Ovulation Trigger Research Articles

P-499 Facilitators and barriers for home-based monitoring to time frozen embryo transfers in IVF

Abstract Study question What are the facilitators and barriers concerning the implementation of home-based monitoring for natural-cycle-frozen-embryo-transfer (NC-FET) from perspective of patients and healthcare providers in the Netherlands? Summary answer Most important facilitator was optimal pregnancy chance, and most important barriers were risk of missing an ovulation for patients and laboratory capacity for healthcare providers. What is known already The number of FET cycles is increasing, mainly due to improvement in laboratory techniques. Based on current evidence, there is no difference in effectiveness when NC-FET is compared to artificial-cycle-FET (AC-FET) in ovulatory women. However, NC-FET is associated with lower risk of adverse obstetric and neonatal outcomes compared with AC-FET. NC-FET is performed based on ovulation monitoring, which can be hospital-based (ultrasounds and ovulation triggering) or home-based (LH-urine-tests). Home-based-monitoring has the advantage of being the most natural protocol for FET. A systematic approach for the implementation of home-based monitoring has to start with exploring the perspectives of all stakeholders. Study design, size, duration Both patients and healthcare providers participated in the present study. A panel of experts (n = 8) hypothesised on barriers and facilitators for the implementation of home-based-monitoring during the proposal phase of the Antarctica-2 randomised controlled trial. Two different questionnaires were developed in order to investigate facilitators and barriers for patients and for health care providers. Participants/materials, setting, methods The following stakeholders participated in the study: Patients – represented by the Dutch Patient Organisation for Couples with Fertility Problems. Healthcare providers – represented by gynaecologists (Netherlands Society of Obstetrics and Gynaecology), embryologists (Dutch Federation of Clinical Embryology) and fertility doctors. Based on our power analysis we aimed for 300 completed questionnaires for the patients and a 90 completed questionnaires for the health care providers. Facilitators and barriers were analysed using frequencies, mean (SD) and ranking. Main results and the role of chance A total of 311 patients filled out the questionnaire of whom 86.8% underwent FET previously. The facilitators and barriers were ranked on a scale of 1-10 with 10 being very important. The highest priority for the patients was to implement the strategy with the highest chance of pregnancy (mean 9.7; 95% CI 9.6 – 9.7) and the lowest priority risk of missing the ovulation (mean 8.4; 95% CI 8.2 – 8.6)). A total of 96 health care providers filled out the questionnaire. According to health care providers patients would accept the strategy when it causes less interference with patients’ work and private life (mean 7.5; 95% CI 7.1 – 8.0) and with a low risk of missing the ovulation (mean 7.6; 95% CI 7.1 – 8.0). The most important facilitator for implementation of home-based monitoring for health care workers was optimising cumulative pregnancy rates (mean 8.1; 95% CI 7.7 – 8.4) and most important barrier the lack of laboratory capacity and flexibility (mean 6.4; 95% CI 5.8 – 7.0). Limitations, reasons for caution The barrier lack of laboratory capacity especially in weekends might differ between centres. We did not identify the number of centres who might experience this problem. Furthermore, these results only apply for the applicability of NC-FET in the Netherlands. Wider implications of the findings Our interpretation is that NC-FET is the preferred treatment in ovulatory women. We gained insight in the facilitators and barriers for implementation of NC-FET. Discussing results of this study with all stakeholders involved should stimulate incorporation in guidelines, especially as key professionals in guideline development took part in this study. Trial registration number The Antarctica-2 RCT (NTR: 27578) is supported by a grant of the Netherlands Organisation for Health Research and Development (ZonMw 843002807).

P-621 Different gonadotrophins adopted for controlled ovarian stimulation do not affect metaphase-II oocyte competence. A matched case-control study on 351 patients and 2258 oocytes

Abstract Study question Do different gonadotrophins for controlled-ovarian-stimulation (COS) affect metaphase-II (MII) oocyte competence? Summary answer Euploid blastocyst rate (EBR) per cohort of MII-oocytes, live-birth-rate (LBR) per first vitrified-warmed euploid single-embryo-transfer (SET) and cumulative-LBR are independent from the gonadotrophins used. What is known already Controlled-ovarian-stimulation (COS) is a cornerstone of IVF. Its purpose is maximizing ovarian reserve exploitation and obtaining ≥1 euploid blastocyst to transfer. Indeed, ovarian reserve decreases and blastocyst aneuploidy rates increase with increasing maternal age, making this task quite complicated in advanced maternal age. Old-fashioned studies suggested an association between COS and embryonic aneuploidy rates. Conversely, recent studies excluded an impact of COS dosage, duration, ovarian response, and ovulation trigger, on blastocyst aneuploidy rate. An aspect, though, needs more clarity: do different gonadotropins impact oocyte competence after COS, comprehensively defined as EBR per cohort of MII-oocytes? Study design, size, duration Out of 3169 PGT cycles with ³1 MII oocyte conducted between 2014-2018, we excluded (i)PGT-M/-SR, (ii)women<35yr, (iii)severe-male-factor, (iv)DuoStim or long-active FSH, (v)culture with sequential-media, and (v)multiple cycles. Among the 784 cycles left, a propensity-score-matching (PSM) based on the number of inseminated MII-oocytes was adopted to match patients using recFSH [without (N = 57; 337 MII-oocytes)/with recLH (N = 55; 374 MII-oocytes)] and Human-Menopausal-Gonadotrophin (HMG; N = 127; 835 MII-oocytes). The patients using recFSH+HMG were all included (N = 112; 712 MII-oocytes). Participants/materials, setting, methods Only GnRH-antagonist COS, ICSI with fresh MII-oocytes, single culture in continuous-media, trophectoderm biopsy without assisted-hatching, comprehensive-chromosome-testing to assess full-chromosome non-mosaic aneuploidies and vitrified-warmed euploid SET were conducted. Oocyte competence was comprehensively defined as EBR per cohort of MII-oocytes with all intermediate outcomes (fertilization, blastulation and euploidy). LBR per first vitrified-warmed euploid SET and cumulative-LBR per retrieval were also assessed. Generalized-linear-models and multivariate regressions were adopted to adjust the results for confounders. All cycles were concluded. Main results and the role of chance Patients using recFSH+recLH and recFSH+HMG (40.7 yr) were older than patients using recFSH-only or HMG-only (40 yr; ANOVA<0.01). No other difference was reported in the 4 patient populations. The overall gonadotrophins dosage (2615±977, 3601±1889, 3818±946 and 2892±911 IU in the recFSH-only, recFSH+recLH, recFSH+HMG and HMG-only groups, respectively) and duration of COS (9.7±1.9, 9.4±1.5, 9.9±1.8 and 10.2±1.8 days) were different (Kruskal-Wallis tests=0.02). The number of cumulus-oocyte-complexes (9.2±6.5) and MII-oocytes collected (6.4±4.4) were instead well-matched across the groups. The EBR per cohort of inseminated MII-oocytes was different in the four groups (20.7±27.1%, 9.6±12.9%, 12.4±18.5% and 16.9±21.8%, respectively), but, when adjusted for maternal age in a generalized-linear-model, the gonadotrophin used for COS did not show any significant association with this outcome (partial-eta2=0.02, p = 0.1, power=0.6). All intermediate embryological outcomes were also similar. The LBR per first vitrified-warmed euploid SET was comparable in the four groups [N = 14/33 (42%), N = 9/22 (41%), N = 26/62 (45%), N = 24/55 (44%), respectively], as confirmed by the logistic regression adjusted for blastocyst quality (multivariate-OR: 0.97, 95%CI 0.73-1.31, adjusted-p=0.9). Lastly, the cumulative-LBRs per retrieval were equivalent [N = 17/57 (30%), N = 14/55 (26%), N = 34/127 (27%), and N = 33/112 (30%), respectively], as confirmed by the logistic regression adjusted for maternal age (multivariate-OR: 1.01, 95%CI 0.8-1.3, adjusted-p=0.9). Limitations, reasons for caution The gonadotrophins were chosen based on patient compliance to their administration route and gynecologist judgement, and only qualitative outcomes were assessed. Therefore, randomized-controlled-trials and cost-effectiveness analysis investigating the efficiency in oocyte recruitment and cumulative-LBR per intention-to-treat are needed. Wider implications of the findings Different gonadotrophins might not affect MII-oocyte competence. This information is key since, in view of the optimization of follicle recruitment through personalized-COS, it allows more flexibility in the choice of the most suitable protocol. Therefore, gynecologists might ponder also features like patient reproductive history and compliance to different administration routes. Trial registration number none

