Cumulative Ongoing Pregnancy Rate Research Articles

O-202 Novel use of hyaluronan enriched media for improving implantation in intrauterine insemination: a prospective randomised controlled trial (HEMI Trial)

Abstract Study question Does the intrauterine instillation of hyaluronan-enriched media influence the implantation rate and reproductive outcomes in patients undergoing controlled ovarian stimulation and intrauterine insemination? Summary answer The intrauterine instillation of Hyaluronan-enriched media significantly improved the implantation rates and ongoing pregnancy rate in women undergoing controlled ovarian stimulation and intrauterine insemination treatment What is known already Hyaluronan is a macromolecule belonging to the glycosaminoglycans family, secreted by cumulus granulosa cells, and is naturally present in the female reproductive tract. Various mechanisms have been proposed to explain the implantation-enhancing properties of Hyaluronan including increased cell-cell and cell-matrix adhesion, by producing a viscous environment for the integration of embryo in intrauterine fluid and its autocrine and paracrine functions via CD44 receptors. This is probably the first trial studying the effect of hyaluronan-enriched media in intrauterine insemination treatment. The proposed novel intervention is based on the biological plausibility and proven safety of hyaluronan in IVF studies. Study design, size, duration This parallel group Randomised Controlled trial was conducted over 2 years of duration, from 2021 to 2023. A total of 100 couples diagnosed with unexplained infertility planned for controlled ovarian stimulation and intrauterine insemination (COS-IUI) treatment were randomized into the intervention and control arm of the trial. Before the commencement of the study, the trial was registered with the Clinical Trial Registry-India (CTRI), and institutional ethical approval was obtained. Participants/materials, setting, methods 100 couples diagnosed with unexplained infertility attending tertiary-level university hospital were allocated to the intervention and control group using block randomization in 1:1 allocation. In the intervention group, the participants underwent intrauterine instillation of 0.4 ml of hyaluronan enriched media, 4 days following intrauterine insemination treatment. The statistical package SPSS (version 21) was used for analysis and results were considered to be statistically significant if the P-value was <0.05. Main results and the role of chance The mean female age of the study population was 28.12±3.74 years with an average duration of infertility of 3.95 ±2.17 years. The study participants underwent an average of 1.7 IUI cycles in the control group and 1.6 cycles in the intervention group. A cumulative biochemical pregnancy rate of 36.5% and 16.6% was observed amid the the intervention group and control group respectively and the difference was statistically significant with a p-value of 0.039. Similarly, the cumulative ongoing pregnancy rate beyond 20 weeks of gestation was statistically significantly higher among the intervention arm of the trial as compared to the control group (31.7% vs 11.9%, p = 0.035). There was a trend of improved clinical pregnancy rate among the intervention participants, however, this difference did not reach statistical significance (34.1% vs 16.6%, p = 0.067). The miscarriage rate was comparable among both groups. The number needed to treat was estimated to be 5, which in effect meant that 5 women would have to receive intrauterine instillation of hyaluronan enriched media for 1 additional ongoing pregnancy. Limitations, reasons for caution The longer follow-up period would have allowed the reporting of live-birth rate which is undeniably the most meaningful parameter to appraise an intervention. Larger multicentric studies are required to establish the clinical benefit and generalisability of the proposed intervention. Wider implications of the findings The study proposes a potential novel, simple, minimally invasive, and patient-acceptable intervention to increase the success rates of intrauterine insemination. Being the first study on the topic, the study can provide a basis for future large multicentric studies on the topic. Trial registration number Clinical Trial Registry-India (CTRI) number- CTRI/2021/10/037064.

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

Living in a low socioeconomic status neighbourhood is associated with lower cumulative ongoing pregnancy rate after IVF treatment

Research questionDoes an association exist between neighbourhood socioeconomic status (SES) and the cumulative rate of ongoing pregnancies after 2.5 years of IVF treatment? DesignA retrospective observational study involving 2669 couples who underwent IVF or IVF and intracytoplasmic sperm injection treatment between 2006 and 2020. Neighbourhood SES for each couple was determined based on their residential postal code. Subsequently, SES was categorized into low (<p20), medium (p20–p80), and high (>p80). Multivariable binary logistic regression analyses were conducted, with the cumulative ongoing pregnancy within 2.5 years as the outcome variable. The SES category (reference category: high), female age (reference category: 32–36 years), body mass index (reference category: 23–25 kg/m2), smoking status (yes/no), number of oocytes after the first ovarian stimulation, embryos usable for transfer or cryopreservation after the first cycle, duration of subfertility before treatment and insemination type were used as covariates. ResultsA variation in ongoing pregnancy rates was observed among SES groups after the first fresh embryo transfer. No difference was found in the median number of IVF treatment cycles carried out. The cumulative ongoing pregnancy rates differed significantly between SES groups (low: 44%; medium: 51%; high: 56%; P < 0.001). Low neighbourhood SES was associated with significantly lower odds for achieving an ongoing pregnancy within 2.5 years (OR 0.66, 95% CI 0.52 to 0.84, P < 0.001). ConclusionLow neighbourhood SES compared with high neighbourhood SES is associated with reducing odds of achieving an ongoing pregnancy within 2.5 years of IVF treatment.

