European Journal of Obstetrics & Gynecology and Reproductive Biology
Volume 160, Issue 1 , Pages 1-5, January 2012

Efficacy of auto-crosslinked hyaluronan gel for adhesion prevention in laparoscopy and hysteroscopy: a systematic review and meta-analysis of randomized controlled trials

  • Valerio Mais

      Affiliations

    • Division of Gynaecology, Obstetrics and Pathophysiology of Human Reproduction, Department of Surgery, Maternal–Fetal Medicine and Imaging, University of Cagliari, 09124 Cagliari, Italy
    • Corresponding Author InformationCorresponding author at: Division of Gynecology, Obstetrics and Pathophysiology of Human Reproduction, Department of Surgery, Maternal–Fetal Medicine and Imaging, University of Cagliari, Ospedale S. Giovanni di Dio, Via Ospedale 46, 09124 Cagliari, Italy. Tel.: +39 070652797; fax: +39 070668575.
    • ,
  • Maria G. Cirronis

      Affiliations

    • Division of Gynaecology, Obstetrics and Pathophysiology of Human Reproduction, Department of Surgery, Maternal–Fetal Medicine and Imaging, University of Cagliari, 09124 Cagliari, Italy
    • ,
  • Michele Peiretti

      Affiliations

    • Division of Gynaecology, European Institute of Oncology, 20141 Milano, Italy
    • ,
  • Giuliano Ferrucci

      Affiliations

    • Informa S.r.l., 00154 Roma, Italy
    • ,
  • Ester Cossu

      Affiliations

    • Division of Gynaecology, Obstetrics and Pathophysiology of Human Reproduction, Department of Surgery, Maternal–Fetal Medicine and Imaging, University of Cagliari, 09124 Cagliari, Italy
    • ,
  • Gian B. Melis

      Affiliations

    • Division of Gynaecology, Obstetrics and Pathophysiology of Human Reproduction, Department of Surgery, Maternal–Fetal Medicine and Imaging, University of Cagliari, 09124 Cagliari, Italy

Received 3 March 2011; received in revised form 12 July 2011; accepted 31 August 2011. published online 15 September 2011.

Article Outline

Abstract 

Prevention of postoperative adhesions is a clinical need. We undertook a systematic review to explore the available clinical evidence of the efficacy of auto-crosslinked hyaluronan gel for postoperative adhesion prevention following endoscopic gynecological surgery. An electronic database search of MEDLINE, Cochrane Database of Systematic Reviews and EMBASE, and a comprehensive hand-search of reference lists of published and review articles were performed. No language restrictions were applied. Randomized controlled trials (RCTs) on the use of auto-crosslinked hyaluronan gel for the prevention of postoperative adhesions in gynecological surgery were included in the meta-analysis if they reported outcomes as evaluated at a blind second-look assessment. Three authors independently selected studies and extracted data on study characteristics, quality and accuracy. The Jadad scoring system was used for validity assessment. Meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The outcome was the incidence of postoperative adhesions based on a binary response (present or not present). Only five RCTs were eligible for inclusion in the meta-analysis. The incidence of postoperative adhesions in patients who received auto-crosslinked hyaluronan gel was significantly lower than in patients who underwent standard surgery only. The gel prevented both intraperitoneal adhesions after laparoscopic myomectomy (OR 0.248, 95% CI 0.098, 0.628) and intrauterine adhesions after hysteroscopic surgery (OR 0.408, 95% CI 0.217, 0.766). Further RCTs are needed to assess the efficacy of auto-crosslinked hyaluronan gel in women undergoing different laparoscopic intra-abdominal surgical procedures.

Keywords: Hyaluronan, Gel, Adhesion prevention, Gynecological surgery

 

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1. Introduction 

The incidence of intraperitoneal postoperative adhesions ranges between 55% and 95% after abdominal or pelvic surgery [1]. More than one third of women undergoing open surgery for gynecological conditions may have from one to 20 hospital readmissions due to adhesion-related conditions over the next 10 years [2]. Intraperitoneal adhesions are a leading cause of female infertility, chronic pelvic pain, intestinal obstruction, and difficult reoperative surgery [1], [2]. Despite careful attention to minimise trauma and ensure hemostasis adhesion reformation after adhesiolysis occurs in 85% of patients [3]. Intraperitoneal adhesions adversely affect patient morbidity following either laparoscopy or laparotomy and are an important and costly burden to health systems. Inadvertent enterotomy during relaparotomies or subsequent adhesion dissection is a well-known complication of surgery after previous abdominal procedures [4].

