The Efficacy of Hyaluronic Acid in Reducing Pelvic Adhesions in Patients Undergoing Gynecologic Laparoscopic Surgery: A Meta-Analysis of Randomized Clinical Trials.

Maryam Mazloomi: conceptualization, data curation, investigation, validation, supervision, resources, project administration, visualization, funding acquisition, writing – original draft, writing – review and editing. Arash Mohazzab: software, methodology, and formal analysis. Kobra Tahermanesh: investigation, validation, supervision, resources, project administration, visualization, writing – review and editing. Maliheh Fakehi: investigation, validation, formal analysis, writing – original draft, writing – review and editing. Maryam Saeedzarandi: investigation, validation, formal analysis, visualization, writing – review and editing, and writing – original draft. Zahra Kooshari: investigation, validation, visualization, writing – review and editing, and writing – original draft. Paria Dehesh: software, methodology, and formal analysis. Seyede Rezieh Ghaffari: conceptualization, methodology, software, data curation, supervision, resources, project administration, visualization, funding acquisition, writing – original draft, writing – review and editing.

Following the initial database screening and elimination of duplicate records, studies were shortlisted based on their relevance to the application of hyaluronic acid gel in preventing pelvic and abdominal adhesions in women undergoing gynecologic procedures. Articles that were reviews, conducted on animals, or published in languages other than English were excluded from the analysis. Additionally, studies that did not report the appropriate outcome measures were excluded from the meta‐analysis. Studies evaluating intrauterine adhesions and fertility rates as outcomes were also included in the meta‐analysis. Eligibility criteria were as follows: (1) participants underwent gynecological surgery, excluding studies focused solely on abdominal procedures; (2) hyaluronic acid gel was applied intraoperatively in the intervention group; (3) the control group underwent an identical surgical procedure without the gel; (4) clinical outcomes such as overall adhesion incidence, adhesion severity (mild, moderate, severe), or adhesion scores were reported; (5) the study design was a randomized controlled trial; and (6) the article was published in English. Review articles, meta‐analyses, observational studies, and laboratory‐based experimental studies were excluded. Meta‐analysis was performed in accordance with the guidelines outlined in the Cochrane Handbook for Systematic Reviews of Interventions [ 13 ]. The following keywords were used to search the databases PubMed, Cochrane Library, Scopus, Embase, and http://ClinicalTrials.gov from the beginning of the database up to July 2023: hyalobarrier, hyaluronic acid, hyaluronan, hyaluronic acid gel, hyaluronan gel, hyaluronic acid, “hyaluronic acid [ 14 ]” AND adhesive, pelvic and abdominal adhesion, postoperative adhesion, and “gynecological surgery [ 14 ]”. No limitations were applied regarding publication status, article type, or years to ensure comprehensive identification of all potentially relevant research. Three authors independently reviewed the searched studies and extracted data related to the articles, quality, and accuracy of the studies. The same three authors also conducted a thorough manual search of reference lists of previously published papers and review articles to guarantee the identification of all potentially relevant research. The search method was based on PICOs. All the clinical trial articles that refer to the use of hyaluronic acid gel to prevent postoperative adhesions in women who had gynecological surgeries were reviewed and identified by two people separately. Data extraction was conducted independently by two reviewers, with discrepancies resolved through consultation with a third investigator. Extracted information included baseline characteristics (year of publication, sample size, participant age, interventions in both experimental and control groups, type of surgical procedure, method of adhesion assessment, and adhesion scoring), outcome measures, and qualitative details from the eligible studies. The quality of the RCTs was assessed using the Jadad scoring system, which evaluates studies based on randomization, blinding, and the description of withdrawals. Studies with a Jadad score of 3 or higher were considered of high quality [ 15 ]. To assess clinical heterogeneity between studies, information on adhesion assessment method, type of surgery, the continent where the study was performed, and specifications for each trial were collected. Risk ratios (RRs) with 95% confidence intervals (CIs) were employed to assess differences in dichotomous outcomes, such as the incidence of adhesions. Standardized mean differences (SMDs) with 95% CIs were used for continuous outcomes, including adhesion scores. A p value of less than 0.05 was considered statistically significant. In cases of low heterogeneity, a fixed‐effects model was applied for pooled estimates, whereas a random‐effects model was used when heterogeneity was higher. Heterogeneity was evaluated using Cochran's Q test, with significant heterogeneity defined as an I ² value greater than 50% [ 13 ]. Also, a meta‐regression and subgroup analysis were performed to identify the reason for the heterogeneity of the research. In addition, the funnel plot and Egger and Bag test were performed to check the publication bias. The trim and fill approach was used to further investigate publication bias. Statistical analysis was performed using STATA 14.0 (Stata Corp, College Station, TX, USA). The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was employed to evaluate the overall quality of evidence for each outcome in the summary of findings table. The GRADEpro GDT online software was utilized for the GRADE approach and to create the summary of findings tables [ 16 , 17 ].

