Poor Responders Research Articles

P-661 Comparative and descriptive molecular analysis of cumulus and luteinized mural granulosa cells for steroidogenic function in IVF patients

Abstract Study question Do cumulus granulosa cells (CCs) have steroidogenic function and gonadotropin response like luteinized mural granulosa cells (LMGCs)? Summary answer Yes. Both types of granulosa cells have similar expression levels for the steroidogenic enzymes and hCG/LH receptors. What is known already CCs and LMGCs have distinct roles in follicular development, oocyte growth and maturation, cumulus expansion, ovulation, and luteinization. CCs support oocytes, especially during meiotic resumption, ovulation, and fertilization. They exhibit specialized functions in response to hormones like LH and participate in bidirectional communication with the oocyte. Although LMGCs are primarily responsible for steroidogenic function and progesterone (P4) production, very limited data is available as to whether CC themselves express the steroidogenic enzymes and gonadotropin receptors and produce sex steroids at basal or after gonadotropin stimulation in humans. We aimed to address this issue in the current study. Study design, size, duration An in-vitro basic science study was designed to compare CCs and LGMCs in the context of vitality, steroidogenic capabilities (both in baseline and response to rec-hCG (10 IU/ml), and EGF pathway responses. The assessment was planned to compare hormonal assay in spent culture and transcriptional levels. The study’s duration encompassed the period of ovarian stimulation, oocyte retrieval, and subsequent cellular analysis. Participants/materials, setting, methods 24 IVF patients undergoing ovarian stimulation with progestin primed (PPOS) and GnRH antagonist protocols for different infertility etiologies were included. Ovarian stimulation and ovulation trigger were done using rec-FSH and rec-hCG, respectively. CCs were collected from the denudation plate. LMGCs were obtained from follicular aspirates during the OPU and cultured individually for each patient without pooling in culture plates. After overnight incubation, the cells were treated with rec-hCG overnight. RNA isolation was performed. Main results and the role of chance The expression of the steroidogenic enzymes (StAR, SCC, 17B-HSD, 3B-HSD, Aromatase), LH receptor and EGF-like amphiregulin (AREG) in CCs were comparable to LMGCs on quantitative RT-PCR analysis. In line with this finding, we found they produced similar amounts of estradiol (E2) and progesterone (P4) in culture. Furthermore, similar to LMGCs, hCG treatment of the CCs resulted in a significant increase in P4 output, indicative of the presence of functional LH receptors. When the culture period was extended to six days, CCs retained their vitality and steroidogenic function like LMGCs and produced detectable E2 and P4. Limitations, reasons for caution Caution should be exercised when interpreting our data as it is unclear if the parameters analyzed here vary according to the infertility etiology, stimulation protocol, mode of trigger and any underlying disease that concomitantly present. Wider implications of the findings Prominent steroidogenic activity of CCs might have other important implications for a successful pregnancy. Moreover, similar expression profiles of steroidogenic pathways and hCG/LH receptors between CCs and LMGCs indicate that CCs can also be used to understand better the luteal function and intricate crosstalk between in oocyte microenvironment. Trial registration number N/A

P-605 Effectiveness of follitropin delta in patients with potential poor response: A post hoc analysis from the ESTHER-1 trial

Abstract Study question What is the effectiveness of individualised follitropin delta dosing compared to conventional follitropin alfa dosing in patients with potential poor response undergoing ovarian stimulation? Summary answer Individualised follitropin delta dosing provides a favourable efficacy and safety balance and is as good as follitropin alfa in patients with potential poor ovarian response. What is known already Poor ovarian response to controlled ovarian stimulation constitutes a challenge in in-vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) treatment. The dosing algorithm of follitropin delta incorporates the prediction of ovarian response based on anti-Müllerian hormone (AMH), an accurate marker of ovarian reserve, and body weight, for an individualised dosing. In the general IVF/ICSI population and potential high responders, individualised follitropin delta reduces the risk of ovarian hyperstimulation syndrome (OHSS) and/or preventive interventions for OHSS, with sustained efficacy compared to conventional follitropin alfa. However, the performance of follitropin delta in the subpopulation of patients with potential poor response has not been evaluated. Study design, size, duration Post hoc analysis of 332 patients with potential poor response from the ESTHER-1 trial (determined by AMH level at screening <9 pmol/L). Patients received the maximum daily dose of 12 µg follitropin delta (fixed dosing throughout stimulation) as stipulated by the dosing algorithm for patients with AMH <15 pmol/l, or follitropin alfa at a starting dose of 150 IU, with potential dose adjustments from stimulation day 6 and onwards (maximum daily dose of 450 IU). Participants/materials, setting, methods Participants were women, 18–40 years, undergoing their first IVF/ICSI cycle in a GnRH antagonist protocol, including triggering with human chorionic gonadotrophin, IVF/ICSI insemination, and single or double blastocyst transfer on Day 5. Ultrasound was performed 10–11 weeks after transfer to confirm ongoing pregnancy. All pregnancies were followed until birth. Study outcomes include number of oocytes retrieved and number of good quality blastocysts, ongoing pregnancy and live birth rates, cycle cancellation and OHSS rates. Main results and the role of chance A total of 332 patients (25.0% of the overall ESTHER-1 population) had serum AMH at screening of < 9 pmol/l and were included in the analysis: 168 were treated with follitropin delta and 164 were treated with follitropin alfa. Baseline characteristics were similar between the treatment groups, with a mean age of 34.8 years, a median AMH of 5.7 pmol/l and a mean weight of 64.5 kg. With follitropin delta, the mean daily dose was 12.0 µg and with follitropin alfa 12.4 µg, resulting in mean total doses of 104.6 µg and 112.3 µg, respectively. The mean number of oocytes retrieved was 5.8 ± 3.5 with follitropin delta and 5.5 ± 3.6 with follitropin alfa and the mean number of good-quality blastocysts was 1.2 ± 1.4 with both treatments. The ongoing pregnancy rate was 29.8% with follitropin delta and 29.3% with follitropin alfa and the live birth rates were 29.2% and 28.7%, respectively. Thirteen patients (7.7%) treated with follitropin delta and 14 (8.5%) treated with follitropin alfa had their cycles cancelled due to poor response. One case of OHSS (0.6%) was observed in the follitropin delta group, and 3 cases (1.8%) were observed in the follitropin alfa group. Limitations, reasons for caution The main limitation of the study is its post hoc nature. Furthermore, the study is based on a relatively small number of patients. Wider implications of the findings This subgroup analysis, alongside the normoresponder and the potential hyperresponder subgroup of the ESTHER-1 trial, adds evidence for the effectiveness of follitropin delta across all ovarian reserve subgroups of the infertile population. Trial registration number NCT01956110

P-594 Retrospective comparative study of follitropin delta vs follitropin alfa in progestin-primed ovarian stimulation (PPOS) protocol in IVF

