HCG/GnRHa support improves outcomes after GnRH antagonist dual trigger and the predictive role of mid-luteal estradiol ratio: a case control study

HCG/GnRHa support improves outcomes after GnRH antagonist dual trigger and the predictive role of mid-luteal estradiol ratio: a case control study | 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 HCG/GnRHa support improves outcomes after GnRH antagonist dual trigger and the predictive role of mid-luteal estradiol ratio: a case control study Ge Chen, Song Jin, Long Zhang, Ping Liu, Meng Cheng This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8142666/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background Optimal luteal phase support after fresh transfer remains a clinical challenge in GnRH antagonist IVF/ICSI cycles triggered with dual trigger. HCG/GnRha supports may improve outcomes, but its safety and ideal application remain uncertain. To investigate the effectiveness and safety of strengthened luteal phase support in fresh embryo transfer cycles following GnRH antagonist protocols with dual trigger, and further to identify patients who best most as well as clinical indicators. Methods This retrospective cohort study included all fresh embryo transfer cycles after dual-trigger oocyte retrieval between January 2020 and May 2024 at a single center. Patients were grouped based on LPS strategy: routine support (RT) or strengthened support (ST) using hCG (S-hCG), GnRHa (S-GnRHa), or both (S-Double). Pregnancy and neonatal outcomes and safety profiles were compared before and after propensity score matching. Subgroup analyses and mid-luteal estradiol ratio (E2 ratio) assessment were performed. Results ST was associated with significantly higher clinical pregnancy (48.2% vs 37.1%) and live birth rates (43.2% vs 34.3%) than RT (P < 0.001) without additional risks including OHSS, birth defects and maternal complications. Subgroup analyses showed benefits across diverse populations, including women ≥ 35 years, those with diminished ovarian reserve, and patients receiving suboptimal embryos. Among ST regimens, hCG supplementation achieved the best outcomes, and patients with a low mid-luteal E2 ratio (< 0.15) derived the greatest benefit. Conclusions Enhanced luteal support improves pregnancy outcomes in antagonist-dual trigger cycles. hCG appears most effective, but individualized strategies using biomarkers such as E2 ratio merit further investigation. Trial registration: Not applicable. HCG/GnRHa support GnRH antagonist dual trigger pregnancy outcomes estradiol ratio Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Infertility is a significant health concern affecting 10–15% of couples worldwide. The in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) have become the most effective treatments ( 1 – 3 ). The GnRH antagonist protocol combined with dual trigger has become increasingly prevalent for numerous advantages, including a reduced treatment duration, greater flexibility, improved oocyte maturation and embryo quality and a lower risk of OHSS when compared to traditional GnRH agonist protocols ( 4 – 6 ). Despite these advancements, the luteal phase in fresh embryo transfer (ET) cycles remains compromised due to inadequate corpus luteum function, leading to implantation failure and early pregnancy loss ( 4 – 7 ). In this scenario, greater attention to strengthened luteal phase support (LPS) is necessary among patients received GnRHa protocol with dual trigger after fresh embryo transfer. Except for routine progesterone agents in various forms and doses, other hormones, such as estradiol, hCG, or GnRHa ( 4 , 5 , 8 ), were introduced to strength the luteal function and improve pregnancy outcomes. The use of hCG suggested to increase implantation rates by rescuing the corpus luteum and preventing luteolysis. However, several studies stayed cautious with dose and time for increased risk of OHSS ( 9 – 11 ). Meanwhile, GnRHa was proposed as alternative strengthened LPS protocol by inducing endogenous LH secretion. Supplement of GnRHa was reported to significantly improve pregnancy and live birth rates without OHSS risks ( 12 – 15 ). However, the clinical utility and effectiveness of various strengthened luteal phase support exhabits heterogeneity and lack of consensus on the optimal regimens ( 16 , 17 ). Other debated issues about strengthened LPS focus on identification of patients who could benefit most for which current evidence limited. Moreover, defining the subgroups and clinical indicators that predict favorable responses to strengthened LPS remains unclear. Limited studies focus on the estradiol levels in case of additional supplements ( 18 ). This study aims to evaluate the overall effects and safety of early strengthened luteal phase support (hCG or GnRHa) on pregnancy outcomes. Additionally, multivariate analysis and assessment of dynamic estradiol changes were used to identify the patients who most likely to benefit and potential clinical indicators. This study would assist clinicians in refining therapeutic protocols and optimizing pregnancy outcomes in IVF/ICSI cycles. Methods Study Design and Patient Selection This retrospective cohort study was conducted at the Department of Reproductive Medicine, West China Second Hospital of Sichuan University, between January 2020 and May 2024. All the participants were women undergoing IVF/ICSI-ET with a GnRH antagonist protocol and a dual trigger for final oocyte maturation. Inclusion and Exclusion Criteria Inclusion criteria: 1) Women aged between 20 and 45 years undergoing their first or second IVF/ICSI cycle. 2) Use of a GnRH antagonist protocol for ovarian stimulation. 3) Dual trigger using a combination of hCG and GnRHa for final oocyte maturation. 4) Fresh embryos transfer (one or two) at the cleavage. Exclusion criteria:1) Patients with uterine abnormalities such as congenital malformations, intrauterine adhesions, or fibroids significantly affecting the embryo implantation. 2) Patients undergoing preimplantation genetic testing (PGT) cycles. 3) Use of donor oocytes or frozen-thawed embryo transfers. 4) Known history of recurrent implantation failure (≥three times failed embryo transfers). 5) Severe male factor infertility requiring the use of testicular sperm aspiration (TESA) or microdissection testicular sperm extraction (micro-TESE). Data Collection Clinical data were retrospectively collected from the electronic medical records of patients who underwent fresh IVF/ICSI-ET cycles using a GnRH antagonist protocol. Baseline characteristics controlled ovarian stimulation parameters, embryo transfer details, and pregnancy outcomes were extracted. Serum hormone levels, including estradiol (E2), progesterone, and LH, were recorded on the day of hCG trigger or mid-luteal phase (8–9 days after oocyte retrieval). Variables related to embryo quality, endometrial thickness, and luteal phase support strategies were also collected. Ovarian Stimulation Protocol and Embryo Transfer All patients underwent controlled ovarian stimulation (COS) using a GnRH antagonist protocol. Recombinant follicle-stimulating hormone (rFSH) or human menopausal gonadotropin (hMG) was administered at individualized doses based on ovarian reserve parameters (age, body mass index, AMH, antral follicle count, and previous response to stimulation). Daily GnRH antagonist (0.25 mg cetrorelix, Merck, Germany or ganirelix, MSD, USA) was initiated from the cycle day 5-6 or when the leading follicle reached 12–14 mm in diameter. Final oocyte maturation was triggered using a dual trigger approach consisting of GnRHa (0.2 mg triptorelin, Ferring, Denmark) combined with hCG (Ovitrelle, 250μg, Merck, Germany). Oocyte retrieval was performed 36 hours later, followed by conventional IVF or ICSI, depending on sperm quality. Fresh embryo transfer was performed on Day 3 (cleavage stage) after oocyte retrieval. One or two embryos were transferred based on patient age, clinical indications, the number and quality of embryos available, following national ART guidelines (19). Luteal phase support was first initiated on the day of oocyte retrieval till the pregnany test day. If the pregnancy was achieved, luteal phase support would continue. Luteal Phase Support Strategies Patients were classified into two groups as follow: 1. Routine LPS group (RT): All the patients received progesterone supplementation, including dydrogesterone (AbbottBiologicalsB.V, USA) orally at 20 mg/d combined with progesterone vaginal gel (Crinone, Merck, Germany) at 90 mg/d. 2. Strengthened LPS group (ST): All the patients in strengthened LPS group received routine LPS support with additional hCG (Livzon Pharmaceutical Group, China) or/and GnRHa injection. The ST group was further divided into three subgroups according to different medications. S-hCG group: patients received 2000 IU hCG every other day began from day 8-9 after retrieval to pregnant test day. S-GnRHa group: patients received GnRHa 0.1mg on day 3 and day 5 after retrieval S-Double group: patients received 2000 IU hCG every other day began from day 8-9 after retrieval to pregnant test day combined with GnRHa 0.1mg on day 3 and day 5 after retrieval Outcome Measures The primary outcomes included: 1) Biochemical pregnancy rate: Defined as a positive serum β-hCG (>25 IU/L) 12-14 days after embryo transfer. 2) Clinical pregnancy rate: Presence of at least one intrauterine gestational sac with a fetal heartbeat under ultrasound image on the day 30–35 after embryo transfer. 3) Ongoing pregnancy rate: A viable pregnancy detected by ultrasound examination beyond 12 weeks of gestation. 4) Abortion rate: Loss of pregnancy before 12 weeks of gestation. 5) Incidence of severe OHSS. Statistical Analysis Statistical analyses were conducted using SPSS software (version 26.0), R (version 4.3.1), Python (3.9.13). Continuous variables were presented as mean ± standard deviation (SD) and compared using independent t-tests or Mann-Whitney U tests, depending on data distribution. Categorical variables were expressed as frequencies and percentages and analyzed using chi-square tests or Fisher’s exact tests, as appropriate. The propensity score was logit-transformed, and a caliper width equal to 0.2 of the standard deviation of the logit of the propensity score was applied. 