Fluid and pharmacological agents for adhesion prevention after gynaecological surgery

  • Conclusions changed
  • Review
  • Intervention

Authors


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).

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.

Résumé scientifique

Liquides et agents pharmacologiques pour la prévention des adhérences après chirurgie gynécologique

Contexte

La chirurgie pelvienne est associée à des taux élevés tant de formation d'adhérences nouvelles que de reformation d'adhérences. La fertilité ultérieure étant d'autant plus réduite que les adhérences péri-annexielles sont graves, les adhérences pelviennes sont appelées à rester un problème clinique chez les patientes souffrant d'infertilité. Les stéroïdes, les antihistaminiques et l'héparine ont été parmi les premières substances préconisées pour la prévention des adhérences. Plus récemment, l'icodextrine 4%, les agents à acide hyaluronique et le SprayGel ont été utilisés. Cette revue visait à évaluer le rôle des liquides et des agents pharmacologiques dans la prévention des adhérences en chirurgie gynécologique préservant la fertilité.

Objectifs

Étudier les liquides et les agents pharmacologiques pour la prévention des adhérences qui sont utilisés comme adjuvants au cours des opérations pelviennes.

Stratégie de recherche documentaire

Cette revue s'est appuyée sur la stratégie de recherche développée pour le groupe sur les troubles menstruels et l'hypofertilité. Les bases de données suivantes ont été examinées : le registre spécialisé des essais du groupe Cochrane sur les troubles menstruels et l'hypofertilité, le registre Cochrane des essais contrôlés (CENTRAL), MEDLINE et EMBASE.

Critères de sélection

Des essais contrôlés randomisés portant sur l'utilisation de liquides et d'agents pharmacologiques pour prévenir la formation d'adhérences après chirurgie gynécologique préservant la fertilité.

Recueil et analyse des données

L'extraction et l'analyse des données ont été réalisées indépendamment par deux auteurs (Metwally M et Watson A). Des tables de deux sur deux ont été générées pour les critères de résultat dichotomiques et exprimées sous forme de rapports des cotes (RC) avec intervalles de confiance (IC) à 95%. Pour les variables continues, la différence moyenne standardisée a été utilisée.

Résultats principaux

Il n'y a pas preuve d'un bénéfice de l'utilisation de stéroïdes, de dextrane ou d'autres agents pharmacologiques pour aucun des critères de résultat. L'utilisation d'agents à acide hyaluronique peut diminuer la formation d'adhérences (RC 0,31 ; IC à 95% 0,19 à 0,51) et prévenir la dégradation d'adhérences pré-existantes (RC 0,28 ; IC à 95% 0,12 à 0,66). Il n'y a pas de preuves suffisantes en faveur de l'utilisation de l'icodextrine 4% ou du SprayGel comme agents de prévention des adhérences. Aucun des agents étudiés ne s'est avéré améliorer le taux de grossesses lorsqu'utilisés en appoint au cours d'une opération pelvienne.

Conclusions des auteurs

On ne dispose actuellement que de données limitées concernant l'utilisation de liquides et d'agents pharmacologiques pour la prévention des adhérences. Il n'y a pas de preuve d'un quelconque bénéfice pour l'amélioration des critères de grossesse de l'utilisation de liquides et d'agents pharmacologiques en appoint au cours d'une opération pelvienne.

Il n'y a pas suffisamment de preuves en faveur de l'utilisation des agents suivants : stéroïdes, icodextrine 4%, SprayGel et dextrane pour l'amélioration des adhérences post-chirurgicales.

Il existe certaines preuves que les agents à acide hyaluronique sont susceptibles de diminuer la proportion d'adhérences et de prévenir la dégradation d'adhérences pré-existantes. Toutefois, en raison du nombre limité d'études disponibles, ce résultat doit être interprété avec prudence et de nouvelles études seront nécessaires.

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.

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.

Résumé simplifié

Utilisation de liquides et d'agents pharmacologiques (médicaments) pour prévenir la formation d'adhérences (tissu cicatriciel) risquant d'influer sur l'obtention d'une grossesse après une opération pelvienne chez la femme.

La formation d'adhérences est un état dans lequel des tissus corporels normalement séparés fusionnent. Cela peut se produire après des interventions chirurgicales telles que les opérations pelviennes chez la femme pour l'ablation d'un kyste, le traitement de l'endométriose, l'arrêt d'une grossesse extra-utérine, ou la suppression d'un fibrome (une tumeur bénigne de l'utérus). Ce tissu cicatriciel peut avoir de graves effets sur la fertilité future de la femme car il peut entrainer une obstruction de ses trompes. La manipulation délicate des tissus lors de l'opération et le contrôle des pertes de sang sont d'importantes façons de réduire le tissu cicatriciel ; cependant, avec les années, d'autres méthodes ont été développées pour minimiser le risque de formation de tissu cicatriciel. Les chirurgiens ont essayé d'utiliser différents types de médicaments ou de laisser différents types de liquides à l'intérieur du pelvis à la fin de l'opération afin d'empêcher les surfaces tissulaires de coller les unes aux autres. Ces liquides sont notamment le dextrane, l'icodextrine (Adept), le SprayGel et les liquides contenant de l'acide hyaluronique chimique (Intergel, acide hyaluronique auto-réticulé, Sepracoat). Les médicaments qui ont été essayés comprennent des stéroïdes (anti-inflammatoires), l'anti-coagulant héparine, la prométhazine et la noxytioline.

Cette revue visait à évaluer le rôle de ces différents agents dans la prévention de la formation d'adhérences. Les résultats ont montré que les données actuelles sont insuffisantes pour pouvoir recommander l'utilisation de stéroïdes, d'icodextrine, de SprayGel ou de dextrane. La revue a montré que les liquides qui contiennent de l'acide hyaluronique peuvent aider à réduire le risque de formation de tissu cicatriciel ; mais de nouvelles études seront nécessaires pour confirmer cela. Il y a aussi des questions de sécurité importantes concernant l'utilisation de l'un de ces agents (Intergel), qui a été retiré du marché en raison d'effets secondaires graves signalés, comme des réactions allergiques et des douleurs.

Les études dans cette revue présentent un problème majeur car la plupart d'entre elles ne s'étaient pas intéressées au taux de grossesses après utilisation de ces substances. La survenue d'une grossesse étant l'étalon de mesure pour évaluer la capacité de ces agents à préserver la fertilité, il est important que les études futures en tiennent compte.

Notes de traduction

Translated by: French Cochrane Centre

Translation supported by: Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux;

Резюме на простом языке

Использование жидкостей и фармакологических средств (лекарственных препаратов) для профилактики спаечной болезни (тканевых рубцов) после операций в области таза женщин

Обзор вопроса: В этом систематическом обзоре Кокрейн была проведена оценка вех жидкостей и фармакологических средств, используемых для профилактики образования спаек после гинекологических операций (гели были определены как жидкие средства).

Актуальность: Спайки это внутренняя рубцовая ткань, которая может формироваться в процессе восстановления организма после операции. Их появление также может быть вызвано инфекциями таза и эндометриозом. Спайки склеивают вместе ткани и органы, которые обычно не соприкасаются. Спайки обычно возникают после гинекологических операций, и могут вызывать боль в области таза, бесплодие и закупорку кишечника. Женщинам со спайками может потребоваться дальнейшая более сложная операция, что может привести к дополнительным осложнениям. Жидкости вводят во время операции в полость малого таза (в котором находятся все женские репродуктивные органы), и это предотвращает физический контакт заживающих тканей. Эти жидкости можно разделить на гидрофлотационные средства и гели. Гидрофлотационные средства это жидкости, которые помещают в полость малого таза в больших объемах (обычно около литра), гели наносят непосредственно в область хирургического вмешательства. Фармакологические средства действуют путем изменения этапов процесса заживления.

