Anti-adhesion Gel versus No gel following Operative Hysteroscopy prior to Subsequent fertility Treatment or timed InterCourse (AGNOHSTIC), a randomised controlled trial: protocol
Van Wessel, S.; Hamerlynck, T.; Schutyser, V.et al.
[en] STUDY QUESTIONS: Does the application of anti-adhesion gel, compared to no gel, following operative hysteroscopy to treat intrauterine pathology in women wishing to conceive increase the chance of conception leading to live birth?
WHAT IS KNOWN ALREADY: Intrauterine adhesions (IUAs) following operative hysteroscopy may impair reproductive success in women of reproductive age. Anti-adhesion barrier gels may decrease the occurrence of IUAs, but the evidence on their effectiveness to improve reproductive outcomes is sparse and of low quality.
STUDY DESIGN, SIZE, DURATION: This multicentre, parallel group, superiority, blinded and pragmatic randomised controlled trial is being carried out in seven participating centres in Belgium. Recruitment started in April 2019. Women will be randomly allocated to treatment with anti-adhesion gel (intervention group) or no gel (control group). Sterile ultrasound gel will be applied into the vagina as a mock-procedure in both treatment arms. The patient, fertility physician and gynaecologist performing the second-look hysteroscopy are unaware of the allocated treatment. Power analysis, based on a target improvement of 15% in conception leading to live birth using
anti-adhesion gel, a power of 85%, a significance level of 5%, and a drop-out rate of 10%, yielded a number of 444 patients to be randomised. The baseline rate of conception leading to live birth in the control group is expected to be 45%.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Women of reproductive age (18–47 years), wishing to conceive (spontaneously or by fertility treatment) and scheduled for operative hysteroscopy to treat intrauterine pathology (endometrial polyps, myomas with uterine cavity deformation, uterine septa, IUAs or retained products of conception) are eligible for recruitment. Women may try to conceive from 3 to 6 weeks after receiving allocated treatment with follow-up ending at 30 weeks after treatment. If the woman fails to conceive within this timeframe, a second-look hysteroscopy will be scheduled within 2–6 weeks to check for IUAs. The primary endpoint is conception leading to live birth, measured at 30 weeks after randomisation. The secondary endpoints are time to conception, clinical pregnancy, miscarriage and ectopic pregnancy rates, measured at 30 weeks after receiving allocated treatment. The long-term follow-up
starts when the patient is pregnant and she will be contacted every trimester. STUDY FUNDING/COMPETING INTEREST(S): This work is funded by the Belgian Healthcare Knowledge Centre (KCE). The antiadhesion gel is supplied at no cost by Nordic Pharma and without conditions. Dr. Tomassetti reports grants and non-financial support from Merck SA, non-financial support from Ferring SA, personal fees and non-financial support from Gedeon-Richter, outside the submitted work. None of the other authors have a conflict of interest.
Disciplines :
Reproductive medicine (gynecology, andrology, obstetrics)
Author, co-author :
Van Wessel, S.
Hamerlynck, T.
Schutyser, V.
Tomassetti, C.
Wyns, C.
Nisolle, Michelle ; Université de Liège - ULiège > Département des sciences cliniques > Gynécologie - Obstétrique
Verguts, J.
Colman, R.
Weyers, S.
Bosteels, J.
Language :
English
Title :
Anti-adhesion Gel versus No gel following Operative Hysteroscopy prior to Subsequent fertility Treatment or timed InterCourse (AGNOHSTIC), a randomised controlled trial: protocol
Acunzo G, Guida M, Pellicano M, Tommaselli GA, Sardo Di SA, Bifulco G, Cirillo D, Taylor A, Nappi C. Effectiveness of autocross- linked hyaluronic acid gel in the prevention of intrauterine adhesions after hysteroscopic adhesiolysis: a prospective, randomized, controlled study. Hum Reprod 2003;18:1918-1921.
Bosteels J, Wessel S van, Weyers S, Broekman F, D'Hooghe T, Bongers M, Mol B. Hysteroscopy for treating subfertility associated with suspected major uterine cavity abnormalities. Cochrane Database Syst Rev 2018;12:CD009461.doi: 10.1002/14651858.CD009461.pub4.
Bosteels J, Weyers S, D'Hooghe TM, Torrance H, Broekmans FJ, Chua SJ, Mol BWJ. Anti-adhesion therapy following operative hysteroscopy for treatment of female subfertility. Cochrane Database Syst Rev2017;11:CD011110.doi: 10.1002/14651858.CD011110.pub3.