Seven clinical trial articles were selected from all the searched articles and included in the meta‐analysis. The total sample size included in this meta‐analysis is 261 women in the control group and 258 women in the intervention group (hyaluronic acid gel). All seven studies reported the prevalence of adherence after gynecological surgery between the control and intervention groups. Among these articles, three reported the mean and standard deviation of adhesion. Figure  1 shows the PRISMA flowchart that displays the search and selection of studies. PRISMA flowchart of the search and selection of studies. Six studies performed laparoscopy as the primary procedure (laparoscopic myomectomy). Two studies have used Ringer's lactate serum in the control group. The ovariopexy method (fixing the ovary to the abdominal wall) was used in the control group in the study by Chaichian et al. Two studies used saline in the control group. Other studies did not provide information on the control group. All studies have used hyaluronic acid and its derivatives as a physical barrier to prevent the formation of adhesions after the operation as an intervention. Table  1 shows the characteristics of the studies included in the meta‐analysis separately. Among the studies included in this meta‐analysis, two studies are related to the Asian continent, three studies are related to Europe, and one study is related to the American continent. Baseline characteristics of the studies included in the meta‐analysis. Ovarian adhesion Severe: 2/47(4.9%)/6/47 (7.7%) Moderate:7/47(14.6%)/23/47 (53.8%) Mild (adhesions covering less than 26% of the total area), moderate (adhesions covering 26–50% of the total area), and severe (adhesions covering at least 51% of the total area). Periovarian adhesions severe: 2/15 (13/3%)/0/15(0%) Moderate:1/15/8/15 Severe: 4/12 (33%)/7/11 (64%) Moderate: 8/21 (38%)/13/22 (59%) Severe:1.5 ± 3.2 2.7 ± 2.4 Moderate:0.3 ± 0.9/0.8 ± 1.0 In the included RCTs, the safety profile of hyaluronic acid was generally well‐tolerated. The majority of studies did not report significant adverse reactions directly related to the hyaluronic acid intervention. However, mild and transient side effects, such as local irritation, redness, or discomfort at the site of application, were observed in a small number of patients. Specifically, Chaichian et al. reported no serious adverse events in either the treatment or control group [ 18 ]. Similarly, Cheong et al. and Fossum et al. noted that no severe adverse reactions were attributed to the hyaluronic acid gel treatment, although minor local inflammation was observed in a few cases [ 19 , 22 ]. The studies by Mais et al. and Pellicano et al. did not provide detailed information regarding adverse effects related to hyaluronic acid gel but did mention that no significant complications were observed during the follow‐up period [ 20 , 21 ]. The studies by Liu et al. and Elkhouly et al. also reported that the use of hyaluronic acid gel did not lead to any severe adverse reactions, although mild temporary swelling or mild pain at the treatment site were occasionally noted [ 23 , 24 ]. Overall, the available evidence suggests that hyaluronic acid, when used in the treatment of adhesions, has a favorable safety profile with a low incidence of adverse reactions. In this meta‐analysis, the quality of clinical trial studies was evaluated using the Jadad scale, the results of which were completed and presented in Table  2 , separated by influencing factors. The evaluation of the quality of clinical trial studies showed that most of these studies had a moderate to high‐quality score. Quality assessment and risk of bias of clinical trial studies evaluated using the Jadad scale. A total of 258 participants were randomly assigned to the hyaluronic acid gel group, and 261 participants were allocated to the control group. Hyaluronic acid gel significantly reduced the adhesion risk after laparoscopic surgery in women. As shown in Figure  2 , hyaluronic acid has a protective role against severe adhesions, and this relation is statistically significant (RR = 0.77; CI: 0.47–1.24). This means that the use of hyaluronic acid gel reduces the risk of abdominal and pelvic adhesions after gynecological laparoscopic surgery by 23% and has a protective role. In this meta‐analysis, five studies were included, and these studies had no heterogeneity, the