Характеристики исследований В этот обзор мы включили 29 рандомизированных контролируемых испытаний (3227 участников). Результаты 18 испытаний из них были объединены (2740 участников). Результаты оставшихся 11 исследований не могли быть использованы в мета-анализе, потому что исследователи не применяли метод измерения спаек, который позволил бы объединить их результаты с другими данными, или потому, что в них не сообщалось важной статистической информации. Мы провели последний поиск доказательств по апрель 2014 года.

Основные результаты: Только в одном исследовании провели оценку боли в области таза, и не было представлено доказательств того, что существует разница между средствами для предотвращения спаек. Не существует доказательств, что какое-либо из исследованных средств повлияло на частоту живорождения. Если говорить о спайках, то, у участниц, которым применяли жидкие средства во время операции, вероятность образования спаек была меньше, чем у участниц, которые не получили жидкого средства. Когда жидкости и гели сравнивали друг с другом, гели оказались лучше, чем жидкости. Не получено убедительных доказательств существенного влияния фармакологических средств на образование спек. Ни в одном исследовании не рассматривали различия в качестве жизни. Все исследования, за исключением одного, показали, что исследователи планировали провести оценку неблагоприятных исходов, связанных с лекарствами, однако о неблагоприятных эффектах не сообщали.

Результаты использования гелей показывают, что у женщин с 77% -ным риском развития спаек без лечения с помощью геля, риск развития спаек после использования геля будет составлять от 26% до 65%. У женщин с 83% -ным риском обострения спаек после отсутствия лечения при первой операции вероятность улучшения состояния после использования геля составит от 16% до 73%. Аналогичным образом для гидрофлотационных жидкостей - у женщин с 84% -ной вероятностью развития спаек без лечения, риск развития спаек при использовании гидрофлотационных жидкостей будет составлять от 53% до 73%.

Жидкие средства и гели эффективны для уменьшении спаек, однако требуется дополнительная информация, чтобы определить, влияют ли они на боли в области таза, частоту живорождения, качество жизни и долгосрочные осложнения, такие как кишечная непроходимость. Кроме того, следует провести обширные исследования высокого качества, в которых исследователи использовали бы стандартный способ измерения спаек, разработанный Американским обществом репродуктивной медицины (модифицированный счет AFS).

Качество доказательств: Качество доказательств варьировало от низкого до высокого. Основными причинами снижения качества доказательств были неточность (малые размеры выборки и широкие доверительные интервалы), и плохое представление методов исследования.

Заметки по переводу

Перевод: Беспалова Ксения Юрьевна. Редактирование: Курбатова Ольга Геннадьевна. Координация проекта по переводу на русский язык: Cochrane Russia - Кокрейн Россия (филиал Северного Кокрейновского Центра на базе Казанского федерального университета). По вопросам, связанным с этим переводом, пожалуйста, обращайтесь к нам по адресу: cochrane.russia.kpfu@gmail.com; cochranerussia@kpfu.ru

Summary of findings(Explanation)

Summary of findings for the main comparison. Hydroflotation agents vs no hydroflotation agents for adhesion prevention after gynaecological surgery
  1. 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.

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
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding 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)
⊕⊕⊕⊝
moderate 1
 
Live birth rate 140 per 1000 98 per 1000
(45-205)
OR 0.67
(0.29-1.58)
208
(2 studies)
⊕⊕⊕⊝
moderate 1
 
Improvement in adhesion score 437 per 1000 496 per 1000
(380-614)
OR 1.27
(0.79-2.05)
665
(4 studies)
⊕⊕⊕⊝
moderate 1,2
 
Number of participants with worsening adhesion score 308 per 1000 111 per 1000
(30-350)
OR 0.28
(0.07-1.21)
53
(1 study)
⊕⊕⊕⊝
moderate 1,3
 
Number of participants with adhesions at second-look laparoscopy 836 per 1000 635 per 1000
(529-738)
OR 0.34
(0.22-0.55)
566
(4 studies)
⊕⊕⊕⊕
high
 
Mean adhesion score at second-look laparoscopy The mean adhesion score at second-look laparoscopy in the intervention 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)
⊕⊕⊕⊝
moderate 1
 
*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.

Summary of findings 2 Gel agents vs no treatment for adhesion prevention after gynaecological surgery

Summary of findings 2. Gel agents vs no treatment for adhesion prevention after gynaecological surgery
  1. 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.

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
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
No treatment Gel agents
Number of participants with improvement in adhesion score 43 per 1000 147 per 1000
(27-515)
OR 3.78
(0.61-23.32)
58
(2 studies)
⊕⊕⊕⊝
moderate 1
 
Number of participants with worsening adhesion score 826 per 1000 432 per 1000
(160-730)
OR 0.16
(0.04-0.57)
58
(2 studies)
⊕⊕⊕⊝
moderate 2
 
Number of participants with adhesions at second-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 laparoscopy 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)
⊕⊕⊕⊝
moderate 3
SMD -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.
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.

Summary of findings 3 Gel agents compared with hydroflotation agents when used as an instillant 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
  1. 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.

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
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Hydroflotation agents when used as an instillant Gel agents
Number of participants with improvement in adhesion score 110 per 1000 161 per 1000
(92-265)
OR 1.55
(0.82-2.92)
342
(2 studies)
⊕⊕⊕⊝
moderate 1
 
Number of participants with worsening adhesion 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 second-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 laparoscopy Mean adhesion score at second-look laparoscopy in the intervention groups was
0.79 lower
(0.79-0.79 lower)
 77
(1 study)
⊕⊕⊕⊝
moderate 2
3
*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.

Summary of findings 4 Steroids (any route) vs no steroids for adhesion prevention after gynaecological surgery

Summary of findings 4. Steroids (any route) vs no steroids for adhesion prevention after gynaecological surgery
  1. 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.

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
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding 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)
⊕⊕⊕⊝
moderate 2
 
Number of participants with improvement in adhesion score 462 per 1000 805 per 1000
(594-921)
OR 4.83
(1.71-13.65)
75
(1 study)
⊕⊕⊝⊝
low 1
4
Number of participants with worsening adhesion score 343 per 1000 124 per 1000
(59-233)
OR 0.27
(0.12-0.58)
176
(2 studies)
⊕⊕⊝⊝
low 1,2
4
Clinical pregnancy rate 297 per 1000 299 per 1000
(218-396)
OR 1.01
(0.66-1.55)
410
(3 studies)
⊕⊕⊕⊝
moderate 1,2
 
Ectopic rate (per pregnancy) 195 per 1000 140 per 1000
(19-580)
OR 0.67
(0.08-5.7)
83
(3 studies)
⊕⊕⊕⊝
moderate 3
 
*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.

Summary of findings 5 Intraperitoneal noxytioline vs no treatment for adhesion prevention after gynaecological surgery

Summary of findings 5. Intraperitoneal noxytioline vs no treatment for adhesion prevention after gynaecological surgery
  1. 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" represents improvement in adhesion disease.