Abstract Study question Could the individualized fixed-dose algorithm with follitropin delta show a similar pregnancy rate to conventional dosing with follitropin alfa in PPOS protocol? Summary answer Individualized fixed-dose algorithm with follitropin delta showed a similar pregnancy rate to follitropin alfa In PPOS protocol. What is known already Follitropin delta (REKOVELLE, Ferring Pharmaceuticals, Switzerland) is the first human cell line driven recombinant follicle-stimulating hormone (FSH) with an individualized fixed-dose algorithm based on serum AMH level and body weight. Follitropin alfa is a Chinese hamster ovarian cell driven recombinant FSH and its dosing is adjusted according to follicular response during the stimulation period. There was no significant difference between follitropin delta and follitropin alfa in terms of pregnancy rate under GnRH antagonist protocol. Study design, size, duration A retrospective analysis of 355 patients aged under 40 years who underwent ovarian stimulation in PPOS protocol using follitropin delta or follitropin alfa and on whom frozen-thawed single blastocyst transfer was conducted between August 2021 and November 2023 was performed. Participants/materials, setting, methods 193 cycles of women who used follitropin delta were compared to 162 cycles of women who used follitropin alfa. The following clinical outcomes on each treatment group were analyzed: chemical pregnancy rate (serum β hCG), clinical pregnancy rate (gestational sac), ongoing pregnancy rate(gestational sac and fetal heartbeat), serum E2 level at trigger day, cycle proportion of ≥ 10 oocytes retrieval, blastocyst formation rate, cycle proportion of ≥ 5 blastocysts and cycle proportion of ≥ 2 good quality blastocysts. Main results and the role of chance Baseline demographics in the follitropin delta group and the follitropin alfa group were not significantly different: age, 33.9 ± 3.5 years vs 34.5 ± 3.2 years; body weight, 53.5 ± 8.3 kg vs 53.8 ± 5.9 kg; number of previous IVF cycles, 0.2 ± 0.6 vs 0.3 ± 0.7; serum AMH level, 5.5 ± 2.9 ng/mL vs 5.3 ± 3.8 ng/mL, respectively. The chemical pregnancy rate (69.9% vs. 64.8%, P = 0.308), clinical pregnancy rate (58.0% vs. 56.2%, P = 0.748) and ongoing pregnancy rate (51.8% vs. 46.3%, P = 0.338) were comparable between the follitropin delta group and the follitropin alfa group. The individualized follitropin delta treatment resulted in a smaller cycle proportion of ≥ 10 oocytes retrieval (77.7% vs. 90.8%, P < 0.001) with lower serum E2 level at trigger day (3273 ± 1577 pg/mL vs. 3927 ± 1732 pg/mL, p < 0.001). However, the blastocyst formation rate was significantly higher in the follitropin delta group (75.5% vs. 68.7%, p < 0.001). Moreover, the cycle proportion of ≥ 5 blastocysts (71.0% vs. 76.4%, P = 0.286) and the cycle proportion of ≥ 2 good quality blastocysts (51.8% vs. 60.3%, P = 0.115) were comparable between the groups. Limitations, reasons for caution This is a non-controlled, retrospective study. Wider implications of the findings Follitropin delta in its individualized fixed-dose regimen could have the potential to decrease the risk of OHSS by minimizing excessive ovarian response, whereas a similar pregnancy rate to conventional dosing regimen could be expected due to the number of good quality blastocysts secured. Trial registration number not applicable

O-009 Comparison of the flexible Progestin-Primed Ovarian Stimulation with the GnRH antagonist protocol in predicted suboptimal responders: a freeze-all randomized controlled trial

Abstract Study question Is the Flexible Progestin-Primed Ovarian Stimulation (fPPOS) non-inferior to GnRH antagonist regarding fertility outcomes in women with a suboptimal response scheduled for freeze-all cycles? Summary answer In predicted suboptimal responders, who do not contemplate a fresh embryo transfer, the ongoing pregnancy outcomes of fPPOS was comparable to that of GnRH-antagonist protocol. What is known already Recent retrospective cohort studies involving donor cycles have demonstrated that Medroxyprogesterone Acetate (MPA) can be effectively and flexibly employed during the mid-follicular phase of the PPOS protocol. This approach prevents premature ovulation without compromising oocyte yields. Given its lesser degree of pituitary suppression, the fPPOS protocol may be particularly relevant for women predicted to have a suboptimal response (defined as AFC < 10) where accumulation of more oocytes could enhance cumulative success rates. Study design, size, duration This is a open-label RCT, performed in a single IVF centre Between July 2019 and June 2023. A total of 484 women scheduled for freeze-all strategy were randomly assigned to fPPOS or GnRH-antagonist protocol. The primary outcome was live birth per woman starting stimulation following18 months of randomization. In this abstract, we present fertility outcomes following the initial frozen embryo transfer (FET) and ongoing pregnancy rates per women within a period of 6 months. Participants/materials, setting, methods Women (AFC<10) referred for IVF/ICSI and did not intend to undergo a fresh transfer, were recruited for this study. MPA (10 mg/day) and Cetrotide (0.25 mg/day) were initiated either when the leading follicle reached 14 mm or on the sixth day of stimulation, whichever occurred first. Due to the COVID-19 pandemic, 22 women withdrew from the study at the stimulation commencement, resulting in 462 women included in the analysis. Data underwent intention-to-treat and per-protocol analyses. Main results and the role of chance No significant difference was observed between the two groups in terms of serum endocrine profiles and stimulation parameters, including the consumption of gonadotropins. Within the 6-month period, 79.5% of women in the fPPOS group and 84.02% in the GnRH antagonist group had undergone at least one cycle of FET (P = 0.234).The ongoing pregnancy rates per women were 48.20% (107/222) in the fPPOS group versus 52.92% (127/240) in the GnRH-anta group (RR: 0.91, 95%CI, 0.76 to 1.09, P = 0.311). There are 62 women who are ongoing pregnancy but do not reached live birth during the follow-up period. Regarding the outcomes of the initial FET cycle, there was no difference in the ongoing pregnancy rate between the two groups (49.01% vs 48.37%, RR: 1.03, 95% CI, 0.81 to 1.26, P = 0.908). Other outcomes including biochemical pregnancy rate (62.25% vs 63.59%), clinical pregnancy rate (60.26% vs 57.61%), and miscarriage rate per pregnancy (16.48% vs 15.09%), also exhibited no significant differences. The number of oocytes retrieved, two-pronuclear oocytes, viable and high-quality embryos, as well as the total number of embryos cryopreserved were also similar between groups. There was one case of premature ovulation in the fPPOS group and none in the GnRH-ant group. Limitations, reasons for caution Due to the distinct administration routes of the medications, blinding was not feasible in this open-label trial, which may affect the assessment of outcomes. All participants were recruited in a single center from one country, limiting the generalizability. In this abstract, we only report on the ongoing pregnancy outcomes. Wider implications of the findings This is the first freeze-all RCT comparing the long-term outcomes of fPPOS and GnRH antagonist in autologous ovarian stimulation cycles. Eliminating the variability of fresh and frozen transfers, the fPPOS seems an efficacious alternative for women with predicted suboptimal response, when a GnRH antagonist would have been the preferred regimen. Trial registration number ChiCTR2000030356

