The Impact Of Dual Trigger Stimulation Upon Reproductive Outcomes In Woman Of Advanced Maternal Age – A Large Retrospective Study

The Impact Of Dual Trigger Stimulation Upon Reproductive Outcomes In Woman Of Advanced Maternal Age – A Large Retrospective Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Impact Of Dual Trigger Stimulation Upon Reproductive Outcomes In Woman Of Advanced Maternal Age – A Large Retrospective Study Stylianos Sergios Chatziioannou, Christoforidis Nikolaos, Alexia Chatziparasidou, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6115929/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Poor ovarian response (POR) in women aged 40 and above presents significant challenges in in vitro fertilization (IVF). This study evaluated whether dual trigger strategy, involving a combination of gonadotropin-releasing hormone (GnRH) agonists and human chorionic gonadotropin (hCG), improves IVF outcomes compared to human chorionic gonadotropin (hCG) alone in women of advanced maternal age. Methods A retrospective cohort study was conducted, analysing 2,199 IVF cycles from 1,451 women between January 2018 and June 2022. Among these cycles, 327 cycles utilized a dual trigger strategy while 1,124 had an hCG trigger. Key outcomes assessed included the number of metaphase II (MII) oocytes, fertilization rates, fresh embryo transfers on days 5/6, and pregnancy outcomes. Multivariate regression was employed to adjust for variables such as age, BMI, gonadotropin dosage, stimulation duration, and anti-Müllerian hormone levels. Results The dual trigger group showed significantly higher rates of embryo transfer on days 5/6 (34.1% vs. 16.5%, p < 0.001). While there were no significant differences in the number of MII oocytes or fertilization rates (p = 0.16), adjusted analysis indicated a modest increase in MII oocytes (RR = 1.1, 95% CI 1.00–1.21). Positive hCG rates were lower in the dual trigger group (18.5% vs. 24.7%, p = 0.007), and cumulative live birth rates were not significantly different (8.9% vs. 13.2%, p = 0.009). Conclusions Dual trigger protocols may enhance certain ovarian response parameters but do not significantly improve pregnancy or live birth rates in older women with diminished ovarian reserve. Future studies are necessary to optimize and personalize treatment strategies for this challenging patient population. Trial Registration: Approved by the local ethical committee (Approval 17/07/2024). Sexual & Reproductive Medicine Obstetrics & Gynecology Dual trigger protocol Metaphase II (MII) oocytes Poor ovarian response (POR) Reproductive outcomes Bologna criteria BACKGROUND In vitro fertilization (IVF) is a pivotal intervention for couples dealing with infertility. However, advancing maternal age poses a significant impediment to IVF success. This is primarily attributed to the age-related decline in ovarian reserve and oocyte quality, culminating in reduced fertility potential and heightened risk of chromosomal abnormalities in the resulting embryos. Consequently, IVF outcomes in this population often manifest as diminished pregnancy rates and elevated rates of pregnancy loss. The Bologna criteria, established by the European Society of Human Reproduction and Embryology (ESHRE), aim to standardize the definition of poor ovarian response (POR) in women undergoing assisted reproduction [ 1 ]. According to these criteria, advanced maternal age, specifically for women over 40 years, is a critical factor in diagnosing POR, alongside a history of poor ovarian response to stimulation and abnormal ovarian reserve tests, such as low antral follicle count (AFC) and anti-Müllerian hormone (AMH) levels [ 1 , 2 ]. The inclusion of women over 40 years of age in the Bologna criteria emphasizes the unique challenges these women face in assisted reproduction. This age group often experiences a significant decline in both ovarian reserve and oocyte quality [ 1 , 2 ]. Although advancements in markers such as AMH and the AFC have improved our ability to predict the ovarian response, they fail to accurately predict oocyte quality and live birth outcomes [ 1 , 2 ]. Therefore, given the heterogeneous nature of poor ovarian response (POR), personalized approaches are essential to enhance the efficacy of reproductive interventions especially for older women [ 3 – 5 ]. The challenge of treating POR has led to the exploration of various treatment modalities that have failed to substantially improve reproductive outcomes. Among these, the concept of dual triggering for final oocyte maturation has emerged as a promising approach [ 6 ]. The dual trigger involves the simultaneous use of human chorionic gonadotropin (hCG) and gonadotropin-releasing hormone (GnRH) agonists. This method capitalizes on the strengths of both agents: hCG mimics the activity of luteinizing hormone (LH), which is essential for oocyte maturation and ovulation, whereas GnRH agonists trigger a surge of both LH and follicle-stimulating hormone (FSH), mimicking the natural menstrual cycle [ 7 ]. The rationale behind dual triggering lies in the synergistic effects of hCG and GnRH agonists. GnRH agonists can induce a normal endogenous LH and FSH surge, thereby initiating the final stages of oocyte maturation (8). Its theoretical advantages are reported in normal responders; however, the efficacy of dual triggering in poor responders, especially in the context of advanced maternal age, remains to be determined [ 9 – 11 ]. This study delves into one of the most challenging aspects of IVF — women of advanced maternal age — and aims to explore the potential of dual-trigger protocols in improving reproductive outcomes in these patients. METHODS Trial Design In this retrospective cohort study, we focused exclusively on women of advanced maternal age, 40 years and above. The subjects were patients who underwent IVF in a GnRH antagonist at a private IVF clinic (EmbryoLab Fertility Clinic, Thessaloniki, Greece). The study period spanned from 1st January 2018 to 1st June 2022. The study was approved by the local ethical committee (Approval 17/07/2024). Study Population The study included all GnRH antagonist cycles performed during the study period. Patients who were euthyroid were included, excluding those with endocrinological disorders. Additionally, women who had uterine anatomical abnormalities, preimplantation genetic screening of chromosomes (PGT-A) and azoospermic couples were excluded. Patients may have contributed to more than one IVF cycle. Intervention/Comparator For all women, conventional ovarian stimulation started on the second or third day of the menstrual cycle. Recombinant FSH (rFSH) and human menopausal gonadotropin (hMG) were used according to the physician’s preference for ovarian stimulation. The GnRH antagonist was administered at a dose of 0.25 mg to suppress the hypothalamic-pituitary-ovarian axis and prevent a premature LH surge. Oocyte triggering was performed when there was at least one follicle of 16–17 mm in diameter. The control group received 250 mcg rhCG subcutaneously (SC), whereas the study group received a dual trigger regimen with 0.2 mg of GnRH agonist and 250 mcg of hCG SC. Oocytes were retrieved through transvaginal ultrasound guidance approximately 35–36 hours after triggering, followed by intracytoplasmic sperm injection (ICSI). A maximum of three embryos were transferred on either day 3 or day 5 after oocyte retrieval. Embryo quality was assessed based on the Istanbul consensus workshop criteria for embryo evaluation. Top-quality embryos on Day 3 were characterized by at least seven blastomeres, uniform cell sizes, and fragmentation not exceeding 10%[ 12 ]. Luteal phase support, using vaginal progesterone, was started either on the day of oocyte retrieval or the day after and continued for at least six weeks, or until menstruation, or a negative pregnancy test, which was performed at least 14 days post-retrieval. Outcomes The primary outcome was the number of metaphase II oocytes. Secondary outcomes included cumulative live birth rates which is the probability of achieving at least one live birth resulting from one initiated or aspirated ART cycle, including all cycles in which fresh and/or frozen embryos are transferred, until one delivery with a live birth occurs or until all embryos are used, whichever occurs first. The delivery of a singleton, twin, or other multiples is registered as one delivery ​ [ 13 ]. Statistical analysis Descriptive summaries