Gonadotropin-releasing Hormone Agonist Down Regulation Combined With Hormone Replacement Therapy Improves the Reproductive Outcome in the Frozen-thawed Embryo Transfer Cycle of Elderly Patients With Idiopathic Recurrent Implantation Failure

Gonadotropin-releasing Hormone Agonist Down Regulation Combined With Hormone Replacement Therapy Improves the Reproductive Outcome in the Frozen-thawed Embryo Transfer Cycle of Elderly Patients With Idiopathic Recurrent Implantation Failure | 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 Gonadotropin-releasing Hormone Agonist Down Regulation Combined With Hormone Replacement Therapy Improves the Reproductive Outcome in the Frozen-thawed Embryo Transfer Cycle of Elderly Patients With Idiopathic Recurrent Implantation Failure Dan Pan, Jie Yang, Ni Zhang, Lei Wang, Na Li, Juanzi Shi, Hanying Zhou This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1090205/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Background To determine whether Gonadotropin-releasing hormone (GnRH) agonist down regulation combined with hormone replacement treatment (HRT) can improve the reproductive outcomes in the frozen thawed embryo transfer (FET) cycle of elderly patients with idiopathic recurrent implantation failure (RIF). Methods This is a retrospective cohort study analyzing 594 elderly patients (aged 36~43 years old) undergoing third cleavage embryo or blastocyst transfer over nearly 5-year period (January 2015–November 2020) at Northwest Women’s and Children’s Hospital after IVF-ICSI cycles. Patients with known endometriosis or adenomyosis were excluded from the study.According to different endometrial preparation protocols, patients were divided into three groups: natural cycle group (NC, n=62), hormone replacement treatment cycle group (HRT, n=194) and GnRH agonist down regulation combined with HRT cycle group (GnRHa-HRT, n=290).Live birth rate was primary outcome while clinical pregnancy rate, miscarriage rate, on going pregnancy rate were secondary outcomes. Results Live birth rate in the GnRHa-HRT group (31.90%) was significantly higher than that in the HRT (21.65%) or NC (16.13%) groups (P<0.0001). Logistic regression model adjusting for the potential confounders showed that patients in the GnRHa-HRT group have significantly higher live birth rate compared with those in the HRT group (OR, 2.708; 95%CI,1.251-5.864, P=0.011). However, live birth rate was not significantly different between GnRHa-HRT and NC groups (OR, 1.509; 95% CI,0.657-3.463, P=0.332), which could be due to the small sample size in the NC group. Conclusions  GnRHa-HRT protocol improves live birth rate in FET cycles of elderly patients with RIF. We hypothesize that GnRHa-HRT protocol enhances implantation related factors and promotes optimal endometrium receptivity, leading to the improved live birth rate. These findings are also useful for further investigating the underlying mechanism of GnRHa-HRT protocol in improving the reproductive outcomes of elderly patients with RIF. Trial registration:The research protocol was approved by the hospital institutional ethics committee (2021002). Endocrinology & Metabolism frozen-thawed embryo transfer (FET) recurrent implantation failure (RIF) Gonadotropin-releasing hormone agonist Hormone replacement cycle Background Despite technical advances in in vitro fertilization (IVF), recurrent implantation failure (RIF), the absence of implantation after repeated embryo transfers, is still the biggest challenge of the current reproductive medicine. At present, there are a wide variety of options for the treatment of RIF, but none of the programs is effective for successful pregnancy. Endometrium is the final destination of embryo implantation and successful implantation requires embryo interacting with a receptive endometrial lining. Endometrium and embryo interact and influence each other before embryo is transferred into the uterine cavity [ 1 ] . Therefore, both adequate endometrial receptivity and high embryonic quality are equally important for implantation. Prospective cohort studies have indicated that frozen-thawed embryo transfer (FET) may improve the reproductive outcomes in women with RIF [ 2 ] . In FET cycles, the embryos may be transferred into a more synchronous uterine environment, which can avoid the disturbed endometrial development due to ovarian stimulation. It is currently still controversial with regard to which endometrial preparation protocol is more effective to promote implantation especially in the population of elderly women with RIF. A previous retrospective self-control study showed that GnRHa combined with hormone replacement therapy (GnRHa-HRT) protocol can increase the pregnancy success rate in FET cycles of patients who had experienced repeated failures of IVF treatment [ 3 ] . Other studies have further shown that the depot GnRHa protocol may protect the expression of endometrial receptivity marker and thereby improves endometrial receptivity [ 4 – 5 ] . Nevertheless, these findings have been questioned in a further retrospective cohort study showing that GnRHa-HRT protocol does not improve live birth rate for patients with RIF. However, patients of all ages were included in that study [ 6 ] . Moreover, increasing maternal age as another risk of embryo-endometrium asynchrony makes the successful embryo implantation further complicated [ 7 – 8 ] .Yet, few studies have focused on reproductive outcomes in the elderly population with RIF. We hypothesized that before FET, elderly patients with idiopathic RIF might benefit from single-agent suppression with the use of GnRH agonist compared with those without GnRH agonist pretreatment. Methods Study Design and Patients This study included elderly patients (aged 36-43 years old) undergoing FET cycle therapy at Northwest Women’s and Children’s Hospital after IVF/ICSI cycles between January 2015 and November 2020. This study only included patients undergoing the third or more embryo transfer after autologous IVF and ICSI (intracytoplasmic sperm injection) (n=594). Women who underwent embryo transfer after donor oocytes, women who were diagnosed with endometriosis, adenomyosis or both, and women whose endometrial thickness did not reach 7 mm on the day of transplantation were excluded. The research protocol was approved by the hospital institutional ethics committee (2021002). Endometrial preparation before frozen-thawed embryo transfer (FET) In the natural cycle (modified natural cycle FET) (NC group), we monitored when the leading follicles reached a mean diameter of >17 mm, human chorionic gonadotropin (hCG,10,000IU) for triggering oocytes ovulation when serum luteinizing hormone (LH) was <20 IU/L, or otherwise transvaginal ultrasound was performed every day until ovulation. FET was performed after 3 (cleavage embryo transfer) or 5 (blastocyst transfer) days. In the HRT cycle (HRT group), starting at cycle day 5, estradiol valerate (Progynova; Bayer Schering Pharma AG, Berlin, Germany) was orally administrated daily. About 10~12 days later, 60 mg/day of natural progesterone in oil (progesterone; Xianju, Zhejiang, China) was injected i.m. to transform the endometrium as soon as the endometrial thickness reached 7 mm and serum P levels serum progesterone (P) level was below 1.5 ng/mL. Then, FET was performed after 4 (cleavage embryo transfer) or 6 (blastocyst transfer) days of progesterone therapy. In the GnRH agonist down regulation combined with HRT cycle (GnRHa-HRT group), patients received single dose injection of 3.75 mg long-acting triptorelin acetate on day 2 of the cycle after the ultrasound scan confirming ovarian quiescence and the presence of a thin endometrium (<5 mm). After 28~30 days, estrogen stimulation was initiated for HRT cycle without GnRH agonist. Luteal support Luteal support schemes included intramuscular injection of 60 mg/day of natural progesterone in oil and oral uptake of 20mg/day progesterone in tablet (Dydrogesterone; Abbott Biologicals B.V., The Netherlands) daily [ 9 – 10 ] . After embryo transfer, all patients received luteal support until the day when plasma β-hCG concentration was determined (D14). If pregnancy was achieved, hormone administration was continued until 10 weeks of pregnancy. Outcome parameters The primary outcome parameter was live birth rate. The delivery of a viable infant after the 22nd gestational week was considered as the live birth. Secondary outcome parameters included clinical pregnancy rate (defined as the rate of an intrauterine gestational sac with fetal heart activity on ultrasound), ongoing pregnancy rate (defined as the rate of an intact pregnancy beyond at 12 weeks of gestation), miscarriagerate (the rate of a loss of clinical pregnancy before the 22nd gestational week per clinical pregnancy cycle) [ 11 ] . Statistical Analysis Analysis of variance (ANOVA) was used for continuous variables (mean ± standard deviation) and x 2 test was used for categorical variables to determine whether the distributions of covariates were statistically significant across treatment protocols. Multivariable logistic regression was used to identify the independent effect of treatment protocol on the live birth rate and miscarriagerate in patients with RIF, adjusting for patients’ age, BMI, basal FSH level, infertility years, infertility type, endometrial