The “freeze-all” strategy seems to improve the chances of birth in adenomyosis-affected women

ObjectiveTo compare assisted reproductive technologies(ART) outcomes between fresh versus freeze-all strategies in infertile women affected with adenomyosis. DesignA single-center observational study SettingsUniversity hospital-based research center PatientsAdenomyosis-affected women undergoing blastocyst embryo transfer following in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) between 01/01/2018 and 31/11/2021. The diagnosis of adenomyosis was based on imaging criteria (i.e., transvaginal ultrasound and/or magnetic resonance imaging). Intervention(s)Women who underwent a freeze-all strategy were compared to those who underwent a fresh embryo transfer (ET) strategy.Main outcome measure(s): cumulative live birth rate (LBR) ResultsA total of 306 women were included in the analysis: 111 in the fresh ET group and 195 in the freeze-all group. The adenomyosis phenotype (internal diffuse adenomyosis, external focal adenomyosis, and adenomyoma) was not significantly different between the two groups. The cumulative LBR [86 (44.1%) vs. 34 (30.6%), respectively; p = 0.020] and the cumulative ongoing pregnancy rate [88 (45.1%) versus 36 (32.4%), respectively; p = 0.029] were significantly higher in the freeze-all group compared to the fresh ET group. After multivariate logistic regression analysis, the freeze-all strategy in women with adenomyosis was associated with significantly higher odds of live birth compared to fresh ET (OR = 1.80; 95% CI = 1.02–3.16). ConclusionThe freeze-all strategy in women afflicted with adenomyosis undergoing ART was associated with significantly higher cumulative live birth rates. Our preliminary results suggest that the freeze-all strategy is an attractive option that increase ART success rates. Additional studies, with a randomized design, should be conducted to further test whether the freeze-all strategy enhances the pregnancy rate in adenomyosis-affected women.

Benefits of Blastocyst Transfer With at Least Three Good-Quality Cleavage-stage Embryos in Women of Advanced Maternal Age: A Retrospective Analysis

ObjectivesLimited studies on the benefits of blastocyst transfer in advanced maternal age (AMA) (≥40 years) have been reported. Our objective was to find whether blastocyst-stage embryo transfer improves pregnancy and live birth rates in women ≥40 years who have 3 or more good-quality cleavage-stage embryos. MethodsAll fresh in vitro fertilization-intracytoplasmic sperm injection cycles performed from January 2020 to December 2021 in AMA women that progressed to transfer were considered for analysis. We compared fresh and cumulative ongoing pregnancy rates in AMA women of those who had a cleavage-stage transfer, while meeting the criteria for extended culture (≥3 high-quality embryos, group 1), and those who underwent blastocyst transfer (group 2). Demographic parameters, stimulation, embryology, fresh and cumulative ongoing pregnancy rates, and clinical miscarriage rates were compared. ResultsDuring the study period, 255 cycles were analyzed including group 1 (n = 99) and group 2 (n = 156). Group 1 participants were older and had a greater number of embryos for transfer. Fresh and cumulative ongoing pregnancy rates per transfer were higher in group 2 compared to group 1 (23.4% vs. 13.1%, P = 0.04; 25.5% vs. 14.1%, P = 0.03), while overall miscarriage rates were higher in group 1 than group 2 (51.7% vs. 25%, P = 0.01). ConclusionsBlastocyst culture provides a benefit to AMA women who have at least 3 good-quality embryos on day 3 resulting in significantly higher fresh and cumulative ongoing pregnancy rates and lower miscarriage compared to cleavage-stage transfers.

Cumulative pregnancy rate via multiple fresh or frozen embryo transfers in women with current, resected, or recurred endometrioma.

This study aimed to retrospectively analyze the cumulative pregnancy rate (PR) via multiple fresh or frozen embryo transfers (ET) in women with current, resected, or recurred endometrioma. The IVF data including oocyte pick-up (OPU) and fresh or frozen ET in women with current (37 women; 56 OPU, 18 fresh and 14 frozen ET), resected (24 women; 50 OPU, 17 fresh and 42 frozen ET), or recurred endometrioma (28 women; 49 OPU, 22 fresh and 24 frozen ET) were obtained. All cycles were performed from 2015 to 2022 in a single university hospital. The median serum AMH level (ng/mL) was 1.44, 1.47, and 0.98, respectively. The number of total or mature oocytes, fertilized oocytes, cleavage embryos at day-3, and top-quality embryos at day-3 were all similar in the three groups. Cycles with no oocyte occurred in 2 (3.6%), 1 (2%), and 3 cycles (6.1%), respectively. Freeze-all was performed in 46.3%, 59.2%, and 47.8% of the cycles, respectively (p>0.05). The cumulative clinical PR per total ET (43.8%, 25.4%, and 21.7%), per OPU (25%, 30%, and 20.4%), and per woman (37.8%, 62.5%, and 35.7%) were all similar in the three groups. The cumulative ongoing pregnancy and live birth rate per total ET, per OPU, and per woman were also similar in the three groups. Similarity in ovarian reserve, number of oocytes, number of embryos, cumulative clinical PR, and live birth in the three endometriosis groups indicates that the IVF outcomes in the 'recurrent endometrioma' group are not inferior to 'current' or 'resected' group.

P-479 Prognosis for ongoing pregnancy after recurrent implantation failure (RIF) following IVF/ICSI treatment

