Experience of KAMC-R using gonadotropin releasing hormone (GnRH) agonist for triggering final oocyte maturation in a GnRH antagonist protocol for prevention of ovarian hyperstimulation syndrome

Experience of KAMC-R using gonadotropin releasing hormone (GnRH) agonist for triggering final oocyte maturation in a GnRH antagonist protocol for prevention of ovarian hyperstimulation syndrome | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Experience of KAMC-R using gonadotropin releasing hormone (GnRH) agonist for triggering final oocyte maturation in a GnRH antagonist protocol for prevention of ovarian hyperstimulation syndrome Haya Al Fozan, Abeer Alkredes, Abdulrahman AlFadhel, Eman Dawood, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9114982/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Objective The utilization of gonadotropin-releasing hormone (GnRH) agonist as a substitute for human chorionic gonadotropin (hCG) as a trigger for final oocyte maturation in antagonist in vitro fertilization (IVF) cycles has been proposed as a strategy for mitigating the risk of ovarian hyperstimulation syndrome (OHSS) in predicted high responders. This study aimed to evaluate the incidence of OHSS at King Abdulaziz Medical City, Riyadh, using GnRH agonist triggering final oocyte maturation in IVF cycles stimulated with gonadotropin-releasing hormone (GnRH) antagonist protocol. Additionally, the clinical outcomes of fresh and frozen-thawed embryo transfers (FET) in these cycles were evaluated. Method A retrospective cohort analysis, clinical trial number not applicable, was undertaken to evaluate the outcomes of GnRH agonist triggering in women at high risk of OHSS who underwent ovarian stimulation using a GnRH antagonist protocol. The study population comprised all women who underwent GnRH agoinst triggered for final oocyte maturation between January 2017 and December 2022 at the Fertility and Reproductive Endocrinology Department, Women’s Health Hospital (WHH), King Abdulaziz Medical City (KAMC), Riyadh, Saudi Arabia. Relevant clinical and demographic data were extracted from electronic medical records and analyzed using Statistical Package for Social Sciences (SPSS) version 28.0. Results A total of 97 infertile women at high risk for OHSS who fulfilled the inclusion criteria were included in the study. The mean age of the women was 30.77 ± 4.94 years. The mean serum estradiol (E2) level on the day of trigger was 18395 ± 4077 pmol/L, and the mean number of follicles at trigger day was 22.9 ± 6.44. The mean number of mature oocytes was 13.9 ± 7.44. Of the 97 women included in the study, 45 underwent fresh embryo transfers, with a pregnancy rate of 49%. While 49 had their embryos frozen and underwent subsequent frozen embryo transfers in later cycles, with a 38.8% pregnancy rate. There was no significant difference in pregnancy rates between fresh and frozen embryo transfers (P value = 0.65). In the fresh embryos transfer group, additional luteal phase support was given in the form of progesterone injection. None of the cases developed OHSS. Conclusion GnRH agonist triggering for IVF is an efficient and safe approach for women at high risk of OHSS, with negligible risk of OHSS and comparable pregnancy rates to hCG triggering, regardless of whether embryos are transferred fresh or frozen. GnRH agonist trigger GnRH antagonist protocol IVF Ovarian Hyperstimulation Syndrome fresh embryo transfer frozen embryo ransfer pregnncy rate Saudi Arabia Introduction Ovarian hyperstimulation syndrome (OHSS) is a complication of controlled ovarian hyperstimulation (COH) which can result in significant morbidity ( 1 ). It is associated with ovarian enlargement, ascites, hydrothorax, thromboembolism, and electrolyte imbalance. It can also lead to the cancellation of IVF cycles, prolonged bed rest and have a significant emotional and economic effect ( 2 ). Although the incidence of severe OHSS is < 2%, but it is a significant medical issue for the fertility and reproductive specialty, especially with the increase in the number of IVF cycles performed annually ( 1 , 3 ). The main characteristic is an increase in capillary permeability due to the release of human chorionic gonadotropin mediators; this mechanism is not fully understood ( 4 ). Continual application of gonadotropin releasing hormone (GnRH)agonist results in the down regulation of receptors. However, in gonadotropin releasing hormone (GnRH) antagonist stimulated cycles, administration of a bolus of GnRH agonist would result in a surge of gonadotropins released by the pituitary and stimulating ovulation and final oocyte maturation ( 3 , 5 ).Administration of GnRH agonist to induce final oocyte maturation in ovarian stimulation with a GnRH antagonist protocol compared with human chorionic gonadotropin (hCG) has been used to reduce the incidence of OHSS ( 6 – 9 ). The GnRH agonist trigger has equal oocyte yield, maturity, fertilization, implantation, and pregnancy when compared with the hCG trigger in stimulation with GnRH antagonist protocol. In addition, greater oocytes were retrieved and more excellent blasts were reported ( 8 ). LH surge induced by GnRH agonist was able to induce oocyte maturation and significantly had a shorter duration than that observed on a natural cycle, which led to compromised corpus luteal function and early luteolysis ( 5 , 9 ). The characteristics of this mechanism have been exploited clinically with the adoption of GnRH agonist trigger in women at risk of OHSS and avoidance of hCG trigger ( 9 ). Bodri et al, was considered the largest study using GnRH agonist to trigger ovulation, where 2,077 stimulated egg donor cycles in 1,171 donors reported an incidence of 1.26% moderate to severe OHSS in the hCG group compared to no cases in the GnRH agonist group ( 10 ). A concern with a GnRH agonist trigger during GnRH antagonist IVF cycles is the potential risk of having an inadequate luteal phase. A single dose of GnRH agonist induces an endogenous LH surge that has a much shorter half life than hCG, resulting in compromised corpus luteum formation and a shorter duration of the luteal phase ( 6 , 11 ). Initial reports indicated poor clinical outcomes, including a higher incidence of early pregnancy loss and compromised pregnancy rates ,when a GnRH agonist was used for final oocyte maturation ( 11 , 12 ). The observed lower success rates in fresh cycles triggered with GnRH agonist is due to issuses with endometrium in the luteal phase rather than the quality of embryos ( 13 ).Therefore, elective cryopreservation of all embryos followed by subsequent transfer presents a preferable approach, with comparable pregnancy rates after frozen embryo transfer in GnRH agonist triggered cycles to hCG triggered cycles ( 14 – 17 ). Griesinger and collegues, in their systematic review reported that the likelihood of an ongoing clinical pregnancy after GnRH agonist triggering is significantly lower as compared to standard hCG treatment ( 18 ). Many studies recommended Freeze all strategy when GnRH agonist is used to trigger ovulation in patients at risk of OHSS to prevent OHSS with a good pregnancy rate( 18 – 20 ). Recent studies have alleviated concerns about GnRHa triggering by showing that intensive luteal phase support protocols can achieve IVF success rates comparable to hCG triggers with moderate quality evidence indicating similar cumulative live birth rates and ongoing pregnancy rates between fresh and frozen embryo transfer strategies ( 21 – 24 ). A systematic review by Tjitske Zaat et al. found moderate quality evidence indicating similar cumulative live birth rates and ongoing pregnancy rates between fresh and frozen embryo transfer strategies( 25 ). In this study, we evaluated the incidence of ovarian hyper stimulation syndrome using gonadotropin releasing hormone agonist (triptorelin dose of 0.2 mg subcutaneous (Decapeptyl triggering final oocyte maturation in IVF cycles stimulated with gonadotropin releasing hormone antagonist