The Efficacy of Self-Cross-Linked Sodium Hyaluronate Gel in the Prevention of Intrauterine Adhesions: A Literature Review

Abstract

Objective:

Intrauterine adhesions (IUAs) are primarily addressed through hysteroscopic surgery, and the clinical application of self-cross-linked sodium hyaluronate gel has progressively gained traction to prevent postoperative recurrence, alterations in uterine morphology, and menstrual irregularities. Clinicians frequently employ sodium hyaluronate gel in combination with an intrauterine device (IUD) or balloon; however, the precise effectiveness of these combined approaches warrants further investigation. Accordingly, this study aimed to synthesize the outcomes of various treatment modalities reported in existing research and summarize the outcome measures employed, thereby providing valuable insights and references for the field.

Findings in Brief:

Our findings indicate that using self-cross-linked sodium hyaluronate gel alone significantly reduces the severity of adhesions in patients with uterine adhesions, but has no considerable effect on those with mild adhesions. The postoperative recurrence rate of adhesions was significantly lower in patients who received a combined therapy of a gel and a uterine balloon or IUD, compared to those treated with the gel alone. Additionally, the combined gel and electrophysiological techniques enhanced local blood circulation in the pelvic floor and mitigated scar tissue formation in the uterus, reducing IUAs. However, none of the three treatment modalities demonstrated a significant impact on the final pregnancy outcomes of the patients.

Conclusions:

Self-cross-linked sodium hyaluronate gel proves effective in preventing postoperative recurrence in patients with IUAs; however, further research is required to elucidate the impact of these gels on patients with mild versus severe adhesions. Future studies should consider conducting high-quality, large-scale randomized controlled trials to compare the therapeutic efficacy of these approaches, thereby advancing their clinical application.

Graphical abstract

Keywords

self-cross-linking sodium hyaluronate gel / intrauterine adhesion / endometrium / operative hysteroscopy

1. Introduction and Background

Intrauterine adhesion (IUA) is a pathological condition resulting from various etiological factors that cause damage to the basal layer of the endometrium, leading to uterine wall adhesions [1, 2]. The primary causes of IUA include excessive manipulation of uterine instruments, surgical trauma, endometrial curettage following pregnancy, intrauterine infections, abdominal and hysteroscopic myomectomy, genital tuberculosis, and cesarean section [3, 4, 5]. In addition, IUA can result in adverse outcomes, such as partial or complete obstruction of the uterine cavity or cervical canal [6], infertility, ectopic pregnancy, recurrent miscarriage, preterm birth, and placental abnormalities. These complications can promote significant clinical and social challenges [7]. While the precise incidence of IUA remains undetermined, studies suggest that approximately 5% of women of reproductive age experience two or more miscarriages, the majority of whom undergo dilation and curettage [8]. Of those who undergo dilation and curettage, 15%–20% develop IUA. Meanwhile, the global number of induced abortions reached 56.3 million annually between 2010 and 2014 [9], which may contribute to more than 10 million cases of IUA each year [10, 11]. Furthermore, IUA may present with few or no obvious symptoms, or patients may fail to recognize the significance of their symptoms, resulting in delayed medical attention and diagnoses [12, 13]. Consequently, the true incidence of IUA is likely underestimated [7].

The standard treatment for IUA typically involves hysteroscopic adhesion lysis. However, postoperative complications often include increased rates of adhesion recurrence and suboptimal pregnancy outcomes [14]. Presently, physical barriers such as balloon catheters and intrauterine devices (IUDs) are employed to mitigate IUA following hysteroscopic adhesion lysis. However, despite the efficacy of these barriers, concerns remain regarding discomfort associated with foreign bodies, elevated infection risks, and potential uterine perforation [15]. In contrast, semi-solid reagents, specifically self-cross-linking hyaluronic acid (ACHA) or hyaluronic acid (HA) gels, have emerged as alternatives in recent years, aiming to overcome the limitations of these physical barriers. Sodium hyaluronate, a glucuronic aldehydic acid family member, constitutes a principal constituent in the cellular and intercellular matrix. The primary mechanisms through which sodium hyaluronate mitigates IUA involve forming a disordered mesh structure in an aqueous solution, both a spatial and mechanical barrier [16]. Additionally, the resultant protective film aids in minimizing surgical trauma. Sodium hyaluronate also inhibits the activation and aggregation of inflammatory cells, thus reducing fibroblast aggregation in traumatized tissues and lowering the risk of IUA. Moreover, the lubricating properties of sodium hyaluronate alleviate friction during the healing process [17]. Furthermore, HA gel offers significant advantages such as reduced degradation and high viscosity, and utilizes an automatic cross-linking technology that activates and modifies linear HA molecules into a three-dimensional network structure. This technology is designed to extend the half-life of the gel, prolonging its absorption time (up to 7 to 14 days). Additionally, the material properties of HA gel contribute to enhancing the quality of the endometrium and improving uterine receptivity (Fig. 1). The ability of HA gel to expand ensures continued isolation of the intrauterine cavity after surgery, effectively reducing the risk of re-adhesion [18]. Notably, no adverse events have been reported in studies utilizing sodium hyaluronate gel to prevent IUA [19, 20, 21].