O-290 Cumulative live birth rates in a freeze-all and fresh transfer strategy after one complete ART cycle in ovulatory women

Abstract Study question Is the cumulative live birth rate(CLBR) similar following a freeze-all and fresh transfer strategy including nearly all subsequent frozen-thaw cycles from the same oocyte retrieval? Summary answer The chance of at least one live birth after use off all fresh and frozen blastocysts is similar following a freeze-all and fresh transfer strategy What is known already Traditionally, ART success rates have been reported as pregnancies per fresh cycle or per embryo transfer. Advancements such as blastocyst culture and vitrification have enhanced survival and improved live birth rates. This facilitates single blastocyst transfer, a steadily increasing use of vitrified-warmed transfers, and a growing implementation of elective freeze-all cycles worldwide. Hence CLBRs, defined as the proportion of deliveries with at least one live birth following the use of all fresh and frozen embryos derived from one ovarian stimulation cycle, constitutes a better measure of IVF treatment success providing an all-inclusive success rate for ART. Study design, size, duration CLBR was a secondary outcome in a multicentre randomised trial with allocation 1:1 to (A) Freeze-all strategy involving GnRH agonist trigger and single vitrified-warmed blastocyst transfer in consecutive modified-natural FET cycles or (B) Fresh transfer strategy with hCG trigger and fresh single blastocyst transfer followed by consecutive single blastocyst FET cycles. The minimum follow-up time from the start of ovarian stimulation was 2 years. Participants/materials, setting, methods 460 women initiating their 1.,2. or 3. ART cycle at eight different clinics in Denmark, Sweden and Spain. The GnRH antagonist protocol and modified-natural frozen-thaw cycles with single blastocyst transfer were applied. Cumulative live birth was defined as at least one live birth per woman after all fresh and/or frozen cycles from a single ovarian stimulation. Women were followed until the first live birth. Analyses were performed according to the ITT principle. Main results and the role of chance Baseline and treatment-related characteristics were similar between the two groups and a similar proportion of women had additional frozen-thawed embryo transfers following the initial fresh or frozen transfer. Combining all fresh and/or frozen transfers from the included oocyte retrieval with a minimum of 2-years of follow-up, the cumulative live birth rate was 42.6% (95/223) in the freeze-all group versus 41.7% (96/230) in the fresh transfer strategy group (risk ratio (RR): 1.0; 95%CI 0.87-1.19, P = 0.93). The median (IQR) time to first pregnancy was 106.0 (80.5-156.5) versus 29.0 (27.0-113.5) days in the Freeze all and Fresh transfer group, respectively. Of all subsequent frozen transfers, a total of 34/103 (33%) cycles resulted in a live birth in the freeze all group compared with 29/108 (26.9%) in the fresh transfer group (risk ratio (RR): 1.09; 95% CI 0.91-1.3; P = 0.41). Finally, a total of three (1.3%) and eight (3.5%) blastocysts in the freeze all and fresh transfer strategy group respectively, did not survive the freezing thawing process (p = 0.24). The number of women with unused cryopreserved embryos at the end of the 2-year follow-up period was four (0.9%) in the freeze all and seven (1.6%) in the fresh transfer group. Limitations, reasons for caution The primary RCT outcome was ongoing pregnancy rate following two treatment strategies within the ART regimen hence two different ovulation trigger modalities were applied, introducing a risk of bias. Furthermore, despite a 2-year follow-up few women (2.4%) still had cryopreserved embryos and no live birth at the end of follow-up. Wider implications of the findings Advancements of embryo culture and freezing-thawing techniques facilitate an elective single embryo transfer policy. CLBRs provide an all-inclusive success rate for ART. A freeze-all strategy can be used as an alternative to a fresh transfer strategy in women at risk of OHSS as CLBRs are similar. Trial registration number NCT02746562

P-283 RCT Comparing day 3 - fresh embryo transfer cycles with freeze all cycles in IVF-ICSI cycles

Abstract Study question Is the Cumulative live birth rate in freeze-all cycles comparable to Day- 3 Fresh Embryo Transfer Cycles ? Summary answer Yes the Cumulative live birth rate in freeze-all cycles is comparable to Day- 3 Fresh Embryo Transfer Cycles. What is known already Freezing of all embryos in IVF-ICSI cycles is beneficial in PCOS- High Responders but not in Normal and Poor-Responders. Freeze-All protocols offers no additional benefit in pregnancy rates in normal responder patients. Increasing pregnancy rates after frozen-thawed embryo transfer have encouraged wider implementation of a freeze-all (elective freezing of all embryos) strategy in assisted reproductive technology treatment A freeze-all strategy that uses gonadotropin releasing hormone agonist triggering can minimise the risk of ovarian hyperstimulation syndrome Existing studies are lacking that compare a freeze-all strategy using gonadotropin releasing hormone agonist triggering with a fresh transfer strategy using human chorionic gonadotropin triggering. Study design, size, duration 112-Non-PCOS-Infertile patients undergoing IVF-ICSI cycles between 2018-2021, were included in this study. Patients were eligible if at day 3 at least two good quality embryos were present. After informed consent, all patients were randomised by computer to either Fresh Day-3 Embryo -Transfer protocol or a Freeze-All protocol. In the freeze-all group, all good embryos were cryopreserved and then thawed on the day of ET in the following cycle. Participants/materials, setting, methods 112-Non-PCOS-Infertile patients were eligible if at day 3 at least two good quality embryos were present. After informed consent, all patients were randomised to either Fresh Day-3 Embryo -Transfer protocol or a Freeze-All protocol. In the freeze-all group, all good embryos were cryopreserved and then thawed on the day of ET in the following cycle. The primary outcome was clinical pregnancy rate. Baseline characteristics of all Infertile patients were comparable in both study groups Main results and the role of chance Clinical Pregnancy Rate was 36% in Fresh Embryo Transfer cycles and 38% in Freeze All cycles, the difference being not statistically significant. Multiple gestation and abortion rates were also comparable in both the groups Ongoing pregnancy rate did not differ significantly between the freeze-all and fresh transfer groups. In women with regular menstrual cycles, a freeze-all strategy with gonadotropin releasing hormone agonist triggering for final oocyte maturation did not result in higher ongoing pregnancy rates than a fresh transfer strategy. By using gonadotropin releasing hormone agonist triggering in the freeze-all group and a predefined cutoff level for ovarian hyperstimulation syndrome risk in the fresh transfer group, ovarian hyperstimulation syndrome was practically eliminated in both groups. Time to pregnancy was longer in the freeze-all group, therefore fresh embryo transfer should be used as the gold standard if no apparent treatment advantage or immediate risk of ovarian hyperstimulation syndrome is present because it is vital for patients not to postpone pregnancy. Limitations, reasons for caution In both treatment groups, the individualised starting dose of gonadotropin was based on female age/weight, AFC, AMH & previous response to stimulation. Randomisation was performed at baseline, and patients and doctors were blinded to the randomisation group until the day of ovulation triggering to avoid influence on ovarian stimulation dosing. Wider implications of the findings Therefore, caution should be exercised while choosing between Fresh ET and Freeze-All protocol in non-PCOS patients. In normal responder patients, a Freeze-All protocol in IVF-ICSI cycles, had comparable pregnancy rates with Day-3 Fresh-ET. Freeze-All protocols offers no additional benefit in normal responder and this technique should be reserved for High Responders. Trial registration number not applicable