percentage of which is equal to ( p value = 0.199, I 2  = 33.3%). The lowest and highest RR among the studies included in the meta‐analysis are 0.33 (95% CI; 0.07–1.57) and 5.00 (95% CI; 0.26–96.13), respectively. Forest plot of the association between the number of severe adhesion cases and the use of hyaluronic acid gel. A funnel plot and Eggers test were used to assess publication bias (Figure  3a ). In this test, the null hypothesis emphasizes the absence of publication bias. The results of Egger's test indicated no publication bias ( β Egger = −0.172, p value = 0.901). When the trim and fill approach (Figure  3b ) was applied to further assess publication bias, no additional hypothesized studies were identified for inclusion in the meta‐analysis. According to the sensitivity analysis, the overall risk ratio regarding the association between hyaluronic acid gel and having severe adhesion after laparoscopic surgery in women did not depend on a single study (Figure  3c ). (a) Funnel plot for publication bias, (b) trim‐and‐fill funnel plot, and (c) sensitivity analysis for the frequency of severe adhesions after surgery. The change in the adhesion score, or in other words, the adhesion score in the control and intervention groups, along with the standard deviation, has been reported in two studies that had gynecological laparoscopic surgery. Both studies utilized the American Fertility Society score. In the meta‐analysis, changes in adhesion scores were reported as a continuous outcome (Figure  4 ). Based on the obtained results, the use of hyaluronic acid gel reduces the extreme adhesion score by 0.65 units (SMD = −0.65 95% confidence interval: (−0.91 and −0.40)). The standardization method has been used in the analysis, which means that the obtained results are not related to the unit of measurement and are standardized. Forest plot of the association of the severe adhesion score after surgery with hyaluronic acid gel. Egger's statistical test was performed to check the publication bias. The results of this test showed that there is no publication bias ( β Egger = −7.28, p value = 0.73). When the trim and fill approach (Figure  5a,b ) was used to further assess publication bias, a hypothetical missing article was imputed, and the “adjusted” estimate showed a similar SMD to the original analysis (SMD = −0.7, 95% confidence interval: −0.93 and −0.47). (a) Funnel plots for publication bias. (b) Trim‐filled funnel plots for the severe adhesion score after surgery. The hyaluronic acid gel was found to significantly reduce the mean adhesion risk after laparoscopic surgery in women. As shown in Figure  6 , hyaluronic acid has a protective role against moderate adhesion, and this relation is statistically significant (RR = 0.32; CI: 0.2–0.45). This means that the use of hyaluronic acid gel reduces the risk of moderate abdominal and pelvic adhesions after gynecological laparoscopic surgery by 68%, and this protective role is statistically significant. In this meta‐analysis, five studies were included, and these studies had heterogeneity, the percentage of which is equal to ( p value < 0.001, I 2  = 76.2%). The lowest and highest RR among the studies included in the meta‐analysis are 0.13 (95% CI; 0.02–0.88) and 0.54 (95% CI; 0.15–1.95), respectively. Forest plot of the association between the use of hyaluronic acid gel and the incidence of moderate postoperative adhesions following surgery. Egger's statistical test and funnel plot were performed to assess the publication bias (Figure  7a ). The results of this test showed that there is a publication bias (null hypothesis rejected) ( β Egger = −1.24, p value < 0.001). When the trim and fill approach (Figure  7b ) was used to further assess publication bias, no hypothetical articles were added. Sensitivity analysis showed the overall risk ratio regarding the association between hyaluronic acid gel and having moderate adhesion after laparoscopic surgery in women did not depend on a single study (Figure  7c ). (a) Funnel plots for publication bias. (b) Trim‐filled funnel plots. (c) Sensitivity analysis for moderate adhesion frequency. Three studies utilized the American Fertility Society score, and in the meta‐analysis, the change in mean adhesion scores was treated as a continuous outcome. The results of the meta‐analysis are shown in Figure  8 . Based on the obtained results, the use of hyaluronic