protocol. Additionally, this study evaluated the clinical outcomes of fresh and frozen thawed embryo transfers in these cycles. Materials and Methods Study Setting: This study was conducted at the Ministry of National Guard Health Affairs (MNGHA), King Abdulaziz Medical City, Riyadh (KAMC-R), Women’s Health Hospital, Department of Fertility and Reproductive Medicine. KAMC-R is one of the largest tertiary medical cities in KSA and the Middle East. It provides the highest level of international health standards. Study Design : This was a retrospective cohort study, clinical trial number: Not applicable. involving all patients from January 2017 to December 2022 who had IVF cycles using GnRH antagonist protocol and GnRH agonist for triggering final oocyte maturation, and were at risk of developing OHSS. Study Subjects: All IVF-ICSI women in a GnRH antagonist protocol cycles at risk of developing OHSS and received GnRH agonist as triggering for final oocyte maturation from January 2017 to December 2022 were included. The criteria used for identifying women with a high risk of developing OHSS included ≥ 15 follicles measuring ≥ 12 mm in size on trigger day and/or a high Estradiol level of ≥ 20,000 pmol/L. All other cycles used alternative techniques to trigger ovulation such as hCG or dual trigger, the use of GnRH agonist triptorelin (Decapeptyl) in the stimulation protocol, and women with no risk of OHSS were excluded. Data Collection and management Data was retrieved from the hospital medical records and exported and interpreted through an Excel sheet. Statistical Package for the Social Sciences (SPSS) (Release 28.0; SPSS, Chicago, IL) was used for analysis. Descriptive analysis including mean, standard deviations were calculated for continuous variables. Frequencies and proportions were calculated for categorical variables. To compare pregnancy rates between the two groups (fresh vs frozen) Chi-Square Test of Independence was used. Ethical Considerations: Subject privacy and confidentiality were assured, no identifiers were collected, and all the data were kept in a secure place within MNGHA premises both hard and soft copies, with access allowed to researchers only. Approval for this study was obtained from the Institutional Review Board IRB at the King Abdullah Medical Research Center (KAMRC) with ethical clearance RYD-23-419812-17800 NRC23R/026/01, date 1-12-2023. Permission to collect data from the hospital was obtained before commencing data collection. Treatment protocol Controlled ovarian hyperstimulation (COH) was achieved using recombinant FSH (rFSH; Follitropin alfa; Merck Serona),Purified Human Menopausal Gonadotropin (Menogon ; Ferring) and highely Purified Human Menopausal Gonadotropin and Merional ( Merional ; Ferring). The starting dose depends on the patient’s age, body mass index, antral follicular count (AFC),FSH level and or AMH, and previous ovarian response. The GnRH agonist Cetrorelex( Cetrotide; Merck Serona ) 0.25 mg subcuteonsouly was started at day 5 of stimulation. Monitoring of follicular growth was achieved with serial ultrasound and serum E 2 measurements, and the dose of gonadotropins is adjusted, if necessary, according to follicular response.When two or three leading follicles were measuring 18 mm in diameter, women received SC Triptorelin ( Decapeptyl ; Ferring) in a dose of 0.2 mg. 35 hours later, ovum pick up (OPU) was performed under ultrasound guidance. If the patient has no OHSS symptoms , they are councelled for fresh transfer .In our standerd IVF protocol, we transfer 2 embryos and Cyclogest vaginal supposoties 400 microgram twice a day is used as leutal phase support. The fresh embryo transfer group received additional luteal phase support in the form of prgesterone injections ,Prolutex 25 mg intramascularly daily. Result A total of 97 infertile women at high risk for OHSS who fulfilled the inclusion criteria were included in the study. The mean age was 30.77 ±4.94 years. The mean BMI was 27.46 ±5.54 and 75% were nulliparous. Table 1 shows the characteristics of infertility. Gonal F was the most commonly used medication for ovarian stumulation , used in 82.7% of the total women .The mean serum estradiol (E2) level on the day of trigger was 18395 ± 4077 pmol/L, and the mean number of follicles before trigger was 22.9 ± 6.44.The mean number of mature oocytes was 13.9 ± 7.44. Table 2 shows the outcomes of ovarian stimulation. Of the 97 patients included in the study, 45 women underwent fresh embryo transfers, resulting in 22 pregnancies with pregnancy rate of 49% . While 49 women had their embryos frozen and underwent subsequent frozen embryo transfer in later cycles, resulting in 19 pregnancies with a 38.8% pregnancy rate. Three patients were singles and were for oocytes cryopreservation. There was no significant difference in pregnancy rates between fresh and frozen embryo transfers ( P value =0.65). None of the cases developed OHSS. Table 3 presents the details of pregnancy outcomes for fresh and frozen embryo transfers. Discussion Our study demonstrated that the use of gonadotropin releasing hormone agonist for triggering of ovulation in gonadotropin releasing hormone antagonist cycles effectively eliminated the risk of OHSS in high risk patients. This finding is consistent with previous studies using prospective randomized controlled studies ,prospective trials and reviews (15, 21,26-29). The mean serum estradiol (E2) level on the day of trigger was 18395 ± 4077 pmol/L, and the mean number of follicles was 22.9 ± 6.44, indicating a high ovarian response. The mean number of mature oocytes was 13.9 ± 7.44, supporting the adequacy of follicular response and oocyte maturation with GnRH agonist triggering. Itskovitz-Eldor and colleagues reported that the median estradiol concentration on the day of trigger was 3,675 pg/ml ( 13,500 pmol/L), and the mean oocyte yield was 23.4 ± 15.4, with 83% of retrieved oocytes being mature (5). Griesinger et al used GnRH agonist triggering when estradiol ≥ 4000 pg/ml ( 14,700 pmol/L), and in both studies none of the recruited patients developed symptoms of OHSS (15).Our findings are consistent with previous studies, demonstrating that GnRH agonist triggering can achieve adequate follicular response and oocyte maturation, with a low risk of OHSS(5,6,8). The estradiol level is comparable with those reported in the literature, supporting the effectiveness of GnRH agonist triggering in high ovarian responders (5,15). In our study, 45 women underwent freshembryo transfers, resulting in 22 pregnancies with a pregnancy rate of 49% .While 49 women had their embryos frozen and underwent subsequent frozen embryos transfer in later cycles, resulting in 19 pregnancies with a 38.8% pregnancy rate. Three patients were singles and were for oocytes cryopreservation. There was no significant difference in pregnancy rates between fresh and frozen embryo transfers ( P value =0.65). A concern with GnRH agonist trigger during GnRH antagonist IVF cycles is the potential risk of having an inadequate luteal phase. Aflatoonianet al , and Kol S and Segal L , used 1500 IU hCG on the day of embryo transfer, in addition to progesterone suppositories for luteal phase support , in patients triggered with GnRH agonist and there were no significant differences between FET and fresh embryo transfer groups regarding chemical,clinical ongoing pregnancy rates, an live birth (30,31). However using GnRH agonist triggering followed by fresh embryo transfer with intensified luteal phase support using low dose hCG was associated with a higher incidence of moderate-to-severe OHSS [23]. Engmann et la used aggressive steroid supplementation with progesterone and estrogen, 50 mg IM Progesterone in oil daily starting the evening after oocyte retrieval and 0.1 mg transdermal E2 patches every other day starting the day after oocyte retrieval (21). Society of Obstetricians and Gynecologist of Canada (SOGC) in their clinical practice guideline, stated that progesterone