Follitropin Alfa Research Articles

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

P-656 Comparative clinical outcome following individualized follitropin delta dosing in Japanese women undergoing progestin-primed ovarian stimulation for in vitro fertilization /intracytoplasmic sperm injection

Abstract Study question Is ovarian stimulation with follitropin delta (FD) in its individualized regimen as efficacious as follitropin alfa and human menopausal gonadotropin (FAHMG)? Summary answer Ovarian stimulation with individualized FD dosing resulted in a significantly higher fertilization rate and number of blastocysts with good quality compared to conventional FAHMG dosing. What is known already Previous randomized controlled trials conducted in Japan, China, Europe, and both North and South America have demonstrated that ovarian stimulation using the individualized FD dosing regimen, which is based on serum anti-Müllerian hormone (AMH) levels and body weight, effectively modulated the ovarian response without compromising pregnancy and live birth rates. Study design, size, duration A retrospective study was conducted by reviewing the medical records of 1,720 IVF/ICSI cycles in 1,272 Japanese patients. The primary endpoint of the study was the ongoing pregnancy rate, assessed at 8 weeks of gestation, in the frozen-thawed embryo transfer. Participants/materials, setting, methods The FD treatment consisted of a fixed daily dose individualized according to each patient’s initial AMH level and body weight (AMH <2.04 ng/ml: 12 μg; AMH ≥2.04 ng/ml: 0.19 to 0.10 μg/kg; min-max 6–12 μg). The FAHMG dose was determined by the antral follicle count (AFC), with the following protocol: for AFC <25, 300 IU/day; for 40> AFC ≥25, 225 IU/day; and for AFC ≥40: 150 IU/day). A progestin-primed ovarian stimulation (PPOS) protocol was applied. Main results and the role of chance Multiple regression analyses (MRA) showed that the use of FD was negatively correlated with the number of oocytes retrieved (NOR) (P = 0.001), and positively correlated with the fertilization rate (FR) (P = 0.02). NOR was comparable between FD and FAHMG (10.9 ± 6.4 versus 11.8 ± 7.8) when the Mann-Whitney test (MW) was applied (P = 0.111), but significantly higher in FAHMG when the patient is younger than 40 years old with AMH ≥2 ng/ml (P < 0.01). The total gonadotropin use was significantly (P < 0.001) reduced from an average of 167.1 ± 46.9 μg (2789.9 ± 782.9 IU) FAHMG to 102.6 ± 31.6 μg FD. FR was significantly higher in FD compared with FAHMG (78.7% versus 74.1%, P < 0.05) on MW. Additionally, MW indicated a significantly higher number of good-quality blastocysts in FD (2.9±2.6) versus with FAHMG (2.4±2.5) (P < 0.05). The blastocysts obtained from FD also showed a significantly higher implantation rate (50.1% versus 39.7%, P < 0.01) and a comparable ongoing pregnancy rate (28.7% versus 25.7%, P = 0.292) compared to those from FAHMG as determined by chi-square test. The higher implantation rate in FD may be attributed to the greater number of good-quality blastocysts obtained compared with FAHMG. Limitations, reasons for caution This study only covered the clinical outcome of women undergoing PPOS protocol with frozen-thawed blastocyst transfers. Wider implications of the findings The present study shows that FD in its individualized fixed-dose regimen has the potential to improve the success rate in frozen-thawed embryo transfer across all ages and with a lower gonadotropin consumption compared to conventional FAHMG dosing. Trial registration number not applicable

P-680 Comparison of ovarian hyperstimulation syndrome (OHSS) rates resulting from conventional dosing versus personalized dosing of follitropin delta in ovarian stimulation, analysis of RITA, ESTHER-1 trials