Abstract Study question What is the cumulative ongoing pregnancy rate within one year after visiting the RIF outpatient clinic in patients with RIF after IVF/ICSI treatment? Summary answer The cumulative ongoing pregnancy rate was 42.9% with a mean time to pregnancy of 8.8 months (95% CI 7.5-10.1 months). What is known already An estimated portion of 10-15% of IVF patients experience RIF. Multiple add-on treatments have been proposed, however, evidence for effective clinical therapeutic options still remain scarce. Although it is described that RIF patients might eventually benefit most from a ‘keep calm and carry on’ approach, in practice patients often seek clearer answers on their pregnancy chance and request further investigations/interventions. It would be helpful to give patients insight in their chances of achieving pregnancy after RIF, but at this moment little is known about their prognosis. This is further complicated by the lack of consistency in the definition of RIF. Study design, size, duration A prospective cohort study on 42 RIF patients after one-year follow-up was performed, as part of the MURIM (Multidisciplinary Research on Repeated Implantation Failure and Recurrent Miscarriages) study. Baseline characteristics including an endometrial assessment and ReceptIVFity (vaginal microbiome) test were collected at the RIF outpatient clinic. After a follow-up duration of minimal one year participants were asked to complete a questionnaire regarding fertility treatment and pregnancy outcome. Missing information was received via medical files. Participants/materials, setting, methods RIF patients aged 18 to 38 years old visiting the RIF outpatient clinic at Maastricht University Medical Centre+ between April 2019 until September 2021 were included. RIF was defined as consecutive implantation failure of three high quality embryos or ten embryos without a quality criterion. Clinical characteristics, pregnancy outcome and time to pregnancy was analyzed by survival analysis and cox hazard regression analysis via SPSS version 20.0. A p-value of &amp;lt; 0.05 was considered statistically significant. Main results and the role of chance Forty-two out of 44 contacted patients responded to the questionnaire (response rate = 95.5%). The ongoing pregnancy rate was 42.9% (Standard Deviation (SD): 0.50%) during the first year after visiting the RIF outpatient clinic. Mean time to ongoing pregnancy was 8.8 months (95%-CI: 7.5-10.1 months). The mean amount of embryo transfers (ETs) during this year was 2 (SD: 1.78). The ongoing pregnancy rate per ET (by survival analysis) for the first, third and sixth ET was 33.1%, 49.3% and 63.8%, respectively. To correct for a possible overestimation of the cumulative ongoing pregnancy rate per ET by normal survival analysis, pregnancy rates were calculated again using the number at risk of the total group during the first ET (pessimistic cumulative pregnancy rate). The pessimistic cumulative ongoing pregnancy rates were 33.1%, 42.9% and 48.6%, respectively. When comparing baseline characteristics by univariable cox hazard regression between women with and without ongoing pregnancy, no significant differences were found. Nineteen pregnancies were reported during the one-year follow-up, one conceived spontaneously (5.3%); four via fresh ET (IVF=15.8% and ICSI=5.3%); and 14 by frozen ET (IVF=26.4% and ICSI=47.4%). The pregnancies resulted in 14 livebirths (73.7%); one miscarriage (5.3%); one stillbirth (5.3%); and three ongoing pregnancies (15.8%). Limitations, reasons for caution Although this is the first study that prospectively describes pregnancy prognosis after RIF, it is limited by the short follow-up period and relatively small sample size. The RIF outpatient clinic consultation might have contributed to the obtained pregnancy results but the proportionality is unclear as there is no control group. Wider implications of the findings The obtained ongoing pregnancy prognosis after RIF is encouraging and justifies a conservative approach after three failed ETs. Furthermore, the high pregnancy rate indicates the need of well-defined, individualized diagnostic criteria to define RIF and to be able to deviate between couples with 'bad luck' and an underlying (treatable) cause. Trial registration number NL66835.068.18/METC18-040

P-658 Clinical outcomes from ART in predicted hyperresponders: in-vitro maturation of oocytes versus conventional ovarian stimulation

Abstract Study question Do ongoing pregnancy rates (OPR) differ in predicted hyperresponders undergoing ART after in-vitro maturation of oocytes (IVM) compared with conventional ovarian stimulation (COS)? Summary answer One cycle of IVM is non-inferior to one cycle of COS in women with serum AMH levels &amp;gt;10ng/mL. What is known already Women with high antral follicle count (AFC) and elevated serum AMH levels, indicating an increased functional ovarian reserve, are prone to hyperresponse during ART treatment. To avoid iatrogenic complications of COS, IVM has been proposed as a mild-approach alternative treatment in predicted hyperresponders, including women with polycystic ovary syndrome (PCOS) who are eligible for ART. To date, inferior pregnancy rates from IVM compared to COS have hampered the uptake of IVM by ART clinics. However, it is unclear whether the efficiency gap between IVM and COS may differ depending on the extent of AMH elevation. Study design, size, duration This study is a retrospective cohort analysis of clinical and laboratory data from the first completed highly purified human menopausal gonadotropin (HP-hMG) primed, non-hCG triggered IVM or COS (FSH or HP-hMG stimulation in a GnRH antagonist protocol) cycle with ICSI in predicted hyperresponders ≤36 years of age at a tertiary referral university hospital. A total of 1707 cycles were included between January 2016 and June 2022. Participants/materials, setting, methods Predicted hyperresponse was defined as a serum AMH level &amp;gt;3.25ng/mL (Elecsys® AMH, Roche Diagnostics). The primary outcome was cumulative ongoing pregnancy rate (OPR) assessed 10-11 weeks after embryo transfer. The predefined non-inferiority limit was -10.0%. The analysis was adjusted for AMH strata. Time-to-pregnancy (TTP), defined by the time interval between egg retrieval and date of successful embryo transfer, was a secondary outcome. Statistical analysis was performed using a multivariable regression model controlling for potential confounders. Main results and the role of chance Data from 463 IVM cycles were compared with those from 1244 COS cycles. Women in the IVM group more often had a diagnosis of Rotterdam PCOS (434/463, 93.7%) compared to those undergoing COS (522/1193, 43.8%), were significantly younger (29.5 years vs 30.5 years, p ≤ 0.001), had a higher BMI (25.7kg/m² vs 25.1kg/m², p ≤ 0.01) and higher AMH (11.6ng/mL vs 5.3ng/mL, p ≤ 0.001). Although IVM cycles yielded more cumulus oocyte complexes (COCs) (25.8 COC vs 15.0 COC, p ≤ 0.001), both groups had similar numbers of mature oocytes (MII) (11.9 MII vs 10.6 MII, p = 0.9). In the entire cohort, non-adjusted cumulative OPR from IVM was significantly lower (198/463, 42.8%) compared to COS (794/1244, 63.8%), p ≤ 0.001. When analysing OPR across different serum AMH strata, cumulative OPR in both groups converged with increasing serum AMH, and OPR from IVM was non-inferior compared to COS from serum AMH levels &amp;gt;10ng/mL onwards (113/221, 51.1% [IVM]; 29/48, 60.4% [COS]). Time-To-Pregnancy was shorter in the IVM group compared to COS (11.3 weeks vs 21.0 weeks, p ≤ 0.001). Multivariable regression analysis adjusting for ART type, age, BMI, oocyte number and PCOS phenotype showed that the number of COCs was the only parameter associated with OPR in predicted hyperresponders with a serum AMH &amp;gt;10ng/mL. Limitations, reasons for caution These data should be interpreted with caution as the retrospective nature of the study holds the possibility of unmeasured confounding factors. Patients enrolled in a clinical IVM program received one-to-one care, in contrast with COS patients who received standard care, which may have influenced TTP. Wider implications of the findings Among subfertile women who are eligible for ART, IVM and COS resulted in comparable reproductive outcomes in a subset of women with a serum AMH &amp;gt;10ng/mL. These findings should be corroborated by an RCT comparing both treatments in selected patients with elevated AMH. Trial registration number Not applicable

