Subsequent Frozen Embryo Transfer Research Articles

IMPACT OF TIME INTERVAL FROM CESAREAN DELIVERY TO FROZEN EMBRYO TRANSFER ON REPRODUCTIVE AND NEONATAL OUTCOMES

To evaluate differences in reproductive and neonatal outcomes based on the time interval from cesarean delivery to subsequent frozen embryo transfer (FET) DESIGN: Retrospective cohort SUBJECTS: Women undergoing autologous elective single embryo transfer (eSET) FET following prior cesarean delivery EXPOSURE: Time from prior cesarean delivery to subsequent FET MAIN OUTCOME MEASURES: Live birth RESULTS: A total of 6,556 autologous eSET FET cycles were included. FET cycles were divided into eight groups based on the time interval from prior cesarean delivery to subsequent FET in months. Time was also evaluated as a continuous variable. The proportion of live births did not differ significantly across all time interval groups and over continuous time (range: 40.0% - 45.6%, adjusted (adj) p = 0.572, continuous adj p = 0.599). Mean gestational age at the time of delivery did not significantly differ as the time between prior cesarean delivery and subsequent FET increased (range: 37.3 - 38.4 weeks, adj p = 0.87, continuous adj p = 0.06). When time was evaluated continuously, the proportion of preterm births was higher with a shorter time between cesarean delivery and subsequent FET (p = 0.02). Mean birth weight ranged from 3181 grams to 3470 grams, with a statistically significant increase over time (continuous adj p = 0.01). However, the proportions of extremely low birth weight, very low birth weight, and low birth weight did not significantly differ. There were no significant differences in reproductive outcomes based on the time interval from cesarean delivery to FET, including live birth. The proportion of preterm deliveries decreased with a longer time between cesarean delivery and FET. Differences in mean neonatal birth weight were not clinically significant, as the proportion of low-birth-weight neonates was not significantly different over time. While large, this sample cannot address all outcomes associated with short interpregnancy intervals, particularly rarer outcomes such as uterine rupture. When counseling patients, the timing of FET following cesarean delivery must be balanced against the risks of increasing maternal age on reproductive and neonatal outcomes.

The details matter: personalized prediction of live birth after in vitro fertilization in women with polycystic ovary syndrome

ObjectiveTo derive and internally validate a clinical prediction model for live birth in women with polycystic ovary syndrome (PCOS) undergoing in-vitro fertilization (IVF) DesignRetrospective cohort study SettingFour academic reproductive endocrinology clinics Patients207 women with PCOS confirmed by Rotterdam criteria undergoing their first fresh IVF cycle InterventionsNone Main Outcome MeasureThe primary outcome was cumulative live birth (LB) per IVF cycle start. This included any LB that resulted from either fresh embryo transfer or any subsequent frozen embryo transfer from embryos obtained at the index oocyte retrieval. A prediction model was derived using multivariable logistic regression. Covariates considered for inclusion in the prediction model included demographic characteristics, medical history, and prior fertility treatment. Predicted probabilities for live birth were calculated using the prediction model which included the 90% shrinkage factor for each adjusted OR. ResultsThe final model, based on maximization of the area under the receiver operating characteristic curve (AUROC), included age <35 years, White race, presence of polycystic ovaries on ultrasound (PCOM), normal BMI (<25 kg/m2), being metabolically healthy (no metabolic risk factors), and being a non-responder to ovulation induction (OI) agents including letrozole and clomiphene citrate. The AUROC for the model was 0.68 (95% CI: 0.60, 0.77). Predicted probabilities of live birth ranged from 8.1% (95% CI 2.8, 21.5) for a woman who had no favorable predictors to 74.2% (95% CI: 59.5, 84.9) for a woman who had all favorable predictors. ConclusionOur study demonstrates that in addition to anovulation, the underlying pathophysiology and associated co-morbidities alter the likelihood of a successful pregnancy in women with PCOS undergoing IVF. Further validation of this model is needed before it, can serve as a tool to personalize prediction estimates for probability of live birth in women with PCOS.

Antibiotic cured chronic endometritis remains a risk factor for early pregnancy loss in the subsequent frozen euploid embryo transfer

Research questionDo patients with antibiotic-cured chronic endometritis (CCE) have a comparable pregnancy outcome to those with non-chronic endometritis (NCE) in the subsequent frozen embryo transfer (FET) cycle? DesignA retrospective cohort analysis included 833 patients in their first FET cycles with single euploid embryo transfer. Chronic endometritis (≥5 CD138+ plasma cells per high-power field [CD138+/HPF]) was treated with standard antibiotic therapy. Patients were classified into two groups: the NCE group (n = 611, <5 CD138+/HPF) and the CCE group (n = 222, ≥5 CD138+/HPF and cured after antibiotic treatment). Pregnancy outcomes were compared. NCE group was divided into subgroup 1 (CD138+/HPF = 0) and subgroup 2 (CD138+/HPF = 1–4) for further analysis. ResultsThe rate of early pregnancy loss (EPL), incorporating all losses before 10 weeks’ gestation, was significantly higher in the CCE group than the NCE group (21.2% versus 14.2%, P = 0.016), and the difference was statistically significant (adjusted odds ratio [AOR] 1.68, 95% confidence interval [CI] 1.11–2.55). No significant differences were observed between the two groups with regard to other pregnancy outcomes. In the subgroup analysis, the EPL rate and biochemical pregnancy rate were significantly higher in subgroup 2 than subgroup 1 (17.2% versus 9.4%, AOR 2.21, 95% CI 1.30–3.74; 12.2% versus 6.9%, AOR 2.01, 95% CI 1.09–3.68). ConclusionsChronic endometritis cured by standard antibiotic therapy remains a risk factor for EPL in FET cycles, although no differences were found in live birth rates between patients with CCE or with NCE.

The association between body mass index and live birth and maternal and perinatal outcomes after in-vitro fertilization: a national cohort study.

To investigate the association between female body mass index (BMI) and live birth rates and maternal and perinatal outcomes after in-vitro fertilization (IVF). We performed a national, population-based cohort study including women undergoing IVF between 2002 and 2020. The cohort included 126,620 fresh cycles and subsequent frozen embryo transfers between 2007 and 2019 (subpopulation 1) and 58,187 singleton deliveries between 2002 and 2020 (subpopulation 2). Exposure was female BMI (kg/m2) categorized according to the World Health Organization as underweight (<18.5), normal weight (18.5-24.9, reference), overweight (25.0-29.9), class I obesity (30.0-34.9), class II obesity (35.0-39.9), and class III obesity (≥40.0). The primary outcome in subpopulation 1 was cumulative live birth per started fresh IVF cycle, including fresh and subsequent frozen embryo transfers. Primary outcomes in subpopulation 2 were hypertensive disorders of pregnancy and preterm birth at less than 37 weeks. Risk ratios (RRs) with 95% confidence intervals (CIs) for the association between BMI class and outcomes were calculated using