acid gel reduces the average adhesion score by 0.65 units. This association is statistically significant (SMD = −1.31 95% CI: −1.99 and −0.62). Forest plot of the association of the moderate postoperative adhesion score after surgery with hyaluronic acid gel. Egger's statistical test and funnel plot were performed to check the publication bias (Figure  9a ). The results of this test showed that there is no publication bias ( β Egger = −1.13, p value = 0.93). When the trim and fill approach (Figure  9b ) was used to further assess publication bias, no hypothesized studies were added to the analysis. (a) Funnel plots for publication bias. (b) Trim‐filled funnel plots for moderate adhesion score. The GRADE results indicate that hyaluronic acid gel may reduce postoperative adhesions in gynecological surgery, though the certainty of evidence varies. For severe adhesion cases, the RR was 0.77 (95% CI: 0.77–1.24), with moderate certainty, suggesting a potential reduction in severe adhesions, though the confidence interval crosses 1, indicating some uncertainty. The severe adhesion score after surgery showed an SMD of −0.65 (95% CI: −0.91 to −0.40) with low certainty, indicating a possible reduction in adhesion severity, but the true effect remains uncertain. For moderate postoperative adhesion frequency, the RR was 0.32 (95% CI: 0.20–0.49), with moderate certainty, demonstrating a significant reduction in moderate adhesions. Finally, the moderate adhesion score after surgery had an SMD of −1.31 (95% CI: −1.99 to −0.69) with low certainty, suggesting a likely reduction in moderate adhesions, though the true effect could vary. These findings support the potential benefit of hyaluronic acid gel, but the low and moderate certainty of evidence emphasizes the need for further high‐quality studies (Table  3 ). GRADE results. ⊕⊕⊕◯ Moderate ⊕⊕◯◯ Low ⊕⊕⊕◯ Moderate ⊕⊕◯◯ Low Note: GRADE Working Group grades of evidence: High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limitedz. The true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect. Abbreviations: CI, confidence interval; RR, risk ratio; SMD, standardized mean difference. *The risk in the intervention group (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).

The current systematic review and meta‐analysis encompassed seven randomized controlled trials and included 219 patients who underwent laparoscopic gynecologic surgeries. The results showed a significant effect of hyaluronic acid and its derivatives compared to placebo/null treatments in the reduction of adhesion formation and adhesion score in patients with moderate pelvic adhesion. An additional significant reduction of the adhesion score in patients with severe pelvic adhesion formation is observed. Moderate heterogeneity was detected. A minimal decrease in the formation of severe adhesion was found in the analysis, although the reduction was not statistically significant. A high level of heterogeneity was observed. To the best of the author's knowledge, this is the first meta‐analysis performed on the results of the hyaluronic acid application in laparoscopic gynecological surgery that focused on pelvic adhesion. Previous meta‐analyses on adhesion formation in gynecological surgeries involved other anti‐adhesion materials [ 25 , 26 , 27 ] or patients with other routes of surgeries, including laparotomy [ 28 ] or hysteroscopic surgeries [ 11 , 29 , 30 ]. Since adhesion formation is considerably lower in laparoscopic surgery, we excluded [ 31 ] all laparotomies to avoid heterogeneity. The last Cochrane review by Ahmad et al. [ 26 ] reported moderate‐quality evidence for the effect of hyaluronic acid in adhesion reduction after laparoscopy since they included only one clinical trial in their analysis which used hyaluronate in combination with carboxymethylcellulose sheets [ 32 ]. We could not find any significant effect of hyaluronic acid on the presence and frequency of adhesion formation, although the results of quantitative evaluation of the adhesion severity showed a significant reduction in severe adhesion score. Among the seven studies included in the analysis, only two studies reported the severe adhesion quantitatively, both of which were conducted on patients with endometriosis, the most prevalent reason for severe adhesion in reproductive‐age women [ 1 ]. Therefore, judgement about levels of severe adhesion is limited to the