P-510 Low neighbourhood socioeconomic status is associated with lower cumulative ongoing pregnancy rate after in vitro fertilization treatment

Abstract Study question Is there an association between neighbourhood socioeconomic status (SES) and cumulative ongoing pregnancy after 2.5 years of in vitro fertilization (IVF) treatment? Summary answer Low and middle neighbourhood SES is associated with lower odds of an ongoing pregnancy within 2.5 years of IVF treatment than high neighbourhood SES. What is known already Low SES is known to have a negative impact on general health and a variety of medical conditions, including perinatal health. However, not much data is available on the impact of SES on IVF treatment outcome. Study design, size, duration This is a retrospective observational study of 3720 couples undergoing IVF or IVF-ICSI treatment between 2006 and 2020. Participants/materials, setting, methods Neighbourhood SES was assigned to each couple based on the postal code of residence. Subsequently, SES was categorized into low (&amp;lt;p20), medium (p20-p80), and high (&amp;gt;p80). Multivariable logistic regression analyses were performed with cumulative ongoing pregnancy within 2.5 years as outcome variable, SES category, female age, BMI, smoking status (yes/no), and interaction terms for age*SES and BMI*SES were used as covariates. Main results and the role of chance There was no difference in ongoing pregnancy rates between SES groups after the first fresh embryo transfer or in the average number of IVF treatment cycles performed. However, the cumulative ongoing pregnancy rates differ significantly between SES groups (Low; 43.6%, medium; 50.9%, high; 54.1%). Low SES had significantly lower odds for achieving an ongoing pregnancy within 2.5 years (OR = 0.06 (95%CI 0.02-0.22)). The interaction terms age*SES and BMI*SES showed attenuation of this association with increasing age and BMI (OR = 1.07 (95%CI 1.022 – 1.12) and OR = 1.61 (95%CI 1.25 – 2.09), respectively). The associations with medium SES were similar, but less pronounced (OR = 0.16 (95%CI 0.05 – 0.50) with OR = 1.04 (95%Cl 1.00 – 1.09) and OR = 1.41 (1.12 – 1.77) for the interaction terms with female age and BMI respectively. Limitations, reasons for caution We were not able to perform additional analysis on individual characteristics like educational level, ethnicity or language proficiency due to lack of data. Wider implications of the findings In the Netherlands, health insurance is mandatory. Our study showed that even with equal access to fertility care, patients living in a low SES neighbourhood are disadvantaged. This underlines the importance of taking the whole wellbeing of the patient into account, before starting an IVF treatment. Trial registration number not applicable

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 &amp;lt; 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

Clinical outcomes of uninterrupted embryo culture with or without time-lapse-based embryo selection versus interrupted standard culture (SelecTIMO): a three-armed, multicentre, double-blind, randomised controlled trial

Time-lapse monitoring is increasingly used in fertility laboratories to culture and select embryos for transfer. This method is offered to couples with the promise of improving pregnancy chances, even though there is currently insufficient evidence for superior clinical results. We aimed to evaluate whether a potential improvement by time-lapse monitoring is caused by the time-lapse-based embryo selection method itself or the uninterrupted culture environment that is part of the system. In this three-armed, multicentre, double-blind, randomised controlled trial, couples undergoing in-vitro fertilisation or intracytoplasmic sperm injection were recruited from 15 fertility clinics in the Netherlands and randomly assigned using a web-based, computerised randomisation service to one of three groups. Couples and physicians were masked to treatment group, but embryologists and laboratory technicians could not be. The time-lapse early embryo viability assessment (EEVA; TLE) group received embryo selection based on the EEVA time-lapse selection method and uninterrupted culture. The time-lapse routine (TLR) group received routine embryo selection and uninterrupted culture. The control group received routine embryo selection and interrupted culture. The co-primary endpoints were the cumulative ongoing pregnancy rate within 12 months in all women and the ongoing pregnancy rate after fresh single embryo transfer in a good prognosis population. Analysis was by intention to treat. This trial is registered on the ICTRP Search Portal, NTR5423, and is closed to new participants. 1731 couples were randomly assigned between June 15, 2017, and March 31, 2020 (577 to the TLE group, 579 to the TLR group, and 575 to the control group). The 12-month cumulative ongoing pregnancy rate did not differ significantly between the three groups: 50·8% (293 of 577) in the TLE group, 50·9% (295 of 579) in the TLR group, and 49·4% (284 of 575) in the control group (p=0·85). The ongoing pregnancy rates after fresh single embryo transfer in a good prognosis population were 38·2% (125 of 327) in the TLE group, 36·8% (119 of 323) in the TLR group, and 37·8% (123 of 325) in the control group (p=0·90). Ten serious adverse events were reported (five TLE, four TLR, and one in the control group), which were not related to study procedures. Neither time-lapse-based embryo selection using the EEVA test nor uninterrupted culture conditions in a time-lapse incubator improved clinical outcomes compared with routine methods. Widespread application of time-lapse monitoring for fertility treatments with the promise of improved results should be questioned. Health Care Efficiency Research programme from Netherlands Organisation for Health Research and Development and Merck.

A short versus a long time interval between semen collection and intrauterine insemination: a randomized controlled clinical trial.

