Randomized Controlled Trial of Hyalobarrier® Versus No Hyalobarrier® on the Ovulatory Status of Women with Periovarian Adhesions: A Pilot Study

Introduction Periadnexal adhesions are known to contribute to subfertility. The restoration of the tubo-ovarian anatomy is one the key principles in reproductive surgery, and this involves adhesiolysis. However, adhesion formation/reformation is very common after periovarian adhesiolysis. It is not known if the application of Hyalobarrier®, an anti-adhesion gel, around the adnexal region postsurgery influences ovulatory status. The study is a pilot randomized controlled trial (RCT) randomizing women into the application of Hyalobarrier® versus no Hyalobarrier® at the time of laparoscopy, where postsurgical ovulatory status and pregnancy rates were evaluated. Methods This was a pilot RCT where women were recruited from the gynecological and subfertility clinic who were deemed to require an operative laparoscopy. If intraoperatively they were found to have periovarian adhesions, they were randomized into having adhesiolysis with and without usage of Hyalobarrier®. Demographic details and intraoperative details including the severity, extent, and the ease of use of Hyalobarrier® were recorded. Prior to the surgery and postoperatively, the participants had their serum hormonal status (day 2 FSH, LH and day 21 progesterone) evaluated. Postoperatively, they underwent a follicular tracking cycle at 3 months. Results Fifteen women were randomized into use of Hyalobarrier® (study group) and 15 into the no Hyalobarrier® group (control group) between December 2011 and January 2014. There was no difference in the patient characteristics in terms of age, BMI, the number of previous pregnancies, or the extent, site, and severity of adhesions between the two groups. There was no significant difference between the study versus control groups in terms of the hormonal profile (day 2 FSH and day 21 progesterone) before or after surgery. The 3-month postoperative day 10–12 follicular tracking findings and endometrial thickness were similar between the study and control groups. Four women were pregnant in the study group (24%) and one in the control group (7%) cumulatively over 2 years. Conclusion The use of Hyalobarrier® post salpingo-ovariolysis did not influence follicular development as inferred from the results of the day 21 progesterone and folliculogram on day 10–12 3-month postsurgery. Trial Registration ISRCTN number, ISRCTN1833588. Funding Nordic Pharma.

There was no difference in the patient characteristics in terms of age, BMI, the number of previous pregnancies, or the extent, site, and severity of adhesions between the two groups. There was no significant difference Enhanced content To view enhanced content for this article go to http://www.medengine.com/Redeem/ D527F06018B08E8F.

INTRODUCTION
Periadnexal adhesions are adhesions which envelop the fimbriae ends, the Fallopian tubes, and/or ovaries. These adhesions can develop postsurgically, after infection and inflammation secondary to pelvic inflammatory disease or as a consequence of other intra-abdominal infective sources. Periadnexal adhesions contribute to subfertility by a combination of ways, namely by the mechanical distortion of the tubo-ovarian anatomy thereby interfering with the transport of the ovum into the Fallopian tube or the disruption of blood supply to the ovary and its follicular development [1][2][3][4]. Indeed, it has been observed that women with periovarian adhesions are significantly more prone to have unruptured follicles [5].
The restoration of the tubo-ovarian anatomy is one of the key principles in reproductive surgery, and this involves adhesiolysis.
However, adhesion formation/reformation is very common after periovarian adhesiolysis (40%) [6]. The natural anatomical position and density of ovaries preclude the hydrofloatation mechanism as an effective adhesion prevention strategy after adnexal surgery [7]. Hence, consideration is required for the application of other forms of adhesion prevention agents such as hyaluronic gel-based products.
Hyalobarrier Ò Gel Endo is a sterile, transparent, and highly viscous gel that forms a