Abstract Study question To compare OHSS rates with conventional dosage of follitropin delta in the RITA-1 and RITA-2 trials (hereafter ‘RITA’) to personalized dosing in the ESTHER-1 trial. Summary answer RITA and ESTHER-1 had similar efficacy and OHSS rates despite differences in dosing regimens, possibly due to differences in fresh transfer cancellation rates. What is known already Follitropin delta is a human cell-line derived follicle stimulating hormone whose fixed dosage in ovarian stimulation, personalized based upon body weight and serum anti-Müllerian hormone (AMH) and body weight, has been shown to be safe and effective in Gonadotrophin Releasing Hormone (GnRH) antagonist ovarian stimulation protocols. In the present trial, conventional dosing of follitropin delta allowing for dose revisions has been evaluated in GnRH antagonist ovarian stimulation protocols to demonstrate the broad utility of this gonadotrophin therapeutic and to address United States (US) regulatory considerations. Study design, size, duration RITA were randomized, double-blind, controlled, US multicentre trials of follitropin delta. The primary endpoint was cumulative ongoing pregnancy rate after fresh/frozen transfers within 12 months of cycle start. 1058 women 18-42 years randomized 10:1 to follitropin delta or placebo. ESTHER-1 was a randomized, European multicentre, assessor-blind, noninferiority trial of follitropin delta. The primary endpoints were fresh transfer ongoing pregnancy and implantation rates. 1329 women 18-40 years randomized 1:1 to follitropin delta or follitropin alfa. Participants/materials, setting, methods In RITA, 12 µg/day, 15 µg/day dosages were used for 4 days: 18-34 or 35-42 years, respectively, with 3 µg dose adjustments thereafter depending on response. Human chorionic gonadotropin (hCG) was used if < 20 follicles of ≥ 12 mm and estradiol level <3,000 pg/mL. Else, agonist trigger and fresh transfer cancellation; ≥20 oocytes retrieved also cancelled fresh transfer. In ESTHER-1, hCG was used if < 25 follicles of ≥ 12 mm. Else, agonist trigger, and fresh transfer cancellation. Main results and the role of chance The ongoing pregnancy rate per fresh transfer with follitropin delta was 41.9% in RITA and 36.3% in ESTHER-1. The primary efficacy endpoint was met for all 3 trials. Rates and severity defined by Golan criteria of OHSS observed in RITA and ESTHER-1 were similar, respectively for: all OHSS, any grade (3.1% versus 3.5%), Grade 1 (0.3% versus 0.5%), Grade 2 (0.8% versus 0.9%), Grade 3 (1.8% versus 1.1%), Grade 4 (0.2% versus 0.6%), and Grade 5 (0.1% versus 0.5%). The rate of early OHSS, defined as onset ≤9 days after trigger of final follicular maturation, was also similar, respectively for any grade (2.2% versus 2.6%), Grade 1 (0.3% versus 0.3%), Grade 2 (0.6% versus 0.9%), Grade 3 (1.1% versus 0.8%), Grade 4 (0.1% versus 0.3%) and Grade 5 (0.1 % versus 0.3%). However, the fresh transfer cancellation rate was >3x higher in RITA (35.2%) than in ESTHER-1 (11.1%). Limitations, reasons for caution Other reasons for transfer cancellation in all trials included adverse events or no blastocyst available for transfer; however, no significant differences were observed. A placebo comparator was selected for RITA to meet regulatory requirements for double-blinding; women with ≤3 oocytes retrieved were offered support for treatment outside of the trials. Wider implications of the findings Stimulation with follitropin delta is effective and associated with low rates of OHSS when used with either conventional or personalized dosing. However, stricter criteria for the use of hCG as trigger and allowance of fresh transfer may be required with conventional dosing to maintain this safety profile. Trial registration number NCT01956110, NCT03740737, NCT03738618

Gonadotropins in assisted reproductive technology programs: A review

Reproductive medicine is actively developing, and new methods, drugs, and protocols are being developed and introduced for the treatment of infertility. Assisted reproductive technologies (ART) are the most effective methods. In ART protocols, ovarian stimulation (OS) is based on gonadotropin use. The choice of the starting dose of gonadotropin is a critical factor in the successful OS and the effectiveness of ART programs. The article describes the development history of gonadotropins and provides current data on their use in ART programs. The use of biosimilars of follitropin alfa in OS is discussed, and the effectiveness of its Russian biosimilar is also addressed. TRANSLATE with x English Arabic Hebrew Polish Bulgarian Hindi Portuguese Catalan Hmong Daw Romanian Chinese Simplified Hungarian Russian Chinese Traditional Indonesian Slovak Czech Italian Slovenian Danish Japanese Spanish Dutch Klingon Swedish English Korean Thai Estonian Latvian Turkish Finnish Lithuanian Ukrainian French Malay Urdu German Maltese Vietnamese Greek Norwegian Welsh Haitian Creole Persian TRANSLATE with COPY THE URL BELOW Back EMBED THE SNIPPET BELOW IN YOUR SITE Enable collaborative features and customize widget: Bing Webmaster Portal Back

Determining the cost-effectiveness of follitropin alfa biosimilar compared to follitropin alfa originator in women undergoing fertility treatment in France

ObjectiveThe study assessed cost-effectiveness of follitropin alfa biosimilar versus the originator in terms of cost per cumulative live-birth (CLB) for the French healthcare system based on real-world evidence. Follitropin alfa biosimilars have been shown to have comparable clinical outcomes to the originator, in both clinical studies and real-world settings, in terms of oocyte retrieval and cumulative live-birth rate (CLBR). Previous health economic studies comparing the cost-effectiveness of follitropin alfa biosimilars against the originator utilised clinical trial data, leaving ambiguity over cost-effectiveness in real-world settings. Additionally, previous cost-effectiveness analysis has been performed for live-births following only fresh embryo transfers, whereas, fresh and frozen transfers are common in clinical practice. This study investigates the cost per CLB, which more closely models clinical practice. Study designA decision-tree cost-effectiveness model was developed based on the total costs and CLBR per ovarian stimulation (OS) for a follitropin alfa biosimilar (Bemfola®, Gedeon Richter Plc, Budapest, Hungary) and the originator (Gonal-f®, Merck KGaA, Darmstadt, Germany). A time horizon of one year from oocyte retrieval to embryo transfer was used but costs from resulting transfers were also included. Clinical inputs were taken from the REOLA real-world study or clinician insights, while acquisition costs were taken from French public databases. The output was cost per CLB following one OS. One-way sensitivity analysis was performed to determine the largest model drivers. ResultsCost per CLB was €18,147 with follitropin alfa biosimilar and €18,834 with the originator, saving €687 per CLB following OS with the biosimilar. When wastage estimates were considered the biosimilar cost saving is estimated to be between €796 and €1,155 per CLB further increasing cost savings. Irrespective of wastage, if used ubiquitously throughout France for ART, the biosimilar could save the French health system €13,994,190 or lead to 771 more births when compared to its higher-cost originator. Sensitivity analysis showed that the originator’s relative CLBR had the greatest impact on the model. ConclusionThis analysis demonstrates that the follitropin alfa biosimilar, Bemfola®, is a more cost-effective option for OS compared with the originator from a French healthcare payer perspective, in terms of cost per CLB.