thickness on transform day, number of embryos transferred and embryo transfer type. The results were manifested as odds ratio and 95% confidence interval (CI). P<0 .05 was considered statistically significant. Data processing and statistical analysis were conducted using Statistical Package for Social science version 19.0 (SPSS, IBM, Inc.). Results A total of 594 women were enrolled into the study. The demographic and clinical characteristics of the patients were presented in Table 1. There were no significant differences in the age, BMI, basal FSH, infertility years and type of infertility among the three groups. The level of progesterone on the transform day in the GnRHa-HRT group was significantly lower than that in the HRT group (P=0.001). In addition, the number of embryos transferred and proportion of transferred blastocyst in the GnRHa-HRT group was significantly higher than those in the HRT group (P=0.003, and P=0.044, respectively). Furthermore, endometrial thickness on transform day was significantly different among the three groups (P=0.002). Table1 Baseline characteristics between different endometrial preparation groups Characteristic GnRHa-HRT (n = 290) HRT (n=194) NC (n=62) P value female age(y) 38.69±2.19 39.16±2.18 38.73±2.00 0.291 BMII (kg/m2) 22.37±2.74 22.72±2.76 22.24±2.51 0.647 bFSH(IU/L) 7.95±3.04 8.28±3.00 7.99±3.16 0.996 Infertility years(y) 5.48±4.13 5.23±4.26 5.66±4.00 0.768 Infertility type (n, %) 0.407 Primary infertility 76(26.21) 46(23.71) 20(32.26） Secondary infertility 214(73.79) 148(76.29) 42(67.74） Fertilization type (n, %) 0.065 IVF 208(71.72) 138(71.13) 47(75.81) ICSI 78(2.69) 53(27.32) 11(17.74) IVF+ICSI 4(1.38) 3(1.55) 4(6.45) Progesterone on the administration day (ng/ml) 0.38±0.29 0.53±0.47 0.001* Endometrial thickness on the day of P administration(mm) 10.36±1.69 9.82±1.57 10.83±2.26 0.002* No. of transferred embryos 1.76±0.52 1.69±0.55 1.65±0.63 0.003* Type of embryo transferred(n, %) 0.044* Cleavage stage embryo 131(45.17) 109(56.19) 34(54.84) Blastocyst 159(54.83) 85(43.81) 28(45.16) Values are means±SD or number (percentage) of patients. ✱ P < 0.05 for t test or chi-squared test; Abbreviations: BMI body mass index; bFSH basal follicle-stimulating hormone; ICSI intracytoplasmic sperm injection; IVF in vitro fertilization Clinical pregnancy rates, ongoing pregnancy rates and live birth rates in GnRHa-HRT group were significantly higher than those in the other two groups. However, the miscarriagerates did not differ significantly among the three groups (Table 2) Table 2 FET treatment and pregnancy outcomes in the three groups pregnancy outcomes GnRHa-HRT HRT NC P value Clinical pregnancy rate 49.31(143/290) 34.54(67/194) 25.81(16/62) 0.000* On going pregnancy rate 37.93(110/290) 22.16(43/194) 17.74(11/62) 0.000* Miscarriage rate 22.38(32/143） 35.82(24/67) 31.25(5/16) 0.114 Live birth rate 36.90(107/290) 21.65(42/194) 16.13(10/62) 0.000* Values are percentage (no./no.) of patients. *P < 0.05 for t test or chi-squared test Univariate analysis was performed to evaluate the effect of each variable on the reproductive outcomes (Table 3). The results showed that patients’ age, number of embryos transferred, embryo transfer type and FET treatment protocol were associated with clinical pregnancy rate, ongoing pregnancy rate and live birth rate, while patients’ age was the only variable associated with miscarriagerate. Table 3 Single-factor analysis of factors related to FET outcomes Clinical indicators Clinical pregnancy rate On going pregnancy rate Value OR value(95% CI) P value OR value(95% CI) P value female age(y) 0.844(0.777-0.915) 0.000* 0.785(0.715-0.861) 0.000* BMI 1.009(0.947-1.074) 0.788 1.008(0.943-1.078) 0.810 bFSH 0.939(0.884-0.996) 0.037* 0.936(0.876-0.999) 0.047* Infertility years 0.965(0.925-1.007) 0.098 0.959(0.915-1.005) 0.078 Infertility type Primary infertility Ref. Ref. Secondary infertility 1.091(0.741-1.606) 0.660  1.161(0.769-1.753) 0.476  Endometrial Preparation Protocols GnRHa-HRT Ref. Ref. HRT 2.797(1.514-5.166) 0.001*   2.833(1.416-5.668) 0.003*   NC 1.517(0.799-2.88) 0.203  1.32(0.633-2.752) 0.458  Progesterone on the administration day  0.585(0.333-1.029) 0.063 0.578(0.311-1.076) 0.084 Endometrial thickness on the day of P administration 1.088(0.986-1.2) 0.092 1.071(0.965-1.188) 0.198 No. of transferred embryos 1.563(1.136-2.15) 0.006*   1.61(1.141-2.27) 0.007*   Type of embryo transferred Cleavage stage embryo Ref. Ref. Blastocyst 0.505(0.357-0.713) 0.000*   0.436(0.299-0.637) 0.000*   Clinical indicators Live birth rate Miscarriage rate Value OR value(95% CI) P value OR value(95% CI) P value Female age 0.79(0.72-0.868) 0.000*   1.24(1.069-1.439) 0.005*  BMI 1.017(0.951-1.088) 0.625  0.992(0.891-1.104) 0.880 bFSH 0.94(0.88-1.004) 0.065  1.023(0.922-1.136) 0.668 Infertility years 0.958(0.914-1.004) 0.076  1.068(0.992-1.149) 0.081 Infertility type Primary infertility Ref. Ref. Secondary infertility 1.128(0.744-1.711) 0.570  0.897(0.456-1.765) 0.752 Endometrial Preparation Protocols GnRHa-HRT Ref. Ref. HRT 3.04(1.484-6.231) 0.002*   0.634(0.205-1.959) 0.429 NC 1.437(0.673-3.067) 0.349  1.228(0.381-3.953) 0.731 Progesterone on the administration day  0.582(0.311-1.087) 0.090 1.179(0.392-3.545) 0.769 Endometrial thickness on the day of P administration 1.096(0.987-1.217) 0.085 0.969(0.813-1.154) 0.72 No. of transferred embryos 1.655(1.169-2.343) 0.005*   0.788(0.435-1.427) 0.432 Type of embryo transferred Cleavage stage embryo Ref. Ref. Blastocyst 0.438(0.299-0.641) 0.000*   1.856(1.025-3.364) 0.041*  *P < 0.05 for Chi-square test Abbreviations: OR odds ratio; CI 95% confidence interval; BMI body mass index; bFSH basal follicle-stimulating hormone; In the adjusted model, GnRHa-HRT treatment protocol significantly increased the live birth rate compared with HRT treatment protocol (OR, 2.708; 95% CI, 1.251-5.864, P = 0.011. However, the live birth rate was not significantly different between GnRHa-HRT and NC groups (Table 4). Table 4 Multifactor analysis results of FET outcome-related factors Clinical indicators Live birth rate Value OR value(95% CI) P value Female age(y) 0.815(0.735-0.904) 0.000* BMI 0.998(0.927-1.075) 0.963 bFSH 0.965(0.897-1.037) 0.333 Infertility years 0.947(0.898-0.999) 0.046* Infertility type Primary infertility Ref. Secondary infertility 1.084(0.661-1.779) 0.748 Endometrial thickness on the day of P administration(mm) 1.067(0.945-1.205) 0.292 No. of transferred embryos 2.017(1.341-3.032) 0.001* Type of embryo transferred Cleavage stage embryo Ref. Blastocyst 0.456(0.290-0.717) 0.001*  Endometrial Preparation Protocols GnRHa-HRT Ref. HRT 2.708(1.251-5.864) 0.011*  NC 1.509(0.657-3.463) 0.332 *P < 0.05 for Chi-square test Abbreviations: OR odds ratio; CI 95% confidence interval; BMI body mass index; bFSH basal follicle-stimulating hormone; Discussion There was insufficient evidence to demonstrate that the use of depot GnRHa is better or worse than the NC or HRT protocol for the reproductive outcome in FET cycles, especially for patients with RIF. Pretreatment with GnRHa before HRT in FET cycles is considered to be ineffective for the elderly patients, but it could be effective for the patients with RIF [12] . Recent studies also failed to demonstrate any significant effect of depot GnRHa-FET protocol in the live birth/ongoing pregnancy rate [6] . However, that study only included younger patients (＜40 years) and thus the effect of depot GnRHa-FET protocol on elderly patients (36~43years) needs to be further evaluated. The present large-scale retrospective cohort study evaluated the reproductive outcomes in natural cycle, HRT cycle, GnRHa-HRT cycle of elderly patients with RIF when referred for FET. Our results showed that there was a significantly higher live birth rate in GnRHa-HRT treatment protocol than that in the NC and HRT protocols, while the miscarriagerate was not significantly different among the three protocols. In addition, we used low-dose drugs in our study. Patients in our study only received one intramuscular injection of 3.75 mg depot leuprolide acetate. Ill-timed administration with the double dose of depot leuprolide acetate may increased not only the hypo-estrogenic side-effects, e.g., hot flushes,vaginal dryness, decreased libido and loss of bone density,but also high cost[13]. In contrast, previous retrospective self-control study suggested that GnRHa-HRT protocol, with 28 days of full-dose depot GnRHa, prolonged downregulation before ovarian stimulation, resulting in relatively high pregnancy success rates in idiopathic RIF patients undergoing IVF [3] . Our results are consistent with previous studies showing that cryopreservation of all viable blastocysts after ICSI followed by a subsequent FET cycle can improve the implantation when compared with fresh ET [3,5,14-16] . Other studies showed that GnRHa may partially restore the endometrial secretion of implantation related factors, e.g., HOXA10, MEIS1 and LIF, which can regulate endometrial development and permit embryo implantation and decidualization [5,17-21] . Another study showed that ovarian stimulation with GnRHa partially restores the expression of endometrial integrin beta 3 and improves uterine receptivity in mice [22] . An interesting observation in our study is that the mean level of progesterone on the administration day in the HRT cycle was