P-593 Low dose clomiphene citrate does not reduce implantation rates - a cohort study based on modified Natural Cycle IVF

Abstract Study question Does low dose clomiphene citrate (CC) reduce implantation and eventually pregnancy and live birth rates? Summary answer Low dose CC does not reduce implantation rate and pregnancy and live birth rates – based on the model of modified Natural Cycle IVF (NC-IVF). What is known already CC is commonly used for ovulation induction in the treatment of anovulation or idiopathic infertility. It is also added to NC-IVF cycles to mildly stimulate follicular growth and to inhibit LH surge. CC reduces endometrial thickness and affects endometrial function. Therefore it is assumed that CC negatively affects implantation and thereby reduced pregnancy and live birth per embryo. However, previous studies have shown inconsistent results as previous studies mainly calculated pregnancy rates per cycle but not implantation rate per embryo. Study design, size, duration This cohort study included embryos transferred in NC–IVF and CC-NC-IVF cycles. Women with a maximum age of 42 years were treated at a university hospital between 2011 and 2016. Clinical pregnancy rate and live birth rate per embryo transferred and miscarriage rate per amniotic sac were calculated. Participants/materials, setting, methods A daily dose of 25mg of CC starting on day 5-7 of the cycle until the day of ovulation trigger was applied. A modified mixed effect Poisson regression model was used to account for the number of cycles in the same women and the number of embryos in the same cycle to achieve rate ratios (RR). Adjustment for maternal age, parity, type of infertility, duration of subfertility and indication for IVF were made. Main results and the role of chance 499 couples underwent a total of 1043 IVF cycles, 453 NC-IVF and 590 CC-NC-IVF cycles. Baseline characteristics of both groups were not different. The additional administration of CC did neither decrease clinical pregnancy rate (aRR 1.16; 95% CI: 0.90 – 1.50)[MV1] nor live birth rate per transferred embryo (aRR 1.20; 95% CI: 0.89 – 1.62). Miscarriage rate was also not different in CC-NC-IVF compared to NC-IVF (aRR 1.05; 95%: CI 0.63 – 1.76). Limitations, reasons for caution This study does not allow to draw any conclusions regarding the effect of higher CC dosages. As randomization was not performed, some bias regarding the choice of IVF treatment cannot be completely excluded. Wider implications of the findings As this study revealed for the first time that low dose CC does not affect implantation, low does CC can be used for many different treatments. However, further studies are required to evaluate if this also applies to higher CC dosages. Trial registration number not applicable

P-655 Insulin like growth factor-1 levels in follicular fluids of patients with poor ovarian response undergoing in vitro fertilization

Abstract Study question Does follicular fluid insulin like growth factor level (IGF-1) in poor responders (PR) differ from normoresponders? Is there a correlation between IGF-1 and IVF outcomes? Summary answer Follicular IGF-1 levels are decreased in poor-responders A positive correlation exists between IGF-1 and number of metaphase II (MII) oocytes, fertilized oocytes and transferred embryos What is known already IGFs are mainly synthesized in liver with growth hormone stimulation. IGF-1 component in follicular fluid has been reported to play a crucial role in follicular and embryonic development. In addition to previously reported positive correlation between follicular IGF-I levels and number of high quality embryos, a significant decrease in IGF-1 levels with PR and advanced maternal age has also been reported. GH supplementation in poor responders undergoing IVF has been suggested to improve IVF outcomes. A recent Cochrane analysis reported that GH slightly increases the number of oocytes retrieved and there is an uncertain effect on live birth rates (LBR). Study design, size, duration Study was designed prospectively. A power analysis, of 91% determined a need for 186 patients. Therefore 186 women undergoing IVF between October 2019 and December 2020 were included. 72 (%38,7) patients were assigned to PRs group according to Bologna criteria (BC) and 114 patients (%61.3) were recruited as controls. Antagonist protocol was used for controlled ovarian hyperstimulation. hCG was administered for ovulation trigger. Participants/materials, setting, methods Following the ovarian hyperstimulation follicular fluid samples were collected during oocyte retrieval. When the total desired number of patients was reached, frozen and preserved follicle fluids were thawed at room temperature. IGF-1 levels in samples were measured using hIGF-1 ELISA kit (BT®, China). Follicular IGF-1 levels in PRs were compared to normoresponders and correlation between IGF-1 levels and AMH levels, number of retrieved oocytes, MII and fertilized oocytes, transferred embriyos and LBR were evaluated. Main results and the role of chance Mean IGF-1 levels of normoresponders and Bologna subgroups (B1, B2, B3, B4) were 13.79±14.50 ng/ml vs 5.75±1.86, 5.47±2.83, 5.96±2.16 and 5.03±1.85 ng/ml respectively (p < 0.001). There was no statistically significant difference in clinical pregnancy (CP) per transfer and LBR per transfer between normoresponders and PRs (CPR/ET: 55.1% vs 43.7%, p:0.375; 26.5% vs 12.5% , p: 0.257). In the ROC analysis for the prediction of collection of fewer than 4 oocytes at retrieval (according to BC definition of PR), statistically determined IGF-1 value was 7.02 with a sensitivity of 83% and a specificity of 38.6%. Patients with an IGF-1 value below 7.02 had a higher risk of having an oocyte number less than 4According to the results of Spearman's correlation analysis, IGF-1 levels were negatively correlated with age and number of previous failed cycles (r:-0.250, p:0,001; r:-0.153, p:0,039 respectively). IGF-1 levels were positively correlated with AMH levels, oocyte, MII oocyte, fertilized oocyte numbers and number of transferred embriyos (r: 0.221, p: 0.007; r: 0.283, p < 0.001; r: 0.293, p < 0.001; r: 0.282, p < 0.001; r: 0.194, p: 0.008 respectively). There was a positive correlation between IGF-1 levels and cycle cancellation rates (r: 0.637, p < 0,001). There was no correlation between IGF-1 levels and LBR (p:0.118). Limitations, reasons for caution Small number of patients was the main limitation of study.Results were not interpreted as LBR in all cases, as 21% (n:24) of the cases had still ongoing pregnancies Wider implications of the findings Detecting lower follicular levels of IGF-1 which plays a crucial role in GH activity may highligt the effect of GH supplementation in poor responders undergoing IVF in terms of improved outcomes. However, there is need for more solid data to employ GH in IVF treatment modalities of poor-responders. Trial registration number not applicable

P-669 The impact of luteal phase support on pregnancy outcomes in relation to serum progesterone levels on the day of frozen embryo transfer in natural cycles