should be used for leutal phase support rather than hCG(24). In our study, Proluton Depot (hydroxyprogesterone caproate) was used for extra luteal phase support, in addition to our standard letualphase support (Cyclogest 400mg twice daily) in fresh embryo transfers, resulting in good comparable pregnancy rates in both fresh and frozen transfers. Notably, adherence to the mentioned criteria for the GnRH agonist trigger, resulted in zero reported cases of OHSS. Conclusion In conclusion, the utilization of GnRH agonist triggering in contemporary IVF practice for high risk women susceptible to OHSS who have undergone ovarian stimulation with a GnRH antagonist protocol is an efficient and safe approach, associated with a negligible risk of OHSS development. The pregnancy rates achieved with GnRH agonist triggering are comparable to those obtained with hCG triggering,irrespective of whether fresh or frozen thawed embryo transfer is employed. Declarations The Helsinki declaration statement: This study was conducted in accordance with the principles of the Declaration of Helsinki . Ethics declaration and consent for publication: Subject privacy and confidentiality were assured, no identifiers were collected, and all the data were kept in a secure place within MNGHA premises both hard and soft copies, with access allowed to researchers only. Approval for this study was obtained from the Institutional Review Board IRB at the King Abdullah Medical Research Center (KAMRC) with ethical clearance RYD-23-419812-17800 NRC23R/026/01, date 1-12-2023. Permission to collect data from the hospital was obtained before commencing data collection. As this was a retrospective secondary data analysis, verbal informed consent was obtained from all participants included in the study. Funding declaration: No, this research did not receive funding. Competing interest declaration: No, I declare that the authors have no competing interests as defined by BMC, or other interests that might be perceived to influence the results and/or discussion reported in this paper. Data availability statement: The datasets generated and/or analysed during the current study are not publicly available but are available from the corresponding author on reasonable request. Availability of Data and Materials (ADM Statement): The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Author contribution decelaration: H.F: Supervised the whole project, collected data, wrote the main manuscript, and did statistical analysis. A.K: Collected data and wrote the main manuscript. A.F: Collected data and wrote the main manuscript. E.D: Statistical analysis. S.A, F.A, and G.D: Collected data. References Abramov Y, Elchalal U, Schenker JG. Severe OHSS: An 'epidemic' of severe OHSS: a price we have to pay? Hum Reprod. 1999;14(9):2181-3. Busso C, Soares S, Pellicer A. Prevention of ovarian hyperstimulation syndrome. In: Connor RF, editor. UpToDate. Wolters Kluwer, Waltham (MA: (2024). https://www.uptodate.com/contents/prevention-of-ovarian-hyperstimulation-syndrom Delvigne A, Rozenberg S. Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review. Hum Reprod Update. 2002;8(6):559-77. Smith V, Osianlis T, Vollenhoven B. Prevention of Ovarian Hyperstimulation Syndrome: A Review. Obstet Gynecol Int. 2015;2015:514159. Itskovitz J, Boldes R, Levron J, Erlik Y, Kahana L, Brandes JM. Induction of preovulatory luteinizing hormone surge and prevention of ovarian hyperstimulation syndrome by gonadotropin-releasing hormone agonist. Fertil Steril. 1991;56(2):213-20. Fauser BC, de Jong D, Olivennes F, Wramsby H, Tay C, Itskovitz-Eldor J, et al. Endocrine profiles after triggering of final oocyte maturation with GnRH agonist after cotreatment with the GnRH antagonist ganirelix during ovarian hyperstimulation for in vitro fertilization. J Clin Endocrinol Metab. 2002;87(2):709-15. Griffin D, Benadiva C, Kummer N, Budinetz T, Nulsen J, Engmann L. Dual trigger of oocyte maturation with gonadotropin-releasing hormone agonist and low-dose human chorionic gonadotropin to optimize live birth rates in high responders. Fertil Steril. 2012;97(6):1316-20. .Gustofson R, Surrey E, Minjarez D, Schoolcraft W. GnRH-agonist (GnRH-A) trigger in GnRH-antagonist cycles compared to human chorionic gonadotropin (hCG) trigger in long luteal leuprolide downregulation (LL) cycles for hyperresponding oocyte donors. Fertil Steril. 2011;96(3):S260. Itskovitz-Eldor J, Kol S, Mannaerts B. Use of a single bolus of GnRH agonist triptorelin to trigger ovulation after GnRH antagonist ganirelix treatment in women undergoing ovarian stimulation for assisted reproduction, with special reference to the prevention of ovarian hyperstimulation syndrome: preliminary report. Hum Reprod. 2000;15(9):1965-8. Bodri D, Guillén JJ, Galindo A, Mataró D, Pujol A, Coll O. Triggering with human chorionic gonadotropin or a gonadotropin-releasing hormone agonist in gonadotropin-releasing hormone antagonist-treated oocyte donor cycles: findings of a large retrospective cohort study. Fertil Steril. 2009;91(2):365-71. Beckers NG, Macklon NS, Eijkemans MJ, Ludwig M, Felberbaum RE, Diedrich K, Bustion S, Loumaye E, Fauser BC. Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment.The Journal of Clinical Endocrinology & Metabolism. 2003 ;88(9):4186-92. Kolibianakis EM, Schultze-Mosgau A, Schroer A, van Steirteghem A, Devroey P, Diedrich K, et al. A lower ongoing pregnancy rate can be expected when GnRH agonist is used for triggering final oocyte maturation instead of HCG in patients undergoing IVF with GnRH antagonists. Hum Reprod 2005;20:2887–92. 51 Garcia-Velasco JA, Motta L, López A, Mayoral M, Cerrillo M, Pacheco A. Low-dose human chorionic gonadotropin versus estradiol/progesterone luteal phase support in gonadotropin-releasing hormone agonist–triggered assisted reproductive technique cycles: understanding a new approach. Fertility and sterility. 2010 ;94(7):2820-3. Eldar-Geva T, Zylber-Haran E, Babayof R, Halevy-Shalem T, Ben-Chetrit A, Tsafrir A, Varshaver I, Brooks B, Margalioth EJ. Similar outcome for cryopreserved embryo transfer following GnRH-antagonist/GnRH-agonist, GnRH-antagonist/HCG or long protocol ovarian stimulation. Reproductive biomedicine online. 2007 ;14(2):148-54. Griesinger G, Von Otte S, Schroer A, Ludwig AK, Diedrich K, Al-Hasani S, Schultze-Mosgau A. Elective cryopreservation of all pronuclear oocytes after GnRH agonist triggering of final oocyte maturation in patients at risk of developing OHSS: a prospective, observational proof-of-concept study. Human Reproduction. 2007 ;22(5):1348-52. Herrero L, Pareja S, Losada C, Cobo AC, Pellicer A, Garcia-Velasco JA. Avoiding the use of human chorionic gonadotropin combined with oocyte vitrification and GnRH agonist triggering versus coasting: a new strategy to avoid ovarian hyperstimulation syndrome. Fertility and sterility. 2011;95(3):1137-40. Deepika K, Suvarna R, Sumi M, Snehal D, Arveen V, Anuja K, Gautham P, Kamini R. HCG trigger versus GnRH agonist trigger in PCOS patients undergoing IVF cycles: frozen embryo transfer outcomes. JBRA Assisted Reproduction. 2021;25(1):48. Griesinger G, Diedrich K, Devroey P, Kolibianakis EM. GnRH agonist for triggering final oocyte maturation in the GnRH antagonist ovarian hyperstimulation protocol: a systematic review and meta-analysis. Human reproduction update. 2006;12(2):159-68. Atkinson P, Koch J, Ledger WL. Gn RH agonist trigger and a freeze‐all strategy to prevent ovarian hyperstimulation syndrome: A retrospective study of OHSS risk and pregnancy rates. Australian and New Zealand Journal of Obstetrics and Gynaecology. 2014;54(6):581-5. Griesinger G, Schultz L, Bauer T, Broessner A, Frambach T, Kissler S. Ovarian hyperstimulation syndrome prevention by gonadotropin-releasing hormone agonist triggering of final oocyte maturation in a gonadotropin-releasing hormone antagonist protocol in combination with a “freeze-all” strategy: a prospective multicentric study. Fertility and sterility. 