Experience in using biosimilars in IVF programs with donor oocytes in protocols with micronized progesterone

Relevance: Stimulation of oocyte donors' superovulation occupies a key place in the development of general assisted reproduction technology (ART). Oocyte donation programs involve young and healthy women undergoing severe ovarian stimulation protocols to obtain good-quality oocytes. Advances in recombinant DNA technology led to the development of recombinant follitropin alfa.The study aimed to evaluate the effectiveness of the biosimilar folitropin alfa in the superovulation stimulation cycles of oocyte donors in comparison with the original medication in Progestin primed ovarian stimulation (PPOS) protocols.Materials and Methods: A prospective cohort study included 25 oocyte donors who underwent superovulation induction. The first group consisted of 25 oocyte donors in whom superovulation was stimulated with a bio-analogue of follitropin alfa. The second group (control) included the same 25 oocyte donors stimulated with the original rFSH medication. The donors of the leading group were stimulated with biosimilar recombinant follicle-stimulating hormone and human menopausal gonadotropin. For the control group, a protocol was used using the original drug rFSH and CHMG in the same doses. The obtained donor oocytes were fertilized with ICSI or frozen. The program's result was determined by taking a blood test for b-hCG 14 days after embryo transfer.Results: The number of mature oocytes in the study groups did not differ significantly, amounting to 20.6 ± 1.1 in group 1 and 21.2 ± 1.3 in group 2. The average number of fertilized oocytes in group 1 was 5.6 ± 0.8, and in group 2 – 6.1 ± 1.1; thus, the fertilization rate in the two groups did not differ (67,5% in group 1 vs 79,2% in group 2, р> 0,05). The blastulation rate (49.1% in group 1 and 52.2% in group 2) did not differ significantly in both the biosimilar group and the original medication. The Top Quality Blastocysts in Group 1 were 1.5 ± 0.7 (55%) vs 1.8 ± 0.5 (48%) in Group 2. At the same time, the level of NNB in both groups also had no statistically significant differences.Conclusion: Sinnal-F was not inferior to the original medication in terms of the proportion of mature oocytes in oocyte donors. The study's results confirm that Synnal-f demonstrates favorable and comparable efficacy to the original medication in oocyte maturation in IVF/ICSI cycles.

Dose accuracy of the follitropin alfa pen injector 2.0, the follitropin alfa:lutropin alfa 2:1 combination pen injector 2.0 and the choriogonadotropin alfa pen injector 1.0 used for fertility treatment

ABSTRACT Background This study aimed to confirm that the incremental dose/clicks system dispenses accurate doses for the Merck family of fertility pen injectors. Research design and methods Set doses (Vset) for three dose dial settings (minimum dose [Vmin], midpoint dose [Vmid] and maximum dose [Vmax] for the follitropin alfa, choriogonadotropin alfa [D2 classification: single use/variable dose], and follitropin alfa:lutropin-alfa 2:1 combination pen injectors) or a single Vset for the choriogonadotropin alfa (D1 classification: single use/single dose) were assessed. Last dose administered by the multi-dose device was assessed for the 900 IU, 450 IU, 300 IU and 150 IU follitropin alfa, and the 900:450 IU, 450:225 IU and 300:150 IU follitropin alfa:lutropin-alfa 2:1 combination pen presentations. Results Dose accuracy tests for Vmin, Vmid and Vmax for the follitropin alfa and the follitropin alfa:lutropin-alfa 2:1 combination pen injectors, and last dose administered, were within acceptable limits according to ISO 11,608-1:2012/2014. Dose accuracy tests for the single use/single dose device classification and the single use/variable dose device classification of the choriogonadotropin alfa pen injector were also within the acceptable limits, according to ISO 11608-1:2000/2014. Conclusions The Merck family of fertility pen injectors functions reliably and the incremental dose/clicks system dispenses accurate doses.

Recombinant Human Follicle-Stimulating Hormone in Controlled Ovarian Hyperstimulation with Assisted Reproductive Technology in China: A Cost-Effectiveness Analysis.

To compare the cost-effectiveness of originator (reference) recombinant human follicle stimulating hormone alfa (rhFSH-α) (follitropin alfa, GONAL-f) and its biosimilar (rhFSH, JinSaiHeng) in assisted reproductive technology (ART) from a Chinese patient perspective. A decision tree model was developed to simulate the treatment pathway of infertile women undergoing ART using GONAL-f or JinSaiHeng. Published clinical and cost data were used to evaluate the cost-effectiveness of the rhFSH-α. The cumulative live birth rate (CLBR), direct medical costs and costs per cumulative live birth were estimated via an analytic decision-tree model. CLBR of GONAL-f was higher than JinSaiHeng preparation (88.3% vs 84.4%), while the cost per cumulative live birth was lower (51,475 vs 52,095 CNY). The originator rhFSH-α was associated with higher CLBR and lower cost per cumulative live birth, with incremental cost per additional live birth of 38,096 CNY (Chinese Yuan).

Comparing CIDR with progesterone injections and eCG with human recombinant FSH for synchronizing estrous cycle in ewes.