Abstract Study question Is luteal phase support (LPS) beneficial in low and normal serum progesterone (P) levels the day of frozen embryo transfer (FET) in natural cycles (NC)? Summary answer LPS in case of low serum P on the day of NC-FET results in similar pregnancy rates as compared to patients with normal P levels. What is known already The use of FET cycles has increased exponentially in recent years. Endometrial preparation in FET cycles can be achieved either in a natural cycle, a stimulated cycle or in an artificial cycle (AC). There is increasing evidence that proper serum P levels around the time of FET are important in AC and NC. Recent studies in AC have shown that enhanced progesterone supplementation in case of low serum P levels could reduce early pregnancy loss rates and normalize live birth rates. Whether this rescue strategy could also be beneficial in NC-FET has not been investigated in detail. Study design, size, duration A retrospective study was conducted at a tertiary university-based referral hospital encompassing 459 unique patients who had a NC-FET with or without hCG trigger from November 2020 onwards. Only patients who had an in-house validated serum P measurement (Cobas 6000®,Roche) on the day of FET were included. Blastocyst transfer was performed 6 days after a spontaneous luteinizing hormone (LH) peak or 7 days after hCG administration. Ongoing pregnancy rate (OPR) was the primary outcome. Participants/materials, setting, methods Outcomes were compared in patients with low serum P (<10ng/dl) levels, who received LPS from the day of FET onwards (group 1) and patients with normal serum P (≥10ng/dl) levels (group 2). Group 2 was subdivided into patients who did not received LPS (group 2a) and patients who did (group 2b), as by practitioner’s choice. Multivariable regression analysis was performed adjusting for age, BMI, endometrial thickness, rank of FET, embryo quality and indication for treatment. Main results and the role of chance Mean ages were 31.8 years (group 1) and 33.3 years (group 2, p = 0.004). BMI was significantly lower in group 2 (23.7 kg/m2) compared to group 1 (26.7 kg/m2, p < 0.001). Indication for treatment, menstrual cycle length, anti-Mullerian hormone (AMH) levels and parity were comparable between both groups. An hCG ovulation trigger was administered in 26.0% of the cycles in group 1 and 20.4% in group 2 (p = 0.28). Endometrial thickness was equal in both groups (8.3mm, p = 0.84). In group 1, 40.3% of the patients had a transfer of a top quality embryo as compared to 46.3% in group 2 (p = 0.33). Positive hCG rate (54.6%, 64.0% and 65.0% for group 1, 2a and 2b respectively, p = 0.26) and miscarriage rate per positive hCG (2.4%, 9.2% and 6.7% for group 1,2a and 2b respectively, p = 0.37) were comparable between groups. OPR per started cycle was similar between groups (46.8%, 55.4% and 55.6% for group 1, 2a and 2b respectively, p = 0.37). Multivariable logistic regression analysis showed no relationship between OPR and the three different groups (p = 0.13). A significant association was observed between OPR and patient age at embryo cryopreservation. Limitations, reasons for caution Although only patients were included who had serum P levels on the day of FET measured by a standardized in-house assay, the results of the study are limited by the retrospective nature and its associated bias. Confirmation of the results should be obtained in prospective studies. Wider implications of the findings Luteal phase deficiency was observed in only 16.8% of patients in our study population. Administration of LPS in patients with low serum P levels on the day of FET could rescue pregnancy outcomes. However, starting LPS when serum P levels are normal appears to have no added value. Trial registration number not applicable

P-127 Identification of the optimal puncture position by image analysis may reduce oocyte degeneration in intracytoplasmic sperm injection (ICSI)

Abstract Study question Is it possible to identify the optimal puncture position by image analysis where oocyte degeneration is reduced in ICSI procedure? Summary answer Visualizing the likelihood of unintentional membrane rupture (UMR) using image analysis can reduce oocyte degeneration and thereby generate more embryos available for treatment. What is known already It is known that the oocyte degeneration after both conventional-ICSI and Piezo-ICSI are often observed when UMR occurs during the puncturing process and the likelihood of UMR may depends on the location of the puncture site on the oolemma. Identifying the appropriate puncturing position may decrease the likelihood of membrane rupture and thus degeneration, however, there are no studies identifying the optimal puncture position during ICSI. Study design, size, duration We have developed the ICSI Position Detector (IPD), which can identify an area where rupture is likely to occur and visualize it on a video monitor. This study included 1,110 mature oocytes retrieved from 190 consenting patients. Matured oocytes were inseminated either by Conventional-ICSI (n = 437, average maternal age: 39.1±4.6 y.o.) or Piezo-ICSI (n = 673, average maternal age: 38.6±4.5 y.o.). ICSI was performed blindly, moving images were recorded and analyzed retrospectively during ICSI using IPD. Participants/materials, setting, methods Inseminated oocytes were subsequently divided into two groups according to IPD results, oocytes on which ICSI was performed at the position with a low chance of UMR (appropriate group), and with a high chance of UMR (non-appropriate group) by IPD. The rates of UMR, degeneration, fertilization (2PN), blastocyst formation, and good-quality blastocyst (Grade 3BB and above on day 5 by the Gardner scoring) were compared between the two groups of both conventional-ICSI and Piezo-ICSI. Main results and the role of chance The areas in which UMR is less likely to occur and more likely to occur are heterogeneously distributed. When ICSI was performed blindly, about half was from the non-appropriate position. In appropriate group of Piezo-ICSI, rates of UMR (4.3% vs. 17.4%, P < 0.001) and degeneration (1.0% vs. 5.7%, P < 0.001) were significantly lower than those of non-appropriate group, whereas rates of fertilization (88.0% vs. 78.4%, P < 0.01) and blastocyst formation (57.8% vs. 45.9%, P < 0.01) were significantly higher than those of non-appropriate group, respectively. The rate of good-quality blastocyst (28.8% vs. 24.9%) was in favor of appropriate group, but not significantly different. In appropriate group of Conventional-ICSI, rates of UMR (6.7% vs. 20.6%, P < 0.001) and degeneration (1.5% vs. 6.6%, P < 0.01) were significantly lower than those of non-appropriate group, whereas rate of fertilization (88.7% vs. 69.5, P < 0.001) was significantly higher than those of non-appropriate group, respectively. The rates of blastocyst formation (37.5% vs. 35.3%), good-quality blastocyst (21.3% vs. 18.7%) were all in favor of appropriate group, but not significantly different. Limitations, reasons for caution This is a single private fertility clinic study. Its reproducibility should be assessed in different laboratory conditions and the hands of different operators. Moreover, specific studies should be addressed on the effect of the other putative confounders under investigation (e.g. kind of ovulation trigger, patient demographics, culture environment, etc.). Wider implications of the findings This study demonstrated that the IPD is useful to identify the optimal puncture location site to prevent UMR on ICSI procedure, resulting in reducing UMR and degeneration of the oocytes and increasing culture results, thereby, generating more embryos available for transfer or cryopreservation. Trial registration number not applicable

P-464 Long-acting GnRH agonist ovulation trigger to avoid ovarian hyperstimulation and to combine oocyte cryopreservation with ovarian suppression during chemotherapy