significantly higher than that in the GnRHa-HRT cycles (0.38±0.29 versus 0.53±0.47, P=0.001), which is consistent with the results in previous studies [12,14,22] . This might be due to a premature rise of LH levels in hormonal stimulation protocol without a GnRH agonist, which negatively alters the receptive window of the endometrium [16] . The NC protocol is one of the most frequently and widely used FET protocols in treatment cycles [24] . However, one previous study suggests that approximately two-thirds of implantation failures are due to disturbed endometrial receptivity and asynchronized embryo-endometrial cross-talk, while the quality of embryo is estimated to be responsible for the remaining one-third implantation failure [25] . However, in this study, we found that live birth rate in NC protocol was not significantly lower than that in the GnRHa-HRT protocol, which may be due to the small sample size in the NC group. According to the histologic endometrial dating, the rate of a“displaced WOI (window of implantation)” in patients with RIF can reach 31.6%, compared with 3.8% in the patients with good-prognosis ( P = 0.003) [26] . This is the first study to evaluate the optimal approach to prepare the endometrium in FET cycles of elderly patients with RIF. The limitation of this study is its retrospective design from a single medical center. However, through the analysis of large sample size using multivariate logistics model, some confounding factors were eliminated. In addition, the type of endometrial preparation was selected by the physician’s preference and such preference may introduce a potential bias. Besides, we did not exclude cleavage stage of embryo transfer. This bias may be eliminated by a Cochrane review that blastocyst transfer over cleavage stage of embryo transfer was of low quality for live birth outcome [27] . Conclusions In conclusion, this nearly 5-year study provides very robust evidence regarding the reproductive potential of RIF women with increasing age. It showed that LBR in GnRHa-HRT protocol was raised compared with HRT protocol while the miscarriage rate was not affected. The live birth rate in NC protocol appears to be undamaged. However, the sample size of natural cycle protocol was too small, which may affect the outcome. Further multi-center randomized clinical trials are needed to confirm the possible benefits of GnRHa-HRT protocol for elderly patients with idiopathic recurrent implantation failure. Abbreviations FET: Frozen embryo transfer; HRT: Hormone replacement treatment; GnRHa-HRT: GnRH antagonist down-regulation combined hormone replacement treatment; RIF: Repeated implantation failure; IVF:in vitro fertilization;ICSI:Intracytoplasmic sperm injection Declarations Ethics approval and consent to participate This study was approved by the Ethics Committee of Northwest Women’s and Children’s Hospital and has been performed in accordance with the principles of Declaration of Helsinki. Consent for publication Not applicable. Availability of data and materials Not applicable. Competing interests The authors declare no competing interests. Funding This work was supported by National Natural Science Foundation of China (82100083) Authors' contributions DP, JY, LW,and NL designed the study, performed data analysis, and drafted the manuscript; NZ, HZ and SZ critically review and corrected the final version of the manuscript. All participants approved the final version to be submitted. Acknowledgements The authors thank the staff from Northwest Women’s and Children’s Hospital for their assistance with the data collection. We thank all participants in this study. Authors' information 1,The Assisted Reproduction Center, Northwest Women’s and Children’s Hospital, No. 73 Houzai Gate, Xincheng District, Xi’an City, Shaanxi Province, China 2 Department of Basic Medicine, Xi’an Medical University,Xin‑Wang Street #1, Xi’an 710021, Shaanxi, China References Margalioth EJ, Ben-Chetrit A, Gal M, Eldar-Geva T: Investigation and treatment of repeated implantation failure following IVF-ET. Hum Reprod 2006, 21: 3036-3043. Magdi Y, El-Damen A, Fathi AM, Abdelaziz AM, Abd-Elfatah Youssef M, Abd-Allah AA, Ahmed Elawady M, Ahmed Ibrahim M, Edris Y: Revisiting the management of recurrent implantation failure through freeze-all policy. Fertil Steril 2017, 108: 72-77. 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A systematic review and meta-analysis. Hum Reprod Update 2017, 23: 255-261. Craciunas L, Gallos I, Chu J, Bourne T, Quenby S, Brosens JJ, Coomarasamy A: Conventional and modern markers of endometrial receptivity: a systematic review and meta-analysis. Hum Reprod Update 2019, 25: 202-223. Li Y, Li XF, Liao JN, Fan XX, Hu YB, Gan R, Lu G, Lin G, Gong F: Clinical value of histologic endometrial dating for personalized frozen-thawed embryo transfer in patients with repeated implantation failure in natural cycles. BMC Pregnancy Childbirth 2020, 20: 527. Glujovsky D, Farquhar C, Quinteiro Retamar AM, Alvarez Sedo CR, Blake D: Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology. Cochrane Database Syst Rev 2016 : CD002118. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 23 Nov, 2021 Reviewers invited by journal 22 Nov, 2021 Editor assigned by journal 19 Nov, 2021 Submission checks completed at journal 18 Nov, 2021 Editor invited by journal 18 Nov, 2021 First submitted to journal 17 Nov, 2021 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-1090205","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research","associatedPublications":[],"authors":[{"id":64873028,"identity":"78e8adad-a2fb-4d14-94cf-e91898b98715","order_by":0,"name":"Dan Pan","email":"","orcid":"","institution":"Xi'an Jiaotong University affiliated Northwest Women and Children's Hospital: Northwest Women and Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Dan","middleName":"","lastName":"Pan","suffix":""},{"id":64873029,"identity":"c6d5ae60-3212-4e5d-b46e-0de9c787207e","order_by":1,"name":"Jie Yang","email":"","orcid":"","institution":"Xi'an Jiaotong University affiliated Northwest Women and Children's Hospital: Northwest Women and Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"Yang","suffix":""},{"id":64873030,"identity":"59685fac-ee69-4dd7-b7bf-4134ce731493","order_by":2,"name":"Ni Zhang","email":"","orcid":"","institution":"Xi'an Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ni","middleName":"","lastName":"Zhang","suffix":""},{"id":64873031,"identity":"5c5dc381-6811-4aa5-982e-45b474a8db7f","order_by":3,"name":"Lei Wang","email":"","orcid":"","institution":"Xi'an Jiaotong University affiliated Northwest Women and Children's Hospital: Northwest Women and Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lei","middleName":"","lastName":"Wang","suffix":""},{"id":64873032,"identity":"5ac42f78-d0ed-4b35-a399-e4237a6e86ba","order_by":4,"name":"Na Li","email":"","orcid":"","institution":"Xi'an Jiaotong University affiliated Northwest Women and Children's Hospital: Northwest Women and Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Na","middleName":"","lastName":"Li","suffix":""},{"id":64873033,"identity":"d3849043-f131-41ca-a260-48aa7f81111c","order_by":5,"name":"Juanzi Shi","email":"","orcid":"","institution":"Xi'an Jiaotong University affiliated Northwest Women and Children's Hospital: Northwest Women and Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Juanzi","middleName":"","lastName":"Shi","suffix":""},{"id":64873034,"identity":"14b0687f-922f-404c-98d0-cf1d0ce154f1","order_by":6,"name":"Hanying Zhou","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA60lEQVRIie3PsWrDMBCAYQWBslzr9UzB2TorGEIhgQx5kRMGZUlKx4wpBXmoS1YPfYg+gowhk7p7jPcOyeapzQMkVO7WQd98P3fHWBD8Q2K4O9rj5gcizqsDdTN/cgt23JaOJ3FuMtkW2p8kSGl6Y3gqnbuPD6LucRhYfQdCqG2zEhuCmkX5K3l+2e7jdwD1XK73DT0sGbrPD8+WyuAXonrBR90QTJnEtSfBTCBIqQyuJk8keJ9E8zEQpQBuwkgseiTgBm1pbYJDk6EqNHh/GeUFs6dvC/OaV6eumyVR/vZ7cgH+Nh4EQRBcdQYLaUmsvKeP4AAAAABJRU5ErkJggg==","orcid":"","institution":"Hospital Group East: Groupement Hospitalier Est","correspondingAuthor":true,"prefix":"","firstName":"Hanying","middleName":"","lastName":"Zhou","suffix":""}],"badges":[],"createdAt":"2021-11-17 17:45:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1090205/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1090205/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":15839973,"identity":"ea4f67fe-3e7a-4eb5-9962-fe145a02fb04","added_by":"auto","created_at":"2021-11-23 19:07:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":979160,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1090205/v1/9872db4d-c714-4b69-9f6c-728e5515cc75.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eGonadotropin-releasing Hormone Agonist Down Regulation Combined With Hormone Replacement Therapy Improves the Reproductive Outcome in the Frozen-thawed Embryo Transfer Cycle of Elderly Patients With Idiopathic Recurrent Implantation Failure\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eDespite technical advances in in vitro fertilization (IVF), recurrent implantation failure (RIF), the absence of implantation after repeated embryo transfers, is still the biggest challenge of the current reproductive medicine. At present, there are a wide variety of options for the treatment of RIF, but none of the programs is effective for successful pregnancy.