In gynecology, surgeons have to deal not only with intraperitoneal adhesions but also with intrauterine adhesions. Any factor leading to a trauma of the endometrium may engender intrauterine bands at opposing walls of the uterus [5]. Intrauterine adhesions represent the major long-term complication of hysteroscopic surgery. They cause hypomenorrhea or amenorrhea, infertility, and recurrent pregnancy loss [5]. The outcome of hysteroscopic management of intrauterine adhesions is affected by the recurrence of adhesions and treatment of intrauterine adhesions is a challenge for practitioners in infertility [5].

In addition to careful surgical technique, a number of approaches have been proposed to prevent intraperitoneal adhesions [1]. By contrast, the use of adhesion preventive agents to reduce intrauterine adhesions has been proposed by few authors only [5].

Among the adhesion preventive agents developed in the last decades, hyaluronan (or hyaluronic acid) based products have been frequently used in different application forms. Hyaluronan based agents seem to prevent adhesions not only by producing a temporary barrier to fibrin-bridge formation but also through their biological actions. In fact, sodium hyaluronate has been reported to increase the proliferation rate of human peritoneal mesothelial cells and this is a possible mechanism of action in peritoneal tissue repair [6].

However, only one systematic review reported in the past on the efficacy of three heterogeneous hyaluronan – containing products in reducing the prevalence of intraperitoneal adhesions after gynecological surgery and three of the four randomized controlled trials (RCTs) included in that systematic review focused on laparotomic surgery [7]. Moreover, one of the three heterogeneous products included in that systematic review, ferric hyaluronate gel, was removed from the market in 2003 after major side effects were reported following its use in laparoscopic surgery and a second product, dilute hyaluronic acid solution, had no further evaluation in randomized trials after 1998 and is no longer on the market [7]. Only auto-crosslinked hyaluronan gel (Hyalobarrier®; Fidia Advanced Biopolymers and now Anika Therapeutics s.r.l., Abano Terme, Padova, Italy), is still on the market and has been considered worthy of investigation in clinical trials [8].

Auto-crosslinked hyaluronan gel is obtained through an internal auto-crosslinking reaction of pure hyaluronan without the introduction of any chemical substance foreign to the native hyaluronan structure to avoid possible side effects [9]. Many pre-clinical trials have been carried out in different gynecological surgery animal models and demonstrated the efficacy of auto-crosslinked hyaluronan gel in all these models [10], [11]. However, the literature specifically investigating the clinical use of auto-crosslinked hyaluronan gel for the prevention of postoperative adhesions in women undergoing gynecological surgery has not been thoroughly reviewed. We therefore decided to review all RCTs specifically investigating the clinical use of auto-crosslinked hyaluronan gel for preventing both intraperitoneal and intrauterine adhesions following endoscopic gynecological surgery.

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2. Materials and methods 

Following a general consensus the authors decided to perform this study in agreement with a review protocol stating the questions to be addressed and the characteristics of the studies to be used as criteria for eligibility. The protocol that preceded this systematic review is described in Sections 2.1, 2.2, 2.3, 2.4.

2.1. Search strategy 

All articles citing the use of auto-crosslinked hyaluronan gel for preventing postoperative adhesions were identified by two authors (V.M. and M.G.C.) who conducted a search limited to text words on computerized databases MEDLINE and EMBASE utilizing the keywords hyalobarrier, hyaluronic acid, hyaluronan, hyalobarrier gel, hyaluronic acid gel, hyaluronan gel, auto-crosslinked hyaluronic acid gel, autocrosslinked hyaluronic acid gel, auto crosslinked hyaluronic acid gel, auto-crosslinked hyaluronan gel, autocrosslinked hyaluronan gel, auto crosslinked hyaluronan gel, ACP gel, auto-crosslinked polysaccharide polymer gel, and adhesions. Each database was searched from its initial inclusion date to October 2010. To ensure identification of all possible relevant studies no restrictions or search filters (years considered, publication status, type of article, or language of publication) were applied to the search. To ensure identification of all possible relevant studies the same two authors (V.M. and M.G.C.) also performed a comprehensive hand-search of reference lists of published articles and review articles and asked for additional studies the authors of published articles. The authors did not check abstract books of current international conferences.