Abstract Study question Is long-acting GnRH agonist (GnRHa) trigger an efficacious and safe option in oocyte cryopreservation cycles before chemotherapy, when ovarian suppression is planned? Summary answer The flare-up effect of long-acting GnRHa is able to induce the final oocytes’ maturation and subsequently suppress ovarian function for chemotherapy What is known already When both oocyte cryopreservation and gonadal suppression during chemotherapy with long-acting GnRHa are accepted by the patient for fertility preservation (FP), the first injection of GnRHa is administered few days after oocyte retrieval in order to start oncological therapies as soon as possible. Some cases of ovarian hyperstimulation (OHSS) have been described in this setting, as a consequence of the initial flare-up effect on recently stimulated ovaries. The subsequent risks (including a possible delay in the start of chemotherapy) may discourage physicians from proposing gonadal suppression in combination with oocyte cryopreservation, denying women a FP opportunity with proven efficacy. Study design, size, duration Prospectively collected data from 75 oncological patients who underwent ovarian stimulation for oocyte cryopreservation from 2016 to 2021 were evaluated. From 2020 all patients for whom ovarian suppression after cryopreservation was planned were offered long-acting GnRHa trigger. All other patients were enrolled as controls, stratified for triggering method used (highly purified Chorionic Gonadotrophin 10000 UI or short acting GnRHa 0.2 mg). Participants/materials, setting, methods All the ovarian stimulation cycles for oocyte cryopreservation in oncological patients before chemotherapy were performed in a single tertiary level public fertility centre. Cycle outcomes were evaluated accordingly to the trigger method. Maturation rate was defined as number of cryopreserved mature oocytes/total number of oocytes retrieved. Results were compared by Mann-Whitney U test or Chi-Square test, as appropriate. When the long-acting GnRHa was used for triggering, luteal phase hormones were assessed. Main results and the role of chance After controlled ovarian stimulation (COS) with standard or random start antagonist protocol, 13 women received the long-acting GnRHa trigger (Triptorelin 3.75 mg. Group A) 36 hours before oocyte retrieval, 37 women received highly purified Chorionic Gonadotrophin 10000 UI (Group B) and 25 women the short-acting GnRHa (Triptorelin 0.2 mg. Group C). The groups were comparable in terms of demographic and clinical parameters. Median number of mature cryopreserved oocytes in group A was 11 (range 7-18) with a maturation rate of 80% (68-100), 9 (0-24) with a maturation rate of 78% (43-100) in group B, and 12 (0-34), 79% (50-100) in group C (no statistically significative difference). There was no case of OHSS in Group A. One patient in group B and one in group C developed OHSS after administration of long-acting GnRH in the luteal phase after COS (five days after oocytes retrieval). Five days after oocyte retrieval (7 days after trigger), serum FSH median level in group A was 1.29 mUI/ml (0.48-2.50) and LH median level was 1.04 mUI/ml (0.26-2.46). Limitations, reasons for caution We are aware that our data should be confirmed by more robust randomized studies and higher numbers. Wider implications of the findings We report for the first time the efficacy of long-acting GnRHa in obtaining mature oocytes and in guaranteeing complete suppression by chemotherapy initiation. The feasibility of this strategy is an important step in reducing the risk of OHSS, giving the opportunity to combine oocyte cryopreservation and ovarian suppression during chemotherapy. Trial registration number not applicable

O-246 A drop in serum progesterone(P4) levels between 5th and 7th days of triggering ovulation is associated with lower ongoing pregnancy rate(OPR) in intrauterine insemination cycles

Abstract Study question Is there any association between early- and mid-luteal phase serum P4 levels and OPR in patients undergoing IUI due to unexplained or mild male-factor infertility? Summary answer A drop in serum progesterone (P4) levels between 5th and 7th day of triggering ovulation is independently associated with lower OPR in IUI cycles. What is known already The definition of luteal phase insufficiency in natural cycles is controversial and might be encountered ∼10% of infertile couples. Serum P4 level measurement is a still the most feasible method for luteal phase monitoring. Recently, some research groups have been focusing on monitoring luteal phase in in-vitro fertilization cycles, however, there is scarce of evidence on luteal phase characteristics and reproductive outcomes in IUI cycles. Study design, size, duration A prospective cohort study. A total of 179 consecutive patients (230 cycles) with unexplained and mild male factor infertility undergoing IUI treatment at Hacettepe University in between June 2020 and May 2021 were included. For ovarian stimulation, of the included 230 cycles, clomiphene citrate and gonadotropin were used consecutively in 161 cycles and only gonadotropin in the remaining 69 cycles. The primary outcome measure was the OPR. No progesterone was administered for luteal phase support. Participants/materials, setting, methods Serum P4 levels were measured on the 5th and 7th day of hCG triggering.P4 level were available in 183 cycles for hCG+5 day, in 161 cycles for hCG+7 day. In order to investigate the effect of P4 levels on OPR, patients were divided into two groups as ≤ 10th percentile and >10th percentile according to serum P4 levels measured on hCG+5 and hCG+7 days, with the cut off values ≤5.6 ng/ml and ≤8.46 ng/ml, respectively. Main results and the role of chance Of the 230 cycles 17 (7.4%) were resulted with ongoing pregnancy. In the univariate analysis, the OPRs of the hCG+5 and hCG+7 serum P4 ≤10% and >10% groups were 10.5% (2/19) versus 5.5% (9/164) (p = 0.80) and 0% (0/16) versus 7.5% (n = 11/145) (p = 0.24), respectively. There was no ongoing pregnancy in patient with ≤8.46 ng/ml serum P4 level on hCG+7 day. The ΔP4 value was calculated by subtracting the serum P4 level measured on hCG+5 from the serum P4 level measured on day hCG+7 (ΔP4= hCG+7 – hCG+5). While none of the 26 patients with negative ΔP4 had ongoing pregnancy, 8 (6.2%) of 130 patients with positive ΔP4 had ongoing pregnancy (p = 0.194). In the multivariate-GEE (generalized estimating equation) analysis, ΔP4 was found to be an independent predictor of ongoing pregnancy alone (ß:0.137, 95% CI = 0.020-0.254, p = 0.02). Limitations, reasons for caution The physiological circadian pulsatile secretion of P4 during the mid-luteal phase and limited sample size are limitations, however, blood sampling was standardized to reduce the impact of timing. Wider implications of the findings Low progesterone level with the threshold ≤8.46 ng/ml on the hCG+7 day is associated lower OPR. Two measurements (hCG+5 day, hCG+7 day) of P4may delineate those patients with a drop in P4, associated lower OPRs. Rescuing these IUI cycles with additional P4supplementation should be tested in future randomized controlled trials. Trial registration number NCT04707430

Effect of Dual Trigger with Follicle Stimulating Hormone and Chorionic Gonadotropin Hormone on Ovulation Rate in Infertile Women received Aromatase Inhibitor Superovulation in Kirkuk City, Iraq

A prospective during the period October 2020 to April 2021, a comparative study was conducted at the Al-Nahrain University’s High Institute for Infertility Diagnosis and Assisted Reproductive Technologies (HIIDART). The study’s primary goal was to determine whether using a dual trigger (FSH and hCG) could increase the likelihood of achieving pregnancy. The participants in this study totaled one hundred women. Before taking part in the study, each participant signed a written informed consent form that was approved by the Al-Nahrain University’s Ethics Committee before participating. A total of one hundred and one women participated in the study, who were chosen from among those who attended the consultant clinic of the High Institute for Infertility Diagnosis and Assisted Reproductive Technologies in New York City. On the day of the IUI An ultrasound scan of the vaginal cavity was performed after 36 to 48 hours of trigger ovulation to confirm ovulation, measure, and evaluate the endometrial pattern, and assess sub endometrial blood flow. FSH, LH, Progesterone, and E2 levels were determined in a blood sample drawn on the same day for hormonal testing. Luteal phase support was initiated on the day of the IUI and continued for two weeks by administering 400 mg of progesterone vaginal suppository daily to the patient. Estimation of Beta human chorionic gonadotropins 14 days after IUI. The distribution of study groups by general characteristics is shown in Table 1. Study patients’ age was ranging from 19 to 39 years with a mean of 29.98 years and a standard deviation (SD) of ± 5.3 years. The highest proportion of study patients in all groups was aged between 25–34 years, overweighed, and complained from infertility for less than five years’ duration. The comparison in hormonal parameters between study groups at day of IUI is shown in Table 4.5. Mean of FSH level was significantly lower (p = 0.031) in group C than that in groups A and B (6.98 versus 9.06 and 9.3 IU/L respectively). Mean of E2 level was significantly higher (p = 0.001) in-group A than that in groups B and C (69.62 versus 53.32 and 36.65 pg/mL, respectively). The comparison in percentage of change in hormonal parameters at day of IUI compared to that at day of trigger according pregnancy outcome is shown in table (4.16). No significant differences between women who get pregnant than that in those who didn’t, in percentage of change of all other hormonal parameters at day of IUI (p ≥ 0.05) compared to that at day of trigger.