\u003c/p\u003e \u003cp\u003eEndometrium is the final destination of embryo implantation and successful implantation requires embryo interacting with a receptive endometrial lining. Endometrium and embryo interact and influence each other before embryo is transferred into the uterine cavity\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Therefore, both adequate endometrial receptivity and high embryonic quality are equally important for implantation. Prospective cohort studies have indicated that frozen-thawed embryo transfer (FET) may improve the reproductive outcomes in women with RIF \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. In FET cycles, the embryos may be transferred into a more synchronous uterine environment, which can avoid the disturbed endometrial development due to ovarian stimulation.\u003c/p\u003e \u003cp\u003eIt is currently still controversial with regard to which endometrial preparation protocol is more effective to promote implantation especially in the population of elderly women with RIF. A previous retrospective self-control study showed that GnRHa combined with hormone replacement therapy (GnRHa-HRT) protocol can increase the pregnancy success rate in FET cycles of patients who had experienced repeated failures of IVF treatment \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. Other studies have further shown that the depot GnRHa protocol may protect the expression of endometrial receptivity marker and thereby improves endometrial receptivity \u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Nevertheless, these findings have been questioned in a further retrospective cohort study showing that GnRHa-HRT protocol does not improve live birth rate for patients with RIF. However, patients of all ages were included in that study \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMoreover, increasing maternal age as another risk of embryo-endometrium asynchrony makes the successful embryo implantation further complicated \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e.Yet, few studies have focused on reproductive outcomes in the elderly population with RIF. We hypothesized that before FET, elderly patients with idiopathic RIF might benefit from single-agent suppression with the use of GnRH agonist compared with those without GnRH agonist pretreatment.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Patients\u003c/h2\u003e \u003cp\u003eThis study included elderly patients (aged 36-43 years old) undergoing FET cycle therapy at Northwest Women\u0026rsquo;s and Children\u0026rsquo;s Hospital after IVF/ICSI cycles between January 2015 and November 2020. This study only included patients undergoing the third or more embryo transfer after autologous IVF and ICSI (intracytoplasmic sperm injection) (n=594). Women who underwent embryo transfer after donor oocytes, women who were diagnosed with endometriosis, adenomyosis or both, and women whose endometrial thickness did not reach 7 mm on the day of transplantation were excluded. The research protocol was approved by the hospital institutional ethics committee (2021002).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eEndometrial preparation before frozen-thawed embryo transfer (FET)\u003c/h2\u003e \u003cp\u003eIn the natural cycle (modified natural cycle FET) (NC group), we monitored when the leading follicles reached a mean diameter of \u0026gt;17 mm, human chorionic gonadotropin (hCG,10,000IU) for triggering oocytes ovulation when serum luteinizing hormone (LH) was \u0026lt;20 IU/L, or otherwise transvaginal ultrasound was performed every day until ovulation. FET was performed after 3 (cleavage embryo transfer) or 5 (blastocyst transfer) days.\u003c/p\u003e \u003cp\u003eIn the HRT cycle (HRT group), starting at cycle day 5, estradiol valerate (Progynova; Bayer Schering Pharma AG, Berlin, Germany) was orally administrated daily. About 10~12 days later, 60 mg/day of natural progesterone in oil (progesterone; Xianju, Zhejiang, China) was injected i.m. to transform the endometrium as soon as the endometrial thickness reached 7 mm and serum P levels serum progesterone (P) level was below 1.5 ng/mL. Then, FET was performed after 4 (cleavage embryo transfer) or 6 (blastocyst transfer) days of progesterone therapy.\u003c/p\u003e \u003cp\u003eIn the GnRH agonist down regulation combined with HRT cycle (GnRHa-HRT group), patients received single dose injection of 3.75 mg long-acting triptorelin acetate on day 2 of the cycle after the ultrasound scan confirming ovarian quiescence and the presence of a thin endometrium (\u0026lt;5 mm). After 28~30 days, estrogen stimulation was initiated for HRT cycle without GnRH agonist.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eLuteal support\u003c/h2\u003e \u003cp\u003eLuteal support schemes included intramuscular injection of 60 mg/day of natural progesterone in oil and oral uptake of 20mg/day progesterone in tablet (Dydrogesterone; Abbott Biologicals B.V., The Netherlands) daily \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. After embryo transfer, all patients received luteal support until the day when plasma β-hCG concentration was determined (D14). If pregnancy was achieved, hormone administration was continued until 10 weeks of pregnancy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eOutcome parameters\u003c/h2\u003e \u003cp\u003eThe primary outcome parameter was live birth rate. The delivery of a viable infant after the 22nd gestational week was considered as the live birth. Secondary outcome parameters included clinical pregnancy rate (defined as the rate of an intrauterine gestational sac with fetal heart activity on ultrasound), ongoing pregnancy rate (defined as the rate of an intact pregnancy beyond at 12 weeks of gestation), miscarriagerate (the rate of a loss of clinical pregnancy before the 22nd gestational week per clinical pregnancy cycle) \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eAnalysis of variance (ANOVA) was used for continuous variables (mean \u0026plusmn; standard deviation) and x\u003csup\u003e2\u003c/sup\u003e test was used for categorical variables to determine whether the distributions of covariates were statistically significant across treatment protocols. Multivariable logistic regression was used to identify the independent effect of treatment protocol on the live birth rate and miscarriagerate in patients with RIF, adjusting for patients\u0026rsquo; age, BMI, basal FSH level, infertility years, infertility type, endometrial thickness on transform day, number of embryos transferred and embryo transfer type. The results were manifested as odds ratio and 95% confidence interval (CI). P\u0026lt;0 .05 was considered statistically significant. Data processing and statistical analysis were conducted using Statistical Package for Social science version 19.0 (SPSS, IBM, Inc.).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 594 women were enrolled into the study. The demographic and clinical characteristics of the patients were presented in Table 1. There were no significant differences in the age, BMI, basal FSH, infertility years and type of infertility among the three groups. The level of progesterone on the transform day in the GnRHa-HRT group was significantly lower than that in the HRT group (P=0.001). In addition, the number of embryos transferred and proportion of transferred blastocyst in the GnRHa-HRT group was significantly higher than those in the HRT group (P=0.003, and P=0.044, respectively). Furthermore, endometrial thickness on transform day was significantly different among the three groups (P=0.002).\u003c/p\u003e\n\n\n\n\n\n\n\n\n\n\u003cp\u003e\u003cstrong\u003eTable1\u0026nbsp;\u003c/strong\u003e \u0026nbsp;Baseline characteristics between different endometrial preparation groups\u003c/p\u003e\n\u003ctable border=\"0\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"39.77485928705441%\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003eGnRHa-HRT\u003c/p\u003e\n \u003cp\u003e(n = 290)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003eHRT\u003c/p\u003e\n \u003cp\u003e(n=194)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003cp\u003e(n=62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.25703564727955%\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"39.77485928705441%\"\u003e\n \u003cp\u003efemale age(y)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e38.69\u0026plusmn;2.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e39.16\u0026plusmn;2.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e38.73\u0026plusmn;2.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.25703564727955%\"\u003e\n \u003cp\u003e0.291\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"39.77485928705441%\"\u003e\n \u003cp\u003eBMII (kg/m2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e22.37\u0026plusmn;2.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e22.72\u0026plusmn;2.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e22.24\u0026plusmn;2.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.25703564727955%\"\u003e\n \u003cp\u003e0.647\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"39.77485928705441%\"\u003e\n \u003cp\u003ebFSH(IU/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e7.95\u0026plusmn;3.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e8.28\u0026plusmn;3.