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
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
No treatment Intraperitoneal noxytioline
Number of participants with worsening adhesion score 205 per 1000 124 per 1000
(42-312)
OR 0.55
(0.17-1.76)
87
(1 study)
⊕⊕⊕⊝
moderate 1
2
Clinical pregnancy rate 302 per 1000 222 per 1000
(115-388)
OR 0.66
(0.3-1.47)
126
(1 study)
⊕⊕⊕⊝
moderate 1
 
Ectopic pregnancy rate (per pregnancy) 53 per 1000 214 per 1000
(24-747)
OR 4.91
(0.45-53.27)
33
(1 study)
⊕⊕⊝⊝
low 1
 
*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.
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.

Summary of findings 6 Intraperitoneal heparin solution vs no intraperitoneal heparin for adhesion prevention after gynaecological surgery

Summary of findings 6. Intraperitoneal heparin solution vs no intraperitoneal heparin for adhesion prevention after gynaecological surgery
  1. 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.

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
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
No intraperitoneal heparin Intraperitoneal heparin solution
Number of participants with improvement in adhesion score 571 per 1000 537 per 1000
(299-758)
OR 0.87
(0.32-2.35)
63
(1 study)
⊕⊕⊝⊝
low 1,2
3
Number of participants with worsening adhesion score 396 per 1000 454 per 1000
(268-656)
OR 1.27
(0.56-2.91)
92
(1 study)
⊕⊕⊝⊝
low 1,2
3
*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.

Summary of findings 7 Systemic promethazine vs no promethazine for adhesion prevention after gynaecological surgery

Summary of findings 7. Systemic promethazine vs no promethazine for adhesion prevention after gynaecological surgery
  1. 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.

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
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
No promethazine Systemic promethazine
Number of participants with improvement in adhesion score 692 per 1000 558 per 1000
(331-763)
OR 0.56
(0.22-1.43)
75
(1 study)
⊕⊕⊝⊝
low 1,2
3
Number of participants with worsening adhesion score 391 per 1000 275 per 1000
(138-477)
OR 0.59
(0.25-1.42)
93
(1 study)
⊕⊕⊝⊝
low 1,2
3
*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.

Background

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 cascade, and a fibrin plug is formed over the damaged mesothelium, which is then broken down to reveal regenerated peritoneum. However, in adhesion formation, fibrinolysis of the fibrin plug is decreased and, consequently, a fibrin matrix develops. Adhesions may be defined as ‘de novo,’ meaning 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. Examples of hydroflotation devices are 4% icodextrin solution (Adept, Baxter, Berkshire, UK), an iso-osmolar and non-viscous high molecular weight glucose polymer, and 32% dextran (Hyskon Pharmacia, Uppsala, Sweden), a polysaccharide-containing solution that is no longer approved for use as an antiadhesion agent. Both agents can be used as intraperitoneal irrigants and/or instillants.

Derivatives of hyaluronic acid form the basis of a number of antiadhesion gels. Hyaluronic acid is a linear polysaccharide with repeating disaccharide units composed of sodium D-glucuronate and N-acetyl-D-glucosamine. SepraSpray (Genzyme Corporation, Cambridge, MA, USA) contains hyaluronic acid in addition to carboxymethylcellulose powder and is applied to relevant tissues with the use of a preloaded delivery device. SepraCoat (Genzyme Corporation) is a dilute hyaluronic acid solution that is applied before and after surgery. Hyalobarrier gel (Nordic Pharma, Reading, UK) contains auto-cross-linked hyaluronic acid. Intergel (Gynecare, Lifecore Biomedical, Chaska, MN, USA) contains ferrous hyaluronic acid, although it has been withdrawn from the market. N,O-carboxymethyl chitosan is a derivative of chitin and is similar in structure to hyaluronic acid and carboxymethylcellulose. It is formed when the gel and solution components are combined. Polyethylene glycol (PEG)-based gels are also available. CoSeal (Baxter) is formed by mixing a powder and a liquid intraoperatively, both of which contain PEG and are then applied as a gel to relevant surfaces using a specific instrument. SprayGel (Confluent Surgical Inc., Waltham, MA, USA) is formed by two PEG-containing liquid precursors, which create a cross-linked gel when combined. Intercoat (FzioMed, San Luis Obispo, CA, USA) is 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 administered in a number of ways, including systemically before, during and after surgery; intraperitoneally during surgery; and via hydrotubation postoperatively. Other pharmacological agents used to prevent adhesions include noxytioline, an antibacterial agent; promethazine, an antihistamine; and reteplase, a thrombolytic drug, all of which are instilled intraperitoneally; as well as heparin, an anticoagulant used for intraoperative irrigation. A nasal gonadotrophin-releasing hormone agonist (GnRHa) has also been used preoperatively and postoperatively.

How the intervention might work

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

Steroids and antihistamines (e.g. promethazine) act as immunomodulating agents and were used in the belief that they promote fibrinolysis during healing, without hindering the healing process. GnRHa may work by decreasing oestrogen-related growth factors and promoting fibroblasts. Fluid agents such as icodextrin and dextran work through the act of hydroflotation, whereby the fluid separates raw opposing surfaces until the healing process has been completed. Fluid agents are believed to remain in the peritoneal cavity for 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. Intraperitoneal adhesions are associated with considerable co-morbidity and have large economic and public health repercussions. They are the most common complication of gynaecological surgery, forming 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 correlation with extent of adhesions and severity of pain is apparent. Nevertheless, these consequences can greatly decrease a woman’s well-being and require further surgery. Subsequent surgery in women with adhesions is more difficult, often takes longer and is associated with a higher complication rate. It is estimated that in the first year after lower abdominal surgery, the cost of adhesion-related readmissions in the UK is £24.2 million, which increases to £95.2 million over the subsequent nine years (Wilson 2002). The Surgical and Clinical Adhesions Research (SCAR) study found that 5% (n = 245) of readmissions 10 years after open gynaecological surgery were due to adhesions (Lower 2000; Lower 2004). An English study estimated that the National Health Service (NHS) could save £700,000 per year if an antiadhesion agent that reduced adhesions by 25% and cost £110 was used or, at worst, that this approach would be cost-neutral (Cheong 2011).

Objectives

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

Methods

Criteria for considering studies for this review

Types of studies

Published and unpublished randomised controlled trials (RCTs) investigating the use of fluid and pharmacological agents to prevent adhesion formation after gynaecological surgery were eligible for inclusion. 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 adhesion prevention in non-gynaecological specialities were not included.

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 (including SepraSpray, SepraCoat, Hyalobarrier gel, Intergel, CoSeal, SprayGel and Intercoat) and pharmacological agents. The following 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-carboxymethyl chitosan (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 outcomes to enable maximum study inclusion.

Primary outcomes

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

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

Secondary outcomes

3. 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.

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: MEDLINE (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 Clinical 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 Fertility 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 confirm 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 independently by two review authors (FM, DI). These included allocation (random sequence generation and allocation concealment); blinding 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 Reviews of Interventions (Higgins 2011) and was entered into the risk of bias 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% was considered moderate heterogeneity, > 50% substantial heterogeneity and > 70% high heterogeneity.

Assessment of reporting biases

In consideration of the difficulty of detecting and correcting publication bias and other reporting bias, we aimed to minimise the impact by ensuring that 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 explored, 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 comparing the effects of antiadhesion agents on de novo adhesions versus 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.