1:1 nearest neighbor matching with replacement was used, allowing control individuals to be matched to more than one treated individual, thereby maximizing the matched sample size. After matching, standardized mean differences (SMD) were calculated for all covariates, with |SMD|<0.1 indicating acceptable balance. Multivariate logistic regression identified predictors of pregnancy outcomes. Subgroup analyses were stratified by age, AMH level, embryo quality, and endometrial thickness. A sliding window multivariable logistic regression analysis using the E2 ratio were performed. Analyses were performed using R (v4.2.1), and P-values <0.05 were considered significant. Ethical Approval This study was approved by the Institutional Review Board (IRB) of West China Second Hospital, Sichuan University (2024253). Informed consent was waived due to the retrospective nature of the study, and all data were anonymized before analysis to protect patient confidentiality. Results Baseline characteristics of ST and RT group Before and After Propensity Score Matching The baseline characteristics of the study population (N = 2,195) were summarized in Supplemental Table 1 . Among them, 1,459 patients were assigned to ST group and 736 to the RT group. Statistically significant differences were observed between the two groups across multiple baseline parameters. Compared with the ST group, patients in the RT group had higher AMH levels (3.04 ± 2.02 vs. 3.36 ± 2.45 ng/mL, P = 0.0026) and higher estradiol (2086.54 ± 1070.15 vs. 2350.85 ± 1141.25, P < 0.0001) and progesterone levels on the day of hCG trigger (0.70 ± 0.25 vs. 0.77 ± 0.28 ng/mL, P < 0.0001). The ST group had significantly fewer retrieved oocytes (8.53 ± 4.12 vs. 9.35 ± 4.27, P < 0.0001), mature (MII) oocytes (6.81 ± 3.62 vs. 7.47 ± 3.70, P = 0.0001), and 2PN fertilized embryos (5.02 ± 2.96 vs. 5.57 ± 3.06, P = 0.0001) and available embryos (4.51± 2.74 vs 4.89± 2.83, P=0.0028). To address these baseline disparities and reduce selection bias, PSM was conducted using 1:1 nearest neighbor matching with a caliper of 0.2. After matching, baseline characteristics between the two groups were well balanced, with no statistically significant differences in demographic or stimulation-related parameters ( Supplemental Table 2 ). Clinical Outcomes and Safety of ST and RT group Before and After Propensity Score Matching As shown in Figure 1 , the ST group demonstrated better pregnancy outcomes both before and after PSM. Before matching, chemical pregnancy was significantly higher in the ST group, compared to the RT group (54.1% vs. 43.2%, P < 0.0001). The differences were observed for the clinical pregnancy rate (48.1% vs. 41.0%, P = 0.0019) and live birth rate (43.1% vs. 37.5%, P = 0.013). No significant difference was found in the abortion rate and severe OHSS incidence ( Figure 1A ). After PSM, the ST group still showed significantly higher chemical pregnancy (54.1% vs. 40.6%, P < 0.0001), clinical pregnancy (48.2% vs. 37.1%, P < 0.0001), and live birth (43.2% vs. 34.3%, P < 0.0001) rates. The abortion rate and severe OHSS remained similar between two groups ( Figure 1B ). Neonatal outcomes and maternal safety were compared between ST and RT groups before and after PSM. As shown in Supplemental figure 1 and Supplemental Table 3 , among singleton births, the ST group had a slightly lower birth weight than the RT group only before PSM (3094.9 ± 512.4 g vs. 3160.2 ± 469.9 g, P = 0.034) ( Supplemental Figure 1 A-B ). Importantly, maternal complications were more frequent in the ST group than in the RT group after PSM (8.9% vs. 2.6%, P = 0.0045), though no significant difference was observed before PSM ( Supplemental figure 1 C-D ). Among twin pregnancies, birth weight and height were similar between ST and RT groups both before and after PSM. The incidence of birth defects and maternal complications was comparable between groups ( Supplemental figure 2 and Supplemental Table 3 ). Subgroup analyses of luteal support for pregnancy outcomes To identify independent predictors of treatment outcomes, multi-variable logistic regression models were performed for chemical pregnancy, clinical pregnancy, and live birth. As shown in Supplemental fig ure 3 and Supplemental Table 4 , ST treatment was significantly associated with improved outcomes after adjusting for multiple confounders, with higher odds of chemical pregnancy (OR=1.75, 95% CI: 1.49-2.05, P < 0.001), clinical pregnancy (OR=1.59, 95% CI 1.36-1.87, P < 0.001), and live birth (OR =1.48, 95% CI: 1.26-1.74, P < 0.001) compared to RT group. Maternal age, endometrial thickness on the day of transfer (ET-EM), the number of high-quality embryos transferred (ET-high-quality-embryo), progesterone levels in trigger day (hCG-P) were significantly associated with pregnancy outcomes. Further subgroup analysis between ST and RT were applied according to above results. Among women aged <35 years, ST was significantly associated with increased rates of chemical pregnancy (OR=1.72, 95% CI 1.43-2.06, P<0.001), clinical pregnancy (OR=1.50, 95% CI 1.25-1.79, P<0.001), and live birth (OR=1.48, 95% CI 1.24-1.78, P<0.001). Comparable benefits were observed in women aged ≥35 years, with slightly larger effect sizes for chemical pregnancy (OR=1.74, 95% CI 1.29-2.34, P<0.001) and clinical pregnancy (OR=1.83, 95% CI 1.33-2.50, P<0.001) (Figure 2 and Supplemental Table 5 ). The benefit of ST was evident in both AMH ≥1.2 and AMH <1.2 groups, with a more pronounced effect among those with lower AMH (chemical pregnancy OR=2.2, 95% CI 1.45-3.35, P<0.001; clinical pregnancy OR=1.89, 95% CI 1.23-2.88, P=0.003) (Figure 2 and Supplemental Table 5 ) . Moreover, ST showed significant advantages regardless of the number of high-quality embryos transferred. Further analyses suggested that the superiority of ST was more evident in patients with ET-EM ≥3.5 mm and in those with hCG-P <1.2 ng/mL, whereas no significant benefit was detected in ET-EM <3.5 mm and in those with hCG-P≥1.2 ng/mL (Figure 2 and Supplemental Table 5 ) . Impact of Strengthened Luteal Phase Support Type on Reproductive Outcomes Before and After PSM To further dissect the impact of different luteal support strategies, we compared pregnancy outcomes among the three strengthened support types (S-GnRHa, S-hCG, and S-Double) relative to the RT group. Before PSM, all five primary outcomes differed significantly among the four luteal support groups ( Figure 3A ). The S-hCG group achieved the highest clinical pregnancy rate (53.9%), followed by the S-Double (45.7%) and S-GnRHa (46.2%) groups, while the RT group had the lowest rate (41.0%). Similar trends were observed for chemical pregnancy and live birth rates. Abortion rates were slightly higher in the S-hCG (6.8%) and S-Double (5.0%) groups, and the incidence of OHSS was significantly increased in the S-GnRHa group (1.2%) compared to the RT group (0.1%, p < 0.05). After PSM ( Figure 3B ), the between-group differences in pregnancy outcomes remained statistically significant. The S-hCG group continued to demonstrate the highest rates of chemical pregnancy (63.0%), clinical pregnancy (54.0%) and live birth rate (47.4%). The S-GnRHa and S-Double group also showed improved outcomes relative to RT. The incidence of OHSS remained notably higher in the S-GnRHa group (1.1%) and S-hCG group (0.3%) than in the RT group (0.1%, p < 0.05). Association Between mid-luteal E2 Ratio and the Effectiveness of Strengthened Luteal Phase Support To investigate the heterogeneity in response to luteal phase support across different patterns of early estradiol decline, we performed a sliding window multivariable logistic regression analysis using the E2 ratio, defined as mid-luteal serum E2 (day 8-9 after oocyte retrieval) divided by E2 on the hCG trigger day, was used as a continuous variable for stratification. As shown in Figure 4A and Supplemental Table 6 , the OR for clinical pregnancy associated with receiving ST peaked at an E2 ratio of 0.05 (adjusted OR=6.21, 95% CI: 2.86-13.52, p = 0.000004), indicating that patients with the most pronounced estradiol decline benefited substantially from ST. A small elevation tendency in OR was observed near an E2 ratio of 0.6, though the magnitude was not statistically significant. Similarly, for live birth ( Figure 4B and Supplemental Table 7 ), the adjusted OR peaked at an E2 ratio of 0.15 (adjusted OR: 5.52, 95% CI: 1.47-20.80, p = 0.012), suggesting that a subset of patients with moderately severe estradiol decline may also derive benefit. However, confidence intervals were wider, and the association was less consistent across the spectrum. Discussion The luteal phase disruption can occur in ART cycles using the antagonist protocol and dual trigger in fresh transfer cycle. Therefore, the individualization of strengthened LPS was essential in improving pregnancy outcomes. In this large, propensity score–matched cohort, the clinical effectiveness and safety of strengthened LPS, particularly hCG-based regimens, was confirmed after adjusting for major confounders. Moreover, patients of advanced age, or diminished ovarian reservation or those receiving embryos of suboptimal quality may particularly benefit from strengthened LPS. Meanwhile, the E2 ratio in mid-luteal phase may be identified as potential indicator for strengthened LPS use. The antagonist protocol triggered by GnRHa, granulosa cells exhibit reduced viability in vivo and fail to maintain sex steroid production compared with the cells retrieved during a natural cycle (20). By contrast, GnRHa induces a shorter duration of endogenous LH secretion(~34 h) compared with the natural LH surge (48 h) or the LH-like activity provided by hCG (21). The luteal phase disruption can occur in ART cycles using the antagonist protocol and dual trigger. Therefore, the individualization of enhanced luteal support, such as E2, hCG, or GnRHa (11, 18, 22, 23) may be helpful in improving pregnancy outcomes. The biological rationale for ST, especially with hCG-based regimens, is well supported. hCG acts directly on LH/hCG receptors in the corpus luteum to promote progesterone and E2 secretion(24-26), critical for maintaining endometrial receptivity in the peri-implantation window(27). Some studies, including those by Svenstrup et al (9), Singh et al (28) highlight that while hCG rescues the corpus luteum, prevents luteolysis and enhances implantation potential, it must be carefully managed in patients at risk for OHSS. Moreover, GnRHa-based support provides an alternative approach, offering adequate luteal phase support. GnRHa supports implantation and pregnancy via stimulating the corpus luteum by LH and favoring the adhesion of the embryo to the endometrial epithelial surface (29). The higher pregnancy rate in the GnRHa group compared with the progesterone group have been shown in some research (14, 15). The study by Dong et al (30) have shown