of baseline characteristics are presented as medians and interquartile ranges (IQRs) for continuous variables and counts and percentages for categorical variables. For univariate group comparisons, the Mann-Whitney and Fisher’s exact tests were used for continuous and categorical variables, respectively, as appropriate. The association of dual trigger with the number of metaphase II oocytes, adjusted for covariates, was examined with mixed-effects Poisson regression models, with an observation-level random effect to address overdispersion; these provide an “Oocyte Ratio” (OoR) for the conditional effect of dual trigger and other covariates on the number of oocytes compared with baseline. The covariates used for adjustment included age (as a categorical variable, given the narrow 40–45 years age range), body mass index (BMI), number of ovarian stimulation days, total gonadotropin dosage, and AMH levels. Statistical significance was set at p < 0.05. All analyses were performed in the R statistical environment, version 4.3.3 [ 15 ]. RESULTS The analysis included 2,199 cycles from 1,451 women (327 women in the dual trigger stimulation group vs. 1,124 women in the hCG trigger stimulation group). Women in the dual trigger stimulation group had an average of 1.34 cycles (range 1–5), while women in the hCG trigger stimulation group had an average of 1.57 cycles (range 1–6). The baseline characteristics of the two groups are presented in ‘Table 1 ’. The two groups were comparable in terms of age, BMI, previous IVF attempts, AMH levels and indication of infertility (p > 0.05). Table 1 Comparison of baseline characteristics between women undergoing dual vs hCG trigger. Dual Trigger hCG Trigger p-value Number of patients 327 1124 Number of cycles 437 1762 Age 41.0 (40.0–42.0) 41.0 (40.0–42.0) 0.81 BMI 24.0 (21.4–28.2) 24.0 (21.5–27.5) 0.85 Previous IVF attempts 1 (0–3) 1 (0–3) 0.79 AMH levels (ng/ml) 1.1 (0.5–1.6) 0.9 (0.6–1.7) 0.69 Treatment Indications: 0.24 male factor 45 (10.3) 242 (13.7) Tubal 15 (3.4) 77 (4.4) Anovulatory 2 (0.5) 12 (0.7) Endometriosis 7 (1.6) 31 (1.8) ovarian insufficiency 174 (39.8) 637 (36.2) Unexplained 41 (9.4) 205 (11.6) lesbian/single 53 (12.1) 216 (12.3) combined 100 (22.9) 342 (19.4) ‘Table 2 ’ presents the differences in reproductive outcomes between the two groups. The number of metaphase II oocytes showed no statistically significant difference between the two groups with the dual trigger group having a median of 3.0 (range: 1.0–5.0) and the hCG trigger group also having a median of 3.0 (range:1.0–5.0), p = 0.16. In addition, the cumulative oocyte complex (COC)and feralization rates showed no difference between the two groups (p = 0.39). The percentage of embryos that were transferred at the blastocyst stage was significantly greater in the dual trigger group (34.1%) compared to the hCG trigger group (16.5%). The hCG trigger group was associated with significantly higher pregnancy rates (positive hCG rates) (24.7%) compared to the dual trigger stimulation group (18.5%), OR = 1.44, 95% CI [1.11, 1.88]. However, the rates of miscarriage, clinical pregnancy and fresh live birth, as well as the total number of frozen embryos (p = 0.68), were not different between the groups (p > 0.05). Furthermore, the cumulative live birth rate (cLBR) was similar between the two groups. The cLBR in the dual trigger group was 8.9% (39 out of 378), whereas in the hCG trigger group, it was 13.2% (233 out of 1470). Table 2 Comparison of primary and secondary outcomes between women undergoing dual vs hCG trigger according to the number of cycles. Dual Trigger hCG Trigger p-value Total Gonadotropin Dosage 2250 (1990–2700) 2140 (1800–2700) 0.28 Stimulation days 10 (9–11) 10 (9–11) < 0.001 Cumulus-Oocyte Complex (COC) 5 (3–9) 5 (3–8) 0.39 Number of MII oocytes 3.0 (1.0–5.0) 3.0 (1.0–5.0) 0.16 Maturation rate 85.7 (66.7–100) 87.5 (70–100) 0.24 Fertilization Rate 60.0 (40.0–80.0) 60.0 (37.5–77.8) 0.2 Embryo transfer (yes/no) 1 378 (86.5) 1470 (83.4) 0.13 Number of Embryos Transferred 2 1 (1–1) 2 (1–2) < 0.001 Embryo Transfer on Day 5/6 129 (34.1) 243 (16.5) < 0.001 Total number of frozen embryos 0 (0–1) 0 (0–1) 0.68 Miscarriage rate 35 (43.2) 197 (45.3) 0.81 Positive hCG rate 81 (18.5) 435 (24.7) 0.007 Clinical Pregnancy 40 (9.2) 205 (11.6) 0.15 Live birth 39 (8.9) 203 (11.5) 0.22 Cumulative Live Birth Rate (cLBR) 39 (8.9) 233 (13.2) 0.009 1: Binary variable that denotes if at least one embryo was successfully transferred. 2: Discrete variable that denotes the number of embryos that were transferred. Influence of Oocyte Ratios ‘Table 3 ’ presents the Rate Ratio (RR), expressed as Oocyte Ratios (OoR), from the unadjusted and adjusted mixed-effects Poisson model, between dual and hCG trigger stimulation. The unadjusted model showed no significant difference between the two groups in terms of the Oocyte Ratio, RR = 1.08, 95% CI [0.99, 1.18]. After adjusting for all relevant factors—age, BMI, total gonadotropin, stimulation days, and AMH—the dual trigger stimulation group was associated with an increased number of MII oocytes compared to hCG trigger, OoR = 1.10, 95% CI [1.00–1.21]. However, the effect was minor. Table 3 Effect of dual trigger therapy and age on number of MII oocytes Rate Ratio 95% CI lower 95% CI upper Dual trigger (Unadjusted) 1.08 0.99 1.18 Dual trigger (Adjusted) 1.1 1.00 1.21 Age 0.97 0.94 1.01 BMI 1.00 0.99 1.01 Total Gonadotropin Dosage 1.00 0.98 1.02 Stimulation days 1.05 1.02 1.07 AMH 1.26 1.22 1.30 DISCUSSION To the best of our knowledge, this is the largest study evaluating the impact of dual trigger (0.2 mg GnRH agonist + 250 mcg hCG) versus hCG trigger (250 mcg hCG alone) on reproductive outcomes in advanced maternal-age women (≥ 40) undergoing IVF. Both groups yielded similar numbers of metaphase II oocytes and maturation/fertilization rates, while most reproductive outcomes included were comparable between the two groups. The cumulative live birth rate was also similar and included both embryos transfer on day 5 and 3. After adjustment for several confounders, patients in the dual trigger group had a statistically significant difference in the number of MII oocytes compared with those in the hCG trigger group, with a 10% increase in MII oocytes; however, the difference was not deemed as clinically relevant. In evaluating the efficacy of dual versus hCG trigger protocols in ovarian stimulation for poor responders, several studies have reported similar findings. Eser et al. investigated 109 poor responders and reported no significant difference in the number of metaphase II (MII) oocytes between the dual and hCG trigger groups, as well as no improvement in clinical pregnancy rates [ 19 ]. Nevertheless, the study did not include enough participants to reliably detect differences or effects in these specific outcomes. Similarly, a pilot study by Haas et al., involving 33 poor responders under the Bologna criteria, confirmed that while dual trigger protocols increased the number of top-quality embryos, it did not significantly affect oocyte yield [ 11 ]. Although its results, the study sample was small, limiting the statistical power and the generalizability of the findings. Expanding on this, Keskin et al. examined 225 women of advanced maternal age with low ovarian reserve and reported no significant improvement in the number of MII oocytes with dual triggering compared with the hCG trigger alone, alongside with a lack of significant increase in live birth rates [ 20 ]. Keskin et al. once again included a small sample size leading to the same limitations as Haas et al. and also lacked homogeneity in the number and day of embryos transferred among Poseidon group 3/4 poor responders. In a larger cohort study, Lin et al. evaluated 427 IVF cycles with fresh embryo transfers and similarly did not observe a statistically significant improvement in the number of MII oocytes with dual triggering [ 21 ]). Although this study benefits from a larger sample size, they have not measured potential cofounders such as body mass index, or possible of causes infertility like endometriosis, male factors or even ovarian insufficiency. The above studies emphasize that dual triggering does not necessarily translate to improved overall pregnancy outcomes for poor responders, highlighting the need for further studies to better understand the impact of dual trigger protocols on clinical outcomes in advanced maternal-aged women undergoing IVF. On the