Estradiol to progesterone ratio is not a predictor of oocyte maturity at time of ovulation trigger

PurposeTo evaluate the relationship between progesterone and oocyte maturity rate via estradiol to progesterone ratio (E/P) at the time of ovulatory trigger.MethodsThis is a retrospective cohort study of first autologous IVF cycles from January to December 2018 from a private practice fertility center. Serum estradiol and progesterone levels were measured on the day of ovulatory trigger. E/P was calculated to control for degree of response. Embryos were cultured to the blastocyst stage for trophectoderm biopsy. Preimplantation genetic testing for aneuploidy (PGT-A) was performed using next-generation sequencing (NGS). Oocyte retrieval rate (oocytes retrieved/follicles ≥ 13 mm), maturity rate (MII/oocytes retrieved), and euploid rate (euploid/total biopsied embryos) were calculated. Clinical pregnancy, ongoing pregnancy (> 10 weeks), and live births following frozen embryo transfer (FET) were examined in relation to E/P. Regression analyses were performed to analyze E/P as a categorical value (defined by quartile) on oocyte maturity.ResultsTwo hundred eleven women underwent controlled ovarian hyperstimulation and had steroid levels at trigger available. Mean E at trigger was 3449 ± 2040 pg/mL while mean P was 1.13 ± 0.58 ng/mL, with mean E/P of 3.36 + 2.04. There were no differences between quartiles of E/P with respect to retrieval, maturity rate, or euploid rate. Two hundred eleven IVF cycles resulted in 138 euploid frozen embryo transfers. There were no differences between quartiles of E/P with respect to clinical pregnancy, ongoing pregnancy, or live birth rate.ConclusionE/P ratio at the time of trigger does not impact oocyte retrieval rate, maturity rate, or euploid rate. Pregnancy and live birth outcomes were also not impacted.

Extended culture of cleavage embryo to blastocyst embryo is among the good predictors of successful outcome in vitrified-thawed ICSI cycles

BackgroundPrevious studies showed that top-quality embryo transfer (ET), number of transferred embryos, endometrial preparation with natural cycles or mild stimulation, and female BMI independently affected the outcome in frozen-thawed ET. However, the effect of culturing thawed cleavage embryos to blastocyst stage on the outcome was not sufficiently elucidated. Our objective is to evaluate the role of this extended culturing as predictor of cycle outcome in vitrified-thawed ICSI cycles.Materials and methodsOne thousand forty-two consecutive cycles of vitrified-thawed ET done in a single IVF unit [Mansoura Integrated Fertility Centre (MIFC)] were reviewed during a period from 2014 to 2017. Endometrial preparation methods were natural, stimulation by antiestrogen and/or gonadotropins, or replacement using sequential estradiol (E2) and progesterone (P4). The primary outcome was the clinical pregnancy rate while the secondary outcome was the chemical and ongoing pregnancy rate.ResultsOverall clinical pregnancy rate (CPR) is 298/1042 is 28.5%, chemical pregnancy rate (326/1042) 31.3%, and ongoing pregnancy rate (167/615) 27.2%. Comparing clinically pregnant (n = 298) and non-pregnant (n = 744) showed, respectively, the following: age 28.76 ± 5.0, 28.85 ± 5.18 (p = 0.8); BMI 31.06 ± 5.9, 32.45 ± 5.9 (p = 0.002); infertility duration 4.17 ± 3.2, 4.6 ± 3.5 (p = 0.038); endometrial thickness 10.82 ± 1.6, 10.13 ± 2.06 (p = 0.0001); and no. of ET 3.35 ± 1.5, 3.12 ± 1.60 (p = 0.035). The clinical pregnancy rate when vitrification was done on cleavage embryos was 198/502 (39.4%), and when vitrification done on blastocyst stage 100/ 536 (18.7%) (P < 0.0001); endometrial preparation: natural 72/240(29.1%), stimulated 204/680 (30.0%) replacement 17/90 (18.8%) (p = 0.09); extended culture of cleavage embryos to blastocyst stage: clinical pregnancy rate 116/194 (59.7%) chemical pregnancy rate 125/194 (64.1%), ongoing pregnancy rate 87/165 (52.7%) and non extended culture clinical pregnancy rate 182/848 (21.4%), chemical pregnancy rate 201/848 (23.7%), and ongoing pregnancy rate 80/450 (17.7%) (P < 0.0001).ConclusionTop-quality ET, number of transferred embryos and extended culture of cleavage embryos to blastocyst stage, cleavage embryos but not infertility duration, BMI, endometrial thickness, or hCG trigger of ovulation independently predict successful outcome in frozen cycle ET and extended culture of cleavage embryos significantly improved clinical and chemical and ongoing pregnancy rates.

Optimal Timing of Ovulation Triggering to Achieve Highest Success Rates in Natural Cycles-An Analysis Based on Follicle Size and Oestradiol Concentration in Natural Cycle IVF.

IntroductionTiming of ovulation triggering is essential in infertility treatments including treatments based on natural menstrual cycles. However, data on follicle size and oestradiol (E2) concentration are limited. Therefore, the model of natural cycle IVF (NC-IVF) was applied to provide more detailed information on these parameters to better schedule the optimal time for triggering ovulation.Materials and MethodsA retrospective cross-sectional analysis of 606 monofollicular NC-IVF cycles was performed at a university-based IVF centre from 2016 to 2019. Follicle size and E2 and LH serum concentrations were evaluated on day -5 to 0 (day 0 = day of oocyte retrieval). Ovulation was triggered if follicle size was 14–22 mm. Patients with irregular cycles, endometriosis >II°, cycles with azoospermia or cryptozoospermia and cycles with inconsistent data were excluded. All parameters were analysed inter- and intraindividually, and associations of the parameters were evaluated. Associations were adjusted for age, cause of infertility and number of previous transfers.ResultsThe mean age of women undergoing NC-IVF was 35.8 ± 4.0 years. Follicle size increased by 1.04 ± 0.03 mm, and E2 concentration by 167 ± 11.0 pmol/l per day.Based on a multivariate adjusted mixed model with follicle size, E2 and their interaction, the number of retrieved oocytes was associated with E2 concentration (aOR 1.91, 95% CI: 1.03–3.56; p = 0.040). Maturity of oocytes was associated not only with E2 concentration (aOR 2.01, 95% CI: 1.17–3.45; p = 0.011) but also with follicle size (aOR 1.27, 95% CI: 1.01–1.60; p = 0.039), as was the interaction of both parameters (aOR 0.96, 95% CI: 0.93–0.99; p = 0.017).LH surge was calculated to start in 25% of cases at an E2 level of 637 pmol/l, in 50% of cases at 911 pmol/l and in 75% of cases at an E2 level of 1,480 pmol/l.The live birth rate per follicle aspiration cycle was (non-significantly) higher in cycles with follicles sizes at the time of oocyte retrieval of 18–22 mm (7.7%–12.5%) versus in cycles with follicles sizes of 14–17 mm (1.6%–4.3%).ConclusionThe study contributes to an optimization of infertility treatments involving natural cycles. The study gives guidance about the number of days required after follicle monitoring to schedule the optimal time for triggering ovulation.