It is desirable in estrus synchronization in sheep to avoid intravaginal devices and to shorten the program from 14 to 6 days. Moreover, replacement of eCG with safe, cheap, and efficient gonadotropin is in worldwide demand. This study investigates the possibility of replacing eCG with human recombinant FSH (hrFSH) and CIDR with progesterone injections for estrous synchronization in ewes. Assaf and Lacaune ewes (n=170) were divided into two groups and synchronized with either progesterone injections for 6 days or CIDR for 14 days. Ewes assigned in the injection group, received progesterone (37.5 mg; SC) and GnRH analogue (7.5 µg Alarelin acetate; IM) on day 0 of the experiment. On days 3 and 6, ewes received 25 and 12.5 mg progesterone (SC), respectively. On day 6, ewes in both groups received prostaglandin F2α (250 µg Cloprostenol; IM), and were divided into two subgroups to receive either hrFSH (75 IU Follitropin alfa; SC) or eCG (400 IU; IM). On day 7, fertile rams were introduced to ewes for 21 days. Data were analyzed using GLM and Glimmix. There was no difference in the respective lambing rates, prolificacy, and fecundity between CIDR (71.1, 1.63, and 1.16%) and injections (66.7, 1.55, and 1.03%); between eCG (71.4, 1.60, and 1.14%), and hrFSH (66.3, 1.58, and 1.05%, P>0.05). In conclusion, 6-day progesterone injection-based protocol produced similar results to 14-day CIDR program and hrFSH could be an effective alternative for eCG during estrus synchronization in ewes.

Clinical outcomes of three follitropin alfa preparations for ovarian stimulation using an oral micronized progesterone-primed protocol in an oocyte donation program.

This large multicenter study aimed to evaluate clinical outcomes using three follitropin alfa preparations within a progestin-primed ovarian stimulation (PPOS) protocol, while identifying contributing factors to cycle success. A retrospective, anonymized cohort analysis was conducted on donor-recipient cycles from 12 clinics during 2019 to 2021. 7389 oocyte donors underwent ovarian stimulation (OS) with three follitropin alfa preparations (Ovaleap® [n=3231], Bemfola® [n=3542], Gonal-F® [n=616]) were included. Stimulation began on cycle days 2 or 3 with daily administration of 150-225 IU follitropin alfa. 10 mg medroxyprogesterone acetate (MPA) was administered daily until GnRH agonist trigger using a single dose of 0.2mg GnRH agonist for final follicular maturation. Statistical analysis included ANOVA, Chi-squared, and logistic regression. Whilst there were some differences in patient and stimulation characteristics, including donor age and number of retrieved oocytes, clinical variables did not significantly differ among the three study groups. Linear regression revealed donor age [0.986 (0.974-0.999)] and number of mature oocytes [1.027 (1.007-1.047)] significantly impacted ongoing pregnancy rates, while the type of follitropin alfa [1.048 (0.956-1.149)] used did not. No significant differences were observed in the cumulative live birth rate (CLBR) among oocytes obtained from stimulation with Bemfola (64.9%), Gonal-F (64.1%) and Ovaleap (66.1%), p= 0.385. This study demonstrated comparable clinical outcomes and CLBR between biosimilars and the reference product of follitropin alfa within PPOS protocols, hence they are interchangeable in a real-world patient setting.

#317 : The Clinical Outcome of Ovarian Stimulation Undergoing Intrauterine Insemination with Follitropin Delta in Indonesian Women

Background and Aims: Intrauterine insemination (IUI) has been widely used as a common treatment for infertile couples due to its simplicity and low cost. Numerous studies have shown that IUI cycles with controlled ovarian stimulation (COS) result in higher pregnancy rates compared to those without COS. Follitropin delta, a novel recombinant FSH (rFSH) can be used for controlled ovarian stimulation in women undergoing assisted reproductive technologies (ART) and was dosed individually based on serum anti-Müllerian hormone (AMH) concentration and body weight. In this study, we used a simplified dosage equivalent method. The aim of this study was to compare the efficacy and safety of follitropin delta in its simplified dosage equivalent regimen with follitropin alfa in a conventional dose regimen in Indonesian women undergoing intrauterine insemination. Method: A single-center, retrospective observational study from January 2020 to December 2022 was performed in 228 IUI cycles in Halim Fertility Center, Indonesia. Controlled Ovarian Stimulation was performed during IUI cycles and divided into two groups: group I received follitropin delta with a simplified dosage equivalent regimen, and group II received follitropin alfa with a conventional dose. The baseline characteristics, cycle parameters, and IUI outcomes of both groups were compared. Results: Our study included 228 IUI cycles with the follitropin delta group (114 IUI cycles) and the follitropin alfa group (114 IUI cycles). The clinical pregnancy rate was higher in the follitropin delta than the follitropin alfa but there was no significant difference between the groups (p>0.05). The multiple pregnancy rate and Ovarian Hyperstimulation Syndrome (OHSS) rates were lower in follitropin delta than follitropin alfa but there was no significant difference between the groups (p>0.05). Conclusion: Follitropin delta with a simplified dosage equivalent regimen showed higher efficacy and similar safety compared with follitropin alfa in conventional dosing regimen in Indonesian women undergoing Intrauterine insemination.