other hand, several studies, such as those by Ben-Haroush et al. and Tulek et al., demonstrated significantly improved oocyte maturation rates, with Tulek et al. also reporting significant gains in the number of metaphase II oocytes, fertilization rates, implantation rates, clinical pregnancy, and live birth rates [ 22 , 23 ]. Mutlu et al. and Zhang et al. similarly showed improvements in oocyte retrieval, maturation, and embryo quality, though Zhang et al. found no significant differences in implantation or clinical pregnancy outcomes [ 24 , 25 ]. Additionally, Maged et al. reported that dual triggering improved the number of retrieved oocytes and clinical pregnancy rates in poor responders [ 26 ]. Chen et al. and Ren et al. reported higher numbers of metaphase II oocytes, with an improvement in fertilization rate and oocyte count, suggesting that dual trigger protocols may enhance reproductive outcomes, though Ren et al. found no improvement in cumulative live birth rates [27,28]. With a sample size of 136 patients, certain subgroup analyses may lack statistical power [ 22 ]. The lack of randomization and blinding may introduce observer bias, while the limited evidence on long-term outcomes, such as cumulative live birth rates, restricts the ability to draw definitive conclusions about the broader efficacy of the dual trigger in IVF cycles [25,26,29].While these studies collectively suggest that dual trigger protocols offer some advantages, particularly in terms of oocyte maturation and retrieval, the impact on clinical pregnancy and live birth rates remains variable, warranting further investigation. The dual trigger protocol in IVF involves the simultaneous use of a GnRH-a and hCG to induce final oocyte maturation. The GnRH-a initially stimulates an endogenous surge of LH and FSH, mimicking the natural LH surge that occurs during ovulation, which is essential for follicular maturation. It also helps prevent premature luteinization by suppressing the pituitary release of gonadotropins. Meanwhile, hCG, which is structurally similar to LH, with a higher half-life, acts on the ovarian follicles to trigger the final maturation of the oocytes, promoting the resumption of meiosis and expansion of the cumulus-oocyte complex. The combination of these two agents works synergistically: GnRH-a ensures that there is no early ovulation, while hCG precisely controls the timing of oocyte maturation. This dual approach improves the synchronization of follicular development, ultimately enhancing the chances of successful IVF outcomes by ensuring the retrieval of fully matured oocytes at the optimal time.(6,26) The major strength of our study lies in its large sample size, comprising 1,451 women of advanced maternal age. This makes it one of the most extensive investigations in this challenging-to-recruit infertile population, thereby ensuring robust statistical power and enhancing the reliability of the results. By adjusting for critical variables that significantly influence IVF cycle outcomes, our study provides valuable insights into the clinical application of the dual trigger protocol. The limitations of our study include its retrospective design, which may introduce selection bias and limit causal inferences. Additional this study was a single-centre study which might limit the generalizability of the results to other setting or populations with different characteristics or treatment protocols. Reliance on medical records can lead to measurement bias, and the nonrandomized nature of the study introduces potential selection bias, where clinical judgement may have influenced patient allocation. Despite statistical adjustments, unmeasured confounding variables may still impact the outcomes. CONCLUSIONS Our study provides valuable insights into the comparative effectiveness of dual trigger and hCG trigger protocols in assisted reproductive technology for women over 40 years of age. Even though there was a marginal significance of 10% increase in metaphase II oocytes after adjustment for confounders, this increase did not translate into a significant clinical impact. Furthermore, the cumulative LBR remains similar, highlighting the lack of impact on embryo quality. Further prospective, randomized controlled trials are essential to confirm these results and refine treatment protocols to enhance clinical outcomes for poor ovarian responders. Abbreviations AFC - Antral Follicle Count AMH - Anti-Müllerian Hormone cLBR - Cumulative Live Birth Rate ESHRE - European Society of Human Reproduction and Embryology FSH - Follicle-Stimulating Hormone GnRH - Gonadotropin-Releasing Hormone GTOC – Granulosa – Theca Oocyte Complex hCG - Human Chorionic Gonadotropin hMG - Human Menopausal Gonadotropin ICSI - Intracytoplasmic Sperm Injection IVF - In Vitro Fertilization LH - Luteinizing Hormone MII - Metaphase II OHSS - Ovarian Hyperstimulation Syndrome OoR - Oocyte Ratio PGT-A – Preimplantation Genetic Screening for Chromosomes POR - Poor Ovarian Response rFSH - Recombinant Follicle-Stimulating Hormone RR - Rate Ratio SC – Subcutaneous Declarations ETHICS APPROVAL AND CONSENT TO PARTICIPATE The study was approved by the local ethical committee (Approval 17/07/2024). CONSENT FOR PUBLICATION Not applicable AVAILABILITY OF DATA AND MATERIALS The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. COMPETING INTEREST The authors declare no competing interests. FUNDING This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. AUTHOR’S CONTRIBUTION SSC and PD contributed to the study design. SSC wrote the original manuscript. TL was responsible for analysing the results. SSC , AC, NC, AP and PD were responsive for revising the manuscript. PD was responsible for supervising the operation of the project. All authors read and approved the manuscript. ACKNOWLEDGEMENTS Not applicable References Ferraretti AP, La Marca A, Fauser BCJM, Tarlatzis B, Nargund G, Gianaroli L. ESHRE consensus on the definition of “poor response” to ovarian stimulation for in vitro fertilization: the Bologna criteria. 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Curr Med Sci [Internet]. 2022 Oct 1 [cited 2024 Oct 26];42(5):1066–70. Available from: https://pubmed.ncbi.nlm.nih.gov/35997911/ Ren Y meng, Wang Y bin, Fu M, Zhang Q xiang, Shen H, Han H jing, et al. Effect of Dual Trigger In Vitro Fertilization and Intracytoplasmic Sperm Injection During the Gonadotropin-releasing Hormone-Antagonist Cycle on Final Oocyte Maturation and Cumulative Live Birth Rate in Women with Diminished Ovarian Reserve. Curr Med Sci [Internet]. 2022 Oct 1 [cited 2024 Oct 26];42(5):1066–70. Available from: https://pubmed.ncbi.nlm.nih.gov/35997911/ Dong L, Lian F, Wu H, Xiang S, Li Y, Wei C, et al. Reproductive outcomes of dual trigger with combination GnRH agonist and hCG versus trigger with hCG alone in women undergoing IVF/ICSI cycles: a retrospective cohort study with propensity score matching. BMC Pregnancy Childbirth [Internet]. 2022 Dec 1 [cited 2024 Nov 13];22(1):1–10. Available from: https://bmcpregnancychildbirth.biomedcentral.com/articles/10.1186/s12884-022-04899-2 Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations The authors declare no competing interests. Supplementary Files Tables.docx Cite Share Download PDF Status: Posted Version 1 posted 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-6115929","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":421449319,"identity":"2b777251-c162-4ec9-affa-5d8f96bf24e4","order_by":0,"name":"Stylianos Sergios Chatziioannou","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA90lEQVRIiWNgGAWjYHACxgMJYDr58IMPQIqNnZAGNgYGqJa0NMMZIAFmYrRAWDkG0jwgmpAW+fnNBw48qKiL5mfPMTC2+bVNno+ZgfHDxxzcWgyOsSUcSDhzOHdmz7OCx7l9tw3bmBmYJWduw6OFjcfgQGLbgdwNN5I3GOf23GYEamFj5sWjRb6N/wNQS13u/hsJBtKWPbftCWphOMbDANTCnLtBIsVAmuHH7USCWgyOpRmA/TLjzLM0w96G28ltzIzNeP0i33z44cMfFXW5/e3AqPzx57bt/Pbmgx8+4nMYCmBsA5MNxKoHgT+kKB4Fo2AUjIKRAgBYpVhS7xVQswAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0009-0008-6394-1891","institution":"European University of Cyprus, School of Medicine, Nicosia, Cyprus","correspondingAuthor":true,"prefix":"","firstName":"Stylianos","middleName":"Sergios","lastName":"Chatziioannou","suffix":""},{"id":421449320,"identity":"84b0c385-e2aa-4549-81e2-6257b8aa6e8f","order_by":1,"name":"Christoforidis Nikolaos","email":"","orcid":"","institution":"Embryolab, Thessaloniki, Greece","correspondingAuthor":false,"prefix":"","firstName":"Christoforidis","middleName":"","lastName":"Nikolaos","suffix":""},{"id":421449321,"identity":"4f53b1a1-a268-40a5-afb6-fd780a8814ec","order_by":2,"name":"Alexia