Numerous extant studies have explored the utilization of sodium hyaluronate in preventing adhesions among patients following uterine maneuvers, yet conclusive evidence remains lacking. Therefore, this review aimed to synthesize the findings regarding the efficacy of sodium hyaluronate in preventing IUA after intrauterine procedures. Moreover, this review aimed to provide healthcare professionals with a comprehensive summary of existing research and to open new avenues for future investigations.

2. Methods

2.1 Search Strategy and Study Selection

To identify relevant studies, we systematically searched several electronic databases, including PubMed, Web of Science, Cochrane, and EMBASE. The search was restricted to articles published in English up to March 11, 2025, which investigated HA gel interventions for patients with IUAs. A combination of standardized terms and keywords was used, including “intrauterine adhesion”, “uterine adhesion”, “tissue adhesions”, “uterine diseases”, “synechia”, “Asherman syndrome”, along with terms related to intervention (“prevent”, “reduce”, “manage”, “decrease”) and hyaluronic acid derivatives (“hyalobarrier”, “hyaluronan gel”). The characteristics of included articles are presented in Table 1 (Ref. [6, 17, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33]).

2.2 Inclusion Criteria

Studies were included upon meeting the following criteria: Female participants with diagnosed IUAs; studies with at least two groups, one receiving a HA gel or related derivatives and the other a placebo or control group post-intrauterine surgery; adhesion severity classification based on the American Fertility Society (AFS) system as determined by hysteroscopic evaluation; primary outcomes focused on the incidence and severity of the IUA.

2.3 Exclusion Criteria

The following studies were excluded: Abstract-only articles, duplicate publications, and studies that did not report specific, usable data on the outcomes of interest.

3. Review

3.1 Evaluation of the Efficacy of Self-Cross-linking HA Gel as a Standalone Treatment for Managing IUAs

Most studies indicate that using HA gel following intrauterine procedures effectively reduces the incidence of postoperative IUA. In a systematic review, Zheng et al. [20] included 952 women of childbearing age who underwent intrauterine surgery. Of these, 455 received HA gel following adhesion separation, while 497 constituted the control group. The findings demonstrated a reduction in the incidence of IUA and IUA severity scores following intrauterine surgery with HA gel administration. Subgroup analysis of this study further revealed that the preventive effect of HA gel on IUA was not influenced by the type of intrauterine surgery or the primary disease. In patients undergoing curettage and hysteroscopy, the application of HA gel significantly prevented IUA (p 0.001). Furthermore, HA gel effectively prevented IUA in patients following a miscarriage and with conditions such as IUA, submucosal uterine fibroids, endometrial polyps, or uterine septum.

Several studies, including those by Acunzo et al. [22], Guida et al. [23], Sroussi et al. [24], and Chen et al. [25], reported a significant reduction in IUAs in the experimental group compared to the control group at the 3-month follow-up. Adhesion staging revealed a marked decrease in adhesion severity among patients treated with HA gel, with no reported adverse effects during its usage. In contrast, Zhou et al. [26] found no statistically significant differences in IUA recurrence rates, the American Fertility Society (AFS) score, or menstrual patterns between patients treated with HA gel and controls postoperatively at 4 weeks. Similarly, research by Thubert et al. [27] indicated that HA gel failed to prevent IUA recurrence or increase pregnancy rates. Nonetheless, the small sample size (90 patients) in the study underscores the need for randomized controlled trials with larger cohorts to explore the efficacy of HA gel further, as emphasized by the authors.

However, the postoperative preventive effect of HA gel in patients with mild IUA remains unclear. A comprehensive review conducted by Liu et al. [28] and Liu et al. [29] on the use of HA gel in patients undergoing intrauterine surgery demonstrated a significant reduction in the incidence of moderate to severe IUA following the application of HA gel; however, it had no observed effects on mild IUAs. Similarly, Fei et al. [30] found that HA gel significantly reduced post-abortion IUA scores, markedly decreasing the occurrence of moderate-to-severe post-abortion IUA (p 0.001), albeit without impacting mild uterine adhesions (p = 0.19). Therefore, the efficacy of HA gel in patients with varying degrees of IUAs requires further investigation. Future studies should focus on stratifying the population to implement targeted intervention strategies.