2.2. Selection criteria 

Literature review focused on clinical trials investigating the use of auto-crosslinked hyaluronan gel to prevent postoperative adhesion formation in women undergoing gynecological surgery. Review articles and abstracts were excluded from systematic review. Non-English-language articles were not specifically excluded.

Meta-analysis was performed on RCTs comparing the incidence of postoperative adhesions evaluated at a blind second-look assessment in women who underwent gynecological surgery plus application of auto-crosslinked hyaluronan gel with the incidence of postoperative adhesions in women who underwent gynecological surgery alone. Where continuous data were presented graphically the data were not considered in the meta-analysis.

Studies were excluded from the meta-analysis if it was impossible to extract the appropriate surgical second-look outcome from the published results.

2.3. Data extraction and qualitative synthesis 

Three of the authors (M.P., E.C., and G.B.M.) independently assessed the quality of all screened studies using a predefined review form (Table 1). To reduce bias, the three reviewers were blinded to the source of the publication and the authors’ names. Inconsistencies between reviewers’ data were resolved through discussion until a consensus was reached.

Table 1. Characteristics of RCTs included in qualitative synthesis.
Included studiesAcunzo et al. [16]De Iaco et al. [17]Guida et al. [19]Pellicano et al. [18]Mais et al. [8]
Randomized?YesYesYesYesYes
Multicenter?NoNoNoNoYes
Sample size (patients)84 (T=43; C=41)a40 (T=18: C=22)a132 (T=67; C=65)a36 (T=18; C=18)a43 (T=21; C=22)a
Age of patients (years; mean±SD)30.2±3.5–36.5±3.129.0±2.733.5±5.1
Treated lesionsIntrauterine adhesionsMyomas, Polyps, Septa, Intrauterine adhesionsMyomas, Polyps, SeptaMyomasMyomas
Surgery typeHysteroscopyHysteroscopyHysteroscopyLaparoscopyLaparoscopy
Second-look timing (days since first surgery)90609060–9084 - 98
Blind second-look assessment?YesYesYesYesYes
Incidence of adhesions recorded?YesYesYesYesYes
Score of adhesions recorded?YesYesYesNoYes
Adhesion score classificationAFSbModified AFSbAFSb–OLSGc
Jadad score44535

aT=treated patients; C=controls.

bAFS=American Fertility Society.

cOLSG=Operative Laparoscopy Study Group.

To assess validity the RCTs were scored for quality using the Jadad scoring system which evaluates the studies based on perfect randomization, proper blinding, and an adequate description of withdrawals and dropouts [12]. If the Jadad score of a study was ≥3 the study was considered to be of high quality.

To assess clinical heterogeneity information was collected for each trial regarding the methodology, the age of patients, the treated lesions, the surgery type, the second-look timing, and the specified outcome (Table 1).

2.4. Quantitative synthesis 

Following a general consensus the authors decided to focus on the incidence of postoperative adhesions based on a binary response (present or nor present at second-look) as the only outcome measure to be used to calculate a pooled effect size in the quantitative synthesis. This decision was motivated by the fact that all papers published about complications of intraperitoneal or intrauterine adhesions were focusing on adhesion presence but not on scores for severity and/or extent of adhesions [2], [3], [4].

The meta-analysis of RCTs was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [13]. The measure of effect was expressed as odds ratios (OR) with 95% confidence interval (CI) and was combined for meta-analysis by Mantel-Haenszel statistic [14]. The level of significance was set at p<.05.

Heterogeneity between studies was determined by χ2 test. Value of p<.1 was considered significant for detecting heterogeneity. Fixed-effects model was used unless statistical heterogeneity was significant, in which case a random-effects model was used.

The analysis of publication bias was assessed by the Duval and Tweedie trim and fill method [15].

Meta-analysis was carried out using the surgery type as moderator.

Statistical analysis was performed by using the Comprehensive Meta Analysis software, version 2 (BIOSTAT, 14 North Dean Street, Englewood, NJ 07631, USA).