Results

Description of studies

Results of the search

Forty-four studies were identified as potentially eligible for inclusion. 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.

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 location.

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 actual 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 participant. 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 participants were women undergoing a gynaecological procedure who had had a second-look laparoscopy. Reasons for surgery included pelvic inflammatory disease (PID), endometriosis, adhesions, fibroids, pelvic pain, pelvic mass, endometrioid cysts and infertility assessment and treatment (e.g. tubal surgery).

Interventions

The numbers of studies entered into 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 adnexa.

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 participants 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 sufficient 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.

Figure 2.

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

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 described 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 authors described an acceptable method of allocation concealment. Eighteen studies did not provide sufficient information on allocation 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 laparoscopy 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.

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 hydrocortisone 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 still included in the analysis. The study by Ten Broek 2012 was "prematurely ended due to financial and organizational reasons. During the conduct of the study, the clinical trial insurance unexpectedly required a separate fee for both laparoscopic procedures in each patient"; 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); 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 removed 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: dextran 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
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 compared 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 treatment; 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.

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 considered 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 antiadhesion 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 not. Lundorff 2005 (Oxiplex/AP gel) found a significant difference 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 participants, 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.

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

Lundorff 2001 reported a lower adhesion score at SLL in participants 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)

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 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.

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 studies, 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.

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 dexamethasone vs no steroids; Rock 1984: intraperitoneal hydrocortisone 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 participants, 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 participants, 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 participants, 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.

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 received 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.

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 antiadhesion agents; however new evidence has come to light since the publication of these studies that led to the withdrawal of Intergel.

Discussion

Summary of main results

Pelvic pain as an outcome was reported by one study evaluating a hydroflotation agent that reported no evidence of an effect. No evidence suggested that any agent significantly affected live birth rate. Hydroflotation agents and gel agents (including those containing 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 lowered the mean adhesion score and led to fewer participants with a worse adhesion score. When gel and hydroflotation agents were compared, participants receiving a gel were less likely to have adhesions present and had a lower mean adhesion score. Noxytioline, heparin and promethazine were found to have no significant effect on adhesion formation, apart from steroids, which were found to decrease the likelihood of worsening in adhesion score (compared with no treatment or placebo). No evidence was found of a higher rate of clinical pregnancy, miscarriage or ectopic pregnancy for any of the interventions. According to one study, steroids improved the adhesion score, but no other agents improved the adhesion score. Quality of life outcomes were not reported. The fluid and pharmacological agents examined in this review appeared to be safe; investigators in all included studies apart from one stated that they were going to assess serious adverse outcomes that may be due to these agents, and none were reported. Several studies could not be included in the meta-analysis but were included within the review; the findings of these studies were broadly consistent with the findings of our meta-analyses.

Overall completeness and applicability of evidence

Adhesion formation is a complex process that is affected by many factors. The ongoing pathological process, the magnitude of surgical insult, infection and haemostasis after surgery may influence the formation of adhesions after surgery. The studies used in this review included heterogeneous participants with diverse gynaecological pathology who were undergoing both minimal access procedures and open surgery. In addition, some studies looked at adhesion prophylaxis as a primary prevention of de novo adhesions after surgery, whilst others looked at secondary prevention after 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 too few studies discriminated between the different types of adhesions.

Only one study explored pelvic pain. It is important to note that although a causal relationship has been established between adhesions and infertility (or bowel obstruction), the correlation between adhesions and pelvic pain is uncertain (Hammoud 2004).

Five studies recorded live birth rate, although these were mainly the earlier studies, conducted in 1984, 1985 and 2003.

A gap in knowledge has been noted regarding the effects that antiadhesion agents have on quality of life, as no studies were found that examined this.

Studies included in this review were performed in Europe, Australia, USA, Canada and Columbia. These results are thought to be applicable to developed countries.

Quality of the evidence

The quality of the evidence was assessed using the GRADE approach. Quality 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.

Only one of the included studies was considered to have a high risk of bias (Mettler 2008) regarding both performance and detection bias. Pilot studies were included, and although eight studies performed a power calculation, most studies were not statistically powered to detect differences between treatments, although this fact would not have affected internal validity. The results of a number of studies could not be included because of the way researchers assessed adhesions. Study authors were contacted for complete results so they could be included in the meta-analyses, but from most, no reply was received. Despite the fact that the American Fertility Society developed a scoring system and advised that it be used in trials, this was not the case, and the SMD had to be used or, as mentioned, results could not be used. The review 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 outcomes investigated regarding measurement of adhesions to allow maximum study inclusion. Additionally, and unfortunately, several studies could not be included in the meta-analysis because statistical data were reported incompletely, thus limiting our meta-analysis. Additionally, the wide variety of methods used to measure adhesions meant that some studies could not be included in the meta-analysis.

Jansen 1990 was included in the previous version, and the same data have been used in this review. Results were obtained from the study author, but little information was available on the characteristics of the study; therefore these results should also be interpreted with caution.

Potential biases in the review process

The review authors made every effort to identify all studies that should be considered for inclusion. Since the time of the previous review, the necessary detail required for inclusion in Cochrane reviews has increased substantially. Although the previously included studies were all reassessed for bias, some information was required from the study authors themselves. We attempted to contact them but to no avail.

Agreements and disagreements with other studies or reviews

A systematic review with meta-analysis of the efficacy of auto-cross-linked hyaluronan gel for adhesion prevention in laparoscopy and hysteroscopy was identified. It concluded that the gel prevented both intraperitoneal adhesions after laparoscopic myomectomy and intrauterine adhesions after hysteroscopic surgery (Mais 2012). A Cochrane review analysing adhesion prevention after non-gynaecological abdominal surgery (Kumar 2009) included a single study (Tang 2006) looking at fluid and pharmacological agents. In this study, participants underwent surgery in which the gastrointestinal tract was opened. An unacceptably higher rate of postoperative complications was reported for participants receiving 0.5% ferric hyaluronate gel. Recruitment was suspended and efficacy was not assessed. Both the Society of Obstetricians and Gynaecologists of Canada and the American Society of Reproductive Medicine Practice Committee have published documents stating that evidence of efficacy for fluid or pharmacological agents was insufficient (ASRM 2008; Robertson 2010). The Anti-Adhesions in Gynaecology Expert Panel for the European Society for Gynaecological Endoscopy has published guidelines to encourage the adoption of adhesion reduction strategies, advising consideration of agents with data supporting safety and efficacy (De Wilde 2012). The same panel published a consensus position that is consistent with the conclusion of our review that evidence for pharmacological agents is lacking, with gels and 4% icodextrin showing efficacy in reducing adhesions (De Wilde 2007).

Authors' conclusions

Implications for practice

Overall, hydroflotation and gel agents appear beneficial in reducing adhesion formation after gynaecological surgery, compared with no treatment. However, a large gap in evidence has been identified regarding actual effects on clinical outcomes, which are more important to patients than the extent of their adhesions.

Implications for research

Studies evaluating antiadhesion agents should report outcomes in a uniform way, using the mAFS. The statistics should be reported in full, as is good practice. The effects that adhesion prevention agents and adhesions themselves have on pelvic pain, live birth rate and quality of life should be explored in greater detail. Knowledge regarding the effects that different adhesion prevention strategies have on various patient subgroups (e.g. patients with and without active endometriosis or PID) and differences noted between de novo and re-formed adhesions is also required. The longer-term effects regarding outcomes such as small bowel obstruction should be evaluated.