P-242 ICSI, the sooner, the better

Abstract Study question What is the impact of different ICSI timing on the efficiency of egg reception cycles concerning both denudation and trigger events? Summary answer The interval between denudation and ICSI significantly compromises cycle efficiency, particularly blastocyst quality. Delayed ICSI impairs this impact relative to the trigger event. What is known already The established consensus on the optimal ICSI timeframe, spanning 2-6 hours post-oocyte retrieval, has been extensively documented. However, the acknowledged variability within this window has prompted a critical review. Recent studies highlight the need for a more nuanced understanding, suggesting that phenomena affecting ICSI outcomes can be better elucidated by adopting stable models such as oocyte reception cycles. By removing the oocyte factor, these models offer a more precise perspective, addressing the temporal intricacies integral to successful ICSI procedures. The present research underscores the imperative of refining the temporal dimension for optimal reproductive results. Study design, size, duration This retrospective study encompassed 1,275 egg reception ICSI-cycles conducted between January 2019 and July 2023. Donors underwent stimulation using a short antagonist protocol, and oocytes were collected 35.5h post-trigger. The impact of both, the time between denudation-ICSI (D-ICSI time) and the time between trigger-ICSI (T-ICSI time) on reproductive outcomes were analysed. Six comparable groups were established by 30-minute intervals, segmenting the sample based on D-ICSI time (0.5h to 3h) and T-ICSI time (38h to 40.5h). Participants/materials, setting, methods A total of 1,275 cycles, involving 11,333 MII-oocytes, were stratified based on D-ICSI time (0.5h:89-cycles/761-MII; 1h:128/1,186; 1.5h:269/2,385; 2h:270/2,415; 2.5h:340/3,064; 3h:179/1,522) and T-ICSI time (38h:183/1,631; 38.5h:131/1,158; 39h:246/2,205; 39.5h:219/1,952; 40h:173/1,534; 40.5h:323/2,853). Comparative analyses were conducted for fertilization, abnormal fertilization, ICSI degeneration, and useful day 5/6 blastocyst outcomes (transferred or cryopreserved; >3BB-top and ≤3BB-good quality by Gardner score), as well as pregnancy and live birth rates (1,594 SET). Statistical methods employed included ANOVA, Chi-square tests, and Pearson’s correlation. Main results and the role of chance Several parameters showed stability across different time intervals of D-ICSI time: fertilization (0.5h:74.6%; 1h:72.6%; 1.5h:74.0%; 2h:75.9%; 2.5h:74.8%; 3h:74.4%; r = 0.3707; p = 0.469), blastocyst (0.5h:65.3%; 1h:62.6%; 1.5h:61.7%; 2h:60.1%; 2.5h:64.8%; 3h:63.8%; r= -0.068; p = 0.898), and live birth rates (0.5h:39.5%; 1h:35.9%; 1.5h:36.6%; 2h:40.2%; 2.5h:39.9%; 3h:39.7%; r = 0.474; p = 0.342). However, an extended interval significantly correlated with increased oocyte ICSI-degeneration (0.5h:5.5%; 1h:6.7%; 1.5h:6.7%; 2h:6.5%; 2.5h:7.4%; 3h:8.5%; r = 0.903; p < 0.05) and a decreased proportion of top-quality blastocysts (0.5h:86.8%; 1h:89.2%; 1.5h:86.4; 2h:85.3%; 2.5h:81.2%; 3h:75.2%; r= -0.879; p < 0.05). Extended culture of cumulus cell-free oocytes may promote oocyte aging and, consequently, compromise optimal development (consistent with findings in other studies). In evaluating T-ICSI time, similar trends to those observed in D-ICSI time persist in fertilization (r = 0.275, p = 0.598), blastocyst (r = 0.233, p = 0.657), live birth (r = 0.516, p = 0.295), and ICSI-degeneration rates (r = 0.864, p < 0.05). The negative correlation in the quality of generated useful blastocysts significantly intensifies (38h:90.6%; 38.5h:87.5%; 39h:84.7%; 39.5h:82.4%; 40h:80.1%; 40.5h:79.7%; r= -0.982, p < 0.05). In a separate analysis, we observed that undetected in vitro matured oocytes, stemming from delayed denudations, lead to a reduction in the top-quality blastocyst ratio. This concept, along with D-ICSI time, seems to synergize, emphasizing the adverse trend when evaluating blastocyst qualities concerning T-ICSI times. Limitations, reasons for caution This study has inherent limitations as a retrospective analysis. Additionally, the potential effects of ICSI earlier than 0.5 hours post denudation and 38 hours post-trigger, not yet standardized in the laboratory, were not assessed. Wider implications of the findings Extended incubation of denuded and non-injected oocytes fosters oocyte aging. Consequently, cycle efficiency is compromised with prolonged incubation times. The reduction of these times holds promise for improving the efficiency of IVF treatments. Additionally, shortening or eliminating incubation periods would enhance the automated sequence of diverse processes during an IVF. Trial registration number not applicable

P-663 Comparing clinical outcomes in PGT-A cycles using donated oocytes between progesterone and GnRH-antagonist protocols

Abstract Study question Does Progesterone Primed Ovarian Stimulation (PPOS) demonstrate comparable efficiency to the GnRH-antagonist protocol in terms of laboratory/reproductive outcomes in PGT-A cycles with donated oocytes? Summary answer PPOS demonstrates efficiency in PGT-A cycles with donated oocytes, comparable to the GnRH-antagonist protocol, providing cost-effectiveness and enhanced donor comfort. What is known already The demand for TRA cycles with donated oocytes steadily rises each year. This treatment instills high hopes for success. Ongoing advancements in donor stimulation protocols prioritize safety and comfort. The shift from LH agonist to antagonist suppresses LH peaks, and recently, PPOS has joined, offering a more comfortable, cost-effective, and equally safe alternative with fewer ultrasound checks, mitigating ovarian hyperstimulation syndrome. Study design, size, duration Retrospective assessment of an oocyte donor cohort undergoing ovarian stimulation: 182 cycles with the GnRH-antagonist protocol (Group 1: G1) and 120 with PPOS (Group 2: G2), conducted between July 2017 and June 2023. Ovarian stimulation involved 225 IU/d of FSHr or FSHu, triggering with a GnRH agonist, and subsequent biopsy of evolutionarily robust embryos after extended culture. Both fresh and vitrified oocytes, inseminated with either self or donor sperm, were included. Participants/materials, setting, methods We analyzed 1188 embryos (G1: 676; G2: 512). Trophoectoderm biopsies from D5/D6 blastocysts underwent NGS using the Illumina platform (VeriSeq Illumina®, San Diego, CA, USA). Comparison included total and MII oocyte numbers, fertilization rates, viable embryos, euploid/aneuploid embryos, mosaic embryos, and clinical outcomes: biochemical pregnancy (BPR), biochemical pregnancy loss (BPLR), clinical pregnancy (CPR), early pregnancy loss (EPLR), ongoing pregnancy (OPR), and live birth (LBR) rates. Statistical analyses were carried out using R statistical software (v.4.3.1). Main results and the role of chance The mean ages of donors (25.57±4.05) and recipients (41.82±4.06) were comparable in both groups. The male partner’s age differed (G1: 40.47±7.87; G2: 42.34±7.65) (p = 0.019). Results were adjusted for confounding factors, including recipient and donor ages, oocyte and seminal origin, and male factor variables. Ovarian stimulation duration (9.26 days), total gonadotropin dose (2015.64 IU), and oocyte origin (fresh G1: 69.8 %; G2: 62.5 %; vitrified G1: 30.2 %; G2: 37.5 %) showed equivalence. Statistical significance emerged in total oocytes retrieved (G1: 17.92±7.64; G2: 20.23±7.89) (p = 0.008), mean microinjected MII (G1: 10.25±1.79; G2: 10.07±1.36) (p = 0.040) and fertilization rate (G1: 73.98 %; G2: 79.44 %) (p = 0.001). The usable embryo rate was similar (G1: 54.78 %; G2: 54.47 %). Significant differences arose in mean biopsied embryos/cycle (G1: 3.71; G2: 4.27) (p = 0.016), but not for aneuploid embryos (G1: 29.71 %; G2: 29.49 %) (p = 0,998). Biochemical pregnancy rates were significant (G1: 48.8 %, G2: 60.4 %) (p = 0.022). Other clinical parameters showed no differences, with LBR at 35.5 % in G1 and 37.8 % in G2 (p = 0.752). Limitations, reasons for caution The study is retrospective, where we addressed potential biases by incorporating confounding variables. However, to confirm our initial findings, randomized prospective studies with an appropriate sample size are essential. Wider implications of the findings In egg donation cycles, PPOS shows optimal embryonic performance resulting in a live birth rate comparable to the GnRH antagonist protocol. Additionally, it offers cost-effectiveness and enhanced comfort for donors. Trial registration number Not applicable

O-012 Three Injections Protocol for IVF; a proof of concept study into elaborating the outmost patient friendly protocol in IVF

Abstract Study question To examine if 3 injections in follicular phase, with long-acting FSH, long-acting antagonist and HCG/Agonist triggering can result in efficient egg retrieval and blastocyst formation. Summary answer In this proof-of-concept study, all patients retrieved mature oocytes and ended having adequate blastocysts by receiving only 3 injections in the follicular phase. What is known already The old-fashioned way with multiple injections (majority minimum 15 injections) is still the golden IVF standard. Twenty years ago, a long-acting FSH gonadotropin brought into market (corifollitropin alpha) which represented a huge step in simplifying the follicular phase Recently, a new long-acting GnRH-antagonist emerged (degarelix) which can downregulate the hypophysis for 30 days. We have published that titrating this long-acting antagonist to 0,1mg single dose we can downregulate hypophysis without LH surge. Study design, size, duration A prospective proof of concept study included in total 15 patients 30-39 years old who followed IVF treatment with homologous oocytes during 2020-2022 in Assisting Nature IVF Clinic, Thessaloniki, Greece. In this study, we test if by delaying one day the long-FSH and also delaying the long-antagonist, still patients can produce mature eggs without needed extra FSH doses. Institutional review board approved the protocol. Participants/materials, setting, methods Patients were enrolled if AMH was 1,5-3,0 ng/ml and antagonist protocol applied. 150IU fixed corifollitropin-a (Elonva) for ovarian stimulation administered either on evening cycle Day-3 or morning day-4. Fixed 0,1 mg of long-acting GnRH-antagonist (Degarelix) administered on cycle Day 8. Fixed 250mcg recombinant-hCG (Ovitrelle) or 0,3 mg of Triptorelin (Arvekap) for ovulation triggering administered as soon as 3 follicles of 18mm were present. Produced blastocysts were all cryopreserved and transferred in subsequent thawed cycles. Main results and the role of chance All 15 patients reached ovum pick-up with mature eggs retrieved (mean 13,5 oocytes). None experienced any LH surge, however, 3/15 (20%) required an extra dose of 300IU FSH (Puregon) to enhance follicular development. The majority 12/15 reached OPU without any FSH adjuvant. All 15 patients had blastocysts formed (mean 3,3) and in their subsequent thawed cycles the cumulative live birth rate was 53,3% (8/15). Patient satisfaction was excellent though closer monitoring was applied due to novelty of the protocol. Limitations, reasons for caution Limited number of patients as it is a complete novel protocol with unknown outcome. Protocol was focused in normo-ovarian-reservers to secure follicular production. Some patients might need an extra dose of gonadotropin. Long-acting antagonist still not registered for IVF use. Wider implications of the findings Current study promising results indicate that a 3-injection follicular stimulation can efficiently produce mature eggs, viable blastocysts and pregnancies. Although, few patients required an extra fourth injection of FSH, if such approach will be tested in larger studies will re-establish our way for stimulation at least for normo-reservers. Trial registration number NCT03877185