Does a short interval (i.e. ≤90 min), compared to a long interval (i.e. ≥180 min), between semen collection and intrauterine insemination (IUI) increase the cumulative chance of an ongoing pregnancy after six IUI cycles? A long interval between semen collection and IUI resulted in a borderline significant improvement in cumulative ongoing pregnancies and a statistically significant shorter time to pregnancy. Retrospective studies assessing the effect of the time interval between semen collection and IUI on pregnancy outcomes have shown inconclusive results. Some studies have indicated a beneficial effect of a short interval between semen collection and IUI on IUI outcomes, while others have not found any differences. To date, no prospective trials have been published on this subject. The study was performed as a non-blinded, single-center RCT with 297 couples undergoing IUI treatment in a natural or stimulated cycle. The study was conducted between February 2012 and December 2018. Couples with unexplained or mild male subfertility and an indication for IUI were randomly assigned for up to six IUI cycles into either the control group (long interval, i.e. 180 min or more between semen collection and insemination) or the study group (short interval, i.e. insemination as soon as possible after semen processing and within 90 min of semen collection). The study was carried out in an academic hospital-based IVF center in the Netherlands. The primary endpoint of the study was ongoing pregnancy rate per couple, defined as a viable intrauterine pregnancy at 10 weeks after insemination. In the short interval group, 142 couples were analyzed versus 138 couples in the long interval group. In the intention-to-treat (ITT) analysis, the cumulative ongoing pregnancy rate was significantly higher in the long interval group (71/138; 51.4%) compared to that in the short interval group (56/142; 39.4%; relative risks 0.77; 95% CI 0.59-0.99; P = 0.044). The time to pregnancy was significantly shorter in the long interval group (log-rank test, P = 0.012). A Cox regression analysis showed similar results (adjusted hazard ratio 1.528, 95% CI 1.074-2.174, P = 0.019). Limitations of our study are the non-blinded design, the long inclusion and follow-up period of nearly seven years and the large number of protocol violations, especially because they predominantly occurred in the short interval group. The non-significant results in the per-protocol (PP) analyses and the weaknesses of the study should be taken into account in the assessment of the borderline significance of the results in the ITT analyses. Because it is not necessary to perform the IUI immediately after semen processing, there can be more time available to choose the optimum work-flow and clinic occupancy. Clinics and laboratories should find their optimal timing of insemination, considering the time between human chorionic gonadotropin injection and insemination in relation to the sperm preparation techniques used as well as the storage time and conditions until insemination. There were no external funding and no competing interests to declare. Dutch trial registry, trial registration number NTR3144. 14 November 2011. 5 February 2012.

The influence of preincubation time of prepared sperm before IVF on fertilization, embryo developmental competence and the reproductive outcomes.

It has been provided that if incubation time of prepared sperm can affect sperm motility and DNA fragment, but little is known about the influence of sperm preincubation time (SI) on the sperm's fertilizing ability, subsequent embryonic development and pregnancy outcomes in in vitro fertilization (IVF). The aim of this study was to explore the association of SI with fertilization rate, embryo development and clinical outcomes in IVF, further, to find an optimal preincubation time for prepared sperm before insemination in IVF. This retrospective cohort study included a total of 1453 infertile couples undergoing IVF in our center performed from January 2016 to January 2019. Sperm were preincubated at 37℃ 6% CO₂ for different times before insemination. Preincubation time associated with fertilization rate (FR), 2PN rate, D3 good quality embryo rate, fresh embryo implantation rate (IR), blastocyst formation rate, cumulative pregnancy rate (CPR), cumulative ongoing pregnancy rate (COPR), cumulative live birth rate (CLBR), newborn health and gender ratio were analyzed by chi-square analysis. FR and 2PN rate of SI more than four hours SI groups (> 4 h SI group) decreased significantly compared with other SI groups (p < 0.01). There were no significant differences of the D3 high quality embryo rate among five SI groups. The blastocyst formation rate of > 4 h SI group was significantly lower than that of 2-3 h SI group (45.5% vs 56.1%, p < 0.05); and 1-2 h SI group also had significant difference with 2-3 h and 3-4 h SI group (48.9% vs 56.1% and 54.6%, p < 0.05). There were a significant decrease of fresh IR and CPR in ≤1 h SI group compared with 1-2 h SI group (19.6% vs. 38.0%, p < 0.05; 62.7% vs 73.7%, p < 0.05); ≤ 1 h SI group also have the lowest CLBR (45.6%), it had statistic differences with 1-2 SI group and 3-4 SI group (45.6% vs 63.2%, p < 0.01; 45.6% vs 61.2%, p < 0.05). The sperm preincubated time at 37℃ 6% CO₂ before insemination could influence sperm fertilizing ability, blastocyst formation, embryo implantation and CLBR in IVF cycles. The best time for prepared sperm preincubation at 37℃ is one to four hours before insemination in IVF.

"Short agonist stop" protocol, an ovarian stimulation for poor responders in in vitro fertilization (IVF): A pilot study.

Poor responder patients remain a challenge in assisted reproductive technologies. The "short agonist stop" (SAS) stimulation protocol uses a double stimulation (flare up effect with the gonadotropin-releasing hormone (GnRH) agonist (GnRH-a) then gonadotropins) associated with a less strenuous blockage (discontinuation of GnRH-a) to favor follicular recruitment in order to obtain a better ovarian response. This study aims to compare the number of oocytes obtained after a SAS stimulation protocol with those obtained after the previous stimulation protocol, in the same women, with poor ovarian response (POR) diagnosed according to the POSEIDON criteria. This therapeutic observational retrospective cohort from 2018 to 2022, with a case-control evaluation compared with the same patients' previous performance, included women with POR undergoing IVF with SAS stimulation protocol. The primary outcome was the number of total oocytes recovered and secondary outcomes were the numbers of mature oocytes, total embryos observed at day 2 and usable cleaved embryos and blastocysts (day 5/6). 63 patients with SAS and previous cycles were included. In the SAS group, the mean number of oocytes was significantly higher: 7.3 vs 5.7, p=0.018 in comparison with the previous attempt. So was the number of mature oocytes (5.8 vs 4.1, p=0.032) and the total mean number of embryos obtained at day 2 (4.1 versus 2.7, p=0.016). The SAS stimulation generated 84 usable embryos: 57 cleaved embryos and 27 blastocysts. The mean number of usable embryos was similar in both groups (1.64 vs 1.31, respectively, p=0.178). In total, out of 63 patients, after the SAS protocol, and subsequent embryo transfers (fresh and frozen, n=54), 9 patients had ongoing pregnancies and no miscarriage occurred. The cumulative ongoing pregnancy rate (cOPR) after the SAS protocol was 14.3% (9/63) per oocyte pick-up and 16.7% (9/54) per transfer. SAS stimulation is a short and original protocol strengthening the therapeutic arsenal of poor responders, that may offer promising results for those patients with low prognosis and previous failed IVF. Results must be confirmed with a randomized controlled trial.