that GnRHa can be an effective alternative to hCG in high responders. In current study, hCG group achieved the best pregnancy outcomes. Other strengthened protocols also showed improved outcomes compared with the routine group. The dual approach combining hCG and GnRHa, referred to as double-strengthened were not superior to single hCG support in our cohort. Our study demonstrates that hCG-based strengthened support remains the most effective protocol, reinforcing its value in corpus luteum rescue. The lack of additional benefit from double-strengthened protocols underscores the importance of a mechanism-based, individualized approach rather than empirical intensification. Previous research suggested that patients with good ovarian reserve benefit more from strengthened luteal support due to their ability to maintain adequate corpus luteum function when supplemented with hCG or GnRHa (9-11, 18). However, our results highlight the clinical utility of ST across diverse patient profiles. Subgroup analyses not only confirm the overall effectiveness of ST but also provide evidence to identify patient groups most likely to benefit, including women of advanced maternal age, diminished ovarian reserve and suboptimal embryo quality. This refined patient stratification may help optimize clinical decision-making and facilitate the individualized luteal phase management in fresh embryo transfer cycles. In addition, this study introduced sliding-window analysis using early luteal E2 dynamics (E2 ratio) to stratify the benefit of ST. We observed a non-linear, bimodal association between E2 ratio and the adjusted OR for pregnancy. The finding suggests that patients with early and substantial E2 depletion may have insufficient luteal function and thus respond more favorably to ST. Although not yet integrated into routine practice, the E2 ratio may serve as a future biomarker to personalize luteal support strategies (18). Limitations of this study include its retrospective design with a single-center dataset. Although propensity score matching and multivariable adjustment were applied, unmeasured confounding cannot be fully excluded. In addition, while the E2 ratio offers a promising direction for individualized support, its clinical thresholds and utility need prospective validation. Conclusion This study suggests that strengthened early LPS should be considered in fresh IVF/ICSI cycles using the antagonist protocol and dual trigger approach. The most effective protocol form of this support was found to be hCG-based regimens. Our results also indicated that early estradiol decline may help identify patients who benefit most from support. These findings support the use of enhanced luteal support and point toward future individualized strategies protocols. Future prospective studies are needed to further validate these findings and refine the most beneficial subgroups for individual luteal support. Abbreviations PSM: propensity score matching hCG: human chorionic gonadotropin GnRha: gonadotropin-releasing hormone agonist LPS: luteal phase support RT: routine support ST: strengthened support OR: odd ratio Declarations Funding Statement: No funding Disclosure Statement: The authors declare that they have no conflicts of interest to disclose. Ethics approval and consent to participate This study was approved by the Institutional Review Board (IRB) of West China Second Hospital, Sichuan University (2024253). Informed consent was waived due to the retrospective nature of the study. Consent for publication Not applicable. Availability of data and materials The data that support the findings of this study are available upon request from the corresponding author. Competing interests All authors have no conflicts of interest. Funding No funding. Authors' contributions G.C.: data collection, data analysis, visualization, draft writing and editing. S.J.: draft reviewing, supervision, administration and investigation. L.Z.: investigation and data collection. P.L.: draft writing and editing, supervision, data analysis and study design. C.M.: draft reviewing, supervision, administration, methodology, data collection and study design. Acknowledgements We would like to thank Lijuan Deng and BopingWang contributing to this study. References Cox CM, Thoma ME, Tchangalova N, Mburu G, Bornstein MJ, Johnson CL, et al. Infertility prevalence and the methods of estimation from 1990 to 2021: a systematic review and meta-analysis. Hum Reprod Open. 2022;2022(4):hoac051. Zhou Z, Zheng D, Wu H, Li R, Xu S, Kang Y, et al. Epidemiology of infertility in China: a population-based study. BJOG. 2018;125(4):432-41. Yu J, Fu Y, Zeng L, Xie P, Li L, Zheng Y. Burden of female infertility in China from 1990 to 2019: a temporal trend analysis and forecasting, and comparison with the global level. Sex Health. 2023;20(6):577-84. Gao F, Wang Y, Fu M, Zhang Q, Ren Y, Shen H, et al. Effect of a "Dual Trigger" Using a GnRH Agonist and hCG on the Cumulative Live-Birth Rate for Normal Responders in GnRH-Antagonist Cycles. Front Med (Lausanne). 2021;8:683210. Haas J, Bassil R, Samara N, Zilberberg E, Mehta C, Orvieto R, et al. GnRH agonist and hCG (dual trigger) versus hCG trigger for final follicular maturation: a double-blinded, randomized controlled study. Hum Reprod. 2020;35(7):1648-54. Casper RF. Basic understanding of gonadotropin-releasing hormone-agonist triggering. Fertil Steril. 2015;103(4):867-9. Kol S, Breyzman T, Segal L, Humaidan P. 'Luteal coasting' after GnRH agonist trigger - individualized, HCG-based, progesterone-free luteal support in 'high responders': a case series. Reprod Biomed Online. 2015;31(6):747-51. van der Linden M, Buckingham K, Farquhar C, Kremer JA, Metwally M. Luteal phase support for assisted reproduction cycles. Cochrane Database Syst Rev. 2015;2015(7):Cd009154. Svenstrup L, Möller S, Fedder J, Pedersen DE, Erb K, Andersen CY, et al. Investigation of luteal HCG supplementation in GnRH-agonist-triggered fresh embryo transfer cycles: a randomized controlled trial. Reprod Biomed Online. 2024;48(5):103415. Kastora SL, Gkova G, Stavridis K, Balachandren N, Kastoras A, Karakatsanis A, et al. Comparison of luteal support protocols in fresh IVF/ICSI cycles: a network meta-analysis. Sci Rep. 2024;14(1):14492. Garg A, Zielinska AP, Yeung AC, Abdelmalak R, Chen R, Hossain A, et al. Luteal phase support in assisted reproductive technology. Nature reviews Endocrinology. 2024;20(3):149-67. Tesarik J, Hazout A, Mendoza-Tesarik R, Mendoza N, Mendoza C. Beneficial effect of luteal-phase GnRH agonist administration on embryo implantation after ICSI in both GnRH agonist- and antagonist-treated ovarian stimulation cycles. Hum Reprod. 2006;21(10):2572-9. Benmachiche A, Benbouhedja S, Zoghmar A, Boularak A, Humaidan P. Impact of Mid-Luteal Phase GnRH Agonist Administration on Reproductive Outcomes in GnRH Agonist-Triggered Cycles: A Randomized Controlled Trial. Frontiers in endocrinology. 2017;8:124. Isik AZ, Caglar GS, Sozen E, Akarsu C, Tuncay G, Ozbicer T, et al. Single-dose GnRH agonist administration in the luteal phase of GnRH antagonist cycles: a prospective randomized study. Reprod Biomed Online. 2009;19(4):472-7. Buhbut E, Nabulsi R, Avigdor G, Ben-Ami I. Comparison of pregnancy rates in antagonist cycles after luteal support with GnRH-agonist versus progesterone: prospective randomized study. Arch Gynecol Obstet. 2023;308(1):255-63. Humaidan P, Polyzos NP, Alsbjerg B, Erb K, Mikkelsen AL, Elbaek HO, et al. GnRHa trigger and individualized luteal phase hCG support according to ovarian response to stimulation: two prospective randomized controlled multi-centre studies in IVF patients. Hum Reprod. 2013;28(9):2511-21. Kol S, Humaidan P, Itskovitz-Eldor J. GnRH agonist ovulation trigger and hCG-based, progesterone-free luteal support: a proof of concept study. Hum Reprod. 2011;26(10):2874-7. Li N, Huang Y, Fan L, Shi Z, Cai H, Shi J, et al. Effect of estradiol supplementation on luteal support following a significant reduction in serum estradiol levels after hCG triggering: a prospective randomized controlled trial. Reprod Biol Endocrinol. 2024;22(1):117. Coticchio G, Ahlström A, Arroyo G, Balaban B, Campbell A, De Los Santos MJ, et al. The Istanbul consensus update: a revised ESHRE/ALPHA consensus on oocyte and embryo static and dynamic morphological assessment†,‡. Hum Reprod. 2025;40(6):989-1035. Bildik G, Akin N, Seyhan A, Esmaeilian Y, Yakin K, Keles I, et al. Luteal granulosa cells from natural cycles are more capable of maintaining their viability, steroidogenic activity and LH receptor expression than those of stimulated IVF cycles. Hum Reprod. 2019;34(2):345-55. Vuong TN, Ho MT, Ha TD, Phung HT, Huynh GB, Humaidan P. Gonadotropin-releasing hormone agonist trigger in oocyte donors co-treated with a gonadotropin-releasing hormone antagonist: a dose-finding study. Fertil Steril. 2016;105(2):356-63. Labarta E, Mariani G, Rodríguez-Varela C, Bosch E. Individualized luteal phase support normalizes live birth rate in women with low progesterone levels on the day of embryo transfer in artificial endometrial preparation cycles. Fertil Steril. 2022;117(1):96-103. Zhao J, Hao J, Li Y. Individualized luteal phase support after fresh embryo transfer: unanswered questions, a review. Reprod Health. 2022;19(1):19. Cole LA. Biological functions of hCG and hCG-related molecules. Reprod Biol Endocrinol. 2010;8:102. Choi J, Smitz J. Luteinizing hormone and human chorionic gonadotropin: distinguishing unique physiologic roles. Gynecol Endocrinol. 2014;30(3):174-81. Nwabuobi C, Arlier S, Schatz F, Guzeloglu-Kayisli O, Lockwood CJ, Kayisli UA. hCG: Biological Functions and Clinical Applications. Int J Mol Sci. 2017;18(10). Smitz J, Platteau P. Influence of human chorionic gonadotrophin during ovarian stimulation: an overview. Reprod Biol Endocrinol. 2020;18(1):80. Singh N, Kashyap A, Malhotra N, Mahey R, Vatsa R, Patel G. Comparison of the effects of two different trigger strategies - dual (hCG + Leuprolide) versus hCG trigger - in antagonist non-donor IVF: a randomized controlled trial. JBRA Assist Reprod. 2023;27(3):467-73. Maggi R, Cariboni AM, Marelli MM, Moretti RM, Andrè V, Marzagalli M, et al. GnRH and GnRH receptors in the pathophysiology of the human female reproductive system. Hum Reprod Update. 2016;22(3):358-81. Dong L, Lian F, Wu H, Xiang S, Li Y, Wei C, et al. Reproductive outcomes of dual trigger with combination GnRH agonist and hCG versus trigger with hCG alone in women undergoing IVF/ICSI cycles: a retrospective cohort study with propensity score matching. BMC Pregnancy Childbirth. 