2011;95(6):2029-33. Engmann L, DiLuigi A, Schmidt D, Nulsen J, Maier D, Benadiva C. The use of gonadotropin-releasing hormone (GnRH) agonist to induce oocyte maturation after cotreatment with GnRH antagonist in high-risk patients undergoing in vitro fertilization prevents the risk of ovarian hyperstimulation syndrome: a prospective randomized controlled study. Fertil Steril 2008;89:84–91. 55. Humaidan P, Bungum L, Bungum M, Yding Andersen C. Rescue of corpus luteum function with peri-ovulatory HCG supplementation in IVF/ICSI GnRH antagonist cycles in which ovulation was triggered with a GnRH agonist: a pilot study. Reprod Biomed Online 2006;13:173–8. Humaidan P, Ejdrup Bredkjaer H, Westergaard LG, Yding Andersen C. 1,500 IU human chorionic gonadotropin administered at oocyte retrieval rescues the luteal phase when gonadotropin-releasing hormone agonist is used for ovulation induction: a prospective, randomized, controlled study. Fertil Steril 2010;93:847–54. 57. Corbett S, Shmorgun D, Claman P, Cheung A, Sierra S, Carranza-Mamane B, Case A, Dwyer C, Graham J, Havelock J, Healey S. The prevention of ovarian hyperstimulation syndrome. Journal of Obstetrics and Gynaecology Canada. 2014;36(11):1024-33. Zaat T, Zagers M, Mol F, Goddijn M, van Wely M, Mastenbroek S. Fresh versus frozen embryo transfers in assisted reproduction. Cochrane Database of Systematic Reviews. 2021(2). Cerrillo M, Rodríguez S, Mayoral M, Pacheco A, Martínez-Salazar J, Garcia-Velasco JA. Differential regulation of VEGF after final oocyte maturation with GnRH agonist versus hCG: a rationale for OHSS reduction. Fertility and sterility. 2009 Apr 1;91(4):1526-8.patients undergoing in vitro fertilization prevents the risk of ovarian hyperstimulation syndrome: a prospective randomized controlled study. Fertility and sterility. 2008 ;89(1):84-91. Miller I, Chuderland D, Ron-El R, Shalgi R, Ben-Ami I. GnRH agonist triggering modulates PEDF to VEGF ratio inversely to hCG in granulosa cells. The Journal of Clinical Endocrinology & Metabolism. 2015 ;100(11):E1428-36. Casper RF. Basic understanding of gonadotropin-releasing hormone–agonist triggering. Fertility and sterility. 2015;103(4):867-9. Castillo JC, Haahr T, Martínez-Moya M, Humaidan P. Gonadotropin-releasing hormone agonist ovulation trigger—beyond OHSS prevention. Upsala journal of medical sciences. 2020;125(2):138-43. Aflatoonian A, Mansoori-Torshizi M, Mojtahedi MF, Aflatoonian B, Khalili MA, Amir-Arjmand MH, Soleimani M, Aflatoonian N, Oskouian H, Tabibnejad N, Humaidan P. Fresh versus frozen embryo transfer after gonadotropin-releasing hormone agonist trigger in gonadotropin-releasing hormone antagonist cycles among high responder women: a randomized, multi-center study. International journal of reproductive biomedicine. 2018;16(1):9. Kol S, Segal L. GnRH agonist triggering followed by 1500 IU of HCG 48 h after oocyte retrieval for luteal phase support. Reprod Biomed Online. 2020;41(5):854-858. Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Tables.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 01 May, 2026 Reviewers agreed at journal 01 May, 2026 Reviewers invited by journal 21 Apr, 2026 Editor assigned by journal 20 Apr, 2026 Editor invited by journal 31 Mar, 2026 Submission checks completed at journal 30 Mar, 2026 First submitted to journal 30 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9114982","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":631078812,"identity":"18511bcd-9b74-4b1d-a2e9-a9650d0c3435","order_by":0,"name":"Haya Al Fozan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5UlEQVRIiWNgGAWjYBAC9gYgwdhgAyR5wAKMDYS08BwAK0sjXcthUrSwtz/8XLjjfLQ5/9qDHxhzbGQb+A8/wK+F50Cy9Mwzt3N3zniXLMG4Lc24QSLNAK8We4mEA9K8bbdzN9w4YwDUcjixQYIBvxYeicTm37xt50BajH8wbvuf2MB//AMBLclsQFsO5G4432MGtOVAYgNDDgFbeI6xWfO2JQNt4TGzSNyWbNwmkVOAXwt7++PbvG12QFvOGN/4uM1Otp//+Aa8WhBAIoGBAYgY2IhUDwT8B4hXOwpGwSgYBSMLAAAgMUqwJSKiiwAAAABJRU5ErkJggg==","orcid":"","institution":"Ministry of National Guard Health Affairs, King Abdulaziz Medical City- R, Women’s Health Hospital","correspondingAuthor":true,"prefix":"","firstName":"Haya","middleName":"Al","lastName":"Fozan","suffix":""},{"id":631078813,"identity":"a5cf0d9f-a506-474b-8473-0bdc6a899bbd","order_by":1,"name":"Abeer Alkredes","email":"","orcid":"","institution":"Ministry of National Guard Health Affairs. King Abdulaziz Medical City-R, Women’s Health Hospital","correspondingAuthor":false,"prefix":"","firstName":"Abeer","middleName":"","lastName":"Alkredes","suffix":""},{"id":631078815,"identity":"5d695645-d185-44ce-8468-426a3b66b628","order_by":2,"name":"Abdulrahman AlFadhel","email":"","orcid":"","institution":"Ministry of National Guard Health Affairs. King Abdulaziz Medical City-R, Women’s Health Hospital","correspondingAuthor":false,"prefix":"","firstName":"Abdulrahman","middleName":"","lastName":"AlFadhel","suffix":""},{"id":631078817,"identity":"840fde0f-0499-4a18-b0d1-6ca1410fb120","order_by":3,"name":"Eman Dawood","email":"","orcid":"","institution":"King Saud bin Abdulaziz University for Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Eman","middleName":"","lastName":"Dawood","suffix":""},{"id":631078821,"identity":"abf34fc6-a7a5-42dc-89c3-9759259764dd","order_by":4,"name":"Sadeem Alsaqer","email":"","orcid":"","institution":"King Saud bin Abdulaziz University for Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Sadeem","middleName":"","lastName":"Alsaqer","suffix":""},{"id":631078825,"identity":"afd7827e-7cfc-4052-b3c6-7908bd265666","order_by":5,"name":"Fatema Alanazi","email":"","orcid":"","institution":"King Saud bin Abdulaziz University for Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Fatema","middleName":"","lastName":"Alanazi","suffix":""},{"id":631078827,"identity":"85bdd639-670a-43b3-8611-f48c3c5bc993","order_by":6,"name":"Ghala Aldarwish","email":"","orcid":"","institution":"King Saud bin Abdulaziz University for Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Ghala","middleName":"","lastName":"Aldarwish","suffix":""}],"badges":[],"createdAt":"2026-03-13 12:54:58","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9114982/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9114982/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108182466,"identity":"5301c9d4-00ad-432f-9c9d-079de7ee23b1","added_by":"auto","created_at":"2026-04-30 08:59:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":171057,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9114982/v1/1182699f-f167-439b-b428-312e6e0d043d.pdf"},{"id":108122610,"identity":"64da4985-8889-4a60-91f8-6b454bb104a1","added_by":"auto","created_at":"2026-04-29 14:46:06","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":34379,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-9114982/v1/027a858ebe81177d6bd1caa9.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Experience of KAMC-R using gonadotropin releasing hormone (GnRH) agonist for triggering final oocyte maturation in a GnRH antagonist protocol for prevention of ovarian hyperstimulation syndrome","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOvarian hyperstimulation syndrome (OHSS) is a complication of controlled ovarian hyperstimulation (COH) which can result in significant morbidity (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). It is associated with ovarian enlargement, ascites, hydrothorax, thromboembolism, and electrolyte imbalance. It can also lead to the cancellation of IVF cycles, prolonged bed rest and have a significant emotional and economic effect (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Although the incidence of severe OHSS is \u0026lt;\u0026thinsp;2%, but it is a significant medical issue for the fertility and reproductive specialty, especially with the increase in the number of IVF cycles performed annually (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The main characteristic is an increase in capillary permeability due to the release of human chorionic gonadotropin mediators; this mechanism is not fully understood (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Continual application of gonadotropin releasing hormone (GnRH)agonist results in the down regulation of receptors. However, in gonadotropin releasing hormone (GnRH) antagonist stimulated cycles, administration of a bolus of GnRH agonist would result in a surge of gonadotropins released by the pituitary and stimulating ovulation and final oocyte maturation (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).Administration of GnRH agonist to induce final oocyte maturation in ovarian stimulation with a GnRH antagonist protocol compared with human chorionic gonadotropin (hCG) has been used to reduce the incidence of OHSS (\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). The GnRH agonist trigger has equal oocyte yield, maturity, fertilization, implantation, and pregnancy when compared with the hCG trigger in stimulation with GnRH antagonist protocol. In addition, greater oocytes were retrieved and more excellent blasts were reported (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). LH surge induced by GnRH agonist was able to induce oocyte maturation and significantly had a shorter duration than that observed on a natural cycle, which led to compromised corpus luteal function and early luteolysis (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). The characteristics of this mechanism have been exploited clinically with the adoption of GnRH agonist trigger in women at risk of OHSS and avoidance of hCG trigger (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Bodri et al, was considered the largest study using GnRH agonist to trigger ovulation, where 2,077 stimulated egg donor cycles in 1,171 donors reported an incidence of 1.26% moderate to severe OHSS in the hCG group compared to no cases in the GnRH agonist group (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). A concern with a GnRH agonist trigger during GnRH antagonist IVF cycles is the potential risk of having an inadequate luteal phase. A single dose of GnRH agonist induces an endogenous LH surge that has a much shorter half life than hCG, resulting in compromised corpus luteum formation and a shorter duration of the luteal phase (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Initial reports indicated poor clinical outcomes, including a higher incidence of early pregnancy loss and compromised pregnancy rates ,when a GnRH agonist was used for final oocyte maturation (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). The observed lower success rates in fresh cycles triggered with GnRH agonist is due to issuses with endometrium in the luteal phase rather than the quality of embryos (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).Therefore, elective cryopreservation of all embryos followed by subsequent transfer presents a preferable approach, with comparable pregnancy rates after frozen embryo transfer in GnRH agonist triggered cycles to hCG triggered cycles (\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eGriesinger and collegues, in their systematic review reported that the likelihood of an ongoing clinical pregnancy after GnRH agonist triggering is significantly lower as compared to standard hCG treatment (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Many studies recommended Freeze all strategy when GnRH agonist is used to trigger ovulation in patients at risk of OHSS to prevent OHSS with a good pregnancy rate(\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRecent studies have alleviated concerns about GnRHa triggering by showing that intensive luteal phase support protocols can achieve IVF success rates comparable to hCG triggers with moderate quality evidence indicating similar cumulative live birth rates and ongoing pregnancy rates between fresh and frozen embryo transfer strategies (\u003cspan additionalcitationids=\"CR22 CR23\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA systematic review by Tjitske Zaat et al. found moderate quality evidence indicating similar cumulative live birth rates and ongoing pregnancy rates between fresh and frozen embryo transfer strategies(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn this study, we evaluated the incidence of ovarian hyper stimulation syndrome using gonadotropin releasing hormone agonist (triptorelin dose of 0.2 mg subcutaneous (Decapeptyl triggering final oocyte maturation in IVF cycles stimulated with gonadotropin releasing hormone antagonist protocol. Additionally, this study evaluated the clinical outcomes of fresh and frozen thawed embryo transfers in these cycles.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy Setting:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted at the Ministry of National Guard Health Affairs (MNGHA), King Abdulaziz Medical City, Riyadh (KAMC-R), Women\u0026rsquo;s Health Hospital, Department of Fertility and Reproductive Medicine. KAMC-R is one of the largest tertiary medical cities in KSA and the Middle East. It provides the highest level of international health standards.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Design\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eThis was a retrospective cohort study, clinical trial number: Not applicable. involving all patients from January 2017 to December 2022 who had IVF cycles using GnRH antagonist protocol and GnRH agonist for triggering final oocyte maturation, and were at risk of developing OHSS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Subjects:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll IVF-ICSI women in a GnRH antagonist protocol cycles at risk of developing OHSS and received GnRH agonist as triggering for final oocyte maturation from January 2017 to December 2022 were included.\u003c/p\u003e\n\u003cp\u003eThe criteria used for identifying women with a high risk of developing OHSS included \u0026ge; 15 follicles measuring \u0026ge; 12 mm in size on trigger day and/or a high Estradiol level of \u0026ge; 20,000 pmol/L. All other cycles used alternative techniques to trigger ovulation such as hCG or dual trigger, the use of GnRH agonist triptorelin (Decapeptyl) in the stimulation protocol, and women with no risk of OHSS were excluded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;Data Collection and management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData was retrieved from the hospital medical records and exported and interpreted through an Excel sheet. Statistical Package for the Social Sciences (SPSS) (Release 28.0; SPSS, Chicago, IL) was used for analysis. Descriptive analysis including mean, standard deviations were calculated for continuous variables. Frequencies and proportions were calculated for categorical variables. To compare pregnancy rates between the two groups (fresh vs frozen) Chi-Square Test of Independence was used.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Considerations:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSubject privacy and confidentiality were assured, no identifiers were collected, and all the data were kept in a secure place within MNGHA premises both hard and soft copies, with access allowed to researchers only. Approval for this study was obtained from the Institutional Review Board IRB at the King Abdullah Medical Research Center (KAMRC) with ethical clearance RYD-23-419812-17800 NRC23R/026/01, date 1-12-2023. Permission to collect data from the hospital was obtained before commencing data collection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment protocol\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eControlled ovarian hyperstimulation (COH) was achieved using recombinant FSH (rFSH; Follitropin alfa; Merck Serona),Purified Human Menopausal Gonadotropin (Menogon ; Ferring) and highely Purified Human Menopausal Gonadotropin and Merional ( Merional ; Ferring). The starting dose depends on the patient\u0026rsquo;s age, body mass index, antral follicular count (AFC),FSH level and or AMH, and previous ovarian response. The GnRH agonist Cetrorelex( Cetrotide; Merck Serona ) 0.25 mg subcuteonsouly was started at day 5 of stimulation. Monitoring of follicular growth was achieved with serial ultrasound and serum E\u003csub\u003e2\u003c/sub\u003e measurements, and the dose of gonadotropins is adjusted, if necessary, according to follicular response.When two or three leading follicles were measuring 18 mm in diameter, women received SC Triptorelin ( Decapeptyl ; Ferring) in a dose of 0.2 mg. 35 hours later, ovum pick up (OPU) was performed under ultrasound guidance.