P-126 The impact of ICSI versus IVF on the reproductive outcomes of couples with non-male factor infertility and frozen-thawed embryo transfer cycles

Abstract Study question Does Intracytoplasmic Sperm Injection (ICSI) improve reproductive outcomes in patients with non-male factor infertility undergoing Frozen-Thawed Embryo Transfer (FET) treatment? Summary answer ICSI showed slightly improved clinical outcomes compared to IVF, but was associated with higher preterm birth rates and low birthweight when twins were born. What is known already The use of ICSI has seen a significant surge globally, particularly in Europe and the USA, as a solution for fertilization failure resulting from male factor infertility. FET presents a viable option for those considering additional children. Numerous studies have investigated the effectiveness of ICSI in couples with non-male factor infertility undergoing fresh embryo transfer in ovarian stimulation cycles. However, there is a dearth of evidence demonstrating whether ICSI, compared to conventional IVF (cIVF), could influence reproductive outcomes in couples with non-male factor infertility undergoing FET treatment. Study design, size, duration This retrospective cohort study included 10,143 cycles from 6,206 couples who underwent FET at the Third Affiliated Hospital of Zhengzhou University between January 2016 and September 2022. Participants/materials, setting, methods Patients were categorized into two groups based on the insemination methods used for the transferred embryos. Patients were excluded if : 1) Embryos were biopsied and tested; 2) Oocytes had been vitrified; 3) Embryos were derived from donor oocytes, AOA treatment, or rescue ICSI; 4) Embryos that were not transferred; and 5) They had undergone fresh embryo transfer. PSM at a ratio of 1:1 was utilized to ensure comparability of reproductive outcomes. Main results and the role of chance Post-PSM, the general characteristics were comparable across both groups. The clinical pregnancy rates (37.6% vs 40.0%, P = 0.311), miscarriage rates (21.4% vs 23.1%, P = 0.597), and live birth rates (28.2% vs 30.4%, P = 0.329) exhibited no significant disparity post-PSM between the two groups. Notably, a marginally elevated live birth rate was observed in the ICSI group when blastocysts were transferred to the women (39.8% vs 48.3%, P = 0.050). However, the GEE models indicated that ICSI did not enhance the likelihood of clinical pregnancy, miscarriage, and live birth relative to IVF in women with non-male factor infertility. Following adjustments for variables, ICSI yielded consistent OR values [1.14(0.92-1.42), P = 0.241; 1.08(0.72-1.61), P = 0.703; and 1.16(0.92-1.46), P = 0.220, respectively]. The perinatal outcomes were similar between the two grousps. However, a significantly higher incidence of preterm birth was observed in the ICSI group compared to the cIVF group (20.0% vs 12.5%, P = 0.026). While pregnancy complications were comparable between the two groups, neonates born as twins in the ICSI group exhibited significantly reduced live birth-weight [2520.8(572.9) vs 2691.9(423.7), P = 0.043] and birth length [47.5(2.8) vs 48.5(2.3), P = 0.031]. Correspondingly, the rate of low birthweight was significantly higher in the ICSI group (38.9% vs 21.0%, P = 0.025). Limitations, reasons for caution The retrospective design may lead to selection bias among the included patients. The use of ICSI in ART has been strictly regulated in our country, limiting the sample size and potentially reducing the statistical power. Wider implications of the findings The value of ICSI should be thoroughly discussed with patients with non-male factor infertility before ovarian stimulation. Further research is needed to better understand the impact of ICSI on reproductive and neonatal outcomes in this population. Trial registration number 2021YFC2700602

O-244 AMH levels in infertile women in APAC region - prospective study in multiple countries, ethnicities and centres

Abstract Secretary General, Asia Pacific Initiative on Reproductive (ASPIRE) President, Taiwan Endometriosis Society Founder & CEO, Taipei Fertility Center AMH is produced by granulosa cells of small growing follicles in the ovary and serum AMH levels strongly correlate with the number of growing follicles, AMH has been used clinically as a marker for ovarian reserve. Despite being of similar ages, with similar AMH levels, durations of ovarian stimulation, and gonadotropin doses, Asian women have been documented as having decreased AFCs and lower yields of total and mature oocytes after ovarian stimulation compared to their Caucasian counter- parts. These earlier data suggested that the effect of ethnicity was as an independent marker of ovarian reserve and potentially subsequent reproductive outcomes. We conducted the first multi-nation, multi-centre, and multi-ethnicity prospective cohort study from January 2020 to May 2021 to investigate serum AMH profiles among infertile Asian women. A total of 4613 women who visited fertility clinics at 12 IVF centres in 11 regions throughout Asia were recruited from Taiwan, China, Hong Kong SAR, India, Indonesia, Japan, Korea, Malaysia (2 centres), Thailand, Vietnam, and Singapore. The inclusion criteria were female partners aged 20–43years and naive to any ovarian stimulation cycle. The AMH measurement was performed using an AMH automated assay on a clinically validated platform. Among the 12 centres that joined the study, most demonstrated racial homogeneity except for Singapore and Malaysia which presented a highly diverse ethnic profile, while others were supposedly monoethnic communities. Unexplained or male infertility is the most common infertility cause in most countries, except for China with a notably high incidence of tubal disease. Age, ethnicity, obesity, and PCOS are significantly associated with ovarian reserve. The highest rates of PCOS were found in Indians (18.6%), Malays (18.9%), and Vietnamese (17.7%), yet remarkably lean with lower obesity rate was found in Vietnamese. Serum AMH levels are not affected by smoking or GnRHa and OCPs pretreatment but are affected by endometrioma surgery. Moreover, the assay can be conveniently conducted on any day of the menstrual cycle and is not influenced by the use of fresh or frozen samples. The rate of decline in ovarian reserve increases with age in Asian women, at 0.13ng/ml/year at 25–33years old and 0.31ng/ ml/year at 33–43 years old. We also found that a cut-off at 4.0 ng/ml could be considered for PCOS diagnosis in the Asian region. Despite limitations, the results can help guide clinicians for personalized infertility treatment, and call for further investigation into the effects of genetic, environmental and lifestyle factors on ovarian reserve.