METHODS
This was a pilot RCT where women were recruited from the gynecological and subfertility clinic who were deemed to require an operative laparoscopy. If intraoperatively they were found to have periovarian adhesions, they were randomized into having adhesiolysis with Hyalobarrier Ò (study group) and without usage of Hyalobarrier Ò (control group). The method of conduct of this RCT is similar to studies previously conducted by our group [9]. Randomization was performed using computer-generated random numbers and the concealed, opaque, unlabeled envelope was opened after it had been determined that the patient met the intraoperative criteria. The patients were blinded to the allocation of treatment, and the assessor during follow-up was blinded to the treatment. The assessor who administered the questionnaires and recruited the patients was the research nurse who did not have prior knowledge of what type of surgery the patients underwent. Consent was obtained prior to any baseline assessments. The operation notes were stored in a sealed envelope within the patient notes and not accessed except during an emergency. In the latter case, the data would be used to the point of unblinding.
The randomization code was broken at the end of the follow-up period, and patients who wished to know were informed of their treatment groups.
Laparoscopic surgeons who were skilled in advanced laparoscopy performed the surgery.
Entry into the abdomen was either via the traditional Veress needle or a modified Hasson's technique of open entry. CO 2 was used for creating a pneumoperitoneum of 20 mmHg before a 10-mm trocar was inserted into the intraumbilical incision. Two or three more lateral ports were inserted depending on the site and extent of surgery. During surgery, the principles of microsurgery were followed, including meticulous hemostatic control and usage of constant irrigation to prevent tissue desiccation. Hyalobarrier Ò was applied to women randomized intraoperatively to the study group, and no Hyalobarrier Ò was applied to the group randomized to the control group.

Statistical Analysis
Given that adhesion reformation is significant after adnexal surgery (up to 90%), taking the mean of day 21 progesterone (±SD) for the control group to be 33 (7) nmol/l and the study group to be 51 (15.7) [5], the sample size for each group required to show a statistical significance at the p = 0.05 level between the study and control groups was calculated to be The data analysis was performed using SPSS.
T test comparisons will be used for continuous variables, and Chi 2 for discrete variables.

Compliance with Ethics Guidelines
The ethics number of this study was 11/H0504/ 6 and the ISRCTN number was ISRCTN1833588.
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Declaration of Helsinki (1964), as revised in 2013. Informed consent was obtained from all patients for being included in the study.
This research conformed to the CONSORT guidelines.

RESULTS
A total of 43 women were screened and 15 were randomized into the study group and 15 into the control group between December 2011 and January 2014. There was no difference in the There was no significant difference in the mean ± SD between the study versus control groups in terms of the hormonal profile (day 2 FSH and day 21 progesterone) before or after surgery ( Table 3). The 3-month postoperative day 10-12 follicular scan showed similar development of mature follicles in the study group (mean diameter of follicle 18.1 ± 3.9 mm) and the control group (mean diameter of follicle 19.8 ± 5.6 mm). There was also no difference in the endometrial thickness in the study (10.4 ± 2.2 mm) versus the control group (8.7 ± 0.6 mm) at the 3-month scan postoperatively (see Table 4).
Four women were pregnant in the study group (24%) and one in the control group (7%) cumulatively over 2 years. Amongst the pregnant patients in the study group, there were three spontaneous pregnancies within 18 months postsurgery and one pregnancy following an in vitro fertilization (IVF) treatment. In the control group, one woman was spontaneously pregnant within 12 months of surgery.
The majority of surgeons reported that the Hyalobarrier Ò Gel Endo was easy to apply. There was one questionnaire which was not returned. adhesiolysis can be as high as 67%, although a substantial number of patients were observed to have adhesion reformation at second-look laparoscopy [10]; but the increased risk of ectopic pregnancy remains high, especially if salpingostomy was also performed [11].

DISCUSSION
However, there are few data on the effects of these agents on fertility and pregnancy outcomes whether when applied intra-abdominally or intrauterine [12]. Very often, RCTs on these agents evaluate end points pertaining to adhesion reformation rather than pregnancy outcomes [13]. No studies have examined the postsurgical ovulatory status, endometrial thickness, and   Disclosures. Ying Cheong is the recipient of the Nordic grant for this study. This study was an investigator-led study with the support of an education grant from Nordic Pharma. Sarah Bailey and Jane Forbes has nothing to disclose.
Compliance to Ethics Guidelines. The ethics number of this study was 11/H0504/6 and the ISRCTN number was ISRCTN1833588. All