Ovulation triggering with hCG alone, GnRH agonist alone or in combination? A randomized controlled trial in advanced-age women undergoing IVF/ICSI cycles.

Is a dual ovulation trigger with a combination of GnRH agonist (GnRHa) and hCG superior to single hCG and/or single GnRHa trigger in improving treatment outcomes in advanced-age women (aged ≥ 35 years) undergoing IVF/ICSI treatment? Co-administration of GnRHa and hCG as a dual trigger increases the number of good-quality embryos but it is not associated with a higher number of oocytes retrieved, compared with single hCG or GnRHa trigger. Many studies have demonstrated that a dual trigger has positive impact on oocyte maturation, retrieval rate and pregnancy rate without increasing the risk of ovarian hyperstimulation syndrome (OHSS) in some groups of IVF patients, when compared with single hCG trigger. Few studies have however been conducted to compare a dual trigger with a single GnRHa trigger, and insufficient evidence exists to support which trigger can achieve the best outcomes in IVF patients aged ≥35 years. This was an open-label randomized controlled trial of 510 participants conducted at single reproductive medical center from January 2019 to December 2021. After a sample size calculation performed by retrospectively analyzing our previous clinical data, we planned to recruit 170 patients in each group and 510 patients in total for the study. Women aged ≥35 years undergoing IVF/ICSI treatment, receiving a non-pituitary down-regulation protocol, and with low risk of OHSS, were enrolled in this trial. On the trigger day, patients were randomized into three groups: hCG alone (who received 6000 IU of hCG), GnRHa alone (who received 0.2 mg of triptorelin) and dual trigger (who received 0.2 mg of triptorelin plus 2000 IU of hCG) groups. The primary outcome parameter was the number of retrieved oocytes. The secondary outcome parameters included, among others, the number and rates of mature oocytes, two pronuclei (2PN) embryos and good-quality embryos, as the rates of OHSS, clinical pregnancy, miscarriage and live birth. There were no significant differences in the baseline demographic characteristics among the three groups. The dual trigger was associated with a higher retrieval rate (87.9% vs 84.1% in the hCG group, P = 0.031; 87.9% vs 83.6% in the GnRHa group, P = 0.014). However, the number of retrieved oocytes in the dual trigger group was comparable with those in the hCG group (4.08 ± 2.79 vs 3.60 ± 2.71, P = 0.080) and the GnRHa group (4.08 ± 2.79 vs 3.81 ± 3.38, P = 0.101); comparable data between the groups were also found when analyzing the number of 2PN embryos and the 2PN rate. In the dual trigger group, the numbers of good-quality embryos and viable embryos were both significantly higher than in the hCG group (1.74 ± 1.90 vs 1.19 ± 1.45, P = 0.016 and 2.19 ± 2.11 vs 1.56 ± 1.66, P = 0.008, respectively) and the GnRHa group (1.74 ± 1.90 vs 1.20 ± 1.67, P = 0.003 and 2.19 ± 2.11 vs 1.45 ± 1.75, P = 0.001, respectively). Pregnancy outcomes after fresh embryo transfer (ET) were comparable between the groups. The live birth rate and ongoing pregnancy rate after frozen ET in the dual trigger group were significantly higher than those in the GnRHa group (32.6% vs 14.1%, P = 0.007 and 34.8% vs 17.6%, P = 0.013, respectively), but not superior to those in the hCG group (32.6% vs 27.9%, P = 0.537 and 34.8% vs 27.9%, P = 0.358, respectively). Women of advanced age are quite a heterogeneous population and overlap with poor ovarian responders or patients with diminished ovarian reserve. We therefore could not entirely exclude selection biases or confounding factors. This study was also not a double-blinded trial; the patients in the GnRHa and dual trigger groups could have been affected by the placebo effect. The results of this study suggest that in advanced-age women with low risk of OHSS, a dual trigger or even a single hCG trigger may be a better choice than a single GnRHa trigger. This study was supported by the Shanghai Municipal Health Commission of Science and Research Fund (20184Y0289). The authors declare no conflict of interest. This trial was registered in the Chinese Clinical Trial Registry (ChiCTR-1800016285). 24 May 2018. 2 January 2019.

Facilitators and barriers for home-based monitoring to time frozen embryo transfers in IVF among women and healthcare providers.

STUDY QUESTIONWhat are the facilitators and barriers concerning the implementation of home-based monitoring for natural cycle frozen embryo transfer (NC-FET) from the perspectives of patients and healthcare providers in the Netherlands?SUMMARY ANSWERThe most important facilitator was optimal pregnancy chance for both the patients and healthcare providers, and the most important barriers were the risk of missing an ovulation for the patients and laboratory capacity for the healthcare providers.WHAT IS KNOWN ALREADYThe share of FET cycles in IVF treatments is increasing and, therefore, it is important to optimize protocols for FET. Monitoring of ovulation, which is used in NC-FET, can be hospital-based (ultrasounds and ovulation triggering) or home-based (LH urine tests). Home-based monitoring has the advantage of being the most natural protocol for FET and provides the feeling of empowerment and discretion for patients. A systematic approach for the implementation of home-based monitoring has to start with an exploration of the perspectives of all stakeholders.STUDY DESIGN, SIZE, DURATIONStakeholders (patients and healthcare providers) involved in the implementation process in the Netherlands participated in the present study. Patients were represented by the Dutch Patient Organisation for Couples with Fertility Problems (FREYA) and healthcare providers were represented by gynaecologists and their society (The Netherlands Society of Obstetrics and Gynaecology), embryologists and their society (The Dutch Federation of Clinical Embryology) as well as fertility doctors. A panel of experts hypothesized on barriers and facilitators for the implementation of home-based monitoring during the proposal phase of the Antarctica-2 randomized controlled trial (RCT).PARTICIPANTS/MATERIALS, SETTING, METHODSAll stakeholders were represented during the study. Two different questionnaires were developed in order to investigate facilitators and barriers for the patients and for healthcare providers. The facilitators and barriers were ranked on a scale of 1–10 with 10 being the most important. Based on our power analysis, we aimed for a minimum of 300 completed questionnaires for the patients and a minimum of 90 completed questionnaires for the healthcare providers. Facilitators and barriers were analysed using frequencies, mean (SD) and ranking.MAIN RESULTS AND THE ROLE OF CHANCEA total of 311 patients filled out the questionnaire of whom 86.8% underwent FET previously. The most important facilitator for the patients was to implement the strategy with the highest chance of pregnancy (mean 9.7; 95% CI 9.6–9.7) and the most important barrier was risk of missing ovulation (mean 8.4; 95% CI 8.2–8.6). A total of 96 healthcare providers filled out the questionnaire. According to healthcare providers, patients would accept the strategy when it causes less interference with their work and private life (mean 7.5; 95% CI 7.1–8.0) and has a low risk of missing the ovulation (mean 7.6; 95% CI 7.1–8.0). The most important facilitator for the implementation of home-based monitoring for healthcare providers was optimizing cumulative pregnancy rates (mean 8.1; 95% CI 7.7–8.4) and the most important barrier was the lack of laboratory capacity and flexibility (mean 6.4; 95% CI 5.8–7.0).LIMITATIONS, REASONS FOR CAUTIONFacilitators and barriers were selected based on expert opinion. Currently, there are no validated questionnaires that aim to assess facilitators and barriers for the implementation of treatments in fertility care.WIDER IMPLICATIONS OF THE FINDINGSDuring our study, we gained insight into barriers and facilitators for the implementation of home-based monitoring of NC-FET at an early phase. Early sharing and discussion of the results of this study with all stakeholders involved should stimulate a fast incorporation in guidelines, especially as key professionals in guideline development took part in this study. Also, based on our results, we can advise guideline developers to add tools to the guideline that may help overcome the implementation barriers.STUDY FUNDING/COMPETING INTERESTSThe Antarctica-2 RCT is supported by a grant from the Netherlands Organisation for Health Research and Development (ZonMw 843002807). No authors have any competing interests to declare.TRIAL REGISTRATION NUMBERTrial NL6414 (NTR6590).