#243 : Comparison of IVF Outcome Following Follitropin Alfa and Follitropin Delta Utilization at Melati Clinic, Harapan Kita Women and Children Hospital

Background and Aims: Follitropin delta is the third recombinant FSH (rFSH) preparation developed with an individualized dosing regimen based on patient’s body weight and AMH level. According to the existing report, a daily dose of follitropin delta provides an equivalent ovarian response to that of follitropin alfa. However, the effect of follitropin delta on the resulting embryo and biochemical pregnancy remains to be elucidated. Hence, the present study aims to evaluate the effect of follitropin delta on embryo quality and biochemical pregnancy rates compared with that of follitropin alfa in an in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycle. Methods: A retrospective cohort study was conducted between January and December 2022 at Melati Clinic, Harapan Kita Women and Children Hospital. A total of 59 IVF/ICSI cycles stimulated with follitropin alfa and 26 IVF/ICSI cycles treated with follitropin delta were subsequently analyzed. Results: After analysis, no significant difference was observed regarding the embryo quality of both treatments (P>0.05). The median of the good, moderate, and poor embryos in the follitropin alfa and follitropin delta group was 2 vs. 3, 1 vs. 2, and 2 vs. 2, respectively. Similarly, the biochemical pregnancy rate between the follitropin alfa and follitropin delta group was comparable (25% vs. 15%, P>0.05). Conclusions: In conclusion, our study suggests that stimulation with follitropin delta in IVF/ICSI cycles yields a similar embryo quality and biochemical pregnancy rates to those of follitropin alfa.

#394 : The Efficacy of an Individualized Dose of Follitropin Delta on Ovary Reproductive Stimulation and Clinical Outcomes

Background and Aims: Follitropin delta is the third recombinant human follicle-stimulating hormone (r-hFSH) expressed in a host cell line of human fetal retinal origin that currently emphasizes that the actual tendency of administration is a personalized dosing algorithm based on the anti-Mullerian hormone (AMH) and body mass index (BMI) for ovarian stimulation. Methods: In this present manuscript, we aimed to gather all available data published between 2018–2022 regarding the co-administration and administration of follitropin delta and the clinical outcomes reported following an in vitro fertilization (IVF). Results: Follitropin delta is non-inferior in contrast to its previously launched agents for ovarian stimulation, enhancing a similar-to-superior response reflected by both the reproductive and pregnancy outcomes in parallel with a low risk of ovarian hyperstimulation syndrome (OHSS), being well tolerated. The body weight and AMH level are factors that may influence the outcome in a patient. Despite controversy and results that refute these arguments on several occasions, follitropin delta exceeds the benefits of conventional dosing with either follitropin alfa or follitropin beta. Therefore, all post hoc derived analyzes and subgroups of patients who participated in subsequent studies support this statement. Conclusion: Despite the relatively limited range of data in the current literature, most authors provide strong evidence to support the later use of this drug according to patient profiles and overcoming ethnic limitations. Others disagree with these observations, but this topic and this drug have great potential. As such, additional research is needed to fill existing knowledge gaps and extend this experience to a larger scale. Demonstrate overcoming all limitations.

Effects of Low Luteinizing Hormone Serum Levels on Oocyte Retrieval, Fertilization Rate, and Embryo Quality during Controlled Ovarian Stimulation: Results from a Prospective Cohort Analysis

Objectives: Luteinizing hormone (LH) plays a key role in normal follicular development and oocyte maturation in controlled ovarian stimulation. LH stimulates the proliferation and differentiation of theca cells for the secretion of androgens, synergistically increasing estrogen production. This study aimed to investigate the effects of low LH concentrations on oocyte retrieval, fertilization, and embryo development in patients undergoing in vitro fertilization/intracytoplasmic sperm injection. Design: We prospectively (ClinicalTrials ID: NCT05755529) analyzed patients undergoing in vitro fertilization/intracytoplasmic sperm injection, subdividing them into three groups according to their age. Serum LH levels were evaluated on day 3, during stimulation (day 10) and before ovulation induction (day 12). Participants/Materials, Setting, Methods: Forty-three consecutive women were scheduled for IVF and received ovarian stimulation with follitropin alfa (Gonal F, Merck Serono, Germany) and ganirelix (Fyremaldel, Sun Pharma, Italy). Statistical analysis was performed with InStat 3.10, GraphPad software, San Diego, CA, USA. Normal distribution was tested by the Shapiro-Wilk test. Continuous variables were expressed as the mean and standard deviation. Categorical variables are expressed as frequencies and percentages. Results: Our data analysis suggests that serum LH levels progressively decrease during controlled ovarian stimulation, and this effect is more evident in the early phase of this procedure. From this perspective, circulating LH levels may significantly decrease during the late follicular phase due to the negative feedback of ovarian hormones from multiple follicular developments or after the suppressive effects of gonadotropin-releasing hormone antagonists. Limitations: Although our study confirms that exogenous LH can be considered a strategy in women with reduced LH levels during ovarian stimulation to improve oocyte quality and reproductive outcome, the generalizability of the results is limited by the low number of participants enrolled. Conclusions: Exogenous LH may be considered a strategy in women with a decrease in LH levels during ovarian stimulation to improve oocyte quality and reproductive outcome.

P-630 Comparison of follitropin delta versus follitropin alfa in progestin-primed ovarian stimulation in IVF