P-623 Post-market analysis of an AI-powered clinical decision support tool for ovarian stimulation

Abstract Study question How do treatment decisions and patient outcomes change with physician utilization of artificial intelligence (AI) to help determine FSH starting dose and trigger injection timing? Summary answer With physician use of an AI platform, patients were treated with significantly less starting and total FSH without statistically significant changes in outcomes. What is known already Stim Assist is an AI clinical decision support software providing physicians with adjunctive information for the prediction of the number of mature (MII) oocytes that may be retrieved from an ovarian stimulation cycle. The software is intended to assist with the selection of the starting dose of FSH as well as the decision of when to administer the trigger injection. Prior studies have retrospectively estimated the benefit of using AI for treatment decisions during ovarian stimulation, but there is a lack of post-market analyses evaluating the true efficacy of these tools when integrated in clinical practice. Study design, size, duration This study was conducted by multiple physicians at a single IVF clinic in the U.S. The treatment arm consisted of 292 patients seen by physicians using Stim Assist between December 2022 - December 2023. The control arm consisted of 292 matched historical control patients, treated between May 2019 - May 2022 at the same clinic without use of Stim Assist. Participants/materials, setting, methods Matching for each patient was performed for each physician individually, comparing each treatment-arm patient to a historical control-arm patient who was seen by the same physician. Patients were matched 1-to-1 based on age, baseline AMH, and baseline antral follicle count. The primary endpoints were the starting FSH and total FSH prescribed to the patient, as well as MIIs retrieved at the end of stimulation. Main results and the role of chance Comparing the treatment arm to the control arm, the average MIIs were 11.17 vs. 11.45 (p = 0.68), the average starting FSH was 397.09 vs. 443.58 (p < 0.01), and the average total FSH was 4181.77 vs 4601.8 (p < 0.01). The results were stratified by age groups of < 35, 35-40, and >40. For patients in the <35 group (N = 122), the average MIIs were 13.99 vs. 16.06 (p = 0.06), the average starting FSH was 346.72 vs. 380.53 (p < 0.01), and the average total FSH was 3525.84 vs. 3927.25 (p < 0.01). For patients in the 35-40 group (N = 129), the average MIIs were 9.46 vs. 8.71 (p = 0.34), the average starting FSH was 420.35 vs. 486.05 (p < 0.01), and the average total FSH was 4568.6 vs. 5063.37 (p < 0.01). For patients in the >40 group (N = 41), the average MIIs were 8.17 vs. 6.34 (p = 0.12), the average starting FSH was 473.78 vs. 497.56 (p = 0.16), and the average total FSH was 4916.46 vs. 5156.71 (p = 0.34). Limitations, reasons for caution This preliminary post-market analysis was performed at a single clinic in the U.S. We could not calculate live birth outcomes. Due to the limited sample size, differences in outcomes were not statistically significant. Wider implications of the findings These findings suggest that physician use of Stim Assist helped significantly reduce the starting and total FSH prescribed to patients. Additionally, MII outcome differences showed a trend towards an increase in MIIs for patients >35 years old, and a slight reduction in MIIs for younger, better prognosis patients. Trial registration number not applicable

O-085 Oocyte cryopreservation: a comprehensive analysis of live birth rate by age and indication of treatment provides reassurance for young cancer patients

Abstract Study question Does the outcome of oocyte cryopreservation vary across different age groups and treatment indications, i.e. cancer diagnosis, other medical conditions or non medical fertility preservation? Summary answer Live birth rate (LBR) is significantly influenced by a woman's age, although not by indication of treatment. What is known already OC is increasingly applied in assisted reproduction, although little is about the outcomes, including livebirth according to indication. Study design, size, duration Retrospective cohort study analyzing all OC and subsequent warmed oocyte cycles in two fertility centers - Melbourne IVF and the Royal Women’s Hospital, Melbourne, Australia, between the years 2014 to 2022. Participants/materials, setting, methods Women undergoing autologous IVF treatment using vitrified and warmed oocytes. Outcome of stimulation cycles and warmed oocyte cycles were assessed according to women’s age at OCP (≤ 35 years, 35-40 years and ≥ 40 years) and treatment indication- cancer diagnosis, other medical conditions and non medical. Main results and the role of chance 2689 women underwent a total of 3801 cycles of OC, comprising 702 cycles for cancer diagnosis (18.6%), 1146 cycles for other medical (30.5%), and 1953 cycles for non-medical (50.9%). Regardless of indication, younger age groups exhibited a higher median number of mature oocytes: <35 (11, 8-17), 35-40 (9, 6-11), and >40 (6, 3-9) (H(2)=15.1, p < 0.05). Among 582 warmed oocytes cycles, the >40 group demonstrated lower rate cycles with at least one good-quality blastocyst (76.7%) compared to 35-40 (87.1%) and <35 (87.2%), p < 0.05. Cumulative live birth rates (cLBR) were also lower in the >40 age group (14.9%) compared to 35-40 (34.9%) and <35 (46.5%), p < 0.01. When analyzing cycles by indication, patients with cancer had lower oocyte survival rate (80.8% vs 84.8% in other medical and 82.1% in non medical, p < 0.01). Nonetheless, no differences in rate of cycles with at least one good quality embryo rates (cancer diagnosis 87.2%, other medical 82.1% and non medical 89.3%, p = 0.06). Patients with cancer diagnosis had higher clinical miscarriage rate (25%) compared with other medical (7%) and non medical (10.5%), p < 0.01. However, cLBR did not differ between the indication groups (29.7% in cancer diagnosis, 35% in other medical and 38.1% in non medical, p = 0.5. Limitations, reasons for caution Retrospective data collection. Wider implications of the findings Our study offers comprehensive data that may assist patients desiring OC, and provides reassurance that even with a cancer diagnosis, outcomes are as favorable as those having non-medical OC. Given the substantial impact of age, health care providers should, when possible, advise to complete this procedure at a young age. Trial registration number Not applicable

P-713 Proposal of model to calculate the trend in the cumulative live birth rate in IVF cycles using Spanish National Register data from 2009 to 2021

Abstract Study question Is it possible to estimate the trend in the cumulative rate of live births in IVF over 12 years, using data from the Spanish Registry? Summary answer With the proposed formula, a constant increase of 1.7% in the cumulative live birth rate is verified throughout the 12 years of study. What is known already The progressive increase in elective freeze-all cycles no longer allows the use of live birth data by fresh transfer, especially in time series. Cumulative live birth rate (CLBR) has been proposed as an appropriate way of reporting success of an IVF program, incorporating both, fresh and frozen embryos. Nevertheless, views on the most appropriate parameters required to calculate such an outcome have been inconsistent and difficult for national aggregate registries. Furthermore, there is not unanimous definition for its calculation and although IVF Register is mandatory in Spain, an analysis of the CLBR has not been carried out. Study design, size, duration Data from the Spanish National Register of Assisted Reproduction including 456302 women undergoing IVF/ICSI (563000 ovarian stimulation cycles started, 359587 fresh transfers, and 36400 cryotransfer) using autologous gametes performed in Spain from 2009 to 2021 were analyzed. Oocyte donation and PGT-a cycles were excluded. Participants/materials, setting, methods The main outcomes of present study were live birth rate per cycle (LBR) and cumulative live birth rate (CLBR). To obtain the CLBR, the probability of achieving at least one live birth for each cycle started was calculated. This includes both live births after fresh transfer and those achieved after cryotransfer of the embryos obtained from each cycle until they have run out, or a full-term pregnancy is obtained. Main results and the role of chance The live birth rate (LBR) per fresh transfer remains steady (around 24%) throughout the period analyzed. However, LBR for started cycle, which remains constant (17%) until 2013, shows a marked decline since then at a rate of 1% per year. In this same period was observed: a progressive increase in the percentage of cycles with frozen embryos (from 29% to 48%), a greater number of cryopreserved embryos (from 0.9 to 1.6 embryos per started cycle), and a constant decrease in the number of embryos in each cryotransfer (from 2.39 to 1.42). LBR after cryotransfer per started cycle has increased exponentially from 4% to 24%. It was also found a steady increase of the percentage of births after a cryotransfer cycle (from 19 to 70%), surpassing since 2017 those obtained after fresh transfer. To calculate the cumulative live birth rate (CLBR), an algorithm has been developed including all pregnancies that can be achieved with the use of all the embryos obtained after each cycle started until alive child is born. CLBR shows a constant increase in the cumulative delivery rate of 1.7% annually since 2012, rising from 22 % to 35% of births per cycle started. Limitations, reasons for caution One of the main weaknesses of the study is that some patients have not attempted a second or third cryotransfer during the timeframe (for unknown reasons), though they had supernumerary embryos available. However, this model reflects the potential capacity to have at least one living child for each cycle started. Wider implications of the findings The LBR per cycle based only on fresh transfers is not useful for a historical analysis of the effectiveness of the technique. Only the calculation of the CLBR per cycle allows us to understand the real progress of IVF effectiveness in recent years. Trial registration number not applicable

P-135 Impact of TE-biopsy practitioners on PGT-A results and live-birth outcomes after single euploid blastocyst transfer: comparison of 19 TE-biopsy practitioners in a single center