Does the HCG trigger dose used for IVF impact luteal progesterone concentrations? a randomized controlled trial

Research questionIs there an association between the ovulation trigger dose of human chorionic gonadotrophin (HCG) and endogenous progesterone production during the luteal phase? DesignThis randomized controlled four-arm study, at the Fertility Clinic, Odense University Hospital, Denmark, included women undergoing gonadotrophin-releasing hormone (GnRH) antagonist IVF treatment with ≤11 follicles ≥12 mm. Group 1–3 were triggered with 5000 IU, 6500 IU or 10,000 IU HCG, respectively, receiving 17α-hydroxyprogesterone caproate intramuscularly for luteal-phase support (LPS) to measure endogenous progesterone production. Group 4 received 6500 IU HCG trigger and vaginal progesterone. During the study, the 5000 IU and 10,000 IU HCG groups were switched from urinary to recombinant HCG, as urinary HCG was removed from market. Eight blood samples were drawn during the luteal phase. ResultsNinety-four participants completed the study. There was a significant positive association between the HCG trigger dose and the progesterone at 8 days (P < 0.001), 10 days (P < 0.001) and 14 days (P < 0.001) post-oocyte retrieval. Comparing the groups individually revealed a significant difference in progesterone concentration between low and high trigger doses at 4 days (P = 0.037) and 8 days (P = 0.007) post-oocyte retrieval and between all intervention groups at oocyte retrieval + 6 days: group 1 and 2 (P = 0.011), group 2 and 3 (P = 0.042) and group 1 and 3 (P < 0.001). Higher HCG trigger dose increased the progesterone from the individual follicle. ConclusionsIncreasing HCG trigger doses significantly increased endogenous progesterone concentration during the mid–late luteal phase.

Nuclear Progestin Receptor-mediated Linkage of Blood Coagulation and Ovulation.

Ovulation is a dramatic remodeling process that includes rupture of blood capillaries and clotting, but coagulation is not thought to directly regulate this process. Herein, we report remarkable increases of coagulation factors V (f5, ~3145-fold) and tissue factor (f3a, ~120-fold) in zebrafish ovarian follicle cells during ovulation. This increase was mediated through the nuclear progestin receptor (Pgr), which is essential for ovulation in zebrafish, and was totally abolished in ovarian follicular cells from pgr-/- mutants. In addition, promoter activities of f5 and f3a were significantly enhanced by progestin (DHP) via Pgr. Similar regulation of human F5 promoter activity was induced via human PGRB, suggesting a conserved mechanism. Site-directed mutagenesis of the zebrafish f5 promoter further demonstrated a direct regulation of coagulation factors via progestin response elements. Moreover, a stark increase of erythrocytes occurred in capillaries meshed in wild-type preovulatory follicles but was absent in pgr-/- mutants. Interestingly, anticoagulants significantly inhibited ovulation both in vitro and in vivo, respectively. Furthermore, reduced fecundity was observed in f5+/- female zebrafish. Taken together, our study provides plausible evidence for steroid regulation of coagulation factors, and a new hypothesis for blood clotting-triggered ovulation in vertebrates.

Stimulation Duration in Patients with Early Oocyte Maturation Triggering Criteria Does Not Impact IVF-ICSI Outcomes.

Results from studies reporting the optimal stimulation duration of IVF-ICSI cycles are inconsistent. The aim of this study was to determine whether, in the presence of early ovulation-triggering criteria, prolonged ovarian stimulation modified the chances of a live birth. This cross-sectional study included 312 women presenting triggering criteria beginning from D8 of ovarian stimulation. Among the 312 women included in the study, 135 were triggered for ovulation before D9 (D ≤ nine group) and 177 after D9 (D > nine group). The issues of fresh +/− frozen embryo transfers were taken into consideration. Cumulative clinical pregnancy and live-birth rates after fresh +/− frozen embryo transfers were similar in both groups (37% versus 46.9%, p = 0.10 and 19.3% versus 28.2%, p = 0.09, respectively). No patient characteristics were found to be predictive of a live birth depending on the day of ovulation trigger. Postponing of ovulation trigger did not impact pregnancy or live-birth rates in early responders. A patient’s clinical characteristics should not influence the decision process of ovulation trigger day in early responders. Further prospective studies should be conducted to support these findings.

CONSEQUENCES OF THE ASSISTANT REPRODUCTIVE TECHNOLOGY PROGRAM IN WOMEN WITH HYPERPLASTIC PROCESSES OF ENDOMETRIUM

In women of reproductive age, reproductive dysfunction is associated with uterine factor, which ranges from 24% to 62% in the population, especially in the case of endocrine and metabolic disorders.&#x0D; Literature sources show a significant decrease in fertility in such patients, 38.6% of women report infertility, 11.9% - recurrent miscarriage.&#x0D; The aim was to study the effectiveness and consequences of in vitro fertilization programs in patients with infertility and hyperplastic processes of endometrium.&#x0D; Materials and methods. A prospective cohort research included 75 patients with history of hyperplastic processes of endometrium and reduced reproductive potential (infertility and history of fetal loss syndrome) - the main group, as well as 40 women without uterine infertility and without menstrual irregularities (comparison group).&#x0D; Results. In the main group, the average age of women was significantly higher and 1.4 times - the average body mass index against the data of the comparison group (p &lt;0,05). The share of comorbidity of somatic pathology and proliferative processes of the reproductive system (fibroids, adenomyosis etc.) was significantly higher in the main group (p &lt;0.05). Assessment of reproductive function and obstetric history allowed to establish a significantly higher number of pregnancies, miscarriages and intrauterine interventions in the main group (p &lt;0,05). The results of indicators of hormonal homeostasis showed a tendency to reduce the level of antimullerian hormone, although it corresponded to the reference values, which can be explained by the older age group of patients in the main group and a high concentration of testosterone (p&lt;0.05), that required a longer period of superovulation stimulation and a higher dose of gonadotropins, while chorionic gonadotropin was more often used as an ovulation trigger. Women of the main group had smaller number of mature oocytes, more oocytes with cytoplasmic and extracytoplasmic dysmorphism and low-quality blastocysts versus data in the comparison group. The incidence of biochemical and clinical pregnancies did not differ significantly between groups, whereas the proportion of spontaneous abortions was 6.4 times higher in the case of uterine infertility (history of endometrial hyperplasia and polyposis), which was accompanied by a lower percentage of live births in this category of patients compared to the comparison group (p &lt;0.05).&#x0D; Conclusions. The research found a reduced chance of prolonging clinical pregnancy and live birth in patients with history of hyperplastic processes of endometrium, as well as a decrease in the effectiveness of assisted reproductive technology programs due to the weaker response of the ovaries to superovulation stimulation. Patients with history of hyperplastic processes of endometrium had a higher BMI, a high proportion of uterine fibroids, adenomyosis and comorbidity of somatic pathology, which is naturally associated with age and pathogenesis of hyperplastic processes of the reproductive system. Patients of the main group were found to have higher androgenic rates and such following features of superovulation stimulation: appointment of combined drugs FSH / LH, high total doses of gonadotropins and chorionic gonadotropin as a trigger of ovulation, also an increase in the duration of superovulation stimulation with increasing BMI.