Acknowledgements

The review authors would like to thank Richard Lilford and Patrick Vanderkerchove, who were co-authors of the original review. We also acknowledge Marian Showell and Helen Nagels for assistance provided with this review. In addition, the review authors thank Dr Jansen for information and data previously supplied with respect to the included study of Jansen 1985.

Data and analyses

Download statistical data

Comparison 1. Hydroflotation agent vs no hydroflotation agent
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Improvement in pelvic pain at second-look laparoscopy1 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
2 Live birth rate2208Odds Ratio (M-H, Fixed, 95% CI)0.67 [0.29, 1.58]
3 Improvement in adhesion score at SLL4665Odds Ratio (M-H, Random, 95% CI)1.27 [0.79, 2.05]
4 Number of participants with worsening adhesion score153Odds Ratio (M-H, Fixed, 95% CI)0.28 [0.07, 1.21]
5 Number of participants with adhesions at second-look laparoscopy4566Odds Ratio (M-H, Fixed, 95% CI)0.34 [0.22, 0.55]
6 Mean adhesion score at second-look laparoscopy4722Std. Mean Difference (IV, Random, 95% CI)-0.06 [-0.20, 0.09]
7 Clinical pregnancy rate3310Odds Ratio (M-H, Fixed, 95% CI)0.64 [0.36, 1.14]
9 Ectopic pregnancy rate (per pregnancy)250Odds Ratio (M-H, Fixed, 95% CI)0.35 [0.06, 1.85]
Analysis 1.1.

Comparison 1 Hydroflotation agent vs no hydroflotation agent, Outcome 1 Improvement in pelvic pain at second-look laparoscopy.

Analysis 1.2.

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

Analysis 1.3.

Comparison 1 Hydroflotation agent vs no hydroflotation agent, Outcome 3 Improvement in adhesion score at SLL.

Analysis 1.4.

Comparison 1 Hydroflotation agent vs no hydroflotation agent, Outcome 4 Number of participants with worsening adhesion score.

Analysis 1.5.

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

Analysis 1.6.

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

Analysis 1.7.

Comparison 1 Hydroflotation agent vs no hydroflotation agent, Outcome 7 Clinical pregnancy rate.

Analysis 1.9.

Comparison 1 Hydroflotation agent vs no hydroflotation agent, Outcome 9 Ectopic pregnancy rate (per pregnancy).

Comparison 2. Gel agent vs no treatment
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Proportion of sites with adhesions at SLL  Other dataNo numeric data
2 Mean change from baseline adhesion score at SLL  Other dataNo numeric data
3 Number of participants with improvement in adhesion score258Odds Ratio (M-H, Fixed, 95% CI)3.78 [0.61, 23.32]
4 Number of participants with worsening adhesion score258Odds Ratio (M-H, Fixed, 95% CI)0.16 [0.04, 0.57]
5 Number of participants with adhesions at second-look laparoscopy4134Odds Ratio (M-H, Fixed, 95% CI)0.25 [0.11, 0.56]
6 Mean adhesion score at second-look laparoscopy258Std. Mean Difference (IV, Fixed, 95% CI)-0.13 [-0.65, 0.39]
7 Decrease in mean adnexal adhesion score  Other dataNo numeric data
8 Recurrence of adhesions at SLL  Other dataNo numeric data

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
StudyProportion in study groupSDnumber of participantsProportion in control groupSDnumber of participants
Thornton 19980.3640.280130.6290.16810

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
StudyMean change in hydrogel groupSDnumber of participantsMean change in control groupSDnumber of participants
Mettler 20080.8-2.0482.6-2.223
Analysis 2.3.

Comparison 2 Gel agent vs no treatment, Outcome 3 Number of participants with improvement in adhesion score.

Analysis 2.4.

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

Analysis 2.5.

Comparison 2 Gel agent vs no treatment, Outcome 5 Number of participants with adhesions at second-look laparoscopy.

Analysis 2.6.

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

Analysis 2.7.

Comparison 2 Gel agent vs no treatment, Outcome 7 Decrease in mean adnexal adhesion score.

Decrease in mean adnexal adhesion score
StudyDecrease in mean adnexal adhesion score in oxiplex groupnumber of participantsDecrease in mean adnexal adhesion score in control groupnumber of particpants
Lundorff 20052.845-7.041

Analysis 2.8.

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

Recurrence of adhesions at SLL
StudyRecurrence at SLL NOCC groupNumber of participantsRecurrence at SLL control groupnumber of participants
Diamond 20030.61170.3817
Comparison 3. Gel agent vs hydroflotation agent when used as an instillant
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
3 Number of participants with improvement in adhesion score2342Odds Ratio (M-H, Fixed, 95% CI)1.55 [0.82, 2.92]
4 Number of participants with worsening adhesion score2342Odds Ratio (M-H, Fixed, 95% CI)0.28 [0.12, 0.66]
5 Number of participants with adhesions at second-look laparoscopy2342Odds Ratio (M-H, Fixed, 95% CI)0.36 [0.19, 0.67]
6 Mean adhesion score at second-look laparoscopy177Mean Difference (IV, Fixed, 95% CI)-0.79 [-0.79, -0.79]
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.

Analysis 3.4.

Comparison 3 Gel agent vs hydroflotation agent when used as an instillant, Outcome 4 Number of participants with worsening adhesion score.

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.

Analysis 3.6.

Comparison 3 Gel agent vs hydroflotation agent when used as an instillant, Outcome 6 Mean adhesion score at second-look laparoscopy.

Comparison 4. Steroid (any route) vs no steroid
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
2 Live birth rate2223Odds Ratio (M-H, Fixed, 95% CI)0.65 [0.26, 1.62]
3 Number of participants with improvement in adhesion score175Odds Ratio (M-H, Fixed, 95% CI)4.83 [1.71, 13.65]
4 Number of participants with worsening adhesion score2182Odds Ratio (M-H, Random, 95% CI)0.27 [0.12, 0.58]
7 Clinical pregnancy rate3410Odds Ratio (M-H, Fixed, 95% CI)1.01 [0.66, 1.55]
9 Ectopic pregnancy rate (per pregnancy)383Odds Ratio (M-H, Random, 95% CI)0.67 [0.08, 5.70]
Analysis 4.2.

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

Analysis 4.3.

Comparison 4 Steroid (any route) vs no steroid, Outcome 3 Number of participants with improvement in adhesion score.

Analysis 4.4.

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

Analysis 4.7.

Comparison 4 Steroid (any route) vs no steroid, Outcome 7 Clinical pregnancy rate.

Analysis 4.9.

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

Comparison 5. Intraperitoneal noxytioline vs no treatment
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
4 Number of participants with worsening adhesion score187Odds Ratio (M-H, Fixed, 95% CI)0.55 [0.17, 1.76]
7 Clinical pregnancy rate1126Odds Ratio (M-H, Fixed, 95% CI)0.66 [0.30, 1.47]
9 Ectopic pregnancy rate (per pregnancy)133Odds Ratio (M-H, Fixed, 95% CI)4.91 [0.45, 53.27]
Analysis 5.4.

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

Analysis 5.7.