Buttram VC, Gomel V, Siegler A, De Cherney A, Gibbons W, March C. 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 Steril1988;49:944-955.
Clark TJ, Stevenson H. Endometrial Polyps and Abnormal Uterine Bleeding (AUB-P): what is the relationship, how are they diagnosed and how are they treated?Best Pract Res Clin Obstet Gynaecol 2017; 40:89-104.
Deans R, Abbott J. Review of intrauterine adhesions.J Minim Invasive Gynecol 2010;17:555-569.
Deans R, Vancaillie T, Ledger W, Liu J, Abbott JA. Live birth rate and obstetric complications following the hysteroscopic management of intrauterine adhesions including Asherman syndrome. Hum Reprod 2018;33:1847-1853.
Di Sardo SA, Spinelli M, Bramante S, Scognamiglio M, Greco E, Guida M, Cela V, Nappi C. Efficacy of a polyethylene oxide-sodium carboxymethylcellulose gel in prevention of intrauterine adhesions after hysteroscopic surgery.J Minim Invasive Gynecol 2011;18: 462-469.
Do JW, Lee YW, Park HJ, Park YS. The effectiveness of hyaluronic acid + sodium carboxymethyl cellulose in the prevention of intrauterine adhesion after intrauterine surgery.J. Korean Gynecol Endoscopy Minimally Invasive Surg2005;17:112-117.
Emanuel MH. Hysteroscopy and the treatment of uterine fibroids. Best Pract Res Clin Obstet Gynaecol 2015;29:920-929.
Guida M, Acunzo G, Spiezio Sardo A, Di Bifulco G, Piccoli R, Pellicano M, Cerrota G, Cirillo D, Nappi C. Effectiveness of autocrosslinked hyaluronic acid gel in the prevention of intrauterine adhesions after hysteroscopic surgery: a prospective, randomized, controlled study. Hum Reprod 2004;19:1461-1464.
Hamerlynck TWO, Vliet HAAM, Van Beerens A-S, Weyers S, Schoot BC. Hysteroscopic morcellation versus loop resection for removal of placental remnants: a randomized trial. J Minim Invasive Gynecol 2016;23:1172-1180.
Hanstede MMF, Meij E, Van Der Goedemans L, Emanuel MH. Results of centralized Asherman surgery, 2003-2013. Fertil Steril 2015;104: 1561-1568.e1.
Hooker AB, Leeuw R, de Ven PM, van de Bakkum EA, Thurkow AL, Vogel NEA, Vliet HAAM, van Bongers MY, Emanuel MH, Verdonkschot AEMet al. Prevalence of intrauterine adhesions after the application of hyaluronic acid gel after dilatation and curettage in women with at least one previous curettage: short-term outcomes of a multicenter, prospective randomized controlled trial. Fertil Steril 2017;107:1223-1231.e3.
Hooker AB, Leeuw RA, de Ven PM, van de Brölmann HAM, Huirne JAF. Reproductive performance after the application of hyaluronic acid gel after dilation and curettage in women who have experienced at least one previous curettage: long-term results of a multicenter prospective randomized trial. Fertil Steril 2018;110: 1231-1238.
Iaco PA, De Muzzupapa G, Bovicelli A, Marconi S, Bitti SR, Sansovini M, Bovicelli L. Hyaluronan derivative gel (HYALOBARRIER(r) gel) in intrauterine adhesion (IUA) prevention after operative hysteroscopy. Ellipse 2003;15-18.
Keltz MD, Greene AD, Morrissey MB, Vega M, Moshier E. Sonohysterographic predictors of successful hysteroscopic myomectomies. J Soc Laparoendosc Surg 2015;19:e2014.00105.
Kliman HJ, Frankfurter D. Clinical approach to recurrent implantation failure: evidence-based evaluation of the endometrium. Fertil Steril 2019;111:618-628.
Kodaman PH, Arici A. Intra-uterine adhesions and fertility outcome: How to optimize success?Curr Opin Obstet Gynecol 2007;19:207-214.
Mais V, Bracco GL, Litta P, Gargiulo T, Melis GB. Reduction of postoperative adhesions with an auto-crosslinked hyaluronan gel in gynaecological laparoscopic surgery: a blinded, controlled, randomized, multicentre study. Hum Reprod 2006;21:1248-1254.