Abstract Study question Is there a difference in a clinical outcome between using follitropin delta and follitropin alfa undergoing a progestin primed ovarian stimulation (PPOS) protocol? Summary answer There was no difference between follitropin delta and follitropin alfa in terms of pregnancy rates. What is known already Follitropin delta (REKOVELLE, Ferring Pharmaceuticals, Switzerland) is the first recombinant human follicle-stimulating hormone (FSH) using the algorithm-based individualized dosing regimen while reducing the risk of ovarian hyperstimulation syndrome (OHSS) as compared with conventional dosing strategies. The efficacy and safety of follitropin delta has been demonstrated in randomized controlled trials (RCTs). Study design, size, duration We performed a retrospective analysis of 645 patients who underwent ovarian stimulation by a PPOS protocol using follitropin delta or follitropin alfa between April 2022 and August 2022. (325 patients using follitropin delta and 320 patients using follitropin alfa, respectively.) Participants/materials, setting, methods 325 cycles of women who used follitropin delta were compared to 320 cycles of women who used follitropin alfa. The following outcomes were analysed; fertilized rate, 2 pronuclear embryo rate, good quality embryo rate, blastocyst rate, good quality blastocyst rate. A total of 499 women who underwent embryo transfer in cryo cycles using natural cycle or hormone replacement cycle were analysed about biochemical pregnancy rate, clinical pregnancy rate. Main results and the role of chance Baseline demographics for 325 women in follitropin delta group and 320 women in follitropin alfa were: age, 35.1±4.3 years and 35.2±4.3 years; number of previous IVF cycles, 1.6±1.6 and 1.7±1.7, respectively. The laboratory data were: fertilization rate, 81.4% and 80.1%, 2 pronuclear embryo rate, 73.9% and 71.5%, good quality cleavage stage embryo rate, 59.4% and 55.9%, blastocyst rate, 58.9% and 55.7%, good quality blastocyst rate, 41.3% and 38.7%, respectively. Only good quality cleavage stage embryo rate and good quality blastocyst rate were significantly higher (P < 0.05) in follitropin delta group. A vitrified-warmed embryo transfer was performed for 257/325 women (79.1%) and 242/320 women (75.6%) and subsequent positive β-human chorionic gonadotropin (βhCG) reported for 218/621 cycles (35.1%) and 194/570 cycles (34.0%), respectively. Ongoing pregnancy rate after embryo transfer were 19.2% (n = 119) and 19.6% (n = 112) and cumulative ongoing pregnancy rate were both 46.3%. Mild OHSS was reported for 131 women (40.3%) and 170 women (53.1%), respectively (P = 0.07). Limitations, reasons for caution This is a non-controlled, retrospective study. Wider implications of the findings The present study shows that in addition to reducing the OHSS risk, follitropin delta in its individualised fixed-dose regimen has the potential to improve the quality of embryos although there was no significant difference in clinical outcomes. Trial registration number not applicable

P-183 Blastocyst speed versus blastocyst look: Which is the better predictor of clinical pregnancy and live birth following time-lapse culture and single blastocyst transfer?

Abstract Study question To compare predictive value for pregnancy and live birth of morphological versus morphokinetic assessment of blastocysts after time-lapse culture and single blastocyst transfer. Summary answer Blastocyst morphokinetic assessment was not superior in predicting pregnancy and live birth compared to blastocyst morphology, but provides additional information, particularly for morphologically poorer-quality blastocysts. What is known already Blastocyst culture with time-lapse technology enables evaluation of both morphokinetic developmental speed and classical morphology including Gardner scoring of the blastocyst. One approach to assess the developmental speed of blastocysts is to use the morphokinetic classification proposed by Campbell, Fishel, et al., based on time to start of blastulation (tSB) and the duration of forming the blastocyst (dB). However, beyond the advantages of undisturbed embryo culture, the value of the kinetic data from time-lapse is debated. Study design, size, duration EDCOS (Embryo Developmental profiles from Controlled Ovarian Stimulation cycles using follitropin alfa) is a multicentre, prospective cohort study of patients undergoing IVF/ICSI whose embryos were cultured in time-lapse incubator devices in 10 ART centres throughout Denmark and Sweden. Patients undergoing IVF/ICSI (including donor oocyte cycles) who had ovarian stimulation with follitropin alfa (Bemfola®) and had zygotes and embryos available for monitoring in the EmbryoScope™ time-lapse incubator device (Vitrolife) were invited to join this study. Participants/materials, setting, methods Morphological and morphokinetic prognostic classifications for single blastocyst transfers (SET) were determined for three study subpopulations: fresh autologous SET (311 women), frozen autologous SET (246 women; 345 transfers) and frozen donor SET (38 women; 59 transfers). All blastocysts were graded morphologically in five grades from Amorph (best) to Emorph (worst) based on their Gardner score and morphokinetically in three grades from Akin (best) to Ckin (worst) based on tSB and dB. Main results and the role of chance Overall ongoing pregnancy and live birth rates (OPR/LBR) for morphokinetic classifications Akin, Bkin and Ckin were 36.1%, 30.0% and 16.3% (P = 0.021) and 30.4%, 21.8% and 9.1% (P = 0.000), respectively. OPR and LBR for morphological classifications Amorph, Bmorph, Cmorph, Dmorph and Emorph were 41.9%, 37.8%, 30.8%, 19.0% and 15.6% (P = 0.000) and 36.6%, 29.1%, 15.6%, 16.5% and 8.3% (P = 0.002), respectively. For Dmorph blastocysts, OPR and LBR for morphokinetic classifications Akin, Bkin and Ckin were 50%, 21.4% and 7.1% (P = 0.009) and 33.3%, 10.8% and 0% (P = 0.003), respectively. Receiver operating characteristic curve analyses achieved areas under the curve for fresh autologous SET of 55.7%, 58.9% and 67.2% for the morphokinetic, morphological and combined classifications, respectively; and 53.4%, 64.0% and 65.6%, respectively, for frozen autologous SET. Limitations, reasons for caution This was an observational study with no control group, conducted under usual clinical practice. Data were collected prospectively, although clinics could deselect and rank blastocysts according to their own procedures. However, the outcome of subsequent frozen blastocyst transfer cycles was also analysed. Wider implications of the findings Selection of a blastocyst for transfer based on morphokinetic assessment at the blastocyst stage was not superior to classical blastocyst morphological assessment after time-lapse culture but is a viable option. Combining morphokinetic and morphological evaluation provides additional supporting information to guide in blastocyst selection, especially for morphologically poorer-quality blastocysts. Trial registration number Not applicable