Abstract Study question Can TE-biopsy practitioners impact pre-implantation genetic test for aneuploidy (PGT-A) results, pregnancy, and live-birth outcomes in a single center that has nineteen biopsy practitioners? Summary answer Yes. Trophectoderm (TE)-biopsy practitioners, especially micromanipulation experience, can impact PGT-A results but do not impact pregnancy or live-birth outcomes after single euploid blastocyst transfer (SeBT). What is known already Recently, PGT-A has become important in in vitro fertilization treatment. However, several factors can impact the accuracy and interpretation of PGT-A results. Several studies have suggested that TE-biopsy practitioners can impact PGT-A results. However, these findings are controversial because these previous studies used data from a low number of TE-biopsy practitioners and from multiple centers. There is, therefore, still limited knowledge of the impact of TE-biopsy practitioners on PGT-A results and their clinical outcomes. Study design, size, duration A total of 3,589 PGT-A cycles (average maternal age, 40.9±3.2; 1,168 patients; February 2020 to November 2022) were retrospectively analyzed. Furthermore, 779 single frozen euploid blastocyst transfer (SeBT) cycles were analyzed. First, we investigated the association between TE-biopsy practitioners and transferable blastocysts that included euploid and low-level mosaic blastocysts (LLM, 20 to 40% abnormal cells). Second, we analyzed the impact of TE-biopsy practitioners on pregnancy and live-birth outcomes after SeBT. Participants/materials, setting, methods The nineteen practitioners (Years of intracytoplasmic sperm injection (ICSI) experience: 2 to 20 years) who received the same training performed a total of 5,613 TE-biopsies for PGT-A. The same practitioner performed both the biopsy and the tubing procedures for each blastocyst they biopsied. The Wald test for multivariable logistic regression analysis (mLR) was used to determine the impact of TE-biopsy practitioners. The confounding factors were selected by univariable logistic regression analysis before mLR. Main results and the role of chance TE-biopsy was carried out by the flicking method with laser assistance and it was taken five to seven TE cells. Overall, 22.9% of blastocysts were transferable blastocysts (euploid: 21.1%, LLM: 1.8%). The results were inconclusive for 0.1% of the blastocysts. Maternal/paternal age, number of previous egg retrieval/embryo transfers, anti-Müllerian hormone, sperm characteristics, indication for PGT-A, number of previous deliveries/chemical abortions, blastocyst quality (the day of vitrification, inner diameters of blastocysts, and Gardner grading) were used as confounding factors on the mLR. TE-biopsy practitioners were significantly associated with both ensuring transferable blastocysts and LLM in transferable blastocysts (p < 0.05). Additionally, the practitioner characteristics that impact ensuring transferable blastocysts or LLM in transferable blastocysts were assessed in a sub-analysis. Years of ICSI experience (p < 0.05), number of ICSI performed during the last years (p < 0.05), and number of TE-biopsies at that point (p < 0.05) were associated with ensuring transferable blastocysts and LLM in transferable blastocysts. On the other hand, TE-biopsy practitioners did not have a significant impact on biological pregnancy, chemical abortion, pregnancy, or live-birth rates after SeBT. Limitations, reasons for caution This study did not determine the influence of TE biopsy itself and the laser assistance on PGT-A and clinical results. And this study was based on a minimal stimulation cycle. Moreover, the patient cohort in this study only included cases involving recurrent implantation failure or repeated pregnancy loss. Wider implications of the findings This study showed that TE-biopsy practitioners could impact decreasing transferable blastocysts, and this depends on their micromanipulation experience. This result suggests TE-biopsy training should be started when embryologists have gained several years of experience with ICSI procedures. This could prevent the decline in the efficacy of PGT-A for clinical results. Trial registration number not applicable

O-292 A three-dimensional ultrasound-based online system for automated ovarian follicle measurement

Abstract Study question Is OSIS Ovary (a three-dimensional ultrasound-based online system for automated ovarian follicle measurement) a reliable tool to track follicle growth during ovarian stimulation cycles? Summary answer We can conclude that OSIS Ovary constitutes a reliable follicle-measurement tool What is known already Ultrasound follicle tracking is a crucial part of cycle monitoring. When the number of follicles increases, the manual measurement process can become tedious, imprecise and can potentially compromise the clinical outcomes The use of automated volumetric software for follicle monitoring makes it possible to overcome these manual limitations, regardless of the moment in the cycle when the metrics are obtained and assessed, providing flexibility for both clinicians and patients At the same time, more objective metrics are obtained with automated volume segmentation than with manual follicle measurement Study design, size, duration A prospective cohort study was performed among 89 patients undergoing ovarian stimulation during in vitro fertilization or oocyte vitrification cycles They were invited to participate in the study between May 2020 and February 2021. All participants signed an informed consent form prior to the start of the study Participants/materials, setting, methods 534 ovarian ultrasound volumes and manual datasets were obtained from ovarian stimulation cycles from the 89 participant patients Three transvaginal (2D and 3D) ultrasounds scans were performed on volunteer patients on the three clinically relevant monitoring days: 4th- 5th day (first follicular assessment), 6th -7th day (introduction of the GnRH antagonist) and 8th-9th day (oocyte pickup scheduling) The mean follicle diameter and the follicle count were estimated manually (2D) and automated (3D with Osis Ovary) Main results and the role of chance Based on the mean follicle diameter and follicle count values obtained, the Pearson/intraclass correlation coefficients were 0.976/0.987 and 0.804/0.889 in ≥ 10mm follicles, 0.989/0.994 and 0.809/0.867 in ≥ 13mm follicles and 0.995/0.997 and 0.791/0.840 in ≥ 16mm follicles. The mean difference (MnD) for the mean diameter and follicle count was,respectively, 0.759/0.161 in ≥ 10mm follicles, 0.486/1.033 in ≥ 13mm follicles and 0.784/0.486 in ≥ 16mm follicles. The upper and lower limits of agreement (ULA and LLA) were 3.641/2.123 and5.392/3.070 in ≥ 10mm follicles, 3.496/2.522 and 4.285/2.218 in ≥ 13mm follicles, and3.723/2.153 and 2.432/1.459 in ≥ 16mm follicles. The limits of agreement range (LoAR) were5.764/8.462 in ≥ 10mm follicles, 6.048/6.503 in ≥ 13mm follicles and 5.876/3.891 in ≥ 16mm follicles Limitations, reasons for caution We can conclude that OSIS Ovary constitutes a reliable follicle-measurement tool. The performance observed can be considered very good and it must be progressively clinical studied to be assessed and optimized in the next future Wider implications of the findings Cloud-based features, such as multi-user functioning in any 3D ultrasound machine, could make OSIS Ovary an attractive resource for reproductive medicine clinics, making it easier to track follicle growth during ovarian stimulation cycles Trial registration number not applicable

O-221 An interpretable deep learning model for predicting the number of mature oocytes retrieved after ovarian hyperstimulation

Abstract Study question Can an interpretable deep learning model successfully predict the number of mature oocytes retrieved after ovarian hyperstimulation and provide the rationale for these predictions? Summary answer An interpretable deep learning model can successfully predict the number of mature oocytes retrieved and provide a rationale for these predictions. What is known already A number of recent studies have used classical machine learning models in order to predict the number of mature oocytes retrieved in IVF cycles, including XGBoost, RandomForests and even basic deep learning models such as feed forward networks. Although these studies predicted the number of mature oocytes with a relatively high performance, the employed methods lack insights into the rationale governing their predictions. This lack of interpretability poses an important limitation when applying these models in a clinical setting. Study design, size, duration This study was a retrospective analysis of a dataset of 6,430 ovarian stimulation cycles performed at a single center in the USA, aimed at building a deep learning based, interpretable model to predict the number of mature oocytes retrieved after ovarian hyperstimulation. Participants/materials, setting, methods An interpretable deep learning model was developed to predict the number of mature oocytes retrieved. The model was evaluated on an out-of-sample test set and compared to baseline models used in prior studies such as XGBoost and Linear Regression. Main results and the role of chance The model successfully predicted the retrieved oocyte count, with a mean absolute error (MAE) deviation of ± 3.14 oocytes from the ground truth. The model outperformed the performance of models used in previous studies such as XGBoost and Linear Regression which achieved a MAE of ± 3.16 and ±3.2 oocytes respectively on the test dataset. Parameter significance was measured by calculating how much parameters aided in the final prediction. The parameters found to be most significant in predicting the number of retrieved mature oocytes were (in order): total number of follicles, number of follicles size 12mm-15mm and number of follicles size 16-17mm. Parameters that were found to be of lower significance but still indicative were follicles larger than 18 mm and estradiol on trigger day. Surprisingly, age and basal FSH were of little significance. Most notably, the number of follicles in the 12mm -15mm bin were much more indicative than larger follicles of size 16-17mm and much more than follicles larger than 18mm. Furthermore, the model generates a transparent breakdown of the prediction for each patient, including a heat map and bar graph highlighting the factors influencing the decision making process at every step, creating a completely transparent prediction process. Limitations, reasons for caution The model was developed on training data from a single clinic, therefore requiring further data collection from diverse global locations to ensure the model’s ability to generalize. Wider implications of the findings This study demonstrates better oocyte prediction accuracy and transparency in the prediction process, surpassing previous models while also building trust. These advancements not only improve the safety of Artificial Intelligence tools for optimizing stimulation protocols but also contribute to reducing regulatory concerns surrounding their deployment in clinical settings. Trial registration number not applicable