\u003c/p\u003e\n\u003cp\u003eIf the patient has no OHSS symptoms , they are councelled for fresh transfer .In our standerd IVF protocol, we transfer 2 embryos and Cyclogest vaginal supposoties 400 microgram twice a day is used as leutal phase support. The fresh embryo transfer group received additional luteal phase support in the form of prgesterone injections ,Prolutex 25 mg intramascularly daily.\u003c/p\u003e"},{"header":"Result","content":"\u003cp\u003eA total of 97 infertile women at high risk for OHSS who fulfilled the inclusion criteria were included in the study. The mean age was 30.77 \u0026plusmn;4.94 years. The mean BMI was 27.46 \u0026plusmn;5.54 and 75% were nulliparous. Table 1 shows the characteristics of infertility.\u003c/p\u003e\n\u003cp\u003eGonal F was the most commonly used medication for ovarian stumulation , used in 82.7% of the total women .The mean serum estradiol (E2) level on the day of trigger was 18395 \u0026plusmn; 4077 pmol/L, and the mean number of follicles before trigger was 22.9 \u0026plusmn; 6.44.The mean number of mature oocytes was 13.9 \u0026plusmn; 7.44. Table 2 shows the outcomes of ovarian stimulation.\u003c/p\u003e\n\u003cp\u003eOf the 97 patients included in the study, 45 women underwent fresh embryo transfers, resulting in 22 pregnancies with pregnancy rate of 49% . While 49 women had their embryos frozen and underwent subsequent frozen embryo transfer in later cycles, resulting in 19 pregnancies with a 38.8% pregnancy rate. Three patients were singles and were for oocytes cryopreservation. There was no significant difference in pregnancy rates between fresh and frozen embryo transfers ( P value =0.65). None of the cases developed OHSS. Table 3 presents the details of pregnancy outcomes for fresh and frozen embryo transfers.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study \u0026nbsp;demonstrated \u0026nbsp; that the use of \u0026nbsp;gonadotropin releasing hormone agonist for triggering of ovulation in gonadotropin releasing hormone antagonist cycles effectively eliminated the risk of \u0026nbsp;OHSS \u0026nbsp;in high risk patients.\u0026nbsp;This \u0026nbsp;finding is consistent \u0026nbsp;with previous studies using prospective randomized controlled \u0026nbsp;studies ,prospective trials and reviews (15, 21,26-29).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe mean serum estradiol (E2) level on the day of trigger was 18395 \u0026plusmn; 4077 pmol/L, and the mean number of follicles was 22.9 \u0026plusmn; 6.44, indicating a high ovarian response. The mean number of mature oocytes was 13.9 \u0026plusmn; 7.44, supporting the adequacy of follicular response and oocyte maturation with \u0026nbsp;GnRH agonist triggering.\u0026nbsp;Itskovitz-Eldor and colleagues reported\u0026nbsp;that the median estradiol concentration on the day of trigger \u0026nbsp;was 3,675 pg/ml ( 13,500 pmol/L), and the mean oocyte yield was 23.4 \u0026plusmn; 15.4, with 83% of retrieved oocytes being mature (5).\u0026nbsp;Griesinger et al \u0026nbsp; used \u0026nbsp;GnRH agonist triggering when estradiol \u0026ge; 4000 pg/ml ( 14,700 pmol/L), and in both studies none of the recruited patients developed symptoms of OHSS (15).Our findings are consistent with previous studies, demonstrating that GnRH agonist triggering can achieve adequate follicular response and oocyte maturation, with a low risk of OHSS(5,6,8). The estradiol level is comparable with those reported in the literature, supporting the effectiveness of GnRH agonist triggering in high ovarian responders (5,15).\u003c/p\u003e\n\u003cp\u003eIn our study, \u0026nbsp;45 women underwent freshembryo transfers, resulting in \u0026nbsp;22 pregnancies with a pregnancy rate \u0026nbsp;of \u0026nbsp;49% .While 49 women had their embryos frozen and underwent subsequent frozen embryos transfer in later cycles, resulting in 19 pregnancies with \u0026nbsp;a 38.8% pregnancy rate. Three patients were singles and were for oocytes cryopreservation. There was no significant difference in pregnancy rates between fresh and \u0026nbsp;frozen embryo transfers ( P value =0.65).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA concern with GnRH agonist trigger during GnRH antagonist IVF cycles is the potential risk of having an inadequate luteal phase. Aflatoonianet al , and \u0026nbsp;Kol S and \u0026nbsp;Segal L , used 1500 IU hCG \u0026nbsp;on the day of embryo transfer, in addition to progesterone suppositories for luteal phase support , in patients \u0026nbsp;triggered with GnRH agonist \u0026nbsp;and there were no significant differences between FET and fresh \u0026nbsp;embryo transfer groups regarding chemical,clinical ongoing pregnancy rates, an live birth (30,31). However using GnRH agonist triggering followed by fresh embryo transfer with intensified luteal phase support using low dose hCG was associated with a higher incidence of moderate-to-severe OHSS [23].\u003c/p\u003e\n\u003cp\u003eEngmann et la used aggressive steroid supplementation with progesterone and estrogen, 50 mg IM Progesterone \u0026nbsp;in oil daily starting the evening after oocyte retrieval and 0.1 mg transdermal E2 patches every other day starting the day after oocyte retrieval (21).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; Society of Obstetricians and Gynecologist of Canada (SOGC) in their clinical practice guideline, stated that \u0026nbsp;progesterone should be used for leutal phase support rather than hCG(24). In our study, Proluton Depot (hydroxyprogesterone caproate) was used for extra luteal phase support, in addition to our standard letualphase support (Cyclogest 400mg twice daily) in fresh embryo transfers, resulting in good comparable pregnancy rates in both fresh and frozen transfers.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNotably, adherence to the \u0026nbsp;mentioned criteria for the \u0026nbsp;GnRH agonist \u0026nbsp;trigger, resulted in zero reported cases of OHSS.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, the utilization of GnRH agonist triggering in contemporary IVF practice for high risk women susceptible to OHSS who have undergone ovarian stimulation with a GnRH antagonist protocol is an efficient and safe approach, associated with a negligible risk of OHSS development. The pregnancy rates achieved with GnRH agonist triggering are comparable to those obtained with hCG triggering,irrespective of whether fresh or frozen thawed embryo transfer is employed.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eThe Helsinki declaration statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted\u003cstrong\u003e\u0026nbsp;\u003cstrong\u003ein accordance with the principles of the Declaration of Helsinki\u003c/strong\u003e\u003c/strong\u003e.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declaration and consent for publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSubject privacy and confidentiality were assured, no identifiers were collected, and all the data were kept in a secure place within MNGHA premises both hard and soft copies, with access allowed to researchers only.\u0026nbsp;Approval for this study was obtained from the Institutional Review Board IRB at the King Abdullah Medical Research Center (KAMRC) with ethical clearance RYD-23-419812-17800 NRC23R/026/01, date 1-12-2023. Permission to collect data from the hospital was obtained before commencing data collection. As this was a retrospective secondary data analysis, verbal informed consent was obtained from all participants included in the study.