydrocortisone, IV dexamethasone and PO prednisolone vs no
steroids; Querleu 1989: IM dexamethasone vs no steroids; Rock
1984: intraperitoneal hydrocortisone vs saline). See Analysis 4.7.
19Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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4.8 Miscarriage rate
This was not assessed by any study.
4.9 Ectopic pregnancy rate
No evidence of a difference between groups was seen (OR 0.67,
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
and PO prednisolone vs no steroids; Querleu 1989: IM dexam-
ethasone vs no steroids; Rock 1984: intraperitoneal hydrocorti-
sone vs saline). See Analysis 4.9.
4.10 Quality of life
This was not assessed by any study.
4.11 Adverse outcomes
No adverse outcomes were reported.
5. Intraperitoneal noxytioline versus no noxytioline
(or placebo)
Noxytioline was examined by only one study: Querleu 1989.
Primary outcomes
5.1 Pelvic pain
This was not assessed by any study.
5.2 Live birth rate
This was not assessed by any study.
Secondary outcomes
5.3 Improvement in adhesion score at SLL
This was not assessed by any study.
5.4 Worsening in adhesion score at SLL
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-
ipants, moderate-quality evidence) (Querleu 1989). See Analysis
5.4.
5.5 Adhesions at SLL
This was not assessed by any study.
5.6 Mean adhesion score at SLL per participant
This was not assessed by any study.
5.7 Clinical pregnancy rate
No evidence of a difference was seen between participants who
received intraperitoneal noxytioline and those who did not (OR
0.66, 95% CI 0.30 to 1.47, P value 0.31, one study, 126 partic-
ipants, moderate-quality evidence) (Querleu 1989). See Analysis
5.7.
5.8 Miscarriage rate
This was not assessed by any study.
5.9 Ectopic pregnancy rate
No evidence of a difference was seen between participants who
received intraperitoneal noxytioline and those who did not (OR
4.91, 95% CI 0.45 to 53.27, P value 0.19, one study, 33 partici-
pants, low-quality evidence) (Querleu 1989). See Analysis 5.9.
5.10 Quality of life
This was not assessed by any study.
5.11 Adverse outcomes
No adverse outcomes were reported.
6. Intraperitoneal heparin versus no heparin (or
placebo)
Heparin was examined by only one study: Jansen 1988.
Primary outcomes
6.1 Pelvic pain
This was not assessed by any study.
6.2 Live birth rate
This was not assessed by any study.
20Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Secondary outcomes
6.3 Improvement in adhesion score at SLL
No evidence of a difference was seen between participants who
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.
6.4 Worsening in adhesion score at SLL
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.
6.5 Adhesions at SLL
This was not assessed by any study.
6.6 Mean adhesion score at SLL per participant
This was not assessed by any study.
6.7 Clinical pregnancy rate
This was not assessed by any study.
6.8 Miscarriage rate
This was not assessed by any study.
6.9 Ectopic pregnancy rate
This was not assessed by any study.
6.10 Quality of life
This was not assessed by any study.
6.11 Adverse outcomes
No adverse outcomes were reported.
7. Systemic promethazine versus no promethazine
(or placebo)
Promethazine was examined by only one study: Jansen 1990.
Primary outcomes
7.1 Pelvic pain
This was not assessed by any study.
7.2 Live birth rate
This was not assessed by any study.
Secondary outcomes
7.3 Improvement in adhesion score at SLL
No significant difference was seen between participants who re-
ceived promethazine and those who did not (OR 0.56, 95% CI
0.22 to 1.43, P value 0.22, one study, 75 participants, low-quality
evidence) (Jansen 1990).
7.4 Worsening in adhesion score at SLL
No evidence of a difference was seen between participants who
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.
7.5 Adhesions at SLL
This was not assessed by any study.
7.6 Mean adhesion score at SLL per participant
This was not assessed by any study.
7.7 Clinical pregnancy rate
This was not assessed by any study.
7.8 Miscarriage rate
This was not assessed by any study.
7.9 Ectopic pregnancy rate
This was not assessed by any study.
7.10 Quality of life
This was not assessed by any study.
21Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
-
7.11 Adverse outcomes
No adverse outcomes were reported.
8. GnRHa versus no GnRHa (or placebo)
This was not assessed by any study eligible for inclusion in the
meta-analysis. Coddington 2009 (GnRHa vs no GnRHa) found
no evidence of a difference in adhesion scores between participants
who received an antiadhesion agent and those who did not. Data
from this study could not be included in the meta-analysis. See
Analysis 8.1.
9. Reteplase plasminogen activator versus no
reteplase plasminogen activator (or placebo)
This was not assessed by any study that could be used in the
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
an antiadhesion agent and those who did not. See Analysis 9.1.
10. N,O-carboxymethyl chitosan versus no N,O-
carboxymethyl chitosan (or placebo)
This was not assessed by any study that could be used in the meta-
analysis.
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-
hesion agents; however new evidence has come to light since the
publication of these studies that led to the withdrawal of Intergel.
22Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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A D D I T I O N A L S U M M A R Y O F F I N D I N G S [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
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed risk Corresponding risk
No treatment Gel agents
Number of participants
with improvement in ad-
hesion score
43 per 1000 147 per 1000
(27-515)
OR 3.78
(0.61-23.32)
58
(2 studies)
⊕⊕⊕©
moderate1
Number of participants
withworseningadhesion
score
826 per 1000 432 per 1000
(160-730)
OR 0.16
(0.04-0.57)
58
(2 studies)
⊕⊕⊕©
moderate2
Number of participants
with adhesions at sec-
ond-look laparoscopy
766 per 1000 450 per 1000
(264-647)
OR 0.25
(0.11-0.56)
134
(4 studies)
⊕⊕⊕⊕
high
Mean adhesion score
at second-look la-
paroscopy
Mean adhesion score at
second-look laparoscopy
in the intervention groups
was
0.13 standard deviations
lower
(0.65 lower-0.39 higher)
58
(2 studies)
⊕⊕⊕©
moderate3SMD -0.13 (-0.65 to 0.
39)4
*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.23F
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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.
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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
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed risk Corresponding risk
Hydroflotation agents
when used as an instil-
lant
Gel agents
Number of participants
with improvement in ad-
hesion score
110 per 1000 161 per 1000
(92-265)
OR 1.55
(0.82-2.92)
342
(2 studies)
⊕⊕⊕©
moderate1
Number of participants
withworseningadhesion
score
139 per 1000 43 per 1000
(19-96)
OR 0.28
(0.12-0.66)
342
(2 studies)
⊕⊕⊕⊕
high
Number of participants
with adhesions at sec-
ond-look laparoscopy
225 per 1000 95 per 1000
(52-163)
OR 0.36
(0.19-0.67)
342
(2 studies)
⊕⊕⊕⊕
high
Mean adhesion score
at second-look la-
paroscopy
Mean adhesion score at
second-look laparoscopy
in the intervention groups
was
0.79 lower
(0.79-0.79 lower)
77
(1 study)
⊕⊕⊕©
moderate2
3
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*The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison
group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio.
GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
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);
therefore for comparison, standardised mean difference was calculated.
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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
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed risk Corresponding risk
No steroids Steroids (any route)
Live birth rate 112 per 1000 76 per 1000
(32-170)
OR 0.65
(0.26-1.62)
223
(2 studies)
⊕⊕⊕©
moderate2
Number of participants
with improvement in ad-
hesion score
462 per 1000 805 per 1000
(594-921)
OR 4.83
(1.71-13.65)
75
(1 study)
⊕⊕©©
low14
Number of participants
withworseningadhesion
score
343 per 1000 124 per 1000
(59-233)
OR 0.27
(0.12-0.58)
176
(2 studies)
⊕⊕©©
low1,24
Clinical pregnancy rate 297 per 1000 299 per 1000
(218-396)
OR 1.01
(0.66-1.55)
410
(3 studies)
⊕⊕⊕©
moderate1,2
Ectopic rate (per preg-
nancy)
195 per 1000 140 per 1000
(19-580)
OR 0.67
(0.08-5.7)
83
(3 studies)
⊕⊕⊕©
moderate3
*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.
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