Individualised versus Standard FSH Dosing in Predicted Poor Responders Undergoing IVF: A Randomised Controlled Trial

Background: Poor responders usually lead to detrimental effects on IVF outcomes due to low oocyte number and quality which further result in low pregnancy outcomes and increased chance of cycle cancellation. Clinicians often individualise the FSH dose using ovarian reserve tests (ORT), including antral follicle count (AFC). However, it is unclear whether individualised FSH dosing improves clinical outcomes. Aim: To understand if there is a difference in live birth rates between individualised or standard FSH dosing in poor responders? Method: Between March 2019 and April 2020, we performed a single center, parallel, open-label randomised controlled trial. Women referred for their first IVF/ICSI cycle, [Formula: see text]43 years of age, AFC[Formula: see text]10 were approached. Eligible women were randomised either to individualised or standard FSH dosing. In the individualised group, women with AFC 1-6 were assigned to 300IU/day, while women with AFC 7-9 were assigned to 225IU/day. In the standard group, women were assigned 150IU/day. The primary outcome was live birth attributable to the first ART cycle within 18 months of randomization. Results: A total of 661 women were randomised, 328 to the individualised group and 333 to the standard group. The live birth rate (follow up still ongoing) was not significantly different between the two groups [49.1% (161/328) vs 42.3% (141/333), RR: 1.16 (95%CI, 0.98-1.37), P=0.082]. The cumulative ongoing pregnancy rate for individualised versus standard dosing was 53.0% (174/328) versus 47.4% (158/333), respectively [RR: 1.12 (95%CI, 0.96-1.30), p=0.150]. The multiple pregnancy rate also did not differ between individualised and standard dosing [5.49% vs 5.71%, RR: 0.96 (95%CI, 0.51-1.80), p=0.903]. Individualised dosing reduced the occurrence of poor response compared to standard dosing [31.1% vs 48.6%, RR: 0.64 (95%CI, 0.53-0.78), p[Formula: see text]0.001]. Conclusion: The individualised dosing strategy led to lower rates of poor response, but it did not result in significantly higher ongoing pregnancy rates.

A novel GnRH antagonist protocol based on LH levels versus traditional flexible GnRH antagonist protocol in PCOS patients undergoing in vitro fertilization: study protocol for a randomized controlled, non-inferiority trial

BackgroundThe gonadotropin-releasing hormone (GnRH) antagonist protocol is advantageous given that it can avoid severe ovarian hyperstimulation syndrome (OHSS), especially for patients with polycystic ovary syndrome (PCOS). Basic and clinical evidence has shown that a threshold of luteinizing hormone (LH) stimulation is required for adequate follicular development and oocyte maturation. Ultra-low or high levels of LH are detrimental to pregnancy outcomes. We previously demonstrated that LH could be an indicator for the timing and dosage of antagonist administration in a retrospective study.Methods/designIn this randomized, single-center, non-inferiority trial, we aim to test the hypothesis that there is no significant difference in cumulative ongoing pregnancy rates between PCOS patients stimulated with LH-based flexible protocol versus traditional flexible GnRH antagonist protocol. The primary efficacy endpoint will be the cumulative ongoing pregnancy rate per cycle. The secondary outcomes will be clinical pregnancy rate, cancelation rate, serious OHSS rate, and cost-efficiency. The cumulative ongoing pregnancy rate per cycle in PCOS women was 80%. Considering that a non-inferiority threshold should retain 80% of the clinical effect of a control treatment, a minimal clinical difference of 16% (two-sided: α, 2.5%; β, 20%) and a total of 196 patients were needed. Anticipating a 10% dropout rate, the total number of patients required was 216.DiscussionThe results of this study will provide evidence for the efficacy and safety of the LH-based flexible GnRH antagonist protocol in PCOS patients. Moreover, it evaluates the cost-efficiency of both protocols.Trial registrationChinese Clinical Trial Registry ChiCTR1800018129. Date assigned: 31 August 2018. Protocol version: 1.0 (18 July 2017)

Luteinizing hormone-based modified GnRH antagonist protocol in normal responders undergoing in vitro fertilization treatment: A multi-center randomized controlled trial.

ObjectiveTo study the clinical efficacy and cost-effectiveness of a modified gonadotrophin-releasing hormone (GnRH) antagonist protocol based on luteinizing hormone (LH) levels through one complete assisted reproductive technology (ART) cycle in normal responders.DesignNon-inferiority, multicenter randomized controlled trial.SettingUniversity-based hospitals and an academic medical center.PatientsA total of 372 patients fulfilled the inclusion criteria and were eligible to participate.Intervention(s)Participants were randomized at a 1:1 ratio and stimulated with the conventional flexible GnRH antagonist protocol (control group) or LH-based modified GnRH antagonist protocol (study group).Main Outcome MeasuresThe primary outcome was the cumulative ongoing pregnancy rate per aspiration. The secondary outcomes were number of oocytes retrieved, number of good quality embryos, cumulative positive βhCG rate, cumulative clinical pregnancy rate, pregnancy loss rate, moderate and severe ovarian hyperstimulation syndrome (OHSS), and financial expenditure.ResultsThe cumulative ongoing pregnancy rate was 65.1% in the study group and 70.1% in the control group (odds ratio, 0.79; 95% confidence interval, 0.50–1.26; P = 0.33). The multivariate regression analyses results showed that the number of retrieved oocytes was positively associated with the odds for a higher cumulative ongoing pregnancy rate (adjusted odds ratio, 1.11, 95% confidence interval, 1.06–1.17, P < 0.001). The treatment protocol, female age, and body mass index were not independent predictors. The incremental cost-effectiveness ratio for luteinizing hormone-based gonadotrophin releasing hormone antagonist protocol versus the conventional flexible gonadotrophin releasing hormone antagonist protocol was estimated at 3568.6 USD for each additional ongoing pregnancy.ConclusionThe luteinizing hormone-based gonadotrophin releasing hormone antagonist protocol had clinical efficacy similar to the conventional flexible gonadotrophin releasing hormone antagonist protocol in normal responders undergoing in vitro fertilization treatment but was more cost-effective considering the cumulative ongoing pregnancy rate in the entire assisted reproductive technology cycle.Clinical Trial Registration www.chictr.org.cn, identifier: ChiCTR1800018077URL of the registration site http://www.chictr.org.cn/edit.aspx?pid=27389&htm=4.Trial registration date29 August 2018.Date of first patient enrollment1 September 2018.