P-693 Retrospective evaluation of the effect of the implementation of the DIVINE dose-calculator in daily practice on ovarian hyperstimulation treatment risk and live birth rate

Abstract Study question Does the implementation of the DIVINE dose-calculator in routine care decrease treatment risk due to ovarian hyperstimulation whilst maintaining treatment efficacy? Summary answer The implementation of the DIVINE dose-calculator significantly decreases treatment risks caused by ovarian hyperstimulation, without affecting treatment efficacy in terms of live birth. What is known already Meta-analyses show that tailoring the gonadotropin starting dose did not affect live birth rates, but reduced treatment risks. The ORT iOS IPD-MA study group used individual participant data to develop and validate a model for ovarian stimulation in IVF/ICSI: the DIVINE dose-calculator. This model scored adequate for assessing hyperstimulation treatment risk and poor for predicting live birth. It provides clinicians an overview of risk percentages per gonadotropin starting dose, which aids in selecting an appropriate, personalized gonadotropin starting dose. This model should be implemented in routine care to confirm the true clinical effect on treatment risk and live birth results. Study design, size, duration Retrospective cohort study using pseudonymized data in two fertility centers in The Netherlands. The dose-calculator was implemented on 15th February 2021. Data from 36 months before and 12 months after implementation were collected. The dose-calculator included female age, AMH and GnRH-type in order to select a starting dose between 100-225 IU. Baseline characteristics and fresh cycle treatment outcomes were extracted from the patient file, checked and cleaned. Missing data were imputed 50 times. Participants/materials, setting, methods Subfertile women younger than 38 years, starting their first IVF/ICSI treatment cycle with follitropin alfa or beta were included. Couples who did not plan to receive a fresh embryo transfer, women diagnosed with PCOS and couples undergoing limited insemination or PGT were excluded. Intention-to-treat and per protocol analyses were completed. Inverse propensity weighting was applied to balance confounders. Weighted regression was then performed using general linear models or ordered logistic regression models. Main results and the role of chance 493 women were included, 401 in the standard group and 92 in the dose-calculator group (per protocol analysis). There was no difference in live birth rate before and after implementation: 25.4% vs 25.0% respectively (OR: 1.01, 95% CI: 0.6 – 1.71). Ovarian hyperstimulation treatment risk clearly decreased after the implementation of the dose-calculator from 11.3% in the pre-implementation period to 4.3% in the post-implementation period (OR: 0.27, 95% CI: 0.08 – 0,91), of which OHSS incidence declined from 6.8% to 0% after implementation. Pre-implementation, women stimulated 1.0 day shorter as compared to the post-implementation period (MD, CI: 0.25 – 1.75), and used 200 IU gonadotropins less per cycle (MD, 95% CI: 48.68 – 352.11). The cancellation rate due to low ovarian response were equal pre- versus post-implementation (OR: 0.94, 95% CI: 0.45 – 1.98) as well as the cancellation rate due to high ovarian response (OR: 0.56, 95% CI: 0.11 – 2.84). Post-implementation 1.05 less oocytes were collected during follicle aspiration (MD, 95% CI: -2.51 – 0.41), which resulted in 0.41 less usable embryos (MD, 95% CI: -1.04 – 0.17). The usable embryo per oocyte was comparable (MD: 0.003, 95% CI: -0.061 – 0.067). The intention-to-treat analysis confirmed these results. Limitations, reasons for caution Results are preliminary and based on single center data. We expect to finalize the analyses including approximately 100 patients from the second center and a cost-effectiveness analysis before ESHRE 2023. Unfortunately, cumulative cycle results including cryopreserved embryo transfers and subsequent treatment cycles are not available. Wider implications of the findings The dose-calculator aids in optimizing ovarian stimulation, without compromising live birth prospects. It is an easy to use model, which substantially reduces risks caused by ovarian hyperstimulation. A free of charge mobile application will be developed to stimulate implementation. Future research should address cumulative cycle results and temporal/geographical validation. Trial registration number Not applicable

P-679 Controlled ovarian stimulation using follitropin delta results in higher cumulative live birth rate compared to follitropin alfa/beta in a large prospective real world dataset