endometriosis studies with lower generalizability and lower sample size. Additionally, postsurgical severe adhesion in patients with endometriosis might be attributed to the nature of the disease and might be a source of observed heterogeneity in the results. On the other hand, the results of the meta‐analysis for the presence and score of adhesion were consistent regarding the significant effect of the intervention in patients with moderate adhesion. There was negligible heterogeneity. A structural heterogeneity was observed in the selection of the control groups, whereas one RCT used ovariopexy as control, besides two studies with isotonic solutions. These differences will not affect the null hypothesis for meta‐analysis since the positive effects of the control group's intervention compared to the placebo dilutes the calculated effect size of hyaluronic acid application compared to the placebo, therefore, the actual difference between the two groups looks higher than observed. Quality assessment using the Jadad scoring system reveals that there are two high‐quality, two moderate‐quality, and three low‐quality randomized controlled trials (RCTs). This distribution of quality ratings leads to partial uncertainty in our judgment regarding the results. The current study included only the RCTs in the analysis, resulting in the lower number of studies for analysis. While the meta‐analysis did not exhibit significant publication bias, it is advisable to expand the search strategies to encompass non‐English studies and explore gray literature. This broader approach may lead to the detection of additional research with potentially higher quality.

Hyaluronic acid and its derivatives are beneficial for patients who underwent gynecological surgeries with a risk of moderate adhesion formation, both to reduce the presence and severity of the adhesions. Evidence about the efficacy of the intervention in patients with severe adhesions is controversial and needs to be implemented with a well‐designed RCT with a higher sample size. We recommend revisiting the meta‐analysis in the future when new, higher‐quality evidence becomes available.

Adhesions are a significant contributing factor to pain, infertility, bowel and ureteral blockages, and other endometriosis‐related symptoms [ 1 ]. Adhesions arise as a result of inflammation, decreased apoptosis, and enhanced angiogenesis [ 2 ]. Surgery in the pelvic region is linked with adhesions and postoperative modification despite great efforts to limit tissue stress and achieve hemostasis. Approximately 80% of gynecological procedures result in adhesions, and 85% of patients require postoperative adhesion resolution [ 2 , 3 ]. Since adhesions may prolong and complicate the surgical procedure as well as create issues like persistent pain and infertility, any surgical operation must be done while minimizing the possibility of adhesions [ 4 ]. Various surgical strategies—such as ovarian suspension—have been employed to minimize pelvic adhesion formation by repositioning the ovaries away from affected areas. Additional preventive measures include the use of agents like normal saline, lactated Ringer's solution, heparin, corticosteroids, 32% dextran lavage, and bioresorbable barriers such as sodium hyaluronic acid combined with carboxymethylcellulose (e.g., Seprafilm). While these interventions have demonstrated some efficacy, none have proven entirely successful in eliminating adhesion recurrence following laparoscopic procedures [ 5 , 6 , 7 , 8 , 9 ]. Hyaluronic acid provides mechanical support and protection, decreasing adhesion probability by controlling the inflammatory response and encouraging vascular regeneration and wound healing. It is advised to use hyaluronic acid gel, also known as hyalobarrier gel (used under several brand names), alone or in conjunction with the carboxymethylcellulose barrier to avoid adhesions [ 10 , 11 ]. Numerous randomized clinical trials and systematic reviews have investigated the safety and effectiveness of hyaluronic acid gel in minimizing pelvic and abdominal adhesions following gynecologic surgery [ 12 ]. This review and meta‐analysis aim to comprehensively assess its clinical utility in reducing postoperative adhesion formation in such surgical contexts.

All the authors affirm that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

The authors declare no conflicts of interest.