Chatziparasidou","email":"","orcid":"","institution":"Embryolab, Thessaloniki, Greece","correspondingAuthor":false,"prefix":"","firstName":"Alexia","middleName":"","lastName":"Chatziparasidou","suffix":""},{"id":421449322,"identity":"ad76bbeb-50f1-43d0-b342-dd1a61feb468","order_by":3,"name":"Achilleas Papatheodorou","email":"","orcid":"","institution":"Embryolab, Thessaloniki, Greece","correspondingAuthor":false,"prefix":"","firstName":"Achilleas","middleName":"","lastName":"Papatheodorou","suffix":""},{"id":421449323,"identity":"9ab5fa6f-b9e3-446c-bb54-2bd0038e3f6a","order_by":4,"name":"Pavlos Kolias","email":"","orcid":"","institution":"Department of Mathematics, Aristotle University of Thessaloniki","correspondingAuthor":false,"prefix":"","firstName":"Pavlos","middleName":"","lastName":"Kolias","suffix":""},{"id":421449324,"identity":"fcd276a6-436e-45fb-9987-1f610f7a5cee","order_by":5,"name":"Panagiotis Drakopoulos","email":"","orcid":"","institution":"European University of Cyprus, School of Medicine, Nicosia, Cyprus","correspondingAuthor":false,"prefix":"","firstName":"Panagiotis","middleName":"","lastName":"Drakopoulos","suffix":""}],"badges":[],"createdAt":"2025-02-26 20:30:14","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6115929/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6115929/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":77393566,"identity":"e61229d3-cc03-4913-b95d-695b0f76f39e","added_by":"auto","created_at":"2025-02-28 07:06:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":588198,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6115929/v1/3c95cc29-c79e-4f75-af0d-3aec2c8ba131.pdf"},{"id":77393067,"identity":"fddc6cc5-3c27-4bc3-a761-af262f5981ea","added_by":"auto","created_at":"2025-02-28 06:58:39","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":21377,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6115929/v1/4aaed22992d36e3b18a267a9.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eThe Impact Of Dual Trigger Stimulation Upon Reproductive Outcomes In Woman Of Advanced Maternal Age – A Large Retrospective Study\u003c/p\u003e","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eIn vitro fertilization (IVF) is a pivotal intervention for couples dealing with infertility. However, advancing maternal age poses a significant impediment to IVF success. This is primarily attributed to the age-related decline in ovarian reserve and oocyte quality, culminating in reduced fertility potential and heightened risk of chromosomal abnormalities in the resulting embryos. Consequently, IVF outcomes in this population often manifest as diminished pregnancy rates and elevated rates of pregnancy loss.\u003c/p\u003e \u003cp\u003eThe Bologna criteria, established by the European Society of Human Reproduction and Embryology (ESHRE), aim to standardize the definition of poor ovarian response (POR) in women undergoing assisted reproduction [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. According to these criteria, advanced maternal age, specifically for women over 40 years, is a critical factor in diagnosing POR, alongside a history of poor ovarian response to stimulation and abnormal ovarian reserve tests, such as low antral follicle count (AFC) and anti-M\u0026uuml;llerian hormone (AMH) levels [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The inclusion of women over 40 years of age in the Bologna criteria emphasizes the unique challenges these women face in assisted reproduction. This age group often experiences a significant decline in both ovarian reserve and oocyte quality [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Although advancements in markers such as AMH and the AFC have improved our ability to predict the ovarian response, they fail to accurately predict oocyte quality and live birth outcomes [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Therefore, given the heterogeneous nature of poor ovarian response (POR), personalized approaches are essential to enhance the efficacy of reproductive interventions especially for older women [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe challenge of treating POR has led to the exploration of various treatment modalities that have failed to substantially improve reproductive outcomes. Among these, the concept of dual triggering for final oocyte maturation has emerged as a promising approach [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The dual trigger involves the simultaneous use of human chorionic gonadotropin (hCG) and gonadotropin-releasing hormone (GnRH) agonists. This method capitalizes on the strengths of both agents: hCG mimics the activity of luteinizing hormone (LH), which is essential for oocyte maturation and ovulation, whereas GnRH agonists trigger a surge of both LH and follicle-stimulating hormone (FSH), mimicking the natural menstrual cycle [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe rationale behind dual triggering lies in the synergistic effects of hCG and GnRH agonists. GnRH agonists can induce a normal endogenous LH and FSH surge, thereby initiating the final stages of oocyte maturation (8). Its theoretical advantages are reported in normal responders; however, the efficacy of dual triggering in poor responders, especially in the context of advanced maternal age, remains to be determined [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. This study delves into one of the most challenging aspects of IVF \u0026mdash; women of advanced maternal age \u0026mdash; and aims to explore the potential of dual-trigger protocols in improving reproductive outcomes in these patients.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eTrial Design\u003c/h2\u003e \u003cp\u003eIn this retrospective cohort study, we focused exclusively on women of advanced maternal age, 40 years and above. The subjects were patients who underwent IVF in a GnRH antagonist at a private IVF clinic (EmbryoLab Fertility Clinic, Thessaloniki, Greece). The study period spanned from 1st January 2018 to 1st June 2022. The study was approved by the local ethical committee (Approval 17/07/2024).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy Population\u003c/h3\u003e\n\u003cp\u003eThe study included all GnRH antagonist cycles performed during the study period. Patients who were euthyroid were included, excluding those with endocrinological disorders. Additionally, women who had uterine anatomical abnormalities, preimplantation genetic screening of chromosomes (PGT-A) and azoospermic couples were excluded. Patients may have contributed to more than one IVF cycle.\u003c/p\u003e\n\u003ch3\u003eIntervention/Comparator\u003c/h3\u003e\n\u003cp\u003eFor all women, conventional ovarian stimulation started on the second or third day of the menstrual cycle. Recombinant FSH (rFSH) and human menopausal gonadotropin (hMG) were used according to the physician\u0026rsquo;s preference for ovarian stimulation. The GnRH antagonist was administered at a dose of 0.25 mg to suppress the hypothalamic-pituitary-ovarian axis and prevent a premature LH surge. Oocyte triggering was performed when there was at least one follicle of 16\u0026ndash;17 mm in diameter. The control group received 250 mcg rhCG subcutaneously (SC), whereas the study group received a dual trigger regimen with 0.2 mg of GnRH agonist and 250 mcg of hCG SC. Oocytes were retrieved through transvaginal ultrasound guidance approximately 35\u0026ndash;36 hours after triggering, followed by intracytoplasmic sperm injection (ICSI). A maximum of three embryos were transferred on either day 3 or day 5 after oocyte retrieval. Embryo quality was assessed based on the Istanbul consensus workshop criteria for embryo evaluation. Top-quality embryos on Day 3 were characterized by at least seven blastomeres, uniform cell sizes, and fragmentation not exceeding 10%[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Luteal phase support, using vaginal progesterone, was started either on the day of oocyte retrieval or the day after and continued for at least six weeks, or until menstruation, or a negative pregnancy test, which was performed at least 14 days post-retrieval.