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding declaration:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo, this research did not receive funding.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest declaration:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo, I declare that the authors have no competing interests as defined by BMC, or other interests that might be perceived to influence the results and/or discussion reported in this paper.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analysed during the current study are not publicly available but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials (ADM Statement):\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contribution decelaration:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eH.F: Supervised the whole project, collected data, wrote the main manuscript, and did statistical analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA.K: Collected data and wrote the main manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA.F: Collected data and wrote the main manuscript.\u003c/p\u003e\n\u003cp\u003eE.D: Statistical analysis.\u003c/p\u003e\n\u003cp\u003eS.A, F.A, and G.D: Collected data.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAbramov Y, Elchalal U, Schenker JG. Severe OHSS: An \u0026apos;epidemic\u0026apos; of severe OHSS: a price we have to pay? Hum Reprod. 1999;14(9):2181-3.\u003c/li\u003e\n\u003cli\u003eBusso C, Soares S, Pellicer A. Prevention of ovarian hyperstimulation syndrome. In: Connor RF, editor. UpToDate. Wolters Kluwer, Waltham (MA: (2024). https://www.uptodate.com/contents/prevention-of-ovarian-hyperstimulation-syndrom\u003c/li\u003e\n\u003cli\u003eDelvigne A, Rozenberg S. Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review. Hum Reprod Update. 2002;8(6):559-77.\u003c/li\u003e\n\u003cli\u003eSmith V, Osianlis T, Vollenhoven B. Prevention of Ovarian Hyperstimulation Syndrome: A Review. Obstet Gynecol Int. 2015;2015:514159.\u003c/li\u003e\n\u003cli\u003eItskovitz J, Boldes R, Levron J, Erlik Y, Kahana L, Brandes JM. Induction of preovulatory luteinizing hormone surge and prevention of ovarian hyperstimulation syndrome by gonadotropin-releasing hormone agonist. Fertil Steril. 1991;56(2):213-20.\u003c/li\u003e\n\u003cli\u003eFauser BC, de Jong D, Olivennes F, Wramsby H, Tay C, Itskovitz-Eldor J, et al. Endocrine profiles after triggering of final oocyte maturation with GnRH agonist after cotreatment with the GnRH antagonist ganirelix during ovarian hyperstimulation for in vitro fertilization. J Clin Endocrinol Metab. 2002;87(2):709-15.\u003c/li\u003e\n\u003cli\u003eGriffin D, Benadiva C, Kummer N, Budinetz T, Nulsen J, Engmann L. Dual trigger of oocyte maturation with gonadotropin-releasing hormone agonist and low-dose human chorionic gonadotropin to optimize live birth rates in high responders. Fertil Steril. 2012;97(6):1316-20.\u003c/li\u003e\n\u003cli\u003e.Gustofson R, Surrey E, Minjarez D, Schoolcraft W. GnRH-agonist (GnRH-A) trigger in GnRH-antagonist cycles compared to human chorionic gonadotropin (hCG) trigger in long luteal leuprolide downregulation (LL) cycles for hyperresponding oocyte donors. Fertil Steril. 2011;96(3):S260.\u003c/li\u003e\n\u003cli\u003eItskovitz-Eldor J, Kol S, Mannaerts B. Use of a single bolus of GnRH agonist triptorelin to trigger ovulation after GnRH antagonist ganirelix treatment in women undergoing ovarian stimulation for assisted reproduction, with special reference to the prevention of ovarian hyperstimulation syndrome: preliminary report. Hum Reprod. 2000;15(9):1965-8.\u003c/li\u003e\n\u003cli\u003eBodri D, Guill\u0026eacute;n JJ, Galindo A, Matar\u0026oacute; D, Pujol A, Coll O. Triggering with human chorionic gonadotropin or a gonadotropin-releasing hormone agonist in gonadotropin-releasing hormone antagonist-treated oocyte donor cycles: findings of a large retrospective cohort study. Fertil Steril. 2009;91(2):365-71.\u003c/li\u003e\n\u003cli\u003eBeckers NG, Macklon NS, Eijkemans MJ, Ludwig M, Felberbaum RE, Diedrich K, Bustion S, Loumaye E, Fauser BC. Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment.The Journal of Clinical Endocrinology \u0026amp; Metabolism. 2003 ;88(9):4186-92.\u003c/li\u003e\n\u003cli\u003eKolibianakis EM, Schultze-Mosgau A, Schroer A, van Steirteghem A, Devroey P, Diedrich K, et al. A lower ongoing pregnancy rate can be expected when GnRH agonist is used for triggering final oocyte maturation instead of HCG in patients undergoing IVF with GnRH antagonists. Hum Reprod 2005;20:2887\u0026ndash;92. 51\u003c/li\u003e\n\u003cli\u003eGarcia-Velasco JA, Motta L, L\u0026oacute;pez A, Mayoral M, Cerrillo M, Pacheco A. Low-dose human chorionic gonadotropin versus estradiol/progesterone luteal phase support in gonadotropin-releasing hormone agonist\u0026ndash;triggered assisted reproductive technique cycles: understanding a new approach. Fertility and sterility. 2010 ;94(7):2820-3.\u003c/li\u003e\n\u003cli\u003eEldar-Geva T, Zylber-Haran E, Babayof R, Halevy-Shalem T, Ben-Chetrit A, Tsafrir A, Varshaver I, Brooks B, Margalioth EJ. Similar outcome for cryopreserved embryo transfer following GnRH-antagonist/GnRH-agonist, GnRH-antagonist/HCG or long protocol ovarian stimulation. Reproductive biomedicine online. 2007 ;14(2):148-54.\u003c/li\u003e\n\u003cli\u003eGriesinger G, Von Otte S, Schroer A, Ludwig AK, Diedrich K, Al-Hasani S, Schultze-Mosgau A. Elective cryopreservation of all pronuclear oocytes after GnRH agonist triggering of final oocyte maturation in patients at risk of developing OHSS: a prospective, observational proof-of-concept study. Human Reproduction. 2007 ;22(5):1348-52.\u003c/li\u003e\n\u003cli\u003eHerrero L, Pareja S, Losada C, Cobo AC, Pellicer A, Garcia-Velasco JA. Avoiding the use of human chorionic gonadotropin combined with oocyte vitrification and GnRH agonist triggering versus coasting: a new strategy to avoid ovarian hyperstimulation syndrome. Fertility and sterility. 2011;95(3):1137-40.\u003c/li\u003e\n\u003cli\u003eDeepika K, Suvarna R, Sumi M, Snehal D, Arveen V, Anuja K, Gautham P, Kamini R. HCG trigger versus GnRH agonist trigger in PCOS patients undergoing IVF cycles: frozen embryo transfer outcomes. JBRA Assisted Reproduction. 2021;25(1):48.\u003c/li\u003e\n\u003cli\u003eGriesinger G, Diedrich K, Devroey P, Kolibianakis EM. GnRH agonist for triggering final oocyte maturation in the GnRH antagonist ovarian hyperstimulation protocol: a systematic review and meta-analysis. Human reproduction update. 2006;12(2):159-68.\u003c/li\u003e\n\u003cli\u003eAtkinson P, Koch J, Ledger WL. Gn RH agonist trigger and a freeze‐all strategy to prevent ovarian hyperstimulation syndrome: A retrospective study of OHSS risk and pregnancy rates. Australian and New Zealand Journal of Obstetrics and Gynaecology. 2014;54(6):581-5.\u003c/li\u003e\n\u003cli\u003eGriesinger G, Schultz L, Bauer T, Broessner A, Frambach T, Kissler S. Ovarian hyperstimulation syndrome prevention by gonadotropin-releasing hormone agonist triggering of final oocyte maturation in a gonadotropin-releasing hormone antagonist protocol in combination with a \u0026ldquo;freeze-all\u0026rdquo; strategy: a prospective multicentric study. Fertility and sterility. 2011;95(6):2029-33.\u003c/li\u003e\n\u003cli\u003eEngmann L, DiLuigi A, Schmidt D, Nulsen J, Maier D, Benadiva C. The use of gonadotropin-releasing hormone (GnRH) agonist to induce oocyte maturation after cotreatment with GnRH antagonist in high-risk patients undergoing in vitro fertilization prevents the risk of ovarian hyperstimulation syndrome: a prospective randomized controlled study. Fertil Steril 2008;89:84\u0026ndash;91. 55.