2022;22(1):583. Additional Declarations No competing interests reported. Supplementary Files SupplementalMaterial.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 22 Dec, 2025 Reviews received at journal 11 Dec, 2025 Reviews received at journal 30 Nov, 2025 Reviewers agreed at journal 30 Nov, 2025 Reviewers agreed at journal 30 Nov, 2025 Reviewers invited by journal 30 Nov, 2025 Editor invited by journal 24 Nov, 2025 Editor assigned by journal 19 Nov, 2025 Submission checks completed at journal 19 Nov, 2025 First submitted to journal 18 Nov, 2025 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8142666","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":553552735,"identity":"3e5692ae-7905-4ab7-8de6-69d30dfa21f4","order_by":0,"name":"Ge Chen","email":"","orcid":"","institution":"West China Second University Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Ge","middleName":"","lastName":"Chen","suffix":""},{"id":553552736,"identity":"b8b96e9a-dc3f-424b-995f-afed456ffb78","order_by":1,"name":"Song Jin","email":"","orcid":"","institution":"West China Second University Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Song","middleName":"","lastName":"Jin","suffix":""},{"id":553552737,"identity":"bf299a3e-15ce-49cd-8987-185f61bd3b93","order_by":2,"name":"Long Zhang","email":"","orcid":"","institution":"West China Second University Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Long","middleName":"","lastName":"Zhang","suffix":""},{"id":553552738,"identity":"be8696fa-9c89-46f2-920f-f840159a6c41","order_by":3,"name":"Ping Liu","email":"","orcid":"","institution":"West China Second University Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Ping","middleName":"","lastName":"Liu","suffix":""},{"id":553552739,"identity":"0bbb73de-347f-4a5d-b358-dd3c4cd77dbf","order_by":4,"name":"Meng Cheng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4ElEQVRIiWNgGAWjYLACxgYgwd6AYBOphecAyVokEojUotvee/jFzx02efKRzx9+5mGwkd1wgPnZA3xazM6cS7PsPZNWbHg7x1iahyHNeMMBNnMDvFpu5JgZM7YdTtw4O4eNmYfhcOKGAzxsEni13H8D0vI/cePM48+AWv4ToeUGj/FjxrYDifMlGMyAWg4QoeVMjhljb1ty4gaeHGPJOQbJxjMPs5nh13L8jPGHn212ifPbjz/88KbCTrbvePMzvFqAAOIMgwNgEoiZCagHKfkAIuUbCKscBaNgFIyCEQoAw0FL/qCh7qgAAAAASUVORK5CYII=","orcid":"","institution":"West China Second University Hospital of Sichuan University","correspondingAuthor":true,"prefix":"","firstName":"Meng","middleName":"","lastName":"Cheng","suffix":""}],"badges":[],"createdAt":"2025-11-18 08:08:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8142666/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8142666/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":97349384,"identity":"146fb542-ae60-4bd7-9801-ce6942ded3fb","added_by":"auto","created_at":"2025-12-03 12:08:46","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":125862,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript20251118.docx","url":"https://assets-eu.researchsquare.com/files/rs-8142666/v1/97b9520df863f4ec6b340a2a.docx"},{"id":97349368,"identity":"cb504df8-827b-443a-8b3c-a9971db8e098","added_by":"auto","created_at":"2025-12-03 12:08:44","extension":"tiff","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":742026,"visible":true,"origin":"","legend":"","description":"","filename":"Figure1.tiff","url":"https://assets-eu.researchsquare.com/files/rs-8142666/v1/7bfd5dfbe1c0b3500c3334fe.tiff"},{"id":97349380,"identity":"4d3f5846-4070-406e-890d-1a5c06e97893","added_by":"auto","created_at":"2025-12-03 12:08:45","extension":"tiff","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":975642,"visible":true,"origin":"","legend":"","description":"","filename":"Figure2.tiff","url":"https://assets-eu.researchsquare.com/files/rs-8142666/v1/1ef6a54064868a1903069cc3.tiff"},{"id":97370474,"identity":"eab0f584-5cef-4175-af55-03bcf1e58d88","added_by":"auto","created_at":"2025-12-03 16:27:28","extension":"tiff","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1082692,"visible":true,"origin":"","legend":"","description":"","filename":"Figure3.tiff","url":"https://assets-eu.researchsquare.com/files/rs-8142666/v1/a7b64a9d86f093f221417a53.tiff"},{"id":97349347,"identity":"f759a6bc-824d-4076-93b3-4bfc5a207781","added_by":"auto","created_at":"2025-12-03 12:08:43","extension":"tiff","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":866572,"visible":true,"origin":"","legend":"","description":"","filename":"Figure4.tiff","url":"https://assets-eu.researchsquare.com/files/rs-8142666/v1/50a420ad8ceb9b399c109989.tiff"},{"id":97349383,"identity":"fc7a975b-f3dd-4c46-bed2-0224106bc3b3","added_by":"auto","created_at":"2025-12-03 12:08:46","extension":"json","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":7068,"visible":true,"origin":"","legend":"","description":"","filename":"ffed35f17a1c48678b4068a6ccc2d31c.json","url":"https://assets-eu.researchsquare.com/files/rs-8142666/v1/7fbec6713aaf5930c14d3bd2.json"},{"id":97349364,"identity":"2a37be19-0797-417e-bb26-37cef41de3b1","added_by":"auto","created_at":"2025-12-03 12:08:44","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2442034,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-8142666/v1/afc7e9434b2a26d0092c1010.docx"},{"id":97349337,"identity":"d7b25a43-1f4e-4e99-b8f7-b229394bb8b2","added_by":"auto","created_at":"2025-12-03 12:08:42","extension":"xml","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":86513,"visible":true,"origin":"","legend":"","description":"","filename":"ffed35f17a1c48678b4068a6ccc2d31c1enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8142666/v1/bd429372ce335a578f627902.xml"},{"id":97349377,"identity":"461a94d2-649c-46f6-af1c-c78b9c5fec40","added_by":"auto","created_at":"2025-12-03 12:08:45","extension":"tiff","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":742026,"visible":true,"origin":"","legend":"","description":"","filename":"Figure1.tiff","url":"https://assets-eu.researchsquare.com/files/rs-8142666/v1/aaa1c5681ce66d17bb5d0ace.tiff"},{"id":97349373,"identity":"49b9a9fd-7e13-4a5d-803d-729bac5ab431","added_by":"auto","created_at":"2025-12-03 12:08:45","extension":"tiff","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":975642,"visible":true,"origin":"","legend":"","description":"","filename":"Figure2.tiff","url":"https://assets-eu.researchsquare.com/files/rs-8142666/v1/87cb0eac97784131fadc2a64.tiff"},{"id":97349378,"identity":"12eb6e78-e9b5-4e05-9c9a-f4953a06b3b3","added_by":"auto","created_at":"2025-12-03 12:08:45","extension":"tiff","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1082692,"visible":true,"origin":"","legend":"","description":"","filename":"Figure3.tiff","url":"https://assets-eu.researchsquare.com/files/rs-8142666/v1/91cdc2f646fde64f7bfbb9a4.tiff"},{"id":97349385,"identity":"4c201dcb-2065-4ebc-a34e-10fdffe52f21","added_by":"auto","created_at":"2025-12-03 12:08:46","extension":"tiff","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":866572,"visible":true,"origin":"","legend":"","description":"","filename":"Figure4.tiff","url":"https://assets-eu.researchsquare.com/files/rs-8142666/v1/3a8be845a66f4ed062e51875.tiff"},{"id":97349371,"identity":"871d9483-d7fd-4ea7-b64e-3748f77b23e0","added_by":"auto","created_at":"2025-12-03 12:08:44","extension":"png","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":82519,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8142666/v1/2a05dd89a6629c95e1dc06ba.png"},{"id":97349365,"identity":"0c442d4f-da22-4d42-ad2a-65b55c8002b1","added_by":"auto","created_at":"2025-12-03 12:08:44","extension":"png","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":143635,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8142666/v1/e67cc9eafa1d95ab7f73fb17.png"},{"id":97349382,"identity":"b2e5f724-7049-40cd-abb3-53d33354bfe0","added_by":"auto","created_at":"2025-12-03 12:08:46","extension":"png","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":139582,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8142666/v1/8b601b096390c0e297eccdaf.png"},{"id":97349374,"identity":"6265e0c5-b1ba-4bc7-aec8-14cb5e522e64","added_by":"auto","created_at":"2025-12-03 12:08:45","extension":"png","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":128646,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure4.png","url":"https://assets-eu.researchsquare.com/files/rs-8142666/v1/fc8e54a462150a7183de5a87.png"},{"id":97349346,"identity":"cca5556e-8eed-4268-b7f5-daa7a2a3fdfd","added_by":"auto","created_at":"2025-12-03 12:08:43","extension":"xml","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":86734,"visible":true,"origin":"","legend":"","description":"","filename":"ffed35f17a1c48678b4068a6ccc2d31c1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8142666/v1/d94d48889b85d273e7e66856.xml"},{"id":97349369,"identity":"108cb72b-7f7c-474e-93c9-20730c2d5ff0","added_by":"auto","created_at":"2025-12-03 12:08:44","extension":"html","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":95295,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8142666/v1/5e091727ccbf98d83b0df44c.html"},{"id":97349367,"identity":"1fe10e38-2e40-421c-94db-04c208d45853","added_by":"auto","created_at":"2025-12-03 12:08:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":748085,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparison of pregnancy outcomes between ST and RT groups before and after PSM.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Pregnancy outcomes in the ST and RT groups before propensity score matching (PSM).\u003c/p\u003e\n\u003cp\u003e(B) Pregnancy outcomes in the ST and RT groups after PSM.\u003c/p\u003e\n\u003cp\u003eNote: Bar plots display the proportions (%) of five clinical outcomes: clinical pregnancy, chemical pregnancy, live birth, abortion, and ovarian hyperstimulation syndrome (OHSS). Error bars represent standard error of the proportion. Asterisks denote statistically significant differences between groups (*p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p\u0026lt; 0.001). ST = strengthened luteal phase support; RT = routine luteal phase support; OHSS = ovarian hyperstimulation syndrome; PSM = propensity score matching.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8142666/v1/b872898f0d3be771a29e6fe7.png"},{"id":97349370,"identity":"81c555cd-1817-49eb-b19c-7857819a31ce","added_by":"auto","created_at":"2025-12-03 12:08:44","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1369958,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plots of adjusted odds ratios for luteal phase support across prespecified subgroups.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Subgroup analysis for clinical pregnancy.\u003c/p\u003e\n\u003cp\u003e(B) Subgroup analysis for chemical pregnancy.