Hum. Reprod. Advance Access originally published online on April 22, 2004
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Human Reproduction, Vol. 19, No. 6, 1461-1464,
June 2004
© 2004 European Society of Human Reproduction and Embryology
Effectiveness of auto-crosslinked hyaluronic acid gel in the prevention of intrauterine adhesions after hysteroscopic surgery: a prospective, randomized, controlled study
Department of Obstetrics and Gynecology, University of Naples "Federico II", Via S. Pansini 5, 80131 Naples, Italy
1 To whom correspondence should be addressed. e-mail: acunzus{at}libero.it
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Abstract |
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BACKGROUND: A prospective, randomized, controlled study was performed to assess the efficacy of auto-crosslinked hyaluronic acid (ACP) gel to prevent the development of de-novo intrauterine adhesions following hysteroscopic surgery. METHODS: One hundred and thirty-two patients with a single surgically remediable intrauterine lesion (myomas, polyps and uterine septa, subgroups I–III) completed the study. Patients were randomized to two different groups: group A underwent hysteroscopic surgery plus intrauterine application of ACP gel (10 ml) while group B underwent hysteroscopic surgery alone (control group). The rate of adhesion formation and the adhesion score was calculated for each group and subgroup 3 months after surgery. RESULTS: Group A showed a significant reduction in the development of de-novo intrauterine adhesions at 3 months follow-up in comparison with the control group. Furthermore, the staging of adhesions showed a significant decrease in adhesion severity in patients treated with ACP gel. CONCLUSIONS: ACP gel significantly reduces the incidence and severity of de-novo formation of intrauterine adhesions after hysteroscopic surgery.
Key words: adhesion score/de-novo intrauterine adhesions/hyaluronic acid gel/hysteroscopic surgery
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Introduction |
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Intrauterine adhesions are the major long-term complication of operative hysteroscopy, with frequency dependent on the pathology initially treated (Taskin et al., 2000
). They may result in infertility, recurrent miscarriages and irregular periods with dysmenorrhea and pelvic pain (Valle and Sciarra, 1988; Menzies, 1993).
Post-operative adhesions are classified as ‘de novo’ when they develop at sites that did not have adhesions initially, and as ‘reformed’ when they redevelop at sites at which adhesiolysis has been performed (Diamond et al., 1987).
We recently reported that the intrauterine application of auto-crosslinked hyaluronic acid (ACP) gel following hysteroscopic adhesiolysis significantly reduces the reformation of post-operative intrauterine adhesions. Furthermore, ACP gel has been associated with a reduction of the severity of post-operative adhesions (Acunzo et al., 2003).
The aim of this prospective, randomized, controlled study was: (i) to assess the efficacy of ACP gel in the reduction of development of de-novo post-surgical adhesions in women undergoing hysteroscopic surgery for submucous myomas, endometrial polyps and uterine septa; and (ii) to evaluate the characteristics of the adhesions at 3 months follow-up.
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Materials and methods |
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The protocol of the study was approved by our Institutional Review Board and the study was conducted according to the guidelines of the Declaration of Helsinki (1975). The study project was conducted according to Consort RCT guidelines (www.consort-statement.org) and the patient flow chart is set out in Figure 1.
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All patients with surgically remediable single lesions at diagnostic hysteroscopy were invited to participate in the study. Between September 2002 and June 2003, 138 women were enrolled in the study.
Inclusion criteria were hysteroscopic diagnosis of submucous myomas or endometrial polyps or uterine septa. Exclusion criteria were: age >50 years, weight >100 kg, menopausal (FSH > 40 mIU/ml, 17
-estradiol <20 pg/ml) or pregnancy (positive -HCG test), presence of uterovaginal prolapse and severe urinary symptoms, presence of malignancy, or presence of severe intercurrent illness (coagulative disorders, systemic disease, severe cardiopathy). The presence of the association of equal or different intrauterine remediable lesions or the presence of intrauterine adhesions was also considered an exclusion criteria.
Diagnostic hysteroscopy was performed using a 3.5 mm instrument (Gynecare Versascope, Gynecare; Ethicon Inc., Somerville, NJ, USA) using normal saline solution (NaCl, 0.9%) as distension medium. Before hysteroscopy, all patients underwent vaginal examination to ascertain the position and size of the uterus, and a speculum was inserted into the vagina to expose the cervix.
The type and characteristics of pathologies were recorded on a dedicated schedule.