P-044 Abnormal sperm morphology, so what? The clinical outcome of medical assisted reproduction is not affected by 100% teratospermic semen samples

Abstract Study question What is the success rate (clinical outcome) in medical assisted reproduction (MAR) when 0% normal spermatozoa forms are observed using strict morphology criteria (SMC)? Summary answer Strict criteria morphology has no predictive value for the clinical outcome of MAR. Absence of normal morphology spermatozoa does not preclude high cumulative pregnancy rates. What is known already Many studies have questioned the clinical value of sperm morphology since no effect on treatment outcome is apparent when sperm samples with &amp;lt;4% normal forms are used. However, data evaluating treatment outcome when 0% normal sperm at diagnose (evaluated by strict morphology criteria, WHO 2010) scarce. While teratozoospermia values are known to have a negative correlation with fertilization per cycle, data on cumulative ongoing pregnancy rates (COPR) or live birth rates (LBR) are missing in this selected group. Study design, size, duration This is a retrospective analysis (January 2010-June 2021) of the clinical outcome for couples when the male partner presents with 0% normal morphology (WHO 2010) at diagnostic semen analysis. Cases with 100% globozoospermia, cilia abnormalities or other MMAF phenotypes were excluded. Depending on the total progressively motile sperm count (TPMSC), couples were referred for MAR. The primary outcome presented is COPR/treatment and LBR/couple. Secondary outcomes were total fertilization failure (TFF) and mean fertilization rate (FR). Participants/materials, setting, methods All 193 cases included in this study presented with 100% teratozoospermia, as evaluated by two independent technicians following WHO 2010 manual recommendations. Couples were treated with IUI,IVF or ICSI depending on TPMSC at diagnosis. A total of 17 couples underwent 68 IUI treatments, 20 couples underwent 36 IVF ovum-pickups (OPU) (with respectively fresh embryo transfer (ET) and frozen ET, FET); 156 couples underwent 394 ICSI-OPU (with respectively fresh-ET and FET). Cumulative-OPR per treatment/couple is presented. Main results and the role of chance From the 17 couples undergoing IUI (mean 4 IUI cycles/couple; with or without mild ovarian stimulation) 3 ongoing pregnancies were reported (all singletons; 18% LBR per couple). Twenty IVF couples (mean 1.8 OPUs/couple) resulted in a total of 13 ongoing pregnancies (12 singletons, 1 twin pregnancy), therefore, the LBR per IVF-couple was 65%. In six cycles a TFF was observed even with sufficient motile sperm during insemination (5x with TPMSC &amp;gt;5 x 10^6/ml). If TFF was observed after IVF cycle, then ICSI was performed in the next cycle. The IVF mean %FR using 100% teratozoospermic samples was 54%, compared to 58% in cases with &amp;gt;1% normal forms. Regarding ICSI, 156 couples underwent a total of 377 cycles (mean of 2.4 OPUs/couple). These treatments resulted in a total of 357 fresh-ET and 458 FET. A total of 103 couples achieved 154 ongoing pregnancies (146 singletons, 7 twins), therefore the COPR was 39%/cycle and LBR was 66%/couple. In 13 cycles (3.4%) TFF was observed and in 15 cases the fertilization rate was &amp;lt;20%. The mean FR with ICSI using teratozoospermic samples was 55%. Comparingly, using samples with &amp;gt;1% normal morphology, the laboratory mean for FR is 68% and 3.7% for TFF. Limitations, reasons for caution This is a retrospective study and not matched case-control cohort was used in this analysis. Not all couples have completed 3 complete IVF/ICSI cycles. As not all frozen embryos have been transferred, cumulative pregnancy rates might be higher than the rates reported here. Wider implications of the findings The data presented here confirms the limited value of the actual strict criteria for sperm morphology evaluation. Morphology is important for identification of sporadic sperm samples with atypical malformations such as globozoospermia, MMAF and other aberrant forms of a genetic origin, however SMC evaluation and interpretation should be reconsidered Trial registration number N.A.

O-011 A prospective multicentre, non-interventional, real-world study to assess the pattern of use, effectiveness and safety of follitropin delta in routine clinical practice (the PROFILE study)