\u003c/p\u003e\n\u003cp\u003e(C) Subgroup analysis for live birth.\u003c/p\u003e\n\u003cp\u003eNote: Forest plots show ORs and 95% CIs for clinical predictors of pregnancy outcomes across predefined subgroups. Subgroups include age, AMH level, BMI, number of high-quality embryos transferred, endometrial thickness, and serum hormone levels on hCG day. The vertical dashed line represents the reference value (OR = 1). AMH = anti-Müllerian hormone, ET-EM = endometrial thickness in embryo transfer day, hCG-E2 = estradiol levels on hCG day, hCG-P = progesterone levels on hCG day, hCG = human chorionic gonadotropin; CI = confidence interval, OR = odds ratio.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8142666/v1/d6c34c15644ef91811fc2def.png"},{"id":97349381,"identity":"9eb5a645-3f00-48e5-8738-6d4c9a1b7f25","added_by":"auto","created_at":"2025-12-03 12:08:45","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1204780,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePrimary reproductive outcomes across four luteal phase support groups before and after PSM.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Pregnancy outcomes in the S-GnRHat, S-hCG, S-Double, and Routine trigger (RT) groups before propensity score matching (PSM).\u003c/p\u003e\n\u003cp\u003e(B) Pregnancy outcomes in the four groups after PSM.\u003c/p\u003e\n\u003cp\u003eNote: The upper panel shows the unadjusted proportions before PSM; the lower panel displays the matched results after PSM. Each bar indicates the proportion (%) of patients achieving the outcome, with absolute counts annotated above the bars. Asterisks (*) indicate statistically significant differences between groups based on pairwise post hoc comparisons using Tukey’s HSD test (p \u0026lt; 0.05).\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8142666/v1/665da2fd231322394cf75cd4.png"},{"id":97349348,"identity":"5a8b3222-a46f-44b4-86f3-f7b34f581107","added_by":"auto","created_at":"2025-12-03 12:08:43","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1641024,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOdds ratios (ORs) for clinical pregnancy associated with luteal phase support across E2 ratio intervals.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Adjusted odds ratios (ORs) for clinical pregnancy and\u003c/p\u003e\n\u003cp\u003e(B) live birth comparing luteal support versus no support across the E2 ratio spectrum using a sliding.\u003c/p\u003e\n\u003cp\u003eNote: Each dot represents the adjusted OR at a given window center, with shaded areas indicating 95% confidence intervals. The horizontal dashed line at OR = 1 indicates no effect. Asterisks denote statistical significance (p \u0026lt; 0.05, *p \u0026lt; 0.01, **p \u0026lt; 0.001).\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-8142666/v1/22199c94482833354c8ed22d.png"},{"id":98622160,"identity":"19c24aa2-56e0-406d-89e1-1e95def82b09","added_by":"auto","created_at":"2025-12-19 16:47:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6506040,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8142666/v1/2e2842f2-22bc-4fed-9f47-6a853bfeaf7e.pdf"},{"id":97349379,"identity":"bbdb40a1-3a37-4010-8092-034b9fde4500","added_by":"auto","created_at":"2025-12-03 12:08:45","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":2442034,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-8142666/v1/d64c04cf9b6d892323030a94.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eHCG/GnRHa support improves outcomes after GnRH antagonist dual trigger and the predictive role of mid-luteal estradiol ratio: a case control study\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eInfertility is a significant health concern affecting 10\u0026ndash;15% of couples worldwide. The in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) have become the most effective treatments (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The GnRH antagonist protocol combined with dual trigger has become increasingly prevalent for numerous advantages, including a reduced treatment duration, greater flexibility, improved oocyte maturation and embryo quality and a lower risk of OHSS when compared to traditional GnRH agonist protocols (\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Despite these advancements, the luteal phase in fresh embryo transfer (ET) cycles remains compromised due to inadequate corpus luteum function, leading to implantation failure and early pregnancy loss (\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn this scenario, greater attention to strengthened luteal phase support (LPS) is necessary among patients received GnRHa protocol with dual trigger after fresh embryo transfer. Except for routine progesterone agents in various forms and doses, other hormones, such as estradiol, hCG, or GnRHa (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), were introduced to strength the luteal function and improve pregnancy outcomes. The use of hCG suggested to increase implantation rates by rescuing the corpus luteum and preventing luteolysis. However, several studies stayed cautious with dose and time for increased risk of OHSS (\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Meanwhile, GnRHa was proposed as alternative strengthened LPS protocol by inducing endogenous LH secretion. Supplement of GnRHa was reported to significantly improve pregnancy and live birth rates without OHSS risks (\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). However, the clinical utility and effectiveness of various strengthened luteal phase support exhabits heterogeneity and lack of consensus on the optimal regimens (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eOther debated issues about strengthened LPS focus on identification of patients who could benefit most for which current evidence limited. Moreover, defining the subgroups and clinical indicators that predict favorable responses to strengthened LPS remains unclear. Limited studies focus on the estradiol levels in case of additional supplements (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). This study aims to evaluate the overall effects and safety of early strengthened luteal phase support (hCG or GnRHa) on pregnancy outcomes. Additionally, multivariate analysis and assessment of dynamic estradiol changes were used to identify the patients who most likely to benefit and potential clinical indicators. This study would assist clinicians in refining therapeutic protocols and optimizing pregnancy outcomes in IVF/ICSI cycles.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy Design and Patient Selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective cohort study was conducted at the Department of Reproductive Medicine, West China Second Hospital of Sichuan University, between January 2020 and May 2024. All the participants were women undergoing IVF/ICSI-ET with a GnRH antagonist protocol and a dual trigger for final oocyte maturation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion and Exclusion Criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInclusion criteria: 1) Women aged between 20 and 45 years undergoing their first or second IVF/ICSI cycle. 2) Use of a GnRH antagonist protocol for ovarian stimulation. 3) Dual trigger using a combination of hCG and GnRHa for final oocyte maturation. 4) Fresh embryos transfer (one or two) at the cleavage.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eExclusion criteria:1) Patients with uterine abnormalities such as congenital malformations, intrauterine adhesions, or fibroids significantly affecting the embryo implantation. 2) Patients undergoing preimplantation genetic testing (PGT) cycles. 3) Use of donor oocytes or frozen-thawed embryo transfers. 4) Known history of recurrent implantation failure (\u0026ge;three times failed embryo transfers). 5) Severe male factor infertility requiring the use of testicular sperm aspiration (TESA) or microdissection testicular sperm extraction (micro-TESE).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinical data were retrospectively collected from the electronic medical records of patients who underwent fresh IVF/ICSI-ET cycles using a GnRH antagonist protocol. Baseline characteristics controlled ovarian stimulation parameters, embryo transfer details, and pregnancy outcomes were extracted. Serum hormone levels, including estradiol (E2), progesterone, and LH, were recorded on the day of hCG trigger or mid-luteal phase (8\u0026ndash;9 days after oocyte retrieval). Variables related to embryo quality, endometrial thickness, and luteal phase support strategies were also collected.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOvarian Stimulation Protocol and Embryo Transfer\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients underwent controlled ovarian stimulation (COS) using a GnRH antagonist protocol. Recombinant follicle-stimulating hormone (rFSH) or human menopausal gonadotropin (hMG) was administered at individualized doses based on ovarian reserve parameters (age, body mass index, AMH, antral follicle count, and previous response to stimulation). Daily GnRH antagonist (0.25 mg cetrorelix,\u0026nbsp;Merck,\u0026nbsp;Germany or ganirelix, MSD, USA) was initiated from the cycle day 5-6 or when the leading follicle reached 12\u0026ndash;14 mm in diameter.\u003c/p\u003e\n\u003cp\u003eFinal oocyte maturation was triggered using a dual trigger approach consisting of GnRHa (0.2 mg triptorelin, Ferring, Denmark) combined with hCG (Ovitrelle, 250\u0026mu;g, Merck, Germany). Oocyte retrieval was performed 36 hours later, followed by conventional IVF or ICSI, depending on sperm quality.\u003c/p\u003e\n\u003cp\u003eFresh embryo transfer was performed on Day 3 (cleavage stage) after oocyte retrieval. One or two embryos were transferred based on patient age, clinical indications, the number and quality of embryos available, following national ART guidelines (19). Luteal phase support was first initiated on the day of oocyte retrieval till the pregnany test day. If the pregnancy was achieved, luteal phase support would continue.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLuteal Phase Support Strategies\u003cbr\u003e\u003c/strong\u003ePatients were classified into two groups as follow:\u003c/p\u003e\n\u003cp\u003e1. Routine LPS group (RT): All the patients received progesterone supplementation, including dydrogesterone (AbbottBiologicalsB.V, USA) orally at 20 mg/d combined with progesterone vaginal gel (Crinone, Merck, Germany) at 90 mg/d.