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3. Results 

The process of literature identification, screening and selection (Trial Flow) is reported in Fig. 1. Six studies were RCTs [8], [16], [17], [18], [19], [20] but one [20] was excluded from meta-analysis because it was reporting a different outcome (pregnancy rate) of a previously published trial reporting as main outcome the incidence of adhesions at second-look [18]. Therefore, only five RCTs were included in the meta-analysis [8], [16], [17], [18], [19].

3.1. Qualitative synthesis 

The characteristics of the five RCTs included in qualitative synthesis are shown in Table 1. Three trials were performed in hysteroscopy and two trials in laparoscopy. No evidence of qualitative heterogeneity between studies was found. The auto-crosslinked hyaluronan gel had the same composition in all five RCTs because all five RCTs used the same product, Hyalobarrier®, indicated for endoscopic applications. The methodology used and patients included in each RCT were similar enough to warrant performing a meta-analysis. No conflict of interest was disclosed by the authors of the analyzed RCTs. All five RCTs had a Jadad score ≥3 and were included in quantitative synthesis.

Adhesions score was recorded in four RCTs (Table 1). The score classification varied widely among studies. The American Fertility Society (AFS) classification of intrauterine adhesions has 3 stages (Mild, Moderate, and Severe) based on extent of uterine cavity involvement, type of adhesions, and menstrual pattern [16], [19]. The Modified AFS classification of intrauterine adhesions has 2 stages (Mild and Severe) based on extent of uterine cavity involvement and type of adhesions [17]. Operative Laparoscopy Study Group scoring system for intraperitoneal adhesions focus on the severity of adhesions on 12 intraperitoneal sites [8]. However, all four trials reported a significant reduction of the severity of adhesions in women receiving auto-crosslinked hyaluronan gel [8], [16], [17], [19].

As far as safety is concerned, all five RCTs followed the women under study from the first surgery up to the second-look, performed two to three months later. A total of six adverse events (three in gel groups and three in control groups) were reported in the two RCTs performed in laparoscopy. In one trial two patients had nausea and one patient had vomiting in gel group and one patient had nausea in control group [8]. In the other trial two patients in control group had postoperative fever (≤38.5°C) [18]. No adverse events were reported in the three RCTs performed in hysteroscopy [16], [17], [19].

3.2. Quantitative synthesis 

The results of the analysis of the publication bias assessed on the five RCTs indicated minimal publication bias.

No evidence of significant statistical heterogeneity between studies was found (Q-value=3.865, p=.425) and the fixed-effects model was used to combine studies within each subgroup defined by surgery type.

The meta-analysis was performed on 335 women (167 women who received auto-crosslinked hyaluronan gel at the end of surgery and 168 women who underwent the same endoscopic gynecological surgery without adhesions prevention). Laparoscopy was performed in 79 women and hysteroscopy in 256 women.

Statistics from fixed-effects model revealed that the proportion of women with adhesions at second look was significantly lower in women who received auto-crosslinked hyaluronan gel than in controls undergoing endoscopic gynecological surgery alone, both in the hysteroscopic subgroup (OR=0.408; 95% CI=0.217–0.766; p=.005) and in the laparoscopic subgroup (OR=0.248; 95% CI=0.098–0.628; p=.003) (Fig. 2).

  • View full-size image.
  • Fig. 2. 

    Forest plot showing Odds Ratio for incidence of postoperative adhesions in hysteroscopic RCTs and laparoscopic RCTs comparing application of auto-crosslinked hyaluronan gel with no application (control).

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4. Comment 

The key finding of our systematic review and meta-analysis is that the application of the auto-crosslinked hyaluronan gel, Hyalobarrier®, significantly reduces the number of women with intraperitoneal adhesions after laparoscopic myomectomy and the number of women with intrauterine adhesions after hysteroscopic surgery. Therefore, auto-crosslinked hyaluronan gel seems to have the potential to address the challenging clinical need of reducing adhesion formation. In fact, the gel has been reported to be able not only to reduce the incidence of adhesions at second-look in infertile women who have undergone laparoscopic myomectomy [8], [18], but also to improve the pregnancy rate of the same women more than laparoscopic myomectomy alone [20]. This last study published by Pellicano et al. [20] on auto-crosslinked hyaluronan gel is the first RCT dealing with an adhesion preventive agent that reports pregnancy rate as primary outcome measure. Pregnancy rate was previously reported as primary outcome measure only by Sawada et al. [21] who performed a retrospective study on adhesion prevention by oxidized regenerated cellulose. Certainly, the attempt to decrease adhesions after fertility-preserving surgery mainly aims at improving reproductive outcome and future studies should focus on live birth rate as the primary outcome measure for women undergoing such surgery.