Comparison 5 Intraperitoneal noxytioline vs no treatment, Outcome 7 Clinical pregnancy rate.

Analysis 5.9.

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

Comparison 6. Intraperitoneal heparin solution vs no intraperitoneal heparin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
3 Number of participants with improvement in adhesion score163Odds Ratio (M-H, Fixed, 95% CI)0.87 [0.32, 2.35]
4 Number of participants with worsening adhesion score192Odds Ratio (M-H, Fixed, 95% CI)1.27 [0.56, 2.91]
Analysis 6.3.

Comparison 6 Intraperitoneal heparin solution vs no intraperitoneal heparin, Outcome 3 Number of participants with improvement in adhesion score.

Analysis 6.4.

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

Comparison 7. Systemic promethazine vs no promethazine
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
3 Number of participants with improvement in adhesion score175Odds Ratio (M-H, Fixed, 95% CI)0.56 [0.22, 1.43]
4 Number of participants with worsening adhesion score193Odds Ratio (M-H, Fixed, 95% CI)0.59 [0.25, 1.42]
Analysis 7.3.

Comparison 7 Systemic promethazine vs no promethazine, Outcome 3 Number of participants with improvement in adhesion score.

Analysis 7.4.

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

Comparison 8. GnRH analogue vs no treatment/ placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Area of adhesions (cm2)  Other dataNo numeric data

Analysis 8.1.

Comparison 8 GnRH analogue vs no treatment/ placebo, Outcome 1 Area of adhesions (cm2).

Area of adhesions (cm2)
StudyArea of adhesions at first surgery GNRHa (cm2)Area of adhesions at SLL GNRHanumber of participantsArea of adhesions at first surgery in control groupArea of adhesions at SLL in cotnrol groupNumber of participants
Coddington 20090.4 (0.1)10.7 (2.2)100.4 (0.1)9.2 (3.8)8
Comparison 9. Plasminogen activator vs control
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of adhesions at SLL (score)  Other dataNo numeric data

Analysis 9.1.

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

Incidence of adhesions at SLL (score)
StudyMean incidence score in treatment groupSDNumber of participantsMean incidence score in control groupSDNumber of participants
Hellebrekers 20091.82.2111.51.714

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$.tw. (7315)
17 exp Tissue Adhesions/ (9668)
18 Adhesion$.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)

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$).tw. (22665)
39 (ovar$ 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)

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)
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)
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"

What's new

DateEventDescription
8 April 2014New citation required and conclusions have changedThis 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 2014New search has been performedThis review has been updated.

History

DateEventDescription
7 November 2008AmendedConverted to new review format.
13 January 2006New citation required and conclusions have changedSubstantive amendment

Contributions of authors

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.

Declarations of interest

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.

Differences between protocol and review

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.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Adhesion SG 1983

MethodsTruly 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
ParticipantsInfertility patients undergoing open pelvic surgery (macrosurgery 53, loupe magnification 32, microsurgery 17)
Condition: pelvic inflammatory disease with distal tubal disease (42), endometriosis (14), pelvic adhesions (46)
Surgery performed: adhesiolysis, tubal surgery
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
InterventionsDextran 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
Postoperative infection rate

NotesAdhesion 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskInsufficient information to permit judgement. "Patients were randomly assigned to either treatment"
Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskInsufficient information to permit judgement. "Blinded"
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information to permit judgement. "Blinded"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskExclusion criteria for randomisation; number of participants randomly assigned not stated. All participants who underwent treatment were accounted for
Selective reporting (reporting bias)Low riskData were presented in full and as stated in the methods section regarding outcomes
Other biasLow riskNo others

Brown 2007

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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Treatment was randomised by computer-generated randomisation on a 1:1 basis"
Allocation concealment (selection bias)Unclear riskAllocation concealment not commented upon
Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Patient number[s] were allocated to treatment group before labelling of the blinded 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 bias)
All outcomes
Unclear risk"The first three patients’ videos recorded by each investigator were assessed by a single, 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)
All outcomes
Low risk

"449 patients were randomised and received 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, leaving 402 patients in the PP population"

Selective reporting (reporting bias)Low riskNo reporting issues identified
Other biasLow 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)

NotesReceived funding from TAP Pharmaceuticals
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskInsufficient information to allow judgement
Allocation concealment (selection bias)Unclear riskInsufficient information to allow judgement
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskInsufficient information to allow judgement
Blinding of outcome assessment (detection bias)
All outcomes
Low risk"The same senior surgeon performed all adhesion scoring and was blinded to the treatment group of the patients. All procedures were videotaped and measurements confirmed by an external reviewer"
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo outcome data missing
Selective reporting (reporting bias)Low riskNo reporting issues identified
Other biasLow risk 

Diamond 1998

MethodsTrue randomisation (randomisation list)
Time of randomisation: preoperative
Multi-centre study: 23 centres in USA
Power calculation: no
Double-blinding: yes
ParticipantsFemales 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
InterventionsSepraCoat 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

NotesAdhesion scoring system used: own system
0 = no adhesions
1 = up to 25%
2 = 26%-50%
3 = more than 50%
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Before their initial procedure, patients at each centre were assigned randomly according 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 (performance bias)
All outcomes
Low risk"Patients were assigned a number that corresponded to an identically numbered set of 2500ml bottles of blinded solution"
Blinding of outcome assessment (detection bias)
All outcomes
Low risk"A videotape recording of the abdominopelvic cavity was made at this time [of second-look laparoscopy]; the video was reviewed later by a blinded, independent reviewer"
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskData were presented in full and as stated in the methods section regarding outcomes
Other biasLow riskSponsored 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

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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskStates: was randomised "just before closure" but method not described
Allocation concealment (selection bias)Unclear riskAllocation concealment not commented on
Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Reviewer-blinded"
Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Each surgical procedure was videotaped in its entirety. After editing to remove application of the test or study agent, the video of each procedure was reviewed by an evaluator who was blinded to group assignment. The reviewer applied the same scoring system as the surgeons"
Incomplete outcome data (attrition bias)
All outcomes
Low risk"All but 1 woman in the NOCC group underwent SLL; this patient developed a reaction that was subsequently attributed to her pre-existing rheumatoid arthritis. A videotape was not made for one participant in the control group and thus was not available for blinded review"
Selective reporting (reporting bias)Low riskNo reporting issues identified, although total adhesion score not used
Other biasLow riskFunded by Chitogenetics. Significant baseline differences between control and treatment groups—co-variate analysis used

diZerega 2002

MethodsTrue randomisation (randomisation list)
Pilot study; therefore no power calculation was performed
Multi-centre: 5 centres in USA
Blinding: assessor blind
ParticipantsAdult 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) and 32 years for control group (range 18-50)
Number eligible: 62
Number undergoing second-look laparoscopy: 53
InterventionsIcodextrin 4% vs Ringer's lactated saline
Timing second-look laparoscopy: 6-12 months
OutcomesAnalysed 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
NotesAdhesion scoring system used
Modified American Fertility Society endometriosis scoring system
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Each patient was assigned the next available study number which was pre-allocated to treatment according to a randomization list"
Allocation concealment (selection bias)Low riskSealed treatment codes provided to centres by the supplier of the investigational product
Blinding of participants and personnel (performance bias)
All outcomes
Low riskOpen label (assessor blinded)
Blinding of outcome assessment (detection bias)
All outcomes
Low riskThird party–blinded videotape review of adhesions at initial and second surgeries
Incomplete outcome data (attrition bias)
All outcomes
Low risk4 withdrawn because of major protocol violation after initial surgery. 1 participant did not return for second surgery. 4 further protocol violators withdrawn (1 because study device was not being used correctly, 3 because of adhesions at more than 50% of sites. 53 of 62 included in per-protocol analysis
Selective reporting (reporting bias)Low riskNo reporting issues identified
Other biasLow 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