3.2 The Therapeutic Efficacy of Using Sodium Hyaluronate Gel in Conjunction With Either a Balloon Catheter or an Intrauterine Device (IUD)

In addition to the standalone use of HA gel to prevent postoperative IUA, it is also clinically utilized in combination with intrauterine balloons or contraceptive devices in patients following adhesion separation surgery. This combined approach has been shown to reduce postoperative adhesions to some extent. Specifically, in patients presenting with IUA, a Foley balloon catheter was inserted into the uterine cavity, followed by injection of 3 mL self-cross-linking HA gel, after adhesion separation. At the 3-month postoperative evaluation, the treatment group showed a significantly greater reduction in adhesions, with 76% and 48% efficacy rates, compared to the control group [31]. Furthermore, total AFS scores were notably lower in the treatment cohort, with significant improvements in adhesion type and menstrual patterns.

Most research suggests that the combined application of HA gel with intrauterine balloons or contraceptive devices is more effective in preventing adhesions than using HA gel alone. Trinh et al. [32] identified distinct treatment categories for patients with IUA, including HA gel treatment alone, IUD treatment alone, and HA gel and IUD treatment. Notably, the recurrence rates and AFS scores were significantly lower in women treated with HA gel and IUD than those treated with HA gel alone. However, no significant difference in pregnancy rate was observed. A comprehensive systematic review by Vitale et al. [34] incorporating data from 1596 women highlighted the substantial effect of combining HA gel with an IUD on mean adhesion scores, with the greatest improvement observed in this group. Noteworthy trends were identified in postoperative adhesion severity, with the HA gel and IUD combination exhibiting the largest cumulative area under the ranking curve (49.9%), followed by IUD alone (30.8%). A similar approach was employed by Xiao et al. [31], who introduced a Foley balloon catheter into the uterine cavity post-adhesion separation, followed by HA gel injection to prevent postoperative re-adhesion. The treatment group showed a significant reduction in re-adhesion rates at the 3-month follow-up, accompanied by improvements in adhesion type and menstrual patterns.

However, most studies have primarily focused on comparing the effects of single use versus combined use of HA gel, without differentiating between the efficacy of HA gel combined with an intrauterine balloon versus HA gel combined with an IUD. Future research should explore and compare the effectiveness of these two intervention strategies in greater detail.

3.3 Efficacy of Sodium Hyaluronate Gel Combined With Bioelectrical Stimulation To Prevent Intrauterine Adhesions

Pelvic floor bioelectrical stimulation has gained traction recently as a complementary treatment modality to using balloons and IUDs combined with HA gel to prevent IUAs. Pelvic floor neuromuscular electrical stimulation (NMES) is designed to enhance the strength and function of the pelvic floor muscles, promoting tissue healing and reducing scar tissue formation by stimulating these muscles and improving local blood circulation [35]. This non-invasive technique targets uterine cavity scarring resulting from endometrial injury. The bioelectrical stimulation of pelvic muscles enhances uterine healing, inhibits excessive scar tissue formation, and supports overall recovery. Recent studies have explored the combination of electrical stimulation with HA gel to prevent adhesions following uterine surgery. A study by Sun et al. [17] examined the efficacy of combining NMES with HA gel to prevent IUAs in a post-abortion experimental group, with the control group solely receiving HA gel injected into the uterine cavity (5 mL). The results indicated a significantly lower incidence of IUAs in the combined treatment group. Furthermore, this combined approach effectively enhanced endometrial thickness and reduced the pulsatility index (PI) and resistance index (RI) in the endometrial spiral arteries.

In a separate study, Shabiti et al. [33] investigated the effects of bionic electrical stimulation combined with Femoston on pregnancy outcomes and endometrial characteristics (including thickness and type) in patients with infertility and thin endometrium. Although the combination therapy resulted in higher endometrial thickness than Femoston alone, no significant improvement was observed in pregnancy rates.

While studies in this field remain limited, the promising potential of combining bioelectrical stimulation with HA gel in patients with IUAs warrants further investigation. Future research should aim to improve elucidation of the therapeutic benefits of this combination treatment and the impacts on uterine cavity healing, adhesion prevention, and pregnancy outcomes.

3.4 Outcome Indicators

Primary short-term outcome indicators for follow-up typically include the incidence of IUAs, which is assessed via repeat hysteroscopy at the 3-month postoperative mark. Secondary outcome indicators commonly encompass the degree of uterine cavity involvement, adhesion type, menstrual pattern, and endometrial thickness. Most studies have reported improvements in these parameters, with sodium hyaluronate gel demonstrating no significant adverse effects throughout the study period. Uterine cavity involvement is generally reassessed by hysteroscopy, usually scheduled 3 to 6 months after surgery, using the AFS adhesion extent, adhesion type score, and menstrual pattern for grading adhesions.