Abstract Study question To observe real-world utilization of algorithm-based dosing of follitropin delta in women naïve to ovarian stimulation (OS) and undergoing either in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). Summary answer Individualized dosing of follitropin delta in real-world clinical practice results in predictable ovarian response while minimizing risk of ovarian hyperstimulation syndrome (OHSS). What is known already Follitropin delta (REKOVELLE, Ferring Pharmaceuticals, Switzerland), is the first recombinant human follicle-stimulating hormone (FSH) to be produced in a human cell line. The algorithm-based individualized dosing regimen for follitropin delta was developed to target an ovarian response of 8–14 oocytes while reducing the risk of extreme ovarian hypo- and hyper-response as compared with conventional dosing strategies. The efficacy and safety of follitropin delta has been demonstrated in randomized controlled trials (RCTs) compared with a standard daily starting dose of 150 IU recombinant FSH. Real-world implementation of individualized follitropin delta dosing using the algorithm in OS cycles is currently unknown. Study design, size, duration PROFILE was a prospective, open-label, non-interventional, multinational study conducted between March 2018 and October 2020 in which 1258 women were screened, 1013 met the inclusion/exclusion criteria and 944 women initiated their first OS cycle. No study drugs were reimbursed or provided by the study sponsor. All IVF/ICSI treatment protocols were conducted according to routine clinical practice, including how to prescribe follitropin delta and undertaking fresh/frozen transfers. Participants were followed for up to three OS cycles. Participants/materials, setting, methods All participants met inclusion criteria: ≥18 years, were naïve to IVF/ICSI treatment and the decision had made before enrolment to use follitropin delta for OS. Main exclusion criteria were any contraindication(s) preventing prescription of follitropin delta, and undergoing OS for oocyte donation or fertility preservation. The main outcomes were use of dosing algorithm, follitropin delta dosing patterns, ovarian response and pregnancy for first OS cycle, and adverse drug reactions (ADRs) for up to three cycles. Main results and the role of chance Baseline demographics for 944 women who initiated Cycle 1 were: age, 33.5±4.7 years; bodyweight, 67.1±13.6 kg; anti-Müllerian hormone, 20.3±16.1 pmol/L (2.84 ng/mL) (mean±standard deviation). Cycles 2 and 3 were initiated by 156 and 29 women, respectively. In Cycle 1, clinicians used the dosing algorithm to calculate the follitropin delta starting dose for 893/944 women (94.5%), although some clinicians adjusted the prescribed daily starting dose. The difference between the calculated and prescribed daily dose was small (0.2±1.40 µg); most women (822/944, 87.1%) were prescribed a daily dose of follitropin delta within 0.33 µg (1 click of pen) of the algorithm-calculated dose. The mean daily starting dose was 10.4 µg and mean total dose administered was 104 µg over 10.1 days. A mean of 10.1±7.03 oocytes were retrieved per woman. A fresh transfer was performed for 592/944 women (62.7%) and subsequent positive β-human chorionic gonadotropin (βhCG) reported for 352/944 women (37.3%). Ongoing pregnancy rate after fresh transfer was 27.0% (n = 255) and cumulative ongoing pregnancy rate after fresh/frozen transfer was 36.4% (n = 344). Four women discontinued follitropin delta due to ADRs. OHSS was reported for 37 women (3.9%); 12 (1.3%) OHSS events were reported as serious ADRs. No new safety signals were reported. Limitations, reasons for caution There may be bias towards IVF/ICSI treatment protocols used in countries with highest enrolment. Reasons for prescribing follitropin delta as part of a mixed FSH regimen in 33/944 women (3.5%) were not reported. Wider implications of the findings In real-world clinical practice, nearly all clinicians use the dosing algorithm to calculate individualized daily follitropin delta dose. Despite some women being prescribed dose deviations, first cycle ovarian response was predictable with good ongoing pregnancy rates. OHSS incidence was within expected range. PROFILE confirms efficacy and safety from pivotal RCTs. Trial registration number NCT03393780

O-291 Cumulative pregnancy rates of two strategies: day 3 fresh embryo transfer followed by day 3 or day 5 frozen embryo transfer, a Randomized Controlled Trial

Abstract Study question Are cumulative pregnancy rates different if supernumerary embryos are vitrified on day 5 instead of day 3? Summary answer Results do not show a significant difference in cumulative pregnancy rates between the vitrification day 3 and day 5 group. What is known already The pregnancy and live birth rates following IVF or ICSI treatment are higher after extended embryo culture and blastocyst transfer (day 5) compared to cleavage-stage (day 3) embryo transfer (Glujovski et al 2016). Cumulative pregnancy rates after fresh and frozen embryo transfers show no significant difference after one oocyte retrieval (OR) but only one study used vitrification for the cryopreservation of supernumerary embryos while four studies used a slow freezing protocol (Fernandez-Shaw et al., 2014). A retrospective analysis by De Vos et al., 2016 concluded significantly less embryo transfers were necessary until live birth for blastocyst-stage embryos. Study design, size, duration A Randomized Controlled Trial was performed in an academic center between 01/01/2018 and 31/07/2020. Patients were randomized in the vitrification day 3 or day 5 group. Primary outcome is the number of embryo transfers needed to reach ongoing pregnancy. Power calculation revealed that 75 patients were needed in each group, assuming a median of 4 transfers in the day 3 group versus a median of 2 transfers in the day 5 group to achieve pregnancy. Participants/materials, setting, methods Patients &amp;lt;38 years undergoing their first/second OR were randomized at the start of the cycle. Embryos with ≥6 cells, &amp;lt;25% fragmentation and equal blastomeres and blastocysts with expansion grade ≥2 with inner cell mass and trophectoderm score A/B were vitrified. A time-to-event analysis was performed with ongoing pregnancy as the event of interest and the number of embryo transfers as the time component. The statistical comparison was performed by a Cox proportional hazards model. Main results and the role of chance By December 2021, 234 transfers (96 fresh and 138 frozen) of 78 patients were performed in the vitrification day 3 group and 207 transfers (83 fresh and 113 frozen) of 80 patients in the vitrification day 5 group. The time-to-event analysis did not show a difference between both arms with regards to ongoing pregnancy as the primary study outcome (HR 1.25, 95% CI 0.81; 1.91, p = 0.31). The cumulative ongoing pregnancy rate after 8 transfers was 56% in the day 3 group versus 57% in the day 5 group. Median number of transfers till pregnancy was 6 versus 4, respectively. Similar results were found for the secondary study outcome (clinical pregnancy with fetal heart rate, HR 1.19, 95% CI 0.80; 1.80, p = 0.407). A total of 225 transfers (93 fresh and 132 frozen) of 78 patients were performed in the vitrification day 3 group and 201 transfers (92 fresh and 109 frozen) in the vitrification day 5 group. The cumulative clinical pregnancy rate after 8 transfers was 62% in the day 3 group versus 59% in the day 5 group. Median number of transfers till pregnancy was 6 versus 4, respectively. Limitations, reasons for caution Although power calculation revealed 75 patients are needed in each study group (β = 0.87, α &amp;lt; 0.05), numbers remain low. Wider implications of the findings A recent systematic review and cumulative meta-analysis of Marconi et al. (2021) suggests day 5 embryo transfer is associated with higher risk of preterm birth although evidence was low. Health/economic analyses should be taken into account to determine the most cost-effective strategy for patient and hospital/society. Trial registration number NCT04196036