Before entering the study, the purpose of the protocol was explained clearly to women attending our Hysteroscopic Unit, and a printed explanatory consent form was signed and obtained by all subjects enrolled.
After diagnostic hysteroscopy and after the written consent form was signed, patients from each pathology subgroup (submucous myomas, endometrial polyps, septa) were randomized into two groups, group A (treatment group) (n = 69) and group B (control group) (n = 69), using a computer-generated randomization list (Figure 1).
The treatment group received an intrauterine application of 10 ml of ACP gel (Hyalobarrier Gel; Baxter, Pisa, Italy) under hysteroscopic view after operative histeroscopy. In the control group, hysteroscopic surgery alone was performed.
Operative hysteroscopy was performed by means of a rigid resectoscope (Gynecare Versascope, Gynecare; Ethicon Inc.) with a 30° fore-oblique telescope with different bipolar electrodes and with a bipolar energy source (Versapoint, Gynecare; Ethicon Inc.); normal saline solution (NaCl, 0.9%) was used as the distension medium. Myomectomy was performed by resecting the free side of the myoma by moving the activated bipolar loop from back to front till the exposure of normal myometrium. Polyps were treated by positioning the loop behind the base of pedicle and pushing from back to front. One or several passages of the activated loop were necessary according to the size of lesion being treated. Hysteroscopic metroplasty was performed under laparoscopic control by the use of a modified 0° equatorial loop: uterine septa were cut in the midline portion from the proximal part to the uterine fundus until a normal fundus shape was achieved.
In group A, ACP gel was introduced into the uterine cavity at the end of the procedure through the out-flow channel of the resectocope, whilst the surgeon progressively limited the entrance of the distension medium through the in-flow channel. The procedure was considered complete when, under hysteroscopic view, the gel seemed to have replaced all the liquid medium and the cavity appeared completely filled by the gel from tubal osthia to internal uterine orifice (Acunzo et al., 2003).
Each patient underwent a follow-up diagnostic hysteroscopy 3 months after the surgical procedure, and the adhesion score (American Fertility Society, 1988) was assessed.
Both the initial diagnostic hysteroscopy and the follow-up diagnostic hysteroscopy were performed by the same operator (G.A.). G.A. evaluated the adhesion score for each patient and was blind for patients’ randomized allocation, whilst operative hysteroscopies and application of ACP gel were performed by a different operator (M.G.). To avoid any bias related to the surgical treatment, the surgeon was informed about patients’ allocation immediately after the surgical removal of the intrauterine lesion.
Statistical analysis was performed with a commercial software program (Statistica for Windows; Statsoft, Inc., Tulsa, UK). Data distribution was performed using Shapiro–Wilks test. Differences in age, weight and parity, which showed a normal distribution, were compared using the two-tailed Student’s t-test for unpaired data. The Wilcoxon sum rank test was used to compare adhesion scores at 3 months between groups A and B, and the 
2-test was used for proportions. P < 0.05 was considered statistically significant.
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Results |
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Between September 2002 and June 2003, 164 patients met the study’s inclusion criteria and were invited to participate in the study. Of these, 26 did not participate in the study: 18 refused to undergo operative hysteroscopy and eight refused to participate after the explanation of the study protocol.
The characteristics of the treated patients are reported in Table I. There were no significant differences in age, weight, uterine size and parity between patients in group A and group B.
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Six women (two from group A and four from group B) did not attend for follow-up hysteroscopy.
As shown in Figure 1, 49 patients presented submucous myomas (subgroup I); 67 patients presented endometrial polyps (subgroup II); and 16 patients presented uterine septa (subgroup III). There were no significant differences in lesions’ size and localization between group A and group B. All submucous myomas were classifiable as G0–G1 myomas, according to the international classification of uterine fibroids. Myomas in group A measured 2.9 ± 0.6 cm (mean ± SD; ultrasonographic measurement), while those in group B measured 3.1 ± 0.7 cm.
At 3 months follow-up, a significantly lower rate of post-surgical intrauterine adhesions was observed in group A (seven out of 67 patients) compared with group B (17 out of 65 women) (10.44 versus 26.15%; P < 0.05) (Table II). This significance was conserved when adhesion rates were evaluated within pathology subgroups (Table II).