Secondary outcome indicators, such as endometrial thickness, uterine artery PI, and RI, have received less attention. Increased endometrial thickness is critical for improving conception rates, particularly relevant for patients undergoing in vitro fertilization (IVF) and women of reproductive age [36]. Additionally, lower values of spiral uterine artery PI and RI indicate enhanced uterine blood flow, which promotes tissue repair and endothelial growth [37]. Future studies should consider incorporating these parameters as additional outcome measures, with long-term follow-up concentrating on sustained pregnancy outcomes, thus broadening the research scope in this field.

Several studies have also explored the ultimate pregnancy outcome following uterine manipulation. Research by Fei et al. [38], Fuchs et al. [39], Tsapanos et al. [40], Liu et al. [28], and Fei et al. [30] exhibited higher conception rates in the experimental groups receiving self-cross-linked sodium hyaluronate after adhesion separation, compared to the control groups. A meta-analysis by Zheng et al. [20] revealed a pregnancy rate of 77.7% among patients treated with HA gel, significantly higher than the 60.0% rate observed in patients treated with IUD. Additionally, Huberlant et al. [41] conducted uterine curettage on 20 New Zealand white rabbits at 10-day intervals, randomly assigning them into two groups. The experimental group received intrauterine anti-adhesion gel drops post-curettage and underwent mating after a recovery period. The experimental group showed a significantly higher number of fetuses than the control group, suggesting the beneficial impact of sodium hyaluronate gel on fertility following curettage.

However, certain studies have reported no significant impact of postoperative sodium HA gel use on pregnancy outcome, highlighting the need for further investigation [32]. A more comprehensive evaluation of the efficacy of HA gel in preventing postoperative IUA requires larger sample sizes, longer follow-up periods, and rigorously designed randomized, controlled clinical studies.

3.5 Clinical Application of Sodium Hyaluronate Acid Gel

HA is a highly polymerized disaccharide chain and a mucopolysaccharide. Meanwhile, due to the irregular coiled structure and unique physicochemical properties of HA [42], it has important physiological functions in the body, including joint lubrication, regulation of vascular wall permeability, modulation of protein and electrolyte diffusion and transport, and promotion of wound healing [43]. Currently, sodium HA gel is widely utilized across various medical fields. In cosmetic surgery, sodium HA gel is a filler for procedures such as rhinoplasty, chin augmentation, nasolabial fold correction, and tear trough treatment, demonstrating effectiveness and stability in facial contouring and rejuvenation [44]. Meanwhile, HA gel is used in dentistry to treat conditions such as dry sockets and chronic periodontitis.

HA is frequently combined with other biopolymers, such as proteins or peptides, through esterification, cross-linking, and other chemical modifications. This has led to the development of various related compounds, such as hyaluronic acid–carboxymethylcellulose gels, which are widely employed to prevent tissue adhesions following surgical procedures [45]. HA gel has garnered significant attention recently for its role in preventing IUAs. Indeed, studies investigating the use of HA gel for this purpose have consistently demonstrated a significant ability for HA gel to reduce the incidence of postoperative IUAs [41, 46]. Furthermore, the safety of HA gel has been confirmed in relevant animal model studies, with no gel-related complications, such as perforation, bleeding, or other injuries, reported in clinical applications [20]. Clinicians can choose different treatment plans for patients with varying degrees of adhesion. For instance, patients with severe adhesions may benefit from a combination of HA gel and an intrauterine balloon or IUD to more effectively prevent the recurrence of adhesions. In contrast, patients with mild to moderate adhesions may require fewer intensive interventions. Additionally, treatment decisions should consider factors such as the patient’s economic situation, insurance coverage, and other relevant considerations to ensure the most appropriate and accessible care.

4. Limitations

Due to the inconsistencies and heterogeneity in treatment methods, including variations in the amount of gel injected into the uterine cavity, baseline patient conditions, follow-up durations, and other factors across the studies, this article adopted a literature review approach. As a result, this review may lack systematic rigor and have no quantitative analysis of objective data. Future studies should aim to narrow the research focus, establish clear inclusion and exclusion criteria, and employ systematic evaluations to improve the synthesis of the available evidence.

5. Conclusions

In conclusion, existing studies have shown that using HA gel alone and combined with other interventions effectively prevents IUAs. However, the precise effects of HA gel on patients with mild, moderate, and severe IUAs still require further investigation. Additionally, this review provides a comprehensive summary of the outcome measures commonly used in related research, offering valuable guidance for selecting appropriate indicators in future studies.

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Funding

Self-crosslinking hyaluronic acid gel for fertility protection in patients undergoing clearance surgery (West China Second University Hospital, Sichuan University)(22H0722)