\u003c/p\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eThe primary outcome was the number of metaphase II oocytes. Secondary outcomes included cumulative live birth rates which is the probability of achieving at least one live birth resulting from one initiated or aspirated ART cycle, including all cycles in which fresh and/or frozen embryos are transferred, until one delivery with a live birth occurs or until all embryos are used, whichever occurs first. The delivery of a singleton, twin, or other multiples is registered as one delivery\u003cem\u003e​\u003c/em\u003e [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eDescriptive summaries of baseline characteristics are presented as medians and interquartile ranges (IQRs) for continuous variables and counts and percentages for categorical variables. For univariate group comparisons, the Mann-Whitney and Fisher\u0026rsquo;s exact tests were used for continuous and categorical variables, respectively, as appropriate. The association of dual trigger with the number of metaphase II oocytes, adjusted for covariates, was examined with mixed-effects Poisson regression models, with an observation-level random effect to address overdispersion; these provide an \u0026ldquo;Oocyte Ratio\u0026rdquo; (OoR) for the conditional effect of dual trigger and other covariates on the number of oocytes compared with baseline. The covariates used for adjustment included age (as a categorical variable, given the narrow 40\u0026ndash;45 years age range), body mass index (BMI), number of ovarian stimulation days, total gonadotropin dosage, and AMH levels. Statistical significance was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. All analyses were performed in the R statistical environment, version 4.3.3 [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eThe analysis included 2,199 cycles from 1,451 women (327 women in the dual trigger stimulation group vs. 1,124 women in the hCG trigger stimulation group). Women in the dual trigger stimulation group had an average of 1.34 cycles (range 1\u0026ndash;5), while women in the hCG trigger stimulation group had an average of 1.57 cycles (range 1\u0026ndash;6). The baseline characteristics of the two groups are presented in \u0026lsquo;Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026rsquo;. The two groups were comparable in terms of age, BMI, previous IVF attempts, AMH levels and indication of infertility (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of baseline characteristics between women undergoing dual vs hCG trigger.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDual Trigger\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ehCG Trigger\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of patients\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e327\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1124\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of cycles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e437\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1762\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41.0 (40.0\u0026ndash;42.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41.0 (40.0\u0026ndash;42.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.0 (21.4\u0026ndash;28.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.0 (21.5\u0026ndash;27.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious IVF attempts\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0\u0026ndash;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0\u0026ndash;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.79\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAMH levels (ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.1 (0.5\u0026ndash;1.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.9 (0.6\u0026ndash;1.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment Indications:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emale factor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 (10.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e242 (13.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTubal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (3.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e77 (4.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnovulatory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (0.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndometriosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (1.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (1.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eovarian insufficiency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e174 (39.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e637 (36.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnexplained\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (9.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e205 (11.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003elesbian/single\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53 (12.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e216 (12.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecombined\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100 (22.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e342 (19.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e\u0026lsquo;Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u0026rsquo; presents the differences in reproductive outcomes between the two groups. The number of metaphase II oocytes showed no statistically significant difference between the two groups with the dual trigger group having a median of 3.0 (range: 1.0\u0026ndash;5.0) and the hCG trigger group also having a median of 3.0 (range:1.0\u0026ndash;5.0), p\u0026thinsp;=\u0026thinsp;0.16. In addition, the cumulative oocyte complex (COC)and feralization rates showed no difference between the two groups (p\u0026thinsp;=\u0026thinsp;0.39). The percentage of embryos that were transferred at the blastocyst stage was significantly greater in the dual trigger group (34.1%) compared to the hCG trigger group (16.5%). The hCG trigger group was associated with significantly higher pregnancy rates (positive hCG rates) (24.7%) compared to the dual trigger stimulation group (18.5%), OR\u0026thinsp;=\u0026thinsp;1.44, 95% CI [1.11, 1.88]. However, the rates of miscarriage, clinical pregnancy and fresh live birth, as well as the total number of frozen embryos (p\u0026thinsp;=\u0026thinsp;0.68), were not different between the groups (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Furthermore, the cumulative live birth rate (cLBR) was similar between the two groups. The cLBR in the dual trigger group was 8.9% (39 out of 378), whereas in the hCG trigger group, it was 13.2% (233 out of 1470).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of primary and secondary outcomes between women undergoing dual vs hCG trigger according to the number of cycles.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eDual Trigger\u003c/span\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003ehCG Trigger\u003c/span\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003ep-value\u003c/span\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal Gonadotropin Dosage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2250 (1990\u0026ndash;2700)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2140 (1800\u0026ndash;2700)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStimulation days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (9\u0026ndash;11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (9\u0026ndash;11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCumulus-Oocyte Complex (COC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (3\u0026ndash;9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (3\u0026ndash;8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of MII oocytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.0 (1.0\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.0 (1.0\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaturation rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e85.7 (66.7\u0026ndash;100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e87.5 (70\u0026ndash;100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFertilization Rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60.0 (40.0\u0026ndash;80.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60.0 (37.5\u0026ndash;77.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmbryo transfer (yes/no)\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e378 (86.