\u003c/p\u003e\n\u003cp\u003e2. Strengthened LPS group (ST): All the patients in strengthened LPS group received\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eroutine LPS support with additional hCG (Livzon Pharmaceutical Group, China) or/and GnRHa injection. The ST group was further divided into three subgroups according to different medications.\u003c/p\u003e\n\u003cp\u003eS-hCG group:\u0026nbsp; \u0026nbsp;\u0026nbsp;patients received 2000 IU hCG every other day began from day 8-9 after retrieval to pregnant test day.\u003c/p\u003e\n\u003cp\u003eS-GnRHa group: patients received\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;GnRHa\u0026nbsp;\u0026nbsp;0.1mg on day 3 and day 5 after retrieval\u003c/p\u003e\n\u003cp\u003eS-Double group: patients received\u0026nbsp;2000 IU hCG every other day began from day 8-9 after retrieval to pregnant test day combined with GnRHa 0.1mg on day 3 and day 5 after retrieval\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome Measures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcomes included: 1) Biochemical pregnancy rate: Defined as a positive serum \u0026beta;-hCG (\u0026gt;25 IU/L) 12-14 days after embryo transfer. 2) Clinical pregnancy rate: Presence of at least one intrauterine gestational sac with a fetal heartbeat under ultrasound image on the day 30\u0026ndash;35 after embryo transfer. 3) Ongoing pregnancy rate: A viable pregnancy detected by ultrasound examination beyond 12 weeks of gestation. 4) Abortion rate: Loss of pregnancy before 12 weeks of gestation. 5) Incidence of severe OHSS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analyses were conducted using SPSS software (version 26.0), R (version 4.3.1), Python (3.9.13). Continuous variables were presented as mean \u0026plusmn; standard deviation (SD) and compared using independent t-tests or Mann-Whitney U tests, depending on data distribution. Categorical variables were expressed as frequencies and percentages and analyzed using chi-square tests or Fisher\u0026rsquo;s exact tests, as appropriate.\u003c/p\u003e\n\u003cp\u003eThe propensity score was logit-transformed, and a caliper width equal to 0.2 of the standard deviation of the logit of the propensity score was applied. 1:1 nearest neighbor matching with replacement was used, allowing control individuals to be matched to more than one treated individual, thereby maximizing the matched sample size. After matching, standardized mean differences (SMD) were calculated for all covariates, with |SMD|\u0026lt;0.1 indicating acceptable balance. Multivariate logistic regression identified predictors of pregnancy outcomes. Subgroup analyses were stratified by age, AMH level, embryo quality, and endometrial thickness. A\u0026nbsp;sliding window multivariable logistic regression analysis using the E2 ratio were performed. Analyses were performed using R (v4.2.1), and P-values \u0026lt;0.05 were considered significant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Board (IRB) of West China Second Hospital, Sichuan University (2024253). Informed consent was waived due to the retrospective nature of the study, and all data were anonymized before analysis to protect patient confidentiality.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eBaseline characteristics of ST and RT group Before and After Propensity Score Matching\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe baseline characteristics of the study population (N = 2,195) were summarized in\u003cstrong\u003e\u0026nbsp;Supplemental Table 1\u003c/strong\u003e. Among them, 1,459 patients were assigned to ST group and 736 to the RT group. Statistically significant differences were observed between the two groups across multiple baseline parameters.\u003c/p\u003e\n\u003cp\u003eCompared with the ST group, patients in the RT group had higher AMH levels (3.04 ± 2.02 vs. 3.36 ± 2.45 ng/mL, P = 0.0026) and higher estradiol (2086.54 ± 1070.15 vs. 2350.85 ± 1141.25, P \u0026lt; 0.0001) and progesterone levels on the day of hCG trigger (0.70 ± 0.25 vs. 0.77 ± 0.28 ng/mL, P \u0026lt; 0.0001). The ST group had significantly fewer retrieved oocytes (8.53 ± 4.12 vs. 9.35 ± 4.27, P \u0026lt; 0.0001), mature (MII) oocytes (6.81 ± 3.62 vs. 7.47 ± 3.70, P = 0.0001), and 2PN fertilized embryos (5.02 ± 2.96 vs. 5.57 ± 3.06, P = 0.0001) and available embryos (4.51± 2.74 vs 4.89± 2.83, P=0.0028).\u003c/p\u003e\n\u003cp\u003eTo address these baseline disparities and reduce selection bias, PSM was conducted using 1:1 nearest neighbor matching with a caliper of 0.2. After matching, baseline characteristics between the two groups were well balanced, with no statistically significant differences in demographic or stimulation-related parameters (\u003cstrong\u003eSupplemental Table 2\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Outcomes and Safety of ST and RT group Before and After Propensity Score Matching\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs shown in \u003cstrong\u003eFigure 1\u003c/strong\u003e, the ST group demonstrated better pregnancy outcomes both before and after PSM. Before matching, chemical pregnancy was significantly higher in the ST group, compared to the RT group (54.1% vs. 43.2%, P \u0026lt; 0.0001). The differences were observed for the clinical pregnancy rate (48.1% vs. 41.0%, P = 0.0019) and live birth rate (43.1% vs. 37.5%, P = 0.013). No significant difference was found in the abortion rate and severe OHSS incidence\u0026nbsp;(\u003cstrong\u003eFigure 1A\u003c/strong\u003e). After PSM, the ST group still showed significantly higher chemical pregnancy (54.1% vs. 40.6%, P \u0026lt; 0.0001), clinical pregnancy (48.2% vs. 37.1%, P \u0026lt; 0.0001), and live birth (43.2% vs. 34.3%, P \u0026lt; 0.0001) rates. The abortion rate and severe OHSS remained similar between two groups\u0026nbsp;(\u003cstrong\u003eFigure 1B\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eNeonatal outcomes and maternal safety were compared between ST and RT groups before and after PSM. As shown in\u003cstrong\u003eSupplemental\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003efigure 1 and\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eSupplemental\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Table 3\u003c/strong\u003e, among singleton births, the ST group had a slightly lower birth weight than the RT group only before PSM (3094.9 ± 512.4 g vs. 3160.2 ± 469.9 g, P = 0.034) (\u003cstrong\u003eSupplemental\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eFigure 1\u003c/strong\u003e\u003cstrong\u003eA-B\u003c/strong\u003e). Importantly, maternal complications were more frequent in the ST group than in the RT group after PSM (8.9% vs. 2.6%, P = 0.0045), though no significant difference was observed before PSM (\u003cstrong\u003eSupplemental\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003efigure 1\u003c/strong\u003e\u003cstrong\u003eC-D\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eAmong twin pregnancies, birth weight and height were similar between ST and RT groups both before and after PSM. The incidence of birth defects and maternal complications was comparable between groups (\u003cstrong\u003eSupplemental figure 2 and\u003c/strong\u003e\u003cstrong\u003eSupplemental\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Table 3\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubgroup analyses of luteal support for pregnancy outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo identify independent predictors of treatment outcomes, multi-variable logistic regression models were performed for chemical pregnancy, clinical pregnancy, and live birth. As shown in\u0026nbsp;\u003cstrong\u003eSupplemental fig\u003c/strong\u003e\u003cstrong\u003eure 3 and\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eSupplemental\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Table 4\u003c/strong\u003e, ST treatment was significantly associated with improved outcomes after adjusting for multiple confounders, with higher odds of chemical pregnancy (OR=1.75, 95% CI: 1.49-2.05, P \u0026lt; 0.001), clinical pregnancy (OR=1.59, 95% CI 1.36-1.87, P \u0026lt; 0.001), and live birth (OR =1.48, 95% CI: 1.26-1.74, P \u0026lt; 0.001) compared to RT group. Maternal age, endometrial thickness on the day of transfer (ET-EM), the number of high-quality embryos transferred (ET-high-quality-embryo), progesterone levels in trigger day (hCG-P) were significantly associated with pregnancy outcomes.\u003c/p\u003e\n\u003cp\u003eFurther subgroup analysis between ST and RT were applied according to above results. Among women aged \u0026lt;35 years, ST was significantly associated with increased rates of chemical pregnancy (OR=1.72, 95% CI 1.43-2.06, P\u0026lt;0.001), clinical pregnancy (OR=1.50, 95% CI 1.25-1.79, P\u0026lt;0.001), and live birth (OR=1.48, 95% CI 1.24-1.78, P\u0026lt;0.001). Comparable benefits were observed in women aged\u0026nbsp;≥35 years, with slightly larger effect sizes for chemical pregnancy (OR=1.74, 95% CI 1.29-2.34, P\u0026lt;0.001) and clinical pregnancy (OR=1.83, 95% CI 1.33-2.50, P\u0026lt;0.001)\u0026nbsp;\u003cstrong\u003e(Figure 2 and\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eSupplemental\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Table 5\u003c/strong\u003e\u003cstrong\u003e).\u003c/strong\u003e The benefit of ST was evident in both AMH\u0026nbsp;≥1.2 and AMH \u0026lt;1.2 groups, with a more pronounced effect among those with lower AMH (chemical pregnancy OR=2.2, 95% CI 1.45-3.35, P\u0026lt;0.001; clinical pregnancy OR=1.89, 95% CI 1.23-2.88, P=0.003)\u0026nbsp;\u003cstrong\u003e(Figure 2 and\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eSupplemental\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Table 5\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e.\u0026nbsp;Moreover, ST showed significant advantages regardless of the number of high-quality embryos transferred.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFurther analyses suggested that the superiority of ST was more evident in patients with ET-EM\u0026nbsp;≥3.5 mm and in those with hCG-P \u0026lt;1.2 ng/mL, whereas no significant benefit was detected in ET-EM \u0026lt;3.5 mm and in those with hCG-P≥1.2 ng/mL\u0026nbsp;\u003cstrong\u003e(Figure 2 and\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eSupplemental\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Table 5\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImpact of Strengthened Luteal Phase Support Type on Reproductive Outcomes Before and After PSM\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo further dissect the impact of different luteal support strategies, we compared pregnancy outcomes among the three strengthened support types (S-GnRHa, S-hCG, and S-Double) relative to the RT group. Before PSM, all five primary outcomes differed significantly among the four luteal support groups (\u003cstrong\u003eFigure 3A\u003c/strong\u003e). The S-hCG group achieved the highest clinical pregnancy rate (53.9%), followed by the S-Double (45.7%) and S-GnRHa (46.2%) groups, while the RT group had the lowest rate (41.0%). Similar trends were observed for chemical pregnancy and live birth rates. Abortion rates were slightly higher in the S-hCG (6.8%) and S-Double (5.0%) groups, and the incidence of OHSS was significantly increased in the S-GnRHa group (1.2%) compared to the RT group (0.1%, p \u0026lt; 0.05).