InterventionsOxiplex/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

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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskStates: was randomised, method not stated
Allocation concealment (selection bias)Unclear riskAllocation concealment method not stated
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot stated
Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Videos of both procedures were scored by a reviewer masked to treatment assignment"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNumber of participants/adnexae analysed not stated, only number randomly assigned
Selective reporting (reporting bias)Low riskNo reporting issues identified
Other biasLow riskSponsored 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

InterventionsSepraSpray 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

NotesFunded by Genzyme
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo comment on randomisation method
Allocation concealment (selection bias)Unclear riskNo comment on allocation concealment
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskInsufficient information to provide judgement
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinded videotaped assessment of mAFS
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo issues identified
Selective reporting (reporting bias)Low riskNo issues identified
Other biasLow 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 regularly, 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

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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomisation
Allocation concealment (selection bias)Unclear riskNo comments regarding allocation concealment—insufficient information to allow judgement
Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Same two gynaecologists performed the second-look laparoscopy and were blinded to the randomisation during both surgical procedures"
Blinding of outcome assessment (detection bias)
All outcomes
Low risk"The surgeon calculated adhesion scores immediately after surgery. Photographs 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"
Incomplete outcome data (attrition bias)
All outcomes
Low risk1 participant refused consent for second-look laparoscopy. No other missing outcome data
Selective reporting (reporting bias)Low riskNo reporting issues identified
Other biasLow risk 

Jansen 1985

MethodsTruly 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

Interventions1. 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
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

NotesAdhesion scoring system used
Modified American Fertility Society endometriosis scoring system (range 0-27)
Results expressed as medians with 95% confidence limits
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Randomization sequences were generated by a random number-generation program, and assignment of adjuncts was carried out strictly in the pre-determined sequence. Two separate randomisations were carried out independently"—1 for dextran or no dextran, and 1 for steroids or no steroids
Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement
Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk"Although completely effective blinding in the allocation of the adjuncts was not practicable (owing to the viscous nature of the dextran solution and the need to administer systemic corticosteroids to some 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 bias)
All outcomes
Low risk"Qualification of adhesions was carried out from operation diagrams at a later date, without knowledge of the patient's identity or the use of an adjunct"
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants accounted for, no missing outcome data
Selective reporting (reporting bias)Low riskData were presented in full and as stated in the methods section regarding outcomes
Other biasLow riskNone detected

Jansen 1988

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

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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Strictly in a pre-determined random sequence"
Allocation concealment (selection bias)Unclear riskInsufficient information available to permit judgement
Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Although completely effective blinding in heparin use was not practicable, owing to its obvious anticoagulant effect during the operation, information on its allocation was not recorded in the operation notes and was not available at the time of postoperative laparoscopy"
Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Improvement scores were derived later, without knowledge of the identity of the patient, or the use of heparin"
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskData were presented in full and as stated in the methods section regarding outcomes
Other biasUnclear riskThe 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

Jansen 1990

MethodsTruly randomised trial (random number sequence)
Timing of randomisation: not stated
Factorial design
Power calculation: yes
Location: Sydney, Australia
Timing and duration: not stated
ParticipantsInfertility 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
Interventions1. 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskStates: was randomised, but method not stated
Allocation concealment (selection bias)Unclear riskNot stated
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot stated
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot stated
Selective reporting (reporting bias)Unclear riskNot stated
Other biasUnclear riskInsufficient information to make any judgement

Johns 2001

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

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"At the time of initial surgical procedure, patients were assigned the next available study number corresponding to study device or control solution as determined by the randomization schedule"
Allocation concealment (selection bias)Low riskStudy device or control solution was maintained in a sealed carton until decision to enroll the participant was made
Blinding of participants and personnel (performance bias)
All outcomes
Low riskTwo methods: "In the first method, the study device or control solution was administered 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 bias)
All outcomes
Low riskBlinded independent review of adhesion data as a quality assurance check
Incomplete outcome data (attrition bias)
All outcomes
Low risk281 randomly assigned participants receiving treatment—a total of 265 completed the study. "Of the 16 patient[s] who did not return for laparoscopy, 9 patients discontinued for reasons unrelated to treatment. Although 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 riskNo reporting issues identified
Other biasLow risk 

Larsson 1985

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

ParticipantsInfertility 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 specified) and laparoscopy; some also had hysterosalpingogram and/or sperm-mucus penetration 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
InterventionsDextran 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

NotesAdhesion 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
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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Random selection sequence"
Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement
Blinding of participants and personnel (performance bias)
All outcomes
Low riskStates: was "double-blinded," although no further information given
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskStates: was "double-blinded," although no further information given. No mention of an independent reviewer or blinding during assessment
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskData were presented in full and as stated in the methods section regarding outcomes
Other biasLow risk 

Lundorff 2001

MethodsRandomised trial (computer-generated schedule)
Third party–blind
Multi-centre: 5 European centres
Time of randomisation: at the time of the procedure
Power calculation: no
Participants14 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
InterventionsIntergel vs lactated Ringer's
Route of administration: intraperitoneal
Dosage/volume: 300 mL of Intergel or Ringer's lactate
Prophylactic antibiotics: no
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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"At the time of initial surgical procedure, patients were assigned the next available study number corresponding to study device or control solution as determined by the randomization schedule"
Allocation concealment (selection bias)Low riskStudy device or control solution was maintained in a sealed carton until decision to enroll the participant was made
Blinding of participants and personnel (performance bias)
All outcomes
Low risk

Two methods: "In the first method, the study device or control solution was administered 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"

Blinded independent review of adhesion data as a quality assurance check

Blinding of outcome assessment (detection bias)
All outcomes
Low riskThird party–blinded review of videotaped second laparoscopy to determine outcome data
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk77 participants completed study. No comment on total number randomly assigned
Selective reporting (reporting bias)Low riskNo reporting issues identified
Other biasLow 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

InterventionsOxiplex/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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Randomisation schedule" was used
Allocation concealment (selection bias)Unclear riskNot stated
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot stated
Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk"The entire procedure was recorded on videotape...blinded reviews to the videotapes were performed to quantify adhesion scores"
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll 86 adnexae that were enrolled were analysed
Selective reporting (reporting bias)Low riskNo selective reporting issues identified
Other biasLow riskFunded 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, insufficient intraoperative haemostasis

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

NotesOperative Laparoscopy Study Group scoring system used
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Computer generated 1:1 random allocation sequence"
Allocation concealment (selection bias)Low risk"Concealed in numbered sealed envelopes until interventions assigned"
Blinding of participants and personnel (performance bias)
All outcomes
Low riskOLSG scoring at initial surgery was performed before assignment
Blinding of outcome assessment (detection bias)
All outcomes
Low risk"The surgeon performing the second look laparoscopy was unaware of the assignment of the patients to the different study groups"
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk"Of 52 patients, five in Hyalobarrier gel group and four in control group...declined to undergo second-look laparoscopy...for personal reasons"
Selective reporting (reporting bias)Low riskNo reporting issues identified
Other biasLow risk 