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The mean adhesion score was significantly lower in group A in comparison with group B (adhesion score of entire group A versus entire group B, mean ± SD: 2.42 ± 0.78 versus 3.83 ± 0.98; P < 0.05). When individual pathology subgroups were compared for the adhesion score, although each treated subgroup (group A) showed a lower score in comparison with the corresponding untreated control subgroup (group B) [mean adhesion score ± SD: subgroup I (myomas): 2.25 ± 0.5 (group A) versus 3.5 ± 1.19 (group B); subgroup II (polyps): 2.0 ± 0.0 (group A) versus 3.5 ± 0.54 (group B); subgroup III (septa): 4.0 ± 0.0 (group A) versus 5.33 ± 1.15 (group B)], we did not represent this difference as statistically significant due to the loss of statistical power. Differences in adhesion score between groups and subgroups at follow-up hysteroscopy are shown in Figure 2. When the intrauterine adhesion staging (American Fertility Society, 1988
) was evaluated, patients from group A showed a significant decrease in adhesion severity (85.71% stage I, mild adhesions; 14.29% stage II, moderate adhesions) in comparison with group B (23.53% stage I; 76.47% stage II). No significant difference was detected in localization of adhesions between different groups and subgroups at follow-up. No adverse gel-related effects were detected in group A.
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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The major long-term complication that all surgeons try to avoid during resectoscopic surgery is post-operative adhesions (Taskin et al., 2000
). Considering the high frequency of intrauterine adhesions after resectoscopic surgery (Taskin et al., 2000), it is cost effective and efficacious to develop new strategies for the prevention of de-novo adhesion formation.
Several methods have been used to prevent intrauterine adhesions in the past (Schenker and Margalioth, 1982; Valle and Sciarra, 1988; Risberg, 1997; Farquhar et al., 2002; Tsapanos et al., 2002; Watson et al., 2002; Acunzo et al., 2003). We recently reported that an auto-cross linked derivative of hyaluronic acid (ACP gel) significantly reduces the reformation of intrauterine adhesions after hysteroscopic adhesiolysis, and that its use is associated with a reduction of the severity of adhesions (Acunzo et al., 2003).
The objective of this prospective study was to evaluate whether ACP gel is also effective in the prevention of post-surgical de-novo adhesions after the most common hysteroscopic surgical procedures (resection of myomas and polyps and metroplasty for uterine septa).
In our experience, high frequencies of post-operative adhesions were observed, especially after resectoscopic myomectomy and metroplasty; hysteroscopic resections of endometrial polyps were associated with a lower incidence of de-novo adhesions.
Our randomized, controlled trial showed a significant reduction in de-novo intrauterine adhesion formation in patients treated with intrauterine application of ACP gel (10 ml) after hysteroscopic surgery in comparison with patients treated with hysteroscopic surgery alone. The difference in adhesion formation was both significant when group A was compared with group B, and when individual pathology subgroups were compared with corresponding controls (P < 0.05).
A significant difference was also observed in mean adhesion score between group A and group B. Although not definitive, our data show that ACP gel seems to be able to prevent de-novo formation of intrauterine adhesions, and also seems to reduce the severity of adhesions that do develop.
This new absorbable barrier agent could represent a safe and effective strategy to improve women’s health, reducing the need for re-intervention after hysteroscopic surgery due to post-operative intrauterine adhesion formation. However, our results need to be confirmed in larger controlled randomized studies.
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References |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Acunzo G, Guida M, Pellicano M, Tommaselli GA, Di Spiezio Sardo A, Bifulco G, Cirillo D, Taylor A and Nappi C (2003) Effectiveness of auto-cross-linked hyaluronic acid gel in the prevention of intrauterine adhesions after hysteroscopic adhesiolysis: a prospective, randomized, controlled study. Hum Reprod 18,1918–1921.
American Fertility Society (1988) The American Fertility Society classifications of adnexal adhesions, distal tubal occlusion, tubal occlusion secondary to tubal ligation, tubal pregnancies, Mullerian anomalies and intrauterine adhesions. Fertil Steril 49,944–955.[Web of Science][Medline]
Diamond MP, Daniell JF, Feste J, Surrey MW, McLaugghlin DS, Friedman S, Vaughn WK and Martin DC (1987) Adhesion reformation and de novo adhesion formation after reproductive pelvic surgery. Fertil Steril 47,864–866.[Web of Science][Medline]
Farquhar C, Vandekerckhove P, Watson A, Vail A and Wiseman D (2002) Barrier agents for preventing adhesions after surgery for subfertility (Cochrane Review). In The Cochrane Library, Issue 1. Oxford Update Software.
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Submitted on November 4, 2003; accepted on February 19, 2004.
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