\u003c/p\u003e\n\u003cp\u003eAfter PSM (\u003cstrong\u003eFigure 3B\u003c/strong\u003e), the between-group differences in pregnancy outcomes remained statistically significant. The S-hCG group continued to demonstrate the highest rates of chemical pregnancy (63.0%), clinical pregnancy (54.0%) and live birth rate (47.4%). The S-GnRHa and S-Double group also showed improved outcomes relative to RT. The incidence of OHSS remained notably higher in the S-GnRHa group (1.1%) and S-hCG group (0.3%) than in the RT group (0.1%, p \u0026lt; 0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssociation Between mid-luteal E2 Ratio and the Effectiveness of Strengthened Luteal Phase Support\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo investigate the heterogeneity in response to luteal phase support across different patterns of early estradiol decline, we performed a sliding window multivariable logistic regression analysis using the E2 ratio, defined as mid-luteal serum E2 (day 8-9 after oocyte retrieval) divided by E2 on the hCG trigger day, was used as a continuous variable for stratification.\u003c/p\u003e\n\u003cp\u003eAs shown in \u003cstrong\u003eFigure 4A\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eand Supplemental Table 6\u003c/strong\u003e, the OR for clinical pregnancy associated with receiving ST peaked at an E2 ratio of 0.05 (adjusted OR=6.21, 95% CI: 2.86-13.52, p = 0.000004), indicating that patients with the most pronounced estradiol decline benefited substantially from ST. A small elevation tendency in OR was observed near an E2 ratio of 0.6, though the magnitude was not statistically significant.\u003c/p\u003e\n\u003cp\u003eSimilarly, for live birth (\u003cstrong\u003eFigure 4B\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eand Supplemental Table 7\u003c/strong\u003e), the adjusted OR peaked at an E2 ratio of 0.15 (adjusted OR: 5.52, 95% CI: 1.47-20.80, p = 0.012), suggesting that a subset of patients with moderately severe estradiol decline may also derive benefit. However, confidence intervals were wider, and the association was less consistent across the spectrum.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe luteal phase disruption can occur in ART cycles using the antagonist protocol and dual trigger in fresh transfer cycle. Therefore, the individualization of strengthened LPS was essential in improving pregnancy outcomes. In this large, propensity score\u0026ndash;matched cohort, the clinical effectiveness and safety of strengthened LPS, particularly hCG-based regimens, was confirmed after adjusting for major confounders. Moreover, patients of advanced age, or diminished ovarian reservation or those receiving embryos of suboptimal quality may particularly benefit from strengthened LPS. Meanwhile, the E2 ratio in mid-luteal phase may be identified as potential indicator for strengthened LPS use.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe antagonist protocol triggered by GnRHa, granulosa cells exhibit reduced viability in vivo and fail to maintain sex steroid production compared with the cells retrieved during a natural cycle (20). By contrast, GnRHa induces a shorter duration of endogenous LH secretion(~34 h) compared with the natural LH surge (48\u0026thinsp;h) or the LH-like activity provided by hCG (21). The luteal phase disruption can occur in ART cycles using the antagonist protocol and dual trigger. Therefore, the individualization of enhanced luteal support, such as E2, hCG, or GnRHa (11, 18, 22, 23) may be helpful in improving pregnancy outcomes.\u003c/p\u003e\n\u003cp\u003eThe biological rationale for ST, especially with hCG-based regimens, is well supported. hCG acts directly on LH/hCG receptors in the corpus luteum to promote progesterone and E2 secretion(24-26), critical for maintaining endometrial receptivity in the peri-implantation window(27). Some studies, including those by Svenstrup et al (9), Singh et al (28) highlight that while hCG rescues the corpus luteum, prevents luteolysis and enhances implantation potential, it must be carefully managed in patients at risk for OHSS. Moreover, GnRHa-based support provides an alternative approach, offering adequate luteal phase support. GnRHa supports implantation and pregnancy via stimulating the corpus luteum by LH and favoring the adhesion of the embryo to the endometrial epithelial surface (29). The higher pregnancy rate in the GnRHa group compared with the progesterone group have been shown in some research (14, 15). The study by Dong et al (30) have shown that GnRHa can be an effective alternative to hCG in high responders. In current study, hCG group achieved the best pregnancy outcomes. Other strengthened protocols also showed improved outcomes compared with the routine group. The dual approach combining hCG and GnRHa, referred to as double-strengthened were not superior to single hCG support in our cohort. Our study demonstrates that hCG-based strengthened support remains the most effective protocol, reinforcing its value in corpus luteum rescue. The lack of additional benefit from double-strengthened protocols underscores the importance of a mechanism-based, individualized approach rather than empirical intensification.\u003c/p\u003e\n\u003cp\u003ePrevious research suggested that patients with good ovarian reserve benefit more from strengthened luteal support due to their ability to maintain adequate corpus luteum function when supplemented with hCG or GnRHa (9-11, 18). However,\u0026nbsp;our results highlight the clinical utility of ST across diverse patient profiles. Subgroup analyses not only confirm the overall effectiveness of ST but also provide evidence to identify patient groups most likely to benefit, including women of advanced maternal age, diminished ovarian reserve and suboptimal embryo quality. This refined patient stratification may help optimize clinical decision-making and facilitate the individualized luteal phase management in fresh embryo transfer cycles.\u003c/p\u003e\n\u003cp\u003eIn addition, this study introduced sliding-window analysis using early luteal E2 dynamics (E2 ratio) to stratify the benefit of ST. We observed a non-linear, bimodal association between E2 ratio and the adjusted OR for pregnancy. The finding suggests that patients with early and substantial E2 depletion may have insufficient luteal function and thus respond more favorably to ST. Although not yet integrated into routine practice, the E2 ratio may serve as a future biomarker to personalize luteal support strategies (18).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLimitations of this study include its retrospective design with a single-center dataset. Although propensity score matching and multivariable adjustment were applied, unmeasured confounding cannot be fully excluded. In addition, while the E2 ratio offers a promising direction for individualized support, its clinical thresholds and utility need prospective validation.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study suggests that strengthened early LPS should be considered in fresh IVF/ICSI cycles using the antagonist protocol and dual trigger approach. The most effective protocol form of this support was found to be hCG-based regimens. Our results also indicated that early estradiol decline may help identify patients who benefit most from support. These findings support the use of enhanced luteal support and point toward future individualized strategies protocols. Future prospective studies are needed to further validate these findings and refine the most beneficial subgroups for individual luteal support.\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003ePSM: propensity score matching\u003c/p\u003e\n\u003cp\u003ehCG: human chorionic gonadotropin\u003c/p\u003e\n\u003cp\u003eGnRha: gonadotropin-releasing hormone agonist\u003c/p\u003e\n\u003cp\u003eLPS: luteal phase support\u003c/p\u003e\n\u003cp\u003eRT: routine support\u003c/p\u003e\n\u003cp\u003eST: strengthened support\u003c/p\u003e\n\u003cp\u003eOR: odd ratio\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding Statement:\u0026nbsp;\u003c/strong\u003eNo funding\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure Statement:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no conflicts of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Board (IRB) of West China Second Hospital, Sichuan University (2024253). Informed consent was waived due to the retrospective nature of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available upon request from the corresponding author.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors have no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eG.C.: data collection, data analysis, visualization, draft writing and editing. S.J.: draft reviewing, supervision, administration and investigation. L.Z.: investigation and data collection. P.L.: draft writing and editing, supervision, data analysis and study design. C.M.: draft reviewing, supervision, administration, methodology, data collection and study design.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Lijuan Deng and BopingWang contributing to this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCox CM, Thoma ME, Tchangalova N, Mburu G, Bornstein MJ, Johnson CL, et al. Infertility prevalence and the methods of estimation from 1990 to 2021: a systematic review and meta-analysis. Hum Reprod Open. 2022;2022(4):hoac051.\u003c/li\u003e\n\u003cli\u003eZhou Z, Zheng D, Wu H, Li R, Xu S, Kang Y, et al. Epidemiology of infertility in China: a population-based study. BJOG. 2018;125(4):432-41.\u003c/li\u003e\n\u003cli\u003eYu J, Fu Y, Zeng L, Xie P, Li L, Zheng Y. Burden of female infertility in China from 1990 to 2019: a temporal trend analysis and forecasting, and comparison with the global level. Sex Health. 2023;20(6):577-84.