\u003c/li\u003e\n\u003cli\u003eHumaidan P, Bungum L, Bungum M, Yding Andersen C. Rescue of corpus luteum function with peri-ovulatory HCG supplementation in IVF/ICSI GnRH antagonist cycles in which ovulation was triggered with a GnRH agonist: a pilot study. Reprod Biomed Online 2006;13:173\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eHumaidan P, Ejdrup Bredkjaer H, Westergaard LG, Yding Andersen C. 1,500 IU human chorionic gonadotropin administered at oocyte retrieval rescues the luteal phase when gonadotropin-releasing hormone agonist is used for ovulation induction: a prospective, randomized, controlled study. Fertil Steril 2010;93:847\u0026ndash;54. 57.\u003c/li\u003e\n\u003cli\u003eCorbett S, Shmorgun D, Claman P, Cheung A, Sierra S, Carranza-Mamane B, Case A, Dwyer C, Graham J, Havelock J, Healey S. The prevention of ovarian hyperstimulation syndrome. Journal of Obstetrics and Gynaecology Canada. 2014;36(11):1024-33.\u003c/li\u003e\n\u003cli\u003eZaat T, Zagers M, Mol F, Goddijn M, van Wely M, Mastenbroek S. Fresh versus frozen embryo transfers in assisted reproduction. Cochrane Database of Systematic Reviews. 2021(2).\u003c/li\u003e\n\u003cli\u003eCerrillo M, Rodr\u0026iacute;guez S, Mayoral M, Pacheco A, Mart\u0026iacute;nez-Salazar J, Garcia-Velasco JA. Differential regulation of VEGF after final oocyte maturation with GnRH agonist versus hCG: a rationale for OHSS reduction. Fertility and sterility. 2009 Apr 1;91(4):1526-8.patients undergoing in vitro fertilization prevents the risk of ovarian hyperstimulation syndrome: a prospective randomized controlled study. Fertility and sterility. 2008 ;89(1):84-91.\u003c/li\u003e\n\u003cli\u003eMiller I, Chuderland D, Ron-El R, Shalgi R, Ben-Ami I. GnRH agonist triggering modulates PEDF to VEGF ratio inversely to hCG in granulosa cells. The Journal of Clinical Endocrinology \u0026amp; Metabolism. 2015 ;100(11):E1428-36.\u003c/li\u003e\n\u003cli\u003eCasper RF. Basic understanding of gonadotropin-releasing hormone\u0026ndash;agonist triggering. Fertility and sterility. 2015;103(4):867-9.\u003c/li\u003e\n\u003cli\u003eCastillo JC, Haahr T, Mart\u0026iacute;nez-Moya M, Humaidan P. Gonadotropin-releasing hormone agonist ovulation trigger\u0026mdash;beyond OHSS prevention. Upsala journal of medical sciences. 2020;125(2):138-43.\u003c/li\u003e\n\u003cli\u003eAflatoonian A, Mansoori-Torshizi M, Mojtahedi MF, Aflatoonian B, Khalili MA, Amir-Arjmand MH, Soleimani M, Aflatoonian N, Oskouian H, Tabibnejad N, Humaidan P. Fresh versus frozen embryo transfer after gonadotropin-releasing hormone agonist trigger in gonadotropin-releasing hormone antagonist cycles among high responder women: a randomized, multi-center study. International journal of reproductive biomedicine. 2018;16(1):9.\u003c/li\u003e\n\u003cli\u003eKol S, Segal L. GnRH agonist triggering followed by 1500 IU of HCG 48 h after oocyte retrieval for luteal phase support. Reprod Biomed Online. 2020;41(5):854-858.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-endocrine-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bend","sideBox":"Learn more about [BMC Endocrine Disorders](http://bmcendocrdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bend/default.aspx","title":"BMC Endocrine Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"GnRH agonist trigger, GnRH antagonist protocol, IVF, Ovarian Hyperstimulation Syndrome, fresh embryo transfer, frozen embryo ransfer, pregnncy rate, Saudi Arabia","lastPublishedDoi":"10.21203/rs.3.rs-9114982/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9114982/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThe utilization of gonadotropin-releasing hormone (GnRH) agonist as a substitute for human chorionic gonadotropin (hCG) as a trigger for final oocyte maturation in antagonist in vitro fertilization (IVF) cycles has been proposed as a strategy for mitigating the risk of ovarian hyperstimulation syndrome (OHSS) in predicted high responders. This study aimed to evaluate the incidence of OHSS at King Abdulaziz Medical City, Riyadh, using GnRH agonist triggering final oocyte maturation in IVF cycles stimulated with gonadotropin-releasing hormone (GnRH) antagonist protocol. Additionally, the clinical outcomes of fresh and frozen-thawed embryo transfers (FET) in these cycles were evaluated.\u003c/p\u003e\u003ch2\u003eMethod\u003c/h2\u003e \u003cp\u003eA retrospective cohort analysis, clinical trial number not applicable, was undertaken to evaluate the outcomes of GnRH agonist triggering in women at high risk of OHSS who underwent ovarian stimulation using a GnRH antagonist protocol. The study population comprised all women who underwent GnRH agoinst triggered for final oocyte maturation between January 2017 and December 2022 at the Fertility and Reproductive Endocrinology Department, Women\u0026rsquo;s Health Hospital (WHH), King Abdulaziz Medical City (KAMC), Riyadh, Saudi Arabia. Relevant clinical and demographic data were extracted from electronic medical records and analyzed using Statistical Package for Social Sciences (SPSS) version 28.0.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 97 infertile women at high risk for OHSS who fulfilled the inclusion criteria were included in the study. The mean age of the women was 30.77\u0026thinsp;\u0026plusmn;\u0026thinsp;4.94 years. The mean serum estradiol (E2) level on the day of trigger was 18395\u0026thinsp;\u0026plusmn;\u0026thinsp;4077 pmol/L, and the mean number of follicles at trigger day was 22.9\u0026thinsp;\u0026plusmn;\u0026thinsp;6.44. The mean number of mature oocytes was 13.9\u0026thinsp;\u0026plusmn;\u0026thinsp;7.44. Of the 97 women included in the study, 45 underwent fresh embryo transfers, with a pregnancy rate of 49%. While 49 had their embryos frozen and underwent subsequent frozen embryo transfers in later cycles, with a 38.8% pregnancy rate. There was no significant difference in pregnancy rates between fresh and frozen embryo transfers (P value\u0026thinsp;=\u0026thinsp;0.65). In the fresh embryos transfer group, additional luteal phase support was given in the form of progesterone injection. None of the cases developed OHSS.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eGnRH agonist triggering for IVF is an efficient and safe approach for women at high risk of OHSS, with negligible risk of OHSS and comparable pregnancy rates to hCG triggering, regardless of whether embryos are transferred fresh or frozen.\u003c/p\u003e","manuscriptTitle":"Experience of KAMC-R using gonadotropin releasing hormone (GnRH) agonist for triggering final oocyte maturation in a GnRH antagonist protocol for prevention of ovarian hyperstimulation syndrome","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-29 14:45:57","doi":"10.21203/rs.3.rs-9114982/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-05-01T10:22:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"267563550210792735573680628557858349646","date":"2026-05-01T04:24:55+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-21T13:05:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-20T08:11:28+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-31T04:19:16+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-30T12:42:07+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Endocrine Disorders","date":"2026-03-30T12:37:09+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-endocrine-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bend","sideBox":"Learn more about [BMC Endocrine Disorders](http://bmcendocrdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bend/default.aspx","title":"BMC Endocrine Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8f557b0b-1504-4711-a80e-62b644d26809","owner":[],"postedDate":"April 29th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"","date":"2026-05-01T10:22:48+00:00","index":62,"fulltext":""},{"type":"reviewerAgreed","content":"267563550210792735573680628557858349646","date":"2026-05-01T04:24:55+00:00","index":61,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-29T14:45:58+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-29 14:45:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9114982","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9114982","identity":"rs-9114982","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}