Abstract Study question Does IVF/ICSI-treatment using follitropin delta (hrFSH) result in higher pregnancy rates (PR) or live birth rates (LBR) compared to follitropin alfa/beta (recFSH)? Summary answer Real world data (RWD) from a large prospective German registry study shows that using hrFSH results in higher pregnancy rates compared to recFSH. What is known already Follitropin delta represents a new recombinant FSH derived from a human cell line. Contrary to follitropin alfa or beta, follitropin delta has a glycolysation pattern consisting of α2,3- and α2,6-linked sialic acids which is more similar to native human FSH. Follitropin delta is approved for use with an individualized dosing algorithm based on serum AMH and body weight, targeting an optimal ovarian response (8-14 oocytes). Efficacy and safety have been demonstrated in numerous clinical trials. Moreover, Follitropin delta seems to reduce the risk of OHSS although its safety with respect to ovarian hyperstimulation using RWD remains to be investigated. Study design, size, duration The German IVF Registry collects prospectively data about IVF/ICSI-treatments from 140 German IVF centers. The underlying analysis of RWD includes controlled ovarian hyperstimulation cycles that have been performed in Germany between 2017-2021. Study groups were built subject to the gonadotropin used for stimulation, irrespective of previous treatments: (1) hrFSH, n = 3002, (2) recFSH, n = 135293. “Pregnancy” was defined as clinically assessed, intrauterine pregnancy, including miscarriages. Biochemical pregnancies were not defined as “pregnant”. Ectopic pregnancies (n = 558) were excluded. Participants/materials, setting, methods PR and LBR were calculated subject to the number of embryo transfers (ET) (n = 2062 (rFSH) vs. n = 103357 (recFSH)) after excluding freeze-all cycles, (n = 529 (hrFSH) vs. n = 13682 (recFSH)) and cycles that ended without ET (n = 411 (hrFSH) vs. n = 18254 (recFSH)). The collected data were saved in compliance with the applicable data processing regulations. Statistical analysis was performed using Fishers-exact- and students-t-test and Microsoft Excel, whereas p < 0.05 was defined as significant. Main results and the role of chance There was no difference between the study groups regarding age (33.9 ± 4.00y (hrFSH) vs. 33.8y±4.34y (recFSH), p = 0.12) or infertility diagnosis. Stimulation with hrFSH resulted in a higher number of oocytes (11.15±7.2 vs. 10.39±7.01, p < 0.01). Antagonist protocol was used less often in the hrFSH-group (78% (2344/3002 vs. 80% (109217/135293), p < 0.01). PR in 2021 were higher (39.2% (222 pregnancies / 567 embryo transfers) vs. 35.2% (6837/19420), OR = 1.18 [0.99-1.41] p = 0.05) while using hrFSH compared to recFSH. The effect was even stronger when comparing patients aged 30-34y (46.2% (98/212) vs. 38.6% (2967/7865), OR = 1.41 [1.07-1.88], p = 0.01). Another quantitative difference could be observed for patients aged 30-34y in their first IVF/ICSI-cycle (PR 48.5% (63/130) vs. 39.5% (1926/4873), OR = 1.44 [1.00-2.07], p = 0.05). Including all cycles between 2017-2021 resulted in higher PR for couples treated with hrFSH (38.3% (790/2062) vs. 36.2% (37439/103357), OR = 1.09 [1.00-1.20], p = 0.049). Cumulative PR including consecutive frozen embryo transfers after the first stimulation showed significantly higher PR while using hrFSH (81.6% (422/517) vs. 71.3% (17373/24367), OR = 1.79 [1.42-2.23], p < 0.01). Finally, cumulative LBR per ET was significantly increased if hrFSH was used for ovarian stimulation (60.0% (310/517) vs. 51.9% (12648/24367), OR = 1.39 [1.16-1.66], p < 0.01) compared to recFSH. Limitations, reasons for caution Since we analyzed RWD, comparison with large clinical trials should be considered carefully. PR and LBR was calculated only using stimulations which successfully generated ET. Moreover, individual AMH values are not transmitted to the German IVF Registry. Therefore, difference in ovarian reserve between study groups can’t be excluded. Wider implications of the findings In this large, prospective RWD, higher cumulative LBR and PR using hrFSH compared to recFSH, irrespective of age or infertility diagnosis, supports the use of individualized fertility treatment approach based on hrFSH. These results are consistent with previous retrospective findings. Trial registration number Not applicable

Differences in Follicle Development and Hormone Dynamics Between Controlled Ovarian Stimulation (COS) Using Follitropin Delta and that Using Follitropin Alfa

Background: We compared the performance of follitropin delta and follitropin alfa in the gonadotropin-releasing hormone (GnRH) antagonist protocol for controlled ovarian stimulation (COS) and discussed the distinctive features of follitropin delta in COS. Methods: Patients underwent COS using the GnRH antagonist protocol with either recombinant follicle-stimulating hormone (FSH) and oocytes were retrieved. We compared the results of COS, oocyte pick up, fertilization, embryo culture, and clinical pregnancy between the follitropin alfa group and the follitropin delta group. Results: The serum estrogen level at trigger was significantly lower in the delta than in the alfa group (3,576.69 ± 1,775.60 vs. 2,833.19 ± 1,567.88) as was serum P4 level (2.14 ± 1.26 vs. 1.19 ± 0.85). The stimulation duration (in days) were longer (12.97 ± 2.38 vs. 13.96 ± 2.26) and total gonadotropin dose significantly lower (199.69 ± 54.47 vs. 114.27 ± 39.92), respectively, in the delta group than in the alfa group. The ovarian hyperstimulation syndrome (OHSS) rate was significantly lower in the delta than in the alfa group (48.1% vs. 58.6%). Fertilization, good blastocyst, and clinical pregnancy rates were not significantly different. COS using follitropin delta is characterized by significantly slower follicle development than COS using follitropin alfa. A comparison of developing follicles showed that the minimum follicle was significantly smaller in the delta group on days 6–8 of COS. The maximum follicle was significantly smaller in the delta group on days 6–8 and 11–13 of COS. The number of follicles larger than 14 mm was significantly lower in the delta group on days 6–8 of COS. Conclusions: Using follitropin delta is associated with slow follicular development, slow serum E2 elevation, and longer stimulation duration; however, excessive elevation of serum estrogen levels during COS is reduced and so is the incidence of mild OHSS.