Mettler 2004

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

InterventionsSprayGel 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

NotesAdhesion scoring system used
Mean adhesion tenacity score
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Computer-generated randomization 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 (performance bias)
All outcomes
Unclear riskInsufficient information to permit judgement
Blinding of outcome assessment (detection bias)
All outcomes
Low risk"The surgeon was blinded to the randomization"; no mention is made of an independent/blinded reviewer at SLL
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskData were presented in full and as stated in the methods section regarding outcomes
Other biasLow riskFunded 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

ParticipantsFemales 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskTreatment assignments had been randomly generated from a list of sequential numbers before first participant was enrolled
Allocation concealment (selection bias)Low riskSealed envelope technique
Blinding of participants and personnel (performance bias)
All outcomes
High riskSingle-blind study: "While study personnel were aware of the treatment assignation, study patients were not told which treatment they had received until after they terminated the study"
Blinding of outcome assessment (detection bias)
All outcomes
High riskParticipants returned for second-look laparoscopy at 6-8 weeks—study personnel appear not to have been blinded at this outcome assessment
Incomplete outcome data (attrition bias)
All outcomes
Low risk"Ten hydrogel and 3 control patients 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 biasLow risk 

Pellicano 2003

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

InterventionsAuto-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

NotesScoring system not used, only rate of presence or absence of adhesions
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated random list
Allocation concealment (selection bias)Unclear riskNo reference to allocation concealment in article
Blinding of participants and personnel (performance bias)
All outcomes
Low riskNo reference to blinding in article, although study author contacted and confirmed double-blinding
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficent information to permit judgement
Incomplete outcome data (attrition bias)
All outcomes
Low risk36 participants enrolled; all evaluated by second-look laparoscopy
Selective reporting (reporting bias)Low riskNo reporting issues identified
Other biasLow risk 

Querleu 1989

MethodsTruly 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
ParticipantsInfertility 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
InterventionsAuto-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 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated
Allocation concealment (selection bias)Unclear riskNot stated
Blinding of participants and personnel (performance bias)
All outcomes
Low riskWas double-blinded according to the study author
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficent information to permit judgement
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants accounted for
Selective reporting (reporting bias)Low riskNo reporting issues identified
Other biasLow riskDid not recruit enough participants to power study as intended

Rock 1984

MethodsRandomised 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
ParticipantsInfertility 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
InterventionsSteroids 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
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

Notes3-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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"A card drawn from a previously randomised deck"
Allocation concealment (selection bias)Unclear riskInsufficent information to permit judgement
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskInsufficent information to permit judgement
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficent information to permit judgement
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskData were presented in full and as stated in the methods section regarding outcomes
Other biasLow riskNone

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

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

InterventionsAbdominal 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

NotesAdhesions not assessed in this paper
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"The assignment was randomised using a random number table"
Allocation concealment (selection bias)Unclear riskNot enough information to allow judgement
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot enough information to allow judgement
Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Patients were not informed of what substance had been added to their abdominal cavities"
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo issues identified
Selective reporting (reporting bias)Low riskNo issues identified
Other biasLow risk 

Rosenberg 1984

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

NotesStandard deviations not reported
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo comment in published text on generation of sequence
Allocation concealment (selection bias)Low risk"Randomized code assigned by institution's research pharmacist..two hundred millilitres 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 (performance bias)
All outcomes
Low risk"Primary surgeon left the table and the test substance was instilled into the peritoneal cavity by the first assistant"
Blinding of outcome assessment (detection bias)
All outcomes
Low risk"All patients were scheduled for follow up laparoscopy by the original surgeon...adhesion scores were reassigned"
Incomplete outcome data (attrition bias)
All outcomes
High riskNo SDs or SEMs given
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 biasLow 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 vaporisation of endometriosis, ovarian cystectomy or oophorectomy (n = 13)

No exclusion criteria stated

InterventionsIntra-abdominal instillation of dextran 70 250 mL, lactated Ringer's solution 250 mL or no fluid following primary surgery
OutcomesVolume of fluid on transvaginal ultrasound scan at 1 hour, 3 hours, 6 hours, 24 hours, 96 hours and 168 hours
NotesAdhesions not assessed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number table
Allocation concealment (selection bias)Unclear riskNot enough information to provide judgement
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot enough information to provide judgement
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot enough information to provide judgement
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo issues identified
Selective reporting (reporting bias)Low riskNo issues identified
Other biasLow 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Patients were randomly assigned—via shuffled sealed envelopes—to treatment"
Allocation concealment (selection bias)Low risk"Sealed envelopes"
Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Single-blinded (patient)"
Blinding of outcome assessment (detection bias)
All outcomes
Low riskNo mention of an independent/blinded reviewer, but surgeons unaware of randomisation until end of initial surgery, and surgeons were blinded at SLL.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskData were presented in full and as stated in the methods section regarding outcomes
Other biasUnclear 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 unexpectedly 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 malignancy; 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

Interventions0.5% 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Randomisation schedule"
Allocation concealment (selection bias)Unclear riskNot stated
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot stated
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
High riskNo SDs or SEMs given
Selective reporting (reporting bias)Unclear riskNo selective reporting issues noted
Other biasLow risk 

Trew 2011

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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Treatment was randomised through a 24-h central randomization telephone system"
Allocation concealment (selection bias)Low risk"Double-blinding was possible as both fluids are clear and odourless solutions with similar viscosities and were packaged identically"
Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Double-blinding was possible as both fluids are clear and odourless solutions with similar viscosities and were packaged identically"
Blinding of outcome assessment (detection bias)
All outcomes
Low risk"The surgery was video recorded according to a detailed protocol to enable all assessments 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)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskData were presented in full and as stated in the methods section regarding outcomes
Other biasLow riskFunded 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

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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo comment on method of sequence generation
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 (performance bias)
All outcomes
Low risk"Selection of group assignment was random and not available to the investigator until all inclusion and exclusion criteria were met, including those determined by surgery"
Blinding of outcome assessment (detection bias)
All outcomes
Low risk"All surgeries were recorded and the videotapes were forwarded to a single masked reviewer to assess"
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll 28 participants randomly assigned were evaluated by second-look laparoscopy. No issues identified
Selective reporting (reporting bias)Low riskNo reporting issues identified
Other biasLow riskData reported in terms of adnexae rather than individual participants

Characteristics of excluded studies [ordered by study ID]

StudyReason 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 2003Adhesions were assessed at caesarean section; not as thorough as at second-look laparoscopy
Johns 2003Used 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 1967Quasi-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

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

InterventionsPretreatment with gonadotrophin-releasing hormone agonist (GnRHa) before myomectomy vs no GnRHa
OutcomesIntraoperative blood loss, duration of surgery, length of hospital stay, preoperative and postoperative complications, final result by second-look laparoscopy (SLL), including adhesions
NotesNeed 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

ParticipantsWomen 23-42 years of age undergoing laparoscopic myomectomy using the Harmonic Ace to improve fertility
InterventionsCross-linked hyaluronic acid applied to myometrial scar vs Ringer's lactate
OutcomesIncidence of adhesions, site-specific
NotesOnly in abstract form at present time

Tchartchian 2009

  1. a

    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.

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

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

InterventionsSprayShield vs no treatment
OutcomesAmerican 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