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1470 (83.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of Embryos Transferred\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1\u0026ndash;1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (1\u0026ndash;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmbryo Transfer on Day 5/6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e129 (34.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e243 (16.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal number of frozen embryos\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0\u0026ndash;1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0\u0026ndash;1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMiscarriage rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (43.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e197 (45.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive hCG rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e81 (18.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e435 (24.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical Pregnancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (9.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e205 (11.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLive birth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39 (8.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e203 (11.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCumulative Live Birth Rate (cLBR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39 (8.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e233 (13.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e1: Binary variable that denotes if at least one embryo was successfully transferred.\u003c/p\u003e \u003cp\u003e2: Discrete variable that denotes the number of embryos that were transferred.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eInfluence of Oocyte Ratios\u003c/h3\u003e\n\u003cp\u003e\u0026lsquo;Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u0026rsquo; presents the Rate Ratio (RR), expressed as Oocyte Ratios (OoR), from the unadjusted and adjusted mixed-effects Poisson model, between dual and hCG trigger stimulation. The unadjusted model showed no significant difference between the two groups in terms of the Oocyte Ratio, RR\u0026thinsp;=\u0026thinsp;1.08, 95% CI [0.99, 1.18]. After adjusting for all relevant factors\u0026mdash;age, BMI, total gonadotropin, stimulation days, and AMH\u0026mdash;the dual trigger stimulation group was associated with an increased number of MII oocytes compared to hCG trigger, OoR\u0026thinsp;=\u0026thinsp;1.10, 95% CI [1.00\u0026ndash;1.21]. However, the effect was minor.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eEffect of dual trigger therapy and age on number of MII oocytes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRate Ratio\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI lower\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e95% CI upper\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDual trigger (Unadjusted)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDual trigger (Adjusted)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal Gonadotropin Dosage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStimulation days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAMH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eTo the best of our knowledge, this is the largest study evaluating the impact of dual trigger (0.2 mg GnRH agonist\u0026thinsp;+\u0026thinsp;250 mcg hCG) versus hCG trigger (250 mcg hCG alone) on reproductive outcomes in advanced maternal-age women (\u0026ge;\u0026thinsp;40) undergoing IVF. Both groups yielded similar numbers of metaphase II oocytes and maturation/fertilization rates, while most reproductive outcomes included were comparable between the two groups. The cumulative live birth rate was also similar and included both embryos transfer on day 5 and 3. After adjustment for several confounders, patients in the dual trigger group had a statistically significant difference in the number of MII oocytes compared with those in the hCG trigger group, with a 10% increase in MII oocytes; however, the difference was not deemed as clinically relevant.\u003c/p\u003e \u003cp\u003eIn evaluating the efficacy of dual versus hCG trigger protocols in ovarian stimulation for poor responders, several studies have reported similar findings. Eser et al. investigated 109 poor responders and reported no significant difference in the number of metaphase II (MII) oocytes between the dual and hCG trigger groups, as well as no improvement in clinical pregnancy rates [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Nevertheless, the study did not include enough participants to reliably detect differences or effects in these specific outcomes. Similarly, a pilot study by Haas et al., involving 33 poor responders under the Bologna criteria, confirmed that while dual trigger protocols increased the number of top-quality embryos, it did not significantly affect oocyte yield [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Although its results, the study sample was small, limiting the statistical power and the generalizability of the findings. Expanding on this, Keskin et al. examined 225 women of advanced maternal age with low ovarian reserve and reported no significant improvement in the number of MII oocytes with dual triggering compared with the hCG trigger alone, alongside with a lack of significant increase in live birth rates [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Keskin et al. once again included a small sample size leading to the same limitations as Haas et al. and also lacked homogeneity in the number and day of embryos transferred among Poseidon group 3/4 poor responders. In a larger cohort study, Lin et al. evaluated 427 IVF cycles with fresh embryo transfers and similarly did not observe a statistically significant improvement in the number of MII oocytes with dual triggering [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]). Although this study benefits from a larger sample size, they have not measured potential cofounders such as body mass index, or possible of causes infertility like endometriosis, male factors or even ovarian insufficiency. The above studies emphasize that dual triggering does not necessarily translate to improved overall pregnancy outcomes for poor responders, highlighting the need for further studies to better understand the impact of dual trigger protocols on clinical outcomes in advanced maternal-aged women undergoing IVF.\u003c/p\u003e \u003cp\u003eOn the other hand, several studies, such as those by Ben-Haroush et al. and Tulek et al., demonstrated significantly improved oocyte maturation rates, with Tulek et al. also reporting significant gains in the number of metaphase II oocytes, fertilization rates, implantation rates, clinical pregnancy, and live birth rates [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Mutlu et al. and Zhang et al. similarly showed improvements in oocyte retrieval, maturation, and embryo quality, though Zhang et al. found no significant differences in implantation or clinical pregnancy outcomes [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Additionally, Maged et al. reported that dual triggering improved the number of retrieved oocytes and clinical pregnancy rates in poor responders [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Chen et al. and Ren et al. reported higher numbers of metaphase II oocytes, with an improvement in fertilization rate and oocyte count, suggesting that dual trigger protocols may enhance reproductive outcomes, though Ren et al. found no improvement in cumulative live birth rates [27,28]. With a sample size of 136 patients, certain subgroup analyses may lack statistical power [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The lack of randomization and blinding may introduce observer bias, while the limited evidence on long-term outcomes, such as cumulative live birth rates, restricts the ability to draw definitive conclusions about the broader efficacy of the dual trigger in IVF cycles [25,26,29].While these studies collectively suggest that dual trigger protocols offer some advantages, particularly in terms of oocyte maturation and retrieval, the impact on clinical pregnancy and live birth rates remains variable, warranting further investigation.