\u003c/li\u003e\n\u003cli\u003eGao F, Wang Y, Fu M, Zhang Q, Ren Y, Shen H, et al. Effect of a \u0026quot;Dual Trigger\u0026quot; Using a GnRH Agonist and hCG on the Cumulative Live-Birth Rate for Normal Responders in GnRH-Antagonist Cycles. Front Med (Lausanne). 2021;8:683210.\u003c/li\u003e\n\u003cli\u003eHaas J, Bassil R, Samara N, Zilberberg E, Mehta C, Orvieto R, et al. GnRH agonist and hCG (dual trigger) versus hCG trigger for final follicular maturation: a double-blinded, randomized controlled study. Hum Reprod. 2020;35(7):1648-54.\u003c/li\u003e\n\u003cli\u003eCasper RF. Basic understanding of gonadotropin-releasing hormone-agonist triggering. Fertil Steril. 2015;103(4):867-9.\u003c/li\u003e\n\u003cli\u003eKol S, Breyzman T, Segal L, Humaidan P. \u0026apos;Luteal coasting\u0026apos; after GnRH agonist trigger - individualized, HCG-based, progesterone-free luteal support in \u0026apos;high responders\u0026apos;: a case series. Reprod Biomed Online. 2015;31(6):747-51.\u003c/li\u003e\n\u003cli\u003evan der Linden M, Buckingham K, Farquhar C, Kremer JA, Metwally M. Luteal phase support for assisted reproduction cycles. Cochrane Database Syst Rev. 2015;2015(7):Cd009154.\u003c/li\u003e\n\u003cli\u003eSvenstrup L, M\u0026ouml;ller S, Fedder J, Pedersen DE, Erb K, Andersen CY, et al. Investigation of luteal HCG supplementation in GnRH-agonist-triggered fresh embryo transfer cycles: a randomized controlled trial. Reprod Biomed Online. 2024;48(5):103415.\u003c/li\u003e\n\u003cli\u003eKastora SL, Gkova G, Stavridis K, Balachandren N, Kastoras A, Karakatsanis A, et al. Comparison of luteal support protocols in fresh IVF/ICSI cycles: a network meta-analysis. Sci Rep. 2024;14(1):14492.\u003c/li\u003e\n\u003cli\u003eGarg A, Zielinska AP, Yeung AC, Abdelmalak R, Chen R, Hossain A, et al. Luteal phase support in assisted reproductive technology. Nature reviews Endocrinology. 2024;20(3):149-67.\u003c/li\u003e\n\u003cli\u003eTesarik J, Hazout A, Mendoza-Tesarik R, Mendoza N, Mendoza C. Beneficial effect of luteal-phase GnRH agonist administration on embryo implantation after ICSI in both GnRH agonist- and antagonist-treated ovarian stimulation cycles. Hum Reprod. 2006;21(10):2572-9.\u003c/li\u003e\n\u003cli\u003eBenmachiche A, Benbouhedja S, Zoghmar A, Boularak A, Humaidan P. Impact of Mid-Luteal Phase GnRH Agonist Administration on Reproductive Outcomes in GnRH Agonist-Triggered Cycles: A Randomized Controlled Trial. Frontiers in endocrinology. 2017;8:124.\u003c/li\u003e\n\u003cli\u003eIsik AZ, Caglar GS, Sozen E, Akarsu C, Tuncay G, Ozbicer T, et al. Single-dose GnRH agonist administration in the luteal phase of GnRH antagonist cycles: a prospective randomized study. Reprod Biomed Online. 2009;19(4):472-7.\u003c/li\u003e\n\u003cli\u003eBuhbut E, Nabulsi R, Avigdor G, Ben-Ami I. Comparison of pregnancy rates in antagonist cycles after luteal support with GnRH-agonist versus progesterone: prospective randomized study. Arch Gynecol Obstet. 2023;308(1):255-63.\u003c/li\u003e\n\u003cli\u003eHumaidan P, Polyzos NP, Alsbjerg B, Erb K, Mikkelsen AL, Elbaek HO, et al. GnRHa trigger and individualized luteal phase hCG support according to ovarian response to stimulation: two prospective randomized controlled multi-centre studies in IVF patients. Hum Reprod. 2013;28(9):2511-21.\u003c/li\u003e\n\u003cli\u003eKol S, Humaidan P, Itskovitz-Eldor J. GnRH agonist ovulation trigger and hCG-based, progesterone-free luteal support: a proof of concept study. Hum Reprod. 2011;26(10):2874-7.\u003c/li\u003e\n\u003cli\u003eLi N, Huang Y, Fan L, Shi Z, Cai H, Shi J, et al. Effect of estradiol supplementation on luteal support following a significant reduction in serum estradiol levels after hCG triggering: a prospective randomized controlled trial. Reprod Biol Endocrinol. 2024;22(1):117.\u003c/li\u003e\n\u003cli\u003eCoticchio G, Ahlstr\u0026ouml;m A, Arroyo G, Balaban B, Campbell A, De Los Santos MJ, et al. The Istanbul consensus update: a revised ESHRE/ALPHA consensus on oocyte and embryo static and dynamic morphological assessment\u0026dagger;,\u0026Dagger;. Hum Reprod. 2025;40(6):989-1035.\u003c/li\u003e\n\u003cli\u003eBildik G, Akin N, Seyhan A, Esmaeilian Y, Yakin K, Keles I, et al. Luteal granulosa cells from natural cycles are more capable of maintaining their viability, steroidogenic activity and LH receptor expression than those of stimulated IVF cycles. Hum Reprod. 2019;34(2):345-55.\u003c/li\u003e\n\u003cli\u003eVuong TN, Ho MT, Ha TD, Phung HT, Huynh GB, Humaidan P. Gonadotropin-releasing hormone agonist trigger in oocyte donors co-treated with a gonadotropin-releasing hormone antagonist: a dose-finding study. Fertil Steril. 2016;105(2):356-63.\u003c/li\u003e\n\u003cli\u003eLabarta E, Mariani G, Rodr\u0026iacute;guez-Varela C, Bosch E. Individualized luteal phase support normalizes live birth rate in women with low progesterone levels on the day of embryo transfer in artificial endometrial preparation cycles. Fertil Steril. 2022;117(1):96-103.\u003c/li\u003e\n\u003cli\u003eZhao J, Hao J, Li Y. Individualized luteal phase support after fresh embryo transfer: unanswered questions, a review. Reprod Health. 2022;19(1):19.\u003c/li\u003e\n\u003cli\u003eCole LA. Biological functions of hCG and hCG-related molecules. Reprod Biol Endocrinol. 2010;8:102.\u003c/li\u003e\n\u003cli\u003eChoi J, Smitz J. Luteinizing hormone and human chorionic gonadotropin: distinguishing unique physiologic roles. Gynecol Endocrinol. 2014;30(3):174-81.\u003c/li\u003e\n\u003cli\u003eNwabuobi C, Arlier S, Schatz F, Guzeloglu-Kayisli O, Lockwood CJ, Kayisli UA. hCG: Biological Functions and Clinical Applications. Int J Mol Sci. 2017;18(10).\u003c/li\u003e\n\u003cli\u003eSmitz J, Platteau P. Influence of human chorionic gonadotrophin during ovarian stimulation: an overview. Reprod Biol Endocrinol. 2020;18(1):80.\u003c/li\u003e\n\u003cli\u003eSingh N, Kashyap A, Malhotra N, Mahey R, Vatsa R, Patel G. Comparison of the effects of two different trigger strategies - dual (hCG + Leuprolide) versus hCG trigger - in antagonist non-donor IVF: a randomized controlled trial. JBRA Assist Reprod. 2023;27(3):467-73.\u003c/li\u003e\n\u003cli\u003eMaggi R, Cariboni AM, Marelli MM, Moretti RM, Andr\u0026egrave; V, Marzagalli M, et al. GnRH and GnRH receptors in the pathophysiology of the human female reproductive system. Hum Reprod Update. 2016;22(3):358-81.\u003c/li\u003e\n\u003cli\u003eDong L, Lian F, Wu H, Xiang S, Li Y, Wei C, et al. Reproductive outcomes of dual trigger with combination GnRH agonist and hCG versus trigger with hCG alone in women undergoing IVF/ICSI cycles: a retrospective cohort study with propensity score matching. BMC Pregnancy Childbirth. 2022;22(1):583.\u003c/li\u003e\n\u003c/ol\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-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"HCG/GnRHa support, GnRH antagonist, dual trigger, pregnancy outcomes, estradiol ratio","lastPublishedDoi":"10.21203/rs.3.rs-8142666/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8142666/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eOptimal luteal phase support after fresh transfer remains a clinical challenge in GnRH antagonist IVF/ICSI cycles triggered with dual trigger. HCG/GnRha supports may improve outcomes, but its safety and ideal application remain uncertain. To investigate the effectiveness and safety of strengthened luteal phase support in fresh embryo transfer cycles following GnRH antagonist protocols with dual trigger, and further to identify patients who best most as well as clinical indicators.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis retrospective cohort study included all fresh embryo transfer cycles after dual-trigger oocyte retrieval between January 2020 and May 2024 at a single center. Patients were grouped based on LPS strategy: routine support (RT) or strengthened support (ST) using hCG (S-hCG), GnRHa (S-GnRHa), or both (S-Double). Pregnancy and neonatal outcomes and safety profiles were compared before and after propensity score matching. Subgroup analyses and mid-luteal estradiol ratio (E2 ratio) assessment were performed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eST was associated with significantly higher clinical pregnancy (48.2% vs 37.1%) and live birth rates (43.2% vs 34.3%) than RT (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) without additional risks including OHSS, birth defects and maternal complications. Subgroup analyses showed benefits across diverse populations, including women\u0026thinsp;\u0026ge;\u0026thinsp;35 years, those with diminished ovarian reserve, and patients receiving suboptimal embryos. Among ST regimens, hCG supplementation achieved the best outcomes, and patients with a low mid-luteal E2 ratio (\u0026lt;\u0026thinsp;0.15) derived the greatest benefit.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eEnhanced luteal support improves pregnancy outcomes in antagonist-dual trigger cycles. hCG appears most effective, but individualized strategies using biomarkers such as E2 ratio merit further investigation.\u003c/p\u003e\u003ch2\u003eTrial registration:\u003c/h2\u003e\u003cp\u003eNot applicable.\u003c/p\u003e","manuscriptTitle":"HCG/GnRHa support improves outcomes after GnRH antagonist dual trigger and the predictive role of mid-luteal estradiol ratio: a case control study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-03 12:08:12","doi":"10.21203/rs.3.rs-8142666/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-22T14:45:32+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-11T08:03:58+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-01T02:06:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"92155211577869244329170500993797591346","date":"2025-12-01T01:40:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"223690326943741560932106030546861169376","date":"2025-12-01T00:55:26+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-30T20:08:52+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-11-24T20:27:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-19T07:27:02+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-19T07:26:43+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pregnancy and Childbirth","date":"2025-11-18T07:58:49+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9c0b6fc2-be39-445c-a2b4-0e64403cd17a","owner":[],"postedDate":"December 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-23T20:23:17+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-03 12:08:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8142666","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8142666","identity":"rs-8142666","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}