O-014 Cumulative live birth associated with number of oocytes in ovarian stimulation with follitropin delta: an individual patient data meta-analysis

Abstract Study question What is the optimum number of oocytes retrieved to maximise cumulative live birth rates in the fresh and subsequent frozen cycles following follitropin delta stimulation? Summary answer The cumulative live birth rate increased steadily with number of oocytes retrieved up to a plateau starting at ∼21 oocytes retrieved. What is known already Live birth rate (LBR) per fresh ovarian stimulation cycle is the conventionally reported outcome of in vitro fertilisation (IVF). In recent years, there has been a marked increase in number and successful outcomes of cryopreserved cycles, suggesting that the cumulative live birth rate (CLBR) has emerged as a more clinically relevant outcome. In the fresh cycle, the number of oocytes retrieved is regarded as a prognostic factor for LBR. A similar association has been shown for CLBR implying that CLBR increases with the number of oocytes and continues to increase beyond the plateau observed for fresh cycle LBR. Study design, size, duration Individual patient data meta-analysis of 1746 patients from 4 randomised controlled trials using follitropin delta for ovarian stimulation. The analysis included patients with ≥1 oocyte retrieved following stimulation. The CLBR in the fresh and subsequent frozen cycles was evaluated. Predicted CLBR was obtained using a logistic regression analysis with fractional polynomials to assess the association between number of oocytes retrieved and CLBR. Subgroup analyses were performed based on age, AMH and number of oocytes retrieved. Participants/materials, setting, methods Participants were women, 18–42 years, undergoing their first or second in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) cycle in a GnRH antagonist/long agonist protocol with human chorionic gonadotrophin or GnRH agonist triggering and IVF/ICSI insemination. Single or double blastocyst transfer was performed on Day 5 and all viable surplus blastocysts were cryopreserved. All pregnancies from the fresh cycle and frozen cycles initiated within 1 year after start of stimulation were followed until birth. Main results and the role of chance The study included 1746 patients who underwent a total of 2948 cycles; 1746 fresh and 1202 frozen. In total, 740 patients (42.4%) initiated frozen cycles (maximum of 6). The study population had a mean age of 33.8 years and a median AMH level of 17.0 pmol/l. The mean number of oocytes retrieved was 12.4, the fresh cycle LBR was 29.1% and the CLBR was 51.4%. The CLBR steadily increased with number of oocytes retrieved, reaching above 60% at > 15 oocytes and above 70% at > 20 oocytes. The CLBR started to plateau at ∼21 oocytes. Subgroup analyses by number of oocytes retrieved, age group or AMH group demonstrated that the CLBR decreased with increasing age (57.1%, 51.6% and 35.8% at < 35, 35-37 and ≥38 years). In comparison it was similar for AMH <15 and ≥15 pmol/l (52.0% and 50.9%, respectively). A continued increase in CLBR from 15 oocytes retrieved was observed in older patients (≥38 years); from 41.3% to 53.4% to 58.7% at 15-19, 20-24 and ≥25 oocytes. No equivalent benefit was observed in younger patients, where corresponding rates were 72.5%, 68.0% and 78.8% in patients <35 years, and 70.3%, 73.1% and 71.5% in patients 35-37 years. Limitations, reasons for caution A limitation of this study is the small number of patients with >20 oocytes retrieved. The individual pooled studies were heterogenous regarding number of blastocysts transferred and hCG/agonist trigger. Wider implications of the findings The current individual patient data meta-analysis suggests an increase in CLBR with number of oocytes retrieved up to a plateau starting at ∼21 oocytes following ovarian stimulation cycles with follitropin delta and subsequent frozen cycles. An increase in CLBR from 20 oocytes was evident in older but not younger patients. Trial registration number NCT01956110, NCT03564509, NCT03740737, NCT03738618

P-655 Live birth rate in the fresh cycle associated with number of oocytes in ovarian stimulation with individualised follitropin delta: an individual patient data meta-analysis

Abstract Study question What is the optimum number of oocytes retrieved to achieve a live birth for women undergoing ovarian stimulation with individualised follitropin delta? Summary answer The live birth rate (LBR) in the fresh cycle was highest in the range of 8-14 oocytes retrieved, peaking at 11 oocytes. What is known already The number of oocytes retrieved following ovarian stimulation for assisted reproductive technologies is regarded a prognostic marker of pregnancy outcome, where high numbers increase chances of live birth but also the risk of complications, especially ovarian hyperstimulation syndrome (OHSS). Thus, an optimum range of oocytes retrieved is essential. Still, there is no consensus regarding this range in fresh cycles. Optimum numbers between 6 and 15 oocytes have been suggested, taking the risk of OHSS into consideration. The individualised dosing algorithm for the recombinant follicle-stimulating hormone follitropin delta has a target range of 8–14 oocytes. Study design, size, duration Individual patient data meta-analysis of 1772 patients from 5 randomised controlled trials using individualised dosing of follitropin delta for ovarian stimulation, with fixed daily dosing based on serum anti-Müllerian hormone (AMH) and body weight. The analysis included patients with ≥1 oocyte retrieved. Outcomes of LBR and OHSS in the fresh stimulation cycle were evaluated in relation to number of oocytes retrieved. Subgroup analyses were performed based on age, AMH and number of oocytes retrieved. Participants/materials, setting, methods Participants were women, 18–42 years, undergoing first or second in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) cycle in a GnRH antagonist/long agonist protocol with human chorionic gonadotrophin or GnRH agonist triggering and IVF/ICSI. Single or double embryo/blastocyst transfer was performed on Day 3/5. All pregnancies were followed until birth. Predicted live birth was obtained using a logistic regression analysis with fractional polynomials to assess the association between number of oocytes retrieved and live birth. Main results and the role of chance The studied population (n = 1772) had a mean age of 32.6 years and median AMH of 17.7 pmol/l. Mean number of oocytes retrieved was 10.4, the LBR was 32.1% and the OHSS rate (any grade and onset) was 6.6%. The LBR steadily increased with the number of oocytes retrieved up to a plateau starting at 8 oocytes, with a LBR above 34% in the range of 8-14 oocytes retrieved, peaking at 34.9% for 11 oocytes. Beyond 14 oocytes, LBR gradually declined. By number of oocytes (grouped), the LBR was 27.8%, 33.6% and 30.9% at 1-7, 8-14 and ≥15 oocytes. In patients with embryo transfer, corresponding rates were 32.8%, 37.2% and 38.7%. In the subgroup analyses, LBR decreased with increasing age (32.7%, 30.7% and 23.4% at < 35, 35-37 and 38-42 years) while it was similar for AMH <15 and ≥15 pmol/l (30.4% and 31.3%, respectively). LBR was highest at 8-14 oocytes in patients <35 years (28.0%, 36.2% and 32.4% at 1-7, 8-14 and ≥15 oocytes), while it was consistently low (<26%) in patients 38-42 years, irrespective of number of oocytes retrieved. The OHSS rate (any grade) increased from 2.1% with 1-7 oocytes, to 5.2% with 8-14 oocytes and 17.0% with ≥15 oocytes. Limitations, reasons for caution A limitation of this study is the small number of patients with >20 oocytes retrieved in the studied population. Wider implications of the findings The current individual patient data meta-analysis suggests an optimum range of 8-14 oocytes retrieved to achieve a live birth in fresh cycles with follitropin delta. Furthermore, the analysis demonstrates a marked increase in OHSS rate from 15 oocytes retrieved. The results support the appropriateness of individualised follitropin delta dosing regimen. Trial registration number NCT01956110, NCT03228680, NCT03296527, NCT03564509, NCT03809429