\u003c/p\u003e \u003cp\u003eThe dual trigger protocol in IVF involves the simultaneous use of a GnRH-a and hCG to induce final oocyte maturation. The GnRH-a initially stimulates an endogenous surge of LH and FSH, mimicking the natural LH surge that occurs during ovulation, which is essential for follicular maturation. It also helps prevent premature luteinization by suppressing the pituitary release of gonadotropins. Meanwhile, hCG, which is structurally similar to LH, with a higher half-life, acts on the ovarian follicles to trigger the final maturation of the oocytes, promoting the resumption of meiosis and expansion of the cumulus-oocyte complex. The combination of these two agents works synergistically: GnRH-a ensures that there is no early ovulation, while hCG precisely controls the timing of oocyte maturation. This dual approach improves the synchronization of follicular development, ultimately enhancing the chances of successful IVF outcomes by ensuring the retrieval of fully matured oocytes at the optimal time.(6,26)\u003c/p\u003e \u003cp\u003eThe major strength of our study lies in its large sample size, comprising 1,451 women of advanced maternal age. This makes it one of the most extensive investigations in this challenging-to-recruit infertile population, thereby ensuring robust statistical power and enhancing the reliability of the results. By adjusting for critical variables that significantly influence IVF cycle outcomes, our study provides valuable insights into the clinical application of the dual trigger protocol.\u003c/p\u003e \u003cp\u003eThe limitations of our study include its retrospective design, which may introduce selection bias and limit causal inferences. Additional this study was a single-centre study which might limit the generalizability of the results to other setting or populations with different characteristics or treatment protocols. Reliance on medical records can lead to measurement bias, and the nonrandomized nature of the study introduces potential selection bias, where clinical judgement may have influenced patient allocation. Despite statistical adjustments, unmeasured confounding variables may still impact the outcomes.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eOur study provides valuable insights into the comparative effectiveness of dual trigger and hCG trigger protocols in assisted reproductive technology for women over 40 years of age. Even though there was a marginal significance of 10% increase in metaphase II oocytes after adjustment for confounders, this increase did not translate into a significant clinical impact. Furthermore, the cumulative LBR remains similar, highlighting the lack of impact on embryo quality. Further prospective, randomized controlled trials are essential to confirm these results and refine treatment protocols to enhance clinical outcomes for poor ovarian responders.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAFC - Antral Follicle Count\u003c/p\u003e\n\u003cp\u003eAMH\u0026nbsp;- Anti-M\u0026uuml;llerian Hormone\u003c/p\u003e\n\u003cp\u003ecLBR\u0026nbsp;- Cumulative Live Birth Rate\u003c/p\u003e\n\u003cp\u003eESHRE\u0026nbsp;- European Society of Human Reproduction and Embryology\u003c/p\u003e\n\u003cp\u003eFSH\u0026nbsp;- Follicle-Stimulating Hormone\u003c/p\u003e\n\u003cp\u003eGnRH\u0026nbsp;- Gonadotropin-Releasing Hormone\u003c/p\u003e\n\u003cp\u003eGTOC \u0026ndash; Granulosa \u0026ndash; Theca Oocyte Complex\u003c/p\u003e\n\u003cp\u003ehCG\u0026nbsp;- Human Chorionic Gonadotropin\u003c/p\u003e\n\u003cp\u003ehMG\u0026nbsp;- Human Menopausal Gonadotropin\u003c/p\u003e\n\u003cp\u003eICSI\u0026nbsp;- Intracytoplasmic Sperm Injection\u003c/p\u003e\n\u003cp\u003eIVF\u0026nbsp;- In Vitro Fertilization\u003c/p\u003e\n\u003cp\u003eLH\u0026nbsp;- Luteinizing Hormone\u003c/p\u003e\n\u003cp\u003eMII\u0026nbsp;- Metaphase II\u003c/p\u003e\n\u003cp\u003eOHSS\u0026nbsp;- Ovarian Hyperstimulation Syndrome\u003c/p\u003e\n\u003cp\u003eOoR\u0026nbsp;- Oocyte Ratio\u003c/p\u003e\n\u003cp\u003ePGT-A \u0026ndash; Preimplantation Genetic Screening for Chromosomes\u003c/p\u003e\n\u003cp\u003ePOR\u0026nbsp;- Poor Ovarian Response\u003c/p\u003e\n\u003cp\u003erFSH\u0026nbsp;- Recombinant Follicle-Stimulating Hormone\u003c/p\u003e\n\u003cp\u003eRR\u0026nbsp;- Rate Ratio\u003c/p\u003e\n\u003cp\u003eSC \u0026ndash; Subcutaneous\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eETHICS APPROVAL AND CONSENT TO PARTICIPATE\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the local ethical committee (Approval 17/07/2024).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCONSENT FOR PUBLICATION\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAVAILABILITY OF DATA AND MATERIALS\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCOMPETING INTEREST\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFUNDING\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003eAUTHOR\u0026rsquo;S CONTRIBUTION\u003c/p\u003e\n\u003cp\u003eSSC and PD contributed to the study design. SSC wrote the original manuscript. TL was responsible for analysing the results. SSC , AC, \u0026nbsp;NC, \u0026nbsp; AP and PD were responsive for revising the manuscript. PD was responsible for supervising the operation of the project. All authors read and approved the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eACKNOWLEDGEMENTS\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFerraretti AP, La Marca A, Fauser BCJM, Tarlatzis B, Nargund G, Gianaroli L. ESHRE consensus on the definition of \u0026ldquo;poor response\u0026rdquo; to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod [Internet]. 2011 [cited 2024 May 21];26(7):1616\u0026ndash;24. Available from: https://pubmed.ncbi.nlm.nih.gov/21505041/\u003c/li\u003e\n\u003cli\u003eEsteves SC, Roque M, Bedoschi GM, Conforti A, Humaidan P, Alviggi C. Defining low prognosis patients undergoing assisted reproductive technology: POSEIDON criteria-the why. Front Endocrinol (Lausanne) [Internet]. 2018 Aug 17 [cited 2024 May 21];9(AUG):390745. Available from: https://www.sealedenvelope.\u003c/li\u003e\n\u003cli\u003eBusnelli A, Somigliana E. Prognosis and cost-effectiveness of IVF in poor responders according to the Bologna Criteria. Minerva Ginecol [Internet]. 2018 Feb 1 [cited 2024 Jul 13];70(1):89\u0026ndash;98. Available from: https://pubmed.ncbi.nlm.nih.gov/28895678/\u003c/li\u003e\n\u003cli\u003ePapathanasiou A. Implementing the ESHRE \u0026ldquo;poor responder\u0026rdquo; criteria in research studies: methodological implications. Hum Reprod [Internet]. 2014 [cited 2024 May 21];29(9):1835\u0026ndash;8. Available from: https://pubmed.ncbi.nlm.nih.gov/24916434/\u003c/li\u003e\n\u003cli\u003eRomito A, Bardhi E, Errazuriz J, Blockeel C, Santos-Ribeiro S, Vos M De, et al. Heterogeneity Among Poor Ovarian Responders According to Bologna Criteria Results in Diverging Cumulative Live Birth Rates. Front Endocrinol (Lausanne) [Internet]. 2020 Apr 16 [cited 2024 May 21];11:208. Available from: /pmc/articles/PMC7179754/\u003c/li\u003e\n\u003cli\u003eJuan Carlos Castilloa, Joaquin Moreno, Miguel Dolz, Fernando Bonilla-Musoles. Successful Pregnancy Following Dual Triggering Concept (rhCG + GnRH Agonist) in a Patient Showing Repetitive Inmature Oocytes and Empty Follicle Syndrome: Case Report. J Med Cases. 2013; \u003c/li\u003e\n\u003cli\u003eChoi J, Smitz J. Luteinizing hormone and human chorionic gonadotropin: a review of their varied clinical applications in assisted reproductive technology. Expert Rev Endocrinol Metab [Internet]. 2015 Jan 1 [cited 2024 Nov 24];10(1):87\u0026ndash;100. Available from: https://pubmed.ncbi.nlm.nih.gov/30289044/\u003c/li\u003e\n\u003cli\u003eTay CCK. Use of gonadotrophin-releasing hormone agonists to trigger ovulation. Hum Fertil (Camb) [Internet]. 2002 [cited 2024 Nov 24];5(1). Available from: https://pubmed.ncbi.nlm.nih.gov/11939159/\u003c/li\u003e\n\u003cli\u003eAlbeitawi S, Marar EA, Reshoud F Al, Hamadneh J, Hamza R, Alhasan G, et al. Dual trigger with gonadotropin-releasing hormone agonist and human chorionic gonadotropin significantly improves oocyte yield in normal responders on GnRH-antagonist cycles. JBRA Assist Reprod [Internet]. 2022 [cited 2024 Jul 3];26(1):28\u0026ndash;32. Available from: https://pubmed.ncbi.nlm.nih.gov/34463444/\u003c/li\u003e\n\u003cli\u003eGao F, Wang Y, Fu M, Zhang Q, Ren Y, Shen H, et al. Effect of a \u0026ldquo;Dual Trigger\u0026rdquo; Using a GnRH Agonist and hCG on the Cumulative Live-Birth Rate for Normal Responders in GnRH-Antagonist Cycles. Front Med (Lausanne) [Internet]. 