Mais V, Cirronis MG, Peiretti M, Ferrucci G, Cossu E, Melis GB. Efficacy of auto-crosslinked hyaluronan gel for adhesion prevention in laparoscopy and hysteroscopy: a systematic review and metaanalysis of randomized controlled trials. Eur J Obstet Gynecol Reprod Biol 2012;160:1-5. Elsevier Ireland Ltd.
Metwally M, Gorvy D, Watson A, Li TC. Hyaluronic acid fluid agents for the prevention of adhesions after fertility-preserving gynecological surgery: a meta-analysis of randomized controlled trials. Fertil Steril 2007;87:1139-1146.
Munro MG, Critchley HOD, Fraser IS. The FIGO classification of causes of abnormal uterine bleeding in the reproductive years. Fertil Steril 2011;95:2204-2208.e3.
Pellicano M, Bramante S, Cirillo D, Palomba S, Bifulco G, Zullo F, Nappi C. Effectiveness of autocrosslinked hyaluronic acid gel after laparoscopic myomectomy in infertile patients: aprospective, randomized, controlled study. Fertil Steril 2003;80:441-444.
Pellicano M, Guida M, Bramante S, Acunzo G, Sardo ADS, Tommaselli GA, Nappi C. Reproductive outcome after autocrosslinked hyaluronic acid gel application in infertile patients who underwent laparoscopic myomectomy. Fertil Steril 2005;83: 498-500.
Salazar CA, Isaacson K, Morris S.A comprehensive review of Asherman's syndrome: causes, symptoms and treatment options. Curr Opin Obstet Gynecol 2017;29:249-256.
Schenker JG, Margalioth EJ. Intrauterine adhesions: an updated appraisal. Internet1982;37:593-610.
Sellmyer MA, Desser TS, Maturen KE, Jeffrey RB, Kamaya A. Physiologic, histologic, and imaging features of retained products of conception. Radio Graphics [Internet]2013;33:781-796.
Taskin O, Sadik S, Onoglu A, Gokdeniz R, Erturan E, Burak F, Wheeler JM. Role of endometrial suppression on the frequency of intrauterine adhesions after resectoscopic surgery.J Am Assoc Gynecol Laparosc 2000;7:351-354.
Yang JH, Chen MJ, Chen C, Der Chen SU, Ho HN, Yang YS. Optimal waiting period for subsequent fertility treatment after various hysteroscopic surgeries. Fertil Steril 2013;99:2092-2096.e3. Elsevier Inc.
Zegers-Hochschild F, Adamson GD, J De M, Ishihara O, Mansour R, Nygren K, Sullivan E, Vanderpoel S. International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary of ART terminology. Res Train Hum Reprod World Heal Organ 2009;2009:92: 1520-1524.
Chan YY, Jayaprakasan K, Tan A, Thornton JG, Coomarasamy A, Raine-Fenning NJ. Reproductive outcomes in women with congenital uterine anomalies: a systematic review. Ultrasound Obstet Gynecol 2011;38:371-382.
Grimbizis GF, Gordts S, Spiezio Sardo A, Di Brucker S, Angelis C, De Gergolet M, Li T-C, Tanos V, Brölmann H, Gianaroli Let al. The ESHRE-ESGE consensus on the classification of female genital tract congenital anomalies. Gynecol Surg2013;10:199-212.
Iaco PA, De Muzzupapa G, Bigon E, Pressato D, Donà M, Pavesio A, Bovicelli L. Efficacy of a hyaluronan derivative gel in postsurgical adhesion prevention in the presence of inadequate hemostasis. Surgery 2001;130:60-64.
Moher D, Hopewell S, Schulz KF, Montori V, Gøtzsche PC, Devereaux PJ, Elbourne D, Egger M, Altman DG. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010;340:c869-c869.
Pucciarelli S, Codello L, Rosato A, Bianco P, Del Vecchiato G, Lise M. Effect of antiadhesive agents on peritoneal carcinomatosis in an experimental model. Br J Surg 2003;90:66-71.
Renier D, Bellato P, Bellini D, Pavesio A, Pressato D, Borrione A. Pharmacokinetic behaviour of ACP gel, an autocrosslinked hyaluronan derivative, after intraperitoneal administration. Biomaterials 2005;26:5368-5374.
Ventolini G, Zhang M, Gruber J. Hysteroscopy in the evaluation of patients with recurrent pregnancy loss: a cohort study in a primary care population. Surg Endosc2004;18:1782-1784.