P-536 Preimplantation Genetic Testing for hereditary breast and ovarian cancer syndrome due to BRCA pathogenic variant : the parisian center experience

Abstract Study question What are the outcomes of Preimplantation genetic testing for monogenic disease (PGT-M) for BRCA pathogenic variants? Summary answer Among couples entering a PGT-M program for BRCA pathogenic variants, 23.5% achieved a live-birth. What is known already BRCA pathogenic variants are associated with an oncologic predisposition with variable penetrance and are accessible to screening and preventive procedures to avoid or early detect the development of cancer. Transmission of BRCAmutations to offspring poses a significant reproductive concern for BRCA mutation carriers. PGT-M offers a solution to prevent this mutation transmission. Despite reproductive challenges related to BRCA status, there are no existing international guidelines for applying PGT-M in these situations. In France, authorization for BRCA related PGT-M is case-specific, considering the personal and familial severity of the disease and submitted to a multidisciplinary prenatal diagnosis center (CPDPN). Study design, size, duration This retrospective observational study, is a single-center analysis of 46 requests for PGT-M related to BRCA pathogenic variants at our PGT center from January 2015 to December 2022. Participants/materials, setting, methods Forty-six couples asked for PGT-M for BRCA pathogenic variant carried by one of the partner. The present study involves the examination of data encompassing referrals, decisions as well as clinical outcomes associated with PGT-M. Main results and the role of chance Forty-six requests for PGT-M due to the risk of hereditary predisposition to breast and ovarian cancer have been received: 36 for a pathogenic variant in the BRCA1 gene and 10 for BRCA2. Nine couples ultimately did not proceed and dropped out. Eight requests were declined, either due to the refusal of the multidisciplinary prenatal diagnosis center (CPDPN) based on family history (n = 4) or alteration of ovarian reserve (n = 4), the 2 latter requests are still under investigation. In total, requests from 27 couples (55%) were considered eligible and feasible. Among them, 17 (63%) underwent at least one PGT-M cycles (5 dropped out before the beginning and 5 are still pending). Overall, 33 ovarian stimulation cycles for in vitro fertilization were initiated, resulting in the retrieval of 192 mature oocytes and the formation of 145 embryos. Of these, 97 were biopsied, and 38 did not carried the BRCA pathogenic variant. A total of 21 fresh or frozen embryo transfers were performed and 8 pregnancies were achieved, leading to 4 deliveries and 5 live births (23.5% of couples who started a PGT-M cycle). Limitations, reasons for caution In the absence of established guidelines, there is variability in information regarding PGT-M among oncogeneticists. Thus, only selected carriers of BRCA pathogenic variants are addressed to our PGT centers. Additionally, women participating in a fresh PGT cycle were selected on several criteria including ovarian reserve parameters. Wider implications of the findings PGT-M provides a viable alternative for couples seeking to prevent the transmission of BRCA mutations. To increase the PGT-M cumulative live birth rate, the transfer of male embryos carrying the variant, assumed to have lower tumor risks, should be considered and discussed with patients. Trial registration number Not applicable

O-302 Feasibility and efficacy of a flexible and simplified ovarian stimulation protocol for oocyte donors, combining random-start corifollitropin alpha and progestin primed ovarian stimulation protocol (PPOS)

Abstract Study question Is the total number of retrieved oocytes in donors equivalent, according to the onset phase of stimulation with corifollitropin alpha in a random-start PPOS protocol? Summary answer The total number of retrieved and mature oocytes were not different after starting stimulation in the early, mid or late follicular or luteal phases. What is known already Recent studies have shown the ability to obtain oocytes of equivalent quality after follicular or luteal phase ovarian stimulation and have also demonstrated the efficacy and safety of the PPOS protocol in oocytes donors. In order to provide a more friendly, simplified and flexible ovarian stimulation protocol reducing the burden for donors, we studied the impact on oocyte yield of combining a random start corifollitropin alpha stimulation with the concomitant prevention of premature LH surge by progestin administration. Study design, size, duration This multicenter open-labelled RCT was performed in 4 oocytes donation centers from July 2020 to September 2023 to assess the equivalence in terms of number of retrieved oocytes of a delayed onset of corifollitropin alpha stimulation with concomitant administration of desogestrel in Mid Follicular Phase (MFP/D4-D7 of the natural cycle), Late Follicular Phase (LFP/D8-D11), Ovulatory Phase (OP/D12-D15) or Luteal Phase (LP/D16-D30) compared to the standard start in Early Follicular Phase (EFP/D1-D3). Participants/materials, setting, methods From 110 randomized oocyte donors,102 reached triggering of ovulation with triptoreline acetate and OPU : EFP n = 22, MFP n = 20, LFP n = 19, OP n = 18 and LP n = 23. The sample size was calculated to show an equivalence between groups in total number of retrieved oocytes. Secondary endpoints were the number of mature oocytes, premature LH surge and Ovarian Hyperstimulation Syndrome rates. Differences were tested using a ANOVA test or a Pearson’s Chi2 test, as appropriate. Main results and the role of chance Donors were 33 [29.2-35.0] years old [95% Confidence interval] with a mean BMI of 23.4 [21.1-26.3] kg/m2. The mean number (SD) of retrieved oocytes was 14.2 (9.1). In intention to treat analysis, there was no significant difference between the 5 groups, regarding the total number of retrieved oocytes. The mean numbers of retrieved oocytes from the 5 groups were 12.5 (7.7), 13.2 (8.0), 15.7(9.8), 17.8 (11.4), and 12.8(8.3), respectively in the EPF group, the MPF group, the LPF group, the OP group and the FP group, with no significant differences between the groups (p = 0.30). The mean (SD) number of mature oocytes was 11.8 (7.6) with no significant differences between the 5 groups. Only one premature LH surge was reported in the MFP group (0.98%). Four minor to moderate OHSS were reported (3.9%). Limitations, reasons for caution The main limitation of our study is the small sample size responsible for a lack of power. But to our knowledge, this is the first RCT to compare the number of oocytes retrieved, according to the onset phase of ovarian stimulation in a random-start PPOS protocol, for oocyte donors. Wider implications of the findings The proportion of ovarian stimulation cycles with freeze-all is constantly increasing worldwide. Therefore simplified, ultra-flexible ovarian stimulation protocols could be proposed to maintain the spread of the workload along the working days without programming, with fewer injections and reduced burden for patients, with the same efficacy. Trial registration number NCT03895099

The Effect of Progesterone Elevation on the Day of Trigger Administration: A Review of the Literature.

Since the advent of assisted reproductive technology, different variables have been shown to affect pregnancy outcomes. One of the most prevalent studied events is the premature rise in serum progesterone concentrations on the day of trigger administration during cycles of ovarian stimulation. This phenomenon, classically known as premature luteinization, has been observed significantly for decades and has been linked to adverse pregnancy outcomes and lower live birth rates. Ultimately, a quest to find a precise serum progesterone concentration cut-off value that can be effectively used to predict pregnancy outcomes prior to trigger administration is still underway. The purpose of the current research was to study the available literature on the relationship between serum progesterone on the day of trigger administration in controlled ovarian stimulation cycles used for IVF in an attempt to identify a cut-off serum progesterone concentration that can be used to effectively predict future pregnancy outcomes in fresh transfers. This study is a review of the literature and is based on information and data gathered from 36 published articles. The majority of the literature shows that a serum progesterone concentration cut-off of 1.5 ng/ml (4.77 nmol/L) can be used prior to trigger administration to effectively predict pregnancy outcomes. Premature progesterone elevation on the day or prior to the trigger administration is associated with adverse pregnancy outcomes in IVF cycles. Other factors such as follicle number, serum concentration of other hormones, and ovarian response to ovarian stimulation should also be considered to predict the success of IVF protocols.