2021 May 25 [cited 2024 Jul 3];8. 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Available from: https://pubmed.ncbi.nlm.nih.gov/28760517/\u003c/li\u003e\n\u003cli\u003eR: The R Project for Statistical Computing [Internet]. [cited 2024 Jun 22]. Available from: https://www.r-project.org/\u003c/li\u003e\n\u003cli\u003eEser A, Devranoğlu B, Bostancı Ergen E, Yayla Abide \u0026Ccedil;. Dual trigger with gonadotropin-releasing hormone and human chorionic gonadotropin for poor responders. Journal of the Turkish-German Gynecological Association. 2018 Jun 4;19(2):98\u0026ndash;103. \u003c/li\u003e\n\u003cli\u003eKeskin M, Ecemiş T, Atik A, Yeğen P, Kalkan E, Y\u0026uuml;cel GS. Cycle outcomes of dual trigger (GnRH agonist+hCG) versus human chorionic gonadotropin trigger alone in POSEDION group 3-4 poor-responders and normo-responders: A prospective randomized study. J Gynecol Obstet Hum Reprod [Internet]. 2023 Oct 1 [cited 2024 Oct 26];52(8). Available from: https://pubmed.ncbi.nlm.nih.gov/37487959/\u003c/li\u003e\n\u003cli\u003eLin MH, Wu FSY, Hwu YM, Lee RKK, Li RS, Li SH. Dual trigger with gonadotropin releasing hormone agonist and human chorionic gonadotropin significantly improves live birth rate for women with diminished ovarian reserve. Reprod Biol Endocrinol [Internet]. 2019 Jan 4 [cited 2024 Oct 26];17(1). Available from: https://pubmed.ncbi.nlm.nih.gov/30609935/\u003c/li\u003e\n\u003cli\u003eBen-Haroush A, Sapir O, Salman L, Altman E, Garor R, Margalit T, et al. Does \u0026ldquo;Dual Trigger\u0026rdquo; Increase Oocyte Maturation Rate? J Obstet Gynaecol [Internet]. 2020 Aug 17 [cited 2024 Oct 26];40(6):860\u0026ndash;2. Available from: https://pubmed.ncbi.nlm.nih.gov/31790320/\u003c/li\u003e\n\u003cli\u003eTulek F, Kahraman A, Demirel LC. Dual trigger with gonadotropin releasing hormone agonist and human chorionic gonadotropin improves live birth rates in POSEIDON group 3 and 4 expected poor responders. Gynecol Endocrinol [Internet]. 2022 [cited 2024 Oct 26];38(9):731\u0026ndash;5. Available from: https://pubmed.ncbi.nlm.nih.gov/35856433/\u003c/li\u003e\n\u003cli\u003eMutlu I, Demirdag E, Cevher F, Erdem A, Erdem M. Dual trigger with the combination of gonadotropin-releasing hormone agonist and standard dose of human chorionic gonadotropin improves in vitro fertilisation outcomes in poor ovarian responders. J Obstet Gynaecol [Internet]. 2022 [cited 2024 Oct 26];42(5):1239\u0026ndash;44. Available from: https://pubmed.ncbi.nlm.nih.gov/34565274/\u003c/li\u003e\n\u003cli\u003eZhang J, Wang Y, Mao X, Chen Q, Hong Q, Cai R, et al. Dual trigger of final oocyte maturation in poor ovarian responders undergoing IVF/ICSI cycles. Reprod Biomed Online [Internet]. 2017 Dec 1 [cited 2024 Oct 26];35(6):701\u0026ndash;7. Available from: https://pubmed.ncbi.nlm.nih.gov/28993105/\u003c/li\u003e\n\u003cli\u003eMaged AM, Ragab MA, Shohayeb A, Saber W, Ekladious S, Hussein EA, et al. Comparative study between single versus dual trigger for poor responders in GnRH-antagonist ICSI cycles: A randomized controlled study. International Journal of Gynecology and Obstetrics. 2021 Mar 1;152(3):395\u0026ndash;400. \u003c/li\u003e\n\u003cli\u003eChen K, Zhang C, Chen L, Zhao Y, Li H. Reproductive outcomes of dual trigger therapy with GnRH agonist and hCG versus hCG trigger in women with diminished ovarian reserve: a retrospective study. Reprod Biol Endocrinol [Internet]. 2024 Dec 1 [cited 2024 Oct 26];22(1). Available from: https://pubmed.ncbi.nlm.nih.gov/38566172/\u003c/li\u003e\n\u003cli\u003eRen Y meng, Wang Y bin, Fu M, Zhang Q xiang, Shen H, Han H jing, et al. Effect of Dual Trigger In Vitro Fertilization and Intracytoplasmic Sperm Injection During the Gonadotropin-releasing Hormone-Antagonist Cycle on Final Oocyte Maturation and Cumulative Live Birth Rate in Women with Diminished Ovarian Reserve. Curr Med Sci [Internet]. 2022 Oct 1 [cited 2024 Oct 26];42(5):1066\u0026ndash;70. Available from: https://pubmed.ncbi.nlm.nih.gov/35997911/\u003c/li\u003e\n\u003cli\u003eRen Y meng, Wang Y bin, Fu M, Zhang Q xiang, Shen H, Han H jing, et al. Effect of Dual Trigger In Vitro Fertilization and Intracytoplasmic Sperm Injection During the Gonadotropin-releasing Hormone-Antagonist Cycle on Final Oocyte Maturation and Cumulative Live Birth Rate in Women with Diminished Ovarian Reserve. Curr Med Sci [Internet]. 2022 Oct 1 [cited 2024 Oct 26];42(5):1066\u0026ndash;70. Available from: https://pubmed.ncbi.nlm.nih.gov/35997911/\u003c/li\u003e\n\u003cli\u003eDong L, Lian F, Wu H, Xiang S, Li Y, Wei C, et al. Reproductive outcomes of dual trigger with combination GnRH agonist and hCG versus trigger with hCG alone in women undergoing IVF/ICSI cycles: a retrospective cohort study with propensity score matching. BMC Pregnancy Childbirth [Internet]. 2022 Dec 1 [cited 2024 Nov 13];22(1):1\u0026ndash;10. Available from: https://bmcpregnancychildbirth.biomedcentral.com/articles/10.1186/s12884-022-04899-2\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"European University of Cyprus, School of Medicine, Nicosia, Cyprus","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Dual trigger protocol, Metaphase II (MII) oocytes, Poor ovarian response (POR), Reproductive outcomes, Bologna criteria","lastPublishedDoi":"10.21203/rs.3.rs-6115929/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6115929/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePoor ovarian response (POR) in women aged 40 and above presents significant challenges in in vitro fertilization (IVF). This study evaluated whether dual trigger strategy, involving a combination of gonadotropin-releasing hormone (GnRH) agonists and human chorionic gonadotropin (hCG), improves IVF outcomes compared to human chorionic gonadotropin (hCG) alone in women of advanced maternal age.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA retrospective cohort study was conducted, analysing 2,199 IVF cycles from 1,451 women between January 2018 and June 2022. Among these cycles, 327 cycles utilized a dual trigger strategy while 1,124 had an hCG trigger. Key outcomes assessed included the number of metaphase II (MII) oocytes, fertilization rates, fresh embryo transfers on days 5/6, and pregnancy outcomes. Multivariate regression was employed to adjust for variables such as age, BMI, gonadotropin dosage, stimulation duration, and anti-M\u0026uuml;llerian hormone levels.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe dual trigger group showed significantly higher rates of embryo transfer on days 5/6 (34.1% vs. 16.5%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). While there were no significant differences in the number of MII oocytes or fertilization rates (p\u0026thinsp;=\u0026thinsp;0.16), adjusted analysis indicated a modest increase in MII oocytes (RR\u0026thinsp;=\u0026thinsp;1.1, 95% CI 1.00\u0026ndash;1.21). Positive hCG rates were lower in the dual trigger group (18.5% vs. 24.7%, p\u0026thinsp;=\u0026thinsp;0.007), and cumulative live birth rates were not significantly different (8.9% vs. 13.2%, p\u0026thinsp;=\u0026thinsp;0.009).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eDual trigger protocols may enhance certain ovarian response parameters but do not significantly improve pregnancy or live birth rates in older women with diminished ovarian reserve. Future studies are necessary to optimize and personalize treatment strategies for this challenging patient population.\u003c/p\u003e\u003ch2\u003eTrial Registration:\u003c/h2\u003e \u003cp\u003e Approved by the local ethical committee (Approval 17/07/2024).\u003c/p\u003e","manuscriptTitle":"The Impact Of Dual Trigger Stimulation Upon Reproductive Outcomes In Woman Of Advanced Maternal Age – A Large Retrospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-28 06:58:34","doi":"10.21203/rs.3.rs-6115929/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ab2acb04-9ec1-4857-abdb-c60a9a32d866","owner":[],"postedDate":"February 28th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":44994487,"name":"Sexual \u0026 Reproductive Medicine"},{"id":44994488,"name":"Obstetrics \u0026 Gynecology"}],"tags":[],"updatedAt":"2025-02-28T06:58:34+00:00","versionOfRecord":[],"versionCreatedAt":"2025-02-28 06:58:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6115929","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6115929","identity":"rs-6115929","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}