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e7.99\u0026plusmn;3.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.25703564727955%\"\u003e\n \u003cp\u003e0.996\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"39.77485928705441%\"\u003e\n \u003cp\u003eInfertility years(y)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e5.48\u0026plusmn;4.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e5.23\u0026plusmn;4.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e5.66\u0026plusmn;4.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.25703564727955%\"\u003e\n \u003cp\u003e0.768\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"39.77485928705441%\"\u003e\n \u003cp\u003eInfertility type (n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.25703564727955%\"\u003e\n \u003cp\u003e0.407\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"39.77485928705441%\"\u003e\n \u003cp\u003ePrimary infertility\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e76(26.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e46(23.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e20(32.26）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.25703564727955%\"\u003e\n \n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"39.77485928705441%\"\u003e\n \u003cp\u003eSecondary infertility\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e214(73.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e148(76.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e42(67.74）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.25703564727955%\"\u003e\n \n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"39.77485928705441%\"\u003e\n \u003cp\u003eFertilization type (n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.25703564727955%\"\u003e\n \u003cp\u003e0.065\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"39.77485928705441%\"\u003e\n \u003cp\u003eIVF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e208(71.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e138(71.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e47(75.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.25703564727955%\"\u003e\n \n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"39.77485928705441%\"\u003e\n \u003cp\u003eICSI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e78(2.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e53(27.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e11(17.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.25703564727955%\"\u003e\n \n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"39.77485928705441%\"\u003e\n \u003cp\u003eIVF+ICSI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e4(1.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e3(1.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e4(6.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.25703564727955%\"\u003e\n \n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"39.77485928705441%\"\u003e\n \u003cp\u003eProgesterone on the administration day (ng/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e0.38\u0026plusmn;0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e0.53\u0026plusmn;0.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.25703564727955%\"\u003e\n \u003cp\u003e0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"39.77485928705441%\"\u003e\n \u003cp\u003eEndometrial thickness on the day of P administration(mm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e10.36\u0026plusmn;1.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e9.82\u0026plusmn;1.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e10.83\u0026plusmn;2.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.25703564727955%\"\u003e\n \u003cp\u003e0.002\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"39.77485928705441%\"\u003e\n \u003cp\u003eNo. of transferred embryos\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e1.76\u0026plusmn;0.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e1.69\u0026plusmn;0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e1.65\u0026plusmn;0.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.25703564727955%\"\u003e\n \u003cp\u003e0.003\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"39.77485928705441%\"\u003e\n \u003cp\u003eType of embryo transferred(n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.25703564727955%\"\u003e\n \u003cp\u003e0.044\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"39.77485928705441%\"\u003e\n \u003cp\u003eCleavage stage embryo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e131(45.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e109(56.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e34(54.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.25703564727955%\"\u003e\n \n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"39.77485928705441%\"\u003e\n \u003cp\u003eBlastocyst\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e159(54.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e85(43.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.322701688555348%\"\u003e\n \u003cp\u003e28(45.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.25703564727955%\"\u003e\n \n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eValues are means\u0026plusmn;SD or number (percentage) of patients.\u0026nbsp;\u003csup\u003e✱\u003c/sup\u003eP \u0026lt; 0.05 for t test or chi-squared test;\u003c/p\u003e\n\u003cp\u003eAbbreviations: BMI body mass index; bFSH basal follicle-stimulating hormone; ICSI intracytoplasmic sperm injection; IVF in vitro fertilization\u003c/p\u003e\n\u003cp\u003eClinical pregnancy rates, ongoing pregnancy rates and live birth rates in GnRHa-HRT group were significantly higher than those in the other two groups. However, the miscarriagerates did not differ significantly among the three groups (Table 2)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u0026nbsp;\u003c/strong\u003eFET treatment and pregnancy outcomes in the three groups\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"34.52157598499062%\"\u003e\n \u003cp\u003epregnancy outcomes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.823639774859288%\"\u003e\n \u003cp\u003eGnRHa-HRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.823639774859288%\"\u003e\n \u003cp\u003eHRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.636022514071296%\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.195121951219512%\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"34.52157598499062%\"\u003e\n \u003cp\u003eClinical pregnancy rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.823639774859288%\"\u003e\n \u003cp\u003e49.31(143/290)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.823639774859288%\"\u003e\n \u003cp\u003e34.54(67/194)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.636022514071296%\"\u003e\n \u003cp\u003e25.81(16/62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.195121951219512%\"\u003e\n \u003cp\u003e0.000*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"34.52157598499062%\"\u003e\n \u003cp\u003eOn going pregnancy rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.823639774859288%\"\u003e\n \u003cp\u003e37.93(110/290)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.823639774859288%\"\u003e\n \u003cp\u003e22.16(43/194)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.636022514071296%\"\u003e\n \u003cp\u003e17.74(11/62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.195121951219512%\"\u003e\n \u003cp\u003e0.000*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"34.52157598499062%\"\u003e\n \u003cp\u003eMiscarriage rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.823639774859288%\"\u003e\n \u003cp\u003e22.38(32/143）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.823639774859288%\"\u003e\n \u003cp\u003e35.82(24/67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.636022514071296%\"\u003e\n \u003cp\u003e31.25(5/16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.195121951219512%\"\u003e\n \u003cp\u003e0.114\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"34.52157598499062%\"\u003e\n \u003cp\u003eLive birth rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.823639774859288%\"\u003e\n \u003cp\u003e36.90(107/290)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.823639774859288%\"\u003e\n \u003cp\u003e21.65(42/194)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.636022514071296%\"\u003e\n \u003cp\u003e16.13(10/62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.195121951219512%\"\u003e\n \u003cp\u003e0.000*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eValues are percentage (no./no.) of patients. *P \u0026lt; 0.05 for t test or chi-squared test\u003c/p\u003e\n\u003cp\u003eUnivariate analysis was performed to evaluate the effect of each variable on the reproductive outcomes (Table 3). The results showed that patients\u0026rsquo; age, number of embryos transferred, embryo transfer type and FET treatment protocol were associated with clinical pregnancy rate, ongoing pregnancy rate and live birth rate, while patients\u0026rsquo; age was the only variable associated with miscarriagerate.