The most interesting aspect of our systematic review and meta-analysis is that auto-crosslinked hyaluronan gel is the first adhesion preventive gel barrier tested in hysteroscopy. The gel has been demonstrated to be suitable for hysteroscopic application and able to significantly reduce intrauterine adhesions following hysteroscopic surgery. Moreover, no major complications or adverse events related to the use of auto-crosslinked hyaluronan gel in hysteroscopic surgery have been reported [16], [17], [19]. Important are the clinical implications of these findings because the prevention of intrauterine adhesions has always been a challenge for practitioners in infertility and so far has never been guided by the evidence coming from a systematic review [5].

We undertook this systematic review to explore all the available clinical evidence of the efficacy of auto-crosslinked hyaluronan gel for postoperative adhesion prevention following endoscopic gynecological surgery. As with any systematic review, the reliability of the analysis depends on the possibility of publication bias. The search strategy of our systematic review was intentionally broad to reduce any potential for this bias and the trim and fill method confirmed minimal publication bias. However, all the RCTs included in the meta-analysis evaluated the incidence of adhesions at second-look after endoscopic gynecological surgery and no RCTs about the use of auto-crosslinked hyaluronan gel in open surgery were available.

Our systematic review is not the first focusing on adhesion prevention with hyaluronan based products. During the process of literature identification, screening and selection we found two papers by Metwally et al. [7], [22] reviewing the efficacy of hyaluronan fluid agents for the prevention of adhesions after gynecological surgery. However, the meta-analysis published in 2007 in Fertility and Sterility forms part of the Cochrane Review on fluid and pharmacological agents for adhesion prevention published in 2006 and the two papers report the same data and the same analysis [7], [22]. Therefore, only one review evaluated the effects of hyaluronan based fluid agents on adhesion prevention in gynecological surgery before our meta-analysis [7]. Moreover, papers included in that review were all published before November 2005, the search focused only on intraperitoneal adhesions, the majority of studies included in the meta-analysis investigated the effects of hyaluronan based products in open surgery, and these hyaluronan based products have been removed from the market [7]. By contrast, our systematic review and meta-analysis focused on the efficacy of the auto-crosslinked hyaluronan gel, namely Hyalobarrier® that is available for practitioners in infertility for postoperative adhesion prevention following endoscopic gynecological surgery.

Barriers for adhesion prevention can be divided into site-specific gels and site-specific membranes [1]. Hyalobarrier® is the only hyaluronan based site-specific gel and Seprafilm® is the only hyaluronan based site-specific membrane [1]. The use of Seprafilm® has been mainly limited to open surgery [1]. Moreover, looking up in clinical trial databases (clinicaltrials.gov.) we found that trials are focused only on the laparotomic use of Seprafilm® for prevention of adhesions at cesarean delivery, in women undergoing surgical staging and intraperitoneal chemotherapy for advanced ovarian cancer, and in patients undergoing general surgery to reduce the incidence of bowel obstruction.

To confirm that auto-crosslinked hyaluronan gel acts as anti-adhesion barrier in different surgery settings future research agenda should include RCTs investigating the use of the gel in the prevention of postoperative adhesion formation in patients undergoing different laparoscopic intra-abdominal surgical procedures like all gynecological, urologic, and general surgery procedures.

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Conflict of interest 

The Department of Surgery, Maternal–Fetal Medicine and Imaging of the University of Cagliari, Italy, received money from Fidia Advanced Biopolymers, Abano Terme, Padova, Italy, during the years 2008 and 2009 for the expert testimony activity of Professor Valerio Mais.

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Acknowledgments 

This study was supported by the University of Cagliari, Italy, through the Local Research Projects 60% for the year 2009.

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PII: S0301-2115(11)00494-5

doi:10.1016/j.ejogrb.2011.08.002

European Journal of Obstetrics & Gynecology and Reproductive Biology
Volume 160, Issue 1 , Pages 1-5, January 2012

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