\u0026nbsp;\u003c/p\u003e\n\n\n\n\n\n\u003cp\u003e\u003cstrong\u003eTable 3\u0026nbsp;\u003c/strong\u003e Single-factor analysis of factors related to FET outcomes\u003c/p\u003e\n\u003ctable border=\"0\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eClinical indicators\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" width=\"35.99257884972171%\"\u003e\n \u003cp\u003eClinical pregnancy rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" width=\"35.99257884972171%\"\u003e\n \u003cp\u003eOn going pregnancy rate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eValue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003eOR value(95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003eOR value(95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003efemale age(y)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e0.844(0.777-0.915)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.000* \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e0.785(0.715-0.861)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.000*\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eBMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e1.009(0.947-1.074)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.788\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e1.008(0.943-1.078)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.810\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003ebFSH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e0.939(0.884-0.996)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.037* \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e0.936(0.876-0.999)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.047* \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eInfertility years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e0.965(0.925-1.007)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.098\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e0.959(0.915-1.005)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.078\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eInfertility type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003ePrimary infertility\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eSecondary infertility\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e1.091(0.741-1.606)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.660\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e1.161(0.769-1.753)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.476\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"bottom\" width=\"100%\"\u003e\n \u003cp\u003eEndometrial Preparation Protocols\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eGnRHa-HRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eHRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e2.797(1.514-5.166)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.001* \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e2.833(1.416-5.668)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.003* \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e1.517(0.799-2.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.203\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e1.32(0.633-2.752)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.458\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eProgesterone on the administration day\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.675324675324674%\"\u003e\n \u003cp\u003e0.585(0.333-1.029)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.063\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.675324675324674%\"\u003e\n \u003cp\u003e0.578(0.311-1.076)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.084\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eEndometrial thickness on the day of P administration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.675324675324674%\"\u003e\n \u003cp\u003e1.088(0.986-1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.092\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.675324675324674%\"\u003e\n \u003cp\u003e1.071(0.965-1.188)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.198\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eNo. of transferred embryos\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e1.563(1.136-2.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.006* \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e1.61(1.141-2.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.007* \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"bottom\" width=\"100%\"\u003e\n \u003cp\u003eType of embryo transferred\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eCleavage stage embryo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eBlastocyst\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e0.505(0.357-0.713)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.000* \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e0.436(0.299-0.637)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.000* \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eClinical indicators\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003eLive birth rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003eMiscarriage rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eValue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003eOR value(95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003eOR value(95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eFemale age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e0.79(0.72-0.868)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.000* \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e1.24(1.069-1.439)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.005*\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eBMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e1.017(0.951-1.088)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.625\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e0.992(0.891-1.104)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.880\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003ebFSH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e0.94(0.88-1.004)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.065\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e1.023(0.922-1.136)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.668\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eInfertility years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e0.958(0.914-1.004)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.076\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e1.068(0.992-1.149)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.081\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eInfertility type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003ePrimary infertility\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eSecondary infertility\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e1.128(0.744-1.711)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.570\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e0.897(0.456-1.765)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.752\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"bottom\" width=\"100%\"\u003e\n \u003cp\u003eEndometrial Preparation Protocols\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eGnRHa-HRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eHRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e3.04(1.484-6.231)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.002* \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e0.634(0.205-1.959)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.429\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e1.437(0.673-3.067)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.349\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e1.228(0.381-3.953)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.731\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eProgesterone on the administration day\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.675324675324674%\"\u003e\n \u003cp\u003e0.582(0.311-1.087)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.090\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.675324675324674%\"\u003e\n \u003cp\u003e1.179(0.392-3.545)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.769\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.014842300556587%\"\u003e\n \u003cp\u003eEndometrial thickness on the day of P administration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.675324675324674%\"\u003e\n \u003cp\u003e1.096(0.987-1.217)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.085\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.675324675324674%\"\u003e\n \u003cp\u003e0.969(0.813-1.154)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eNo. of transferred embryos\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e1.655(1.169-2.343)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.005* \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e0.788(0.435-1.427)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.432\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"bottom\" width=\"100%\"\u003e\n \u003cp\u003eType of embryo transferred\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eCleavage stage embryo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"28.014842300556587%\"\u003e\n \u003cp\u003eBlastocyst\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e0.438(0.299-0.641)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.000* \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"24.675324675324674%\"\u003e\n \u003cp\u003e1.856(1.025-3.364)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"11.317254174397032%\"\u003e\n \u003cp\u003e0.041*\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*P \u0026lt; 0.05 for Chi-square test\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAbbreviations: OR odds ratio; CI 95% confidence interval; BMI body mass index; bFSH basal follicle-stimulating hormone;\u0026nbsp;\u003c/p\u003e\n\n\u003cp\u003eIn the adjusted model, GnRHa-HRT treatment protocol significantly increased the live birth rate compared with HRT treatment protocol (OR, 2.708; 95% CI, 1.251-5.864, P = 0.011. However, the live birth rate was not significantly different between GnRHa-HRT and NC groups (Table 4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4\u003c/strong\u003e Multifactor analysis results of FET outcome-related factors\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"53.76146788990825%\"\u003e\n \u003cp\u003eClinical indicators\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"bottom\" width=\"46.23853211009175%\"\u003e\n \u003cp\u003eLive birth rate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"53.76146788990825%\"\u003e\n \u003cp\u003eValue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"28.256880733944953%\"\u003e\n \u003cp\u003eOR value(95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" width=\"17.98165137614679%\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"53.76146788990825%\"\u003e\n \u003cp\u003eFemale age(y)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.256880733944953%\"\u003e\n \u003cp\u003e0.815(0.735-0.904)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" width=\"17.98165137614679%\"\u003e\n \u003cp\u003e0.000* \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"53.76146788990825%\"\u003e\n \u003cp\u003eBMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.256880733944953%\"\u003e\n \u003cp\u003e0.998(0.927-1.075)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" width=\"17.98165137614679%\"\u003e\n \u003cp\u003e0.963\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"53.76146788990825%\"\u003e\n \u003cp\u003ebFSH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.256880733944953%\"\u003e\n \u003cp\u003e0.965(0.897-1.037)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" width=\"17.98165137614679%\"\u003e\n \u003cp\u003e0.333\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"53.76146788990825%\"\u003e\n \u003cp\u003eInfertility years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.256880733944953%\"\u003e\n \u003cp\u003e0.947(0.898-0.999)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" width=\"17.98165137614679%\"\u003e\n \u003cp\u003e0.046*\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"bottom\" width=\"100%\"\u003e\n \u003cp\u003eInfertility type\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"53.76146788990825%\"\u003e\n \u003cp\u003ePrimary infertility\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"bottom\" width=\"46.23853211009175%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"53.76146788990825%\"\u003e\n \u003cp\u003eSecondary infertility\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.256880733944953%\"\u003e\n \u003cp\u003e1.084(0.661-1.779)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" width=\"17.98165137614679%\"\u003e\n \u003cp\u003e0.748\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"53.76146788990825%\"\u003e\n \u003cp\u003eEndometrial thickness on the day of P administration(mm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.256880733944953%\"\u003e\n \u003cp\u003e1.067(0.945-1.205)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" width=\"17.98165137614679%\"\u003e\n \u003cp\u003e0.292\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"53.76146788990825%\"\u003e\n \u003cp\u003eNo. of transferred embryos\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.256880733944953%\"\u003e\n \u003cp\u003e2.017(1.341-3.032)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" width=\"17.98165137614679%\"\u003e\n \u003cp\u003e0.001*\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" width=\"99.81651376146789%\"\u003e\n \u003cp\u003eType of embryo transferred\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.1834862385321101%\"\u003e\n \n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"53.76146788990825%\"\u003e\n \u003cp\u003eCleavage stage embryo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" width=\"46.055045871559635%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.1834862385321101%\"\u003e\n \n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"53.76146788990825%\"\u003e\n \u003cp\u003eBlastocyst\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.256880733944953%\"\u003e\n \u003cp\u003e0.456(0.290-0.717)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.798165137614678%\"\u003e\n \u003cp\u003e0.001*\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.1834862385321101%\"\u003e\n \n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" width=\"99.81651376146789%\"\u003e\n \u003cp\u003eEndometrial Preparation Protocols\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.1834862385321101%\"\u003e\n \n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"53.76146788990825%\"\u003e\n \u003cp\u003eGnRHa-HRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" width=\"46.055045871559635%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.1834862385321101%\"\u003e\n \n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"53.76146788990825%\"\u003e\n \u003cp\u003eHRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.256880733944953%\"\u003e\n \u003cp\u003e2.708(1.251-5.864)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.798165137614678%\"\u003e\n \u003cp\u003e0.011*\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.1834862385321101%\"\u003e\n \n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"53.76146788990825%\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.256880733944953%\"\u003e\n \u003cp\u003e1.509(0.657-3.463)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.798165137614678%\"\u003e\n \u003cp\u003e0.332\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.1834862385321101%\"\u003e\n \n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*P \u0026lt; 0.05 for Chi-square test\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAbbreviations: OR odds ratio; CI 95% confidence interval; BMI body mass index; bFSH basal follicle-stimulating hormone;\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThere was insufficient evidence to demonstrate that the use of depot GnRHa is better or worse than the NC or HRT protocol for the reproductive outcome in FET cycles, especially for patients with RIF. Pretreatment with GnRHa before HRT in FET cycles is considered to be ineffective for the elderly patients, but it could be effective for the patients with RIF\u003csup\u003e\u0026nbsp;[12]\u003c/sup\u003e. Recent studies also failed to demonstrate any significant effect of depot GnRHa-FET protocol in the live birth/ongoing pregnancy rate \u003csup\u003e[6]\u003c/sup\u003e. However, that study only included younger patients (＜40 years) and thus the effect of depot GnRHa-FET protocol on elderly patients (36~43years) needs to be further evaluated.\u003c/p\u003e\n\u003cp\u003eThe present large-scale retrospective cohort study evaluated the reproductive outcomes in natural cycle, HRT cycle, GnRHa-HRT cycle of elderly patients with RIF when referred for FET. Our results showed that there was a significantly higher live birth rate in GnRHa-HRT treatment protocol than that in the NC and HRT protocols, while the miscarriagerate was not significantly different among the three protocols. In addition, we used low-dose drugs in our study. Patients in our study only received one intramuscular injection of 3.75 mg depot leuprolide acetate. Ill-timed administration with the double dose of depot leuprolide acetate may increased not only the hypo-estrogenic side-effects, e.g., hot flushes,vaginal dryness, decreased libido and loss of bone density,but also high cost[13].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;In contrast, previous retrospective self-control study suggested that GnRHa-HRT protocol, with 28 days of full-dose depot GnRHa, prolonged downregulation before ovarian stimulation, resulting in relatively high pregnancy success rates in idiopathic RIF patients undergoing IVF \u003csup\u003e[3]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eOur results are consistent with previous studies showing that cryopreservation of all viable blastocysts after ICSI followed by a subsequent FET cycle can improve the implantation when compared with fresh ET\u003csup\u003e\u0026nbsp;[3,5,14-16]\u003c/sup\u003e. Other studies showed that GnRHa may partially restore the endometrial secretion of implantation related factors, e.g., HOXA10, MEIS1 and LIF, which can regulate endometrial development and permit embryo implantation and decidualization\u003csup\u003e\u0026nbsp;[5,17-21]\u003c/sup\u003e. Another study showed that ovarian stimulation with GnRHa partially restores the expression of endometrial integrin beta 3 and improves uterine receptivity in mice \u003csup\u003e[22]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eAn interesting observation in our study is that the mean level of progesterone on the administration day in the HRT cycle was significantly higher than that in the GnRHa-HRT cycles (0.38\u0026plusmn;0.29 versus 0.53\u0026plusmn;0.47, P=0.001), which is consistent with the results in previous studies \u003csup\u003e[12,14,22]\u003c/sup\u003e. This might be due to a premature rise of LH levels in hormonal stimulation protocol without a GnRH agonist, which negatively alters the receptive window of the endometrium \u003csup\u003e[16]\u003c/sup\u003e. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe NC protocol is one of the most frequently and widely used FET protocols in treatment cycles\u003csup\u003e[24]\u003c/sup\u003e. However, one previous study suggests that approximately two-thirds of implantation failures are due to disturbed endometrial receptivity and asynchronized embryo-endometrial cross-talk, while the quality of embryo is estimated to be responsible for the remaining one-third implantation failure \u003csup\u003e[25]\u003c/sup\u003e. However, in this study, we found that live birth rate in NC protocol was not significantly lower than that in the GnRHa-HRT protocol, which may be due to the small sample size in the NC group. According to the histologic endometrial dating, the rate of a\u0026ldquo;displaced WOI (window of implantation)\u0026rdquo; in patients with RIF can reach 31.6%, compared with 3.8% in the patients with good-prognosis ( P = 0.003) \u003csup\u003e[26]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThis is the first study to evaluate the optimal approach to prepare the endometrium in FET cycles of elderly patients with RIF. The limitation of this study is its retrospective design from a single medical center. However, through the analysis of large sample size using multivariate logistics model, some confounding factors were eliminated. In addition, the type of endometrial preparation was selected by the physician\u0026rsquo;s preference and such preference may introduce a potential bias. Besides, we did not exclude cleavage stage of embryo transfer. This bias may be eliminated by a Cochrane review that blastocyst transfer over cleavage stage of embryo transfer was of low quality for live birth outcome \u003csup\u003e[27]\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, this nearly 5-year study provides very robust evidence regarding the reproductive potential of RIF women with increasing age. It showed that LBR in GnRHa-HRT protocol was raised compared with HRT protocol while the miscarriage rate was not affected. The live birth rate in NC protocol appears to be undamaged. However, the sample size of natural cycle protocol was too small, which may affect the outcome. Further multi-center randomized clinical trials are needed to confirm the possible benefits of GnRHa-HRT protocol for elderly patients with idiopathic recurrent implantation failure.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eFET: Frozen embryo transfer; HRT: Hormone replacement treatment; GnRHa-HRT: GnRH antagonist down-regulation combined hormone replacement treatment; RIF: Repeated implantation failure; IVF:in vitro fertilization;ICSI:Intracytoplasmic sperm injection\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch4\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/h4\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of Northwest Women\u0026rsquo;s and Children\u0026rsquo;s Hospital and has been performed in accordance with the principles of Declaration of Helsinki.\u0026nbsp;\u003c/p\u003e\n\u003ch4\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/h4\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch4\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/h4\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch4\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/h4\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003ch4\u003e\u003cem\u003e\u0026nbsp;Funding \u0026nbsp;\u003c/em\u003e\u003c/h4\u003e\n\u003ch4\u003eThis work was supported by National Natural Science Foundation of China (82100083)\u003c/h4\u003e\n\u003ch4\u003e\u003cem\u003eAuthors\u0026apos; contributions\u003c/em\u003e\u003c/h4\u003e\n\u003cp\u003eDP, JY, LW,and NL designed the study, performed data analysis, and drafted the manuscript; NZ, HZ and SZ critically review and corrected the final version of the manuscript. All participants approved the final version to be submitted.\u003c/p\u003e\n\u003ch4\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/h4\u003e\n\u003cp\u003eThe authors thank the staff from Northwest Women\u0026rsquo;s and Children\u0026rsquo;s Hospital for their assistance with the data collection. We thank all participants in this study.\u003c/p\u003e\n\u003ch4\u003e\u003cem\u003eAuthors\u0026apos; information\u0026nbsp;\u003c/em\u003e\u003c/h4\u003e\n\u003cp\u003e1,The Assisted Reproduction Center, Northwest Women\u0026rsquo;s and Children\u0026rsquo;s Hospital, No. 73 Houzai Gate, Xincheng District, Xi\u0026rsquo;an City, Shaanxi Province, China\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2 Department of Basic Medicine, Xi\u0026rsquo;an Medical University,Xin‑Wang Street #1, Xi\u0026rsquo;an 710021, Shaanxi, China\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eMargalioth EJ, Ben-Chetrit A, Gal M, Eldar-Geva T: \u003cstrong\u003eInvestigation and treatment of repeated implantation failure following IVF-ET.\u003c/strong\u003e \u003cem\u003eHum Reprod\u0026nbsp;\u003c/em\u003e2006, \u003cstrong\u003e21:\u003c/strong\u003e3036-3043.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eMagdi Y, El-Damen A, Fathi AM, Abdelaziz AM, Abd-Elfatah Youssef M, Abd-Allah 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Patients with known endometriosis or adenomyosis were excluded from the study.According to different endometrial preparation protocols, patients were divided into three groups: natural cycle group (NC, n=62), hormone replacement treatment cycle group (HRT, n=194) and GnRH agonist down regulation combined with HRT cycle group (GnRHa-HRT, n=290).Live birth rate was primary outcome while clinical pregnancy rate, miscarriage rate, on going pregnancy rate were secondary outcomes. \u003c/p\u003e\u003cp\u003eResults\u003c/p\u003e\u003cp\u003eLive birth rate in the GnRHa-HRT group (31.90%) was significantly higher than that in the HRT (21.65%) or NC (16.13%) groups (P\u0026lt;0.0001). Logistic regression model adjusting for the potential confounders showed that patients in the GnRHa-HRT group have significantly higher live birth rate compared with those in the HRT group (OR, 2.708; 95%CI,1.251-5.864, P=0.011). However, live birth rate was not significantly different between GnRHa-HRT and NC groups (OR, 1.509; 95% CI,0.657-3.463, P=0.332), which could be due to the small sample size in the NC group.\u003c/p\u003e\u003cp\u003eConclusions\u003c/p\u003e\u003cp\u003e\u003cspan class=\"ql-cursor\"\u003e\u003c/span\u003eGnRHa-HRT protocol improves live birth rate in FET cycles of elderly patients with RIF. We hypothesize that GnRHa-HRT protocol enhances implantation related factors and promotes optimal endometrium receptivity, leading to the improved live birth rate. These findings are also useful for further investigating the underlying mechanism of GnRHa-HRT protocol in improving the reproductive outcomes of elderly patients with RIF.\u003c/p\u003e\u003cp\u003eTrial registration:The research protocol was approved by the hospital institutional ethics committee (2021002).\u003c/p\u003e","manuscriptTitle":"Gonadotropin-releasing Hormone Agonist Down Regulation Combined With Hormone Replacement Therapy Improves the Reproductive Outcome in the Frozen-thawed Embryo Transfer Cycle of Elderly Patients With Idiopathic Recurrent Implantation Failure","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-11-23 19:07:16","doi":"10.21203/rs.3.rs-1090205/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2021-11-23T06:37:30+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-11-23T03:53:54+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2021-11-19T06:09:33+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2021-11-18T23:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2021-11-18T23:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"Reproductive Biology and Endocrinology","date":"2021-11-17T12:45:03+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"reproductive-biology-and-endocrinology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"rbej","sideBox":"Learn more about [Reproductive Biology and Endocrinology](http://rbej.biomedcentral.com)","snPcode":"12958","submissionUrl":"https://submission.nature.com/new-submission/12958/3","title":"Reproductive Biology and Endocrinology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"085fbe21-8f8a-4a5b-8e64-d89181af7d6f","owner":[],"postedDate":"November 23rd, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":8705355,"name":"Endocrinology \u0026 Metabolism"}],"tags":[],"updatedAt":"2022-01-19T02:50:42+00:00","versionOfRecord":[],"versionCreatedAt":"2021-11-23 19:07:16","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1090205","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1090205","identity":"rs-1090205","version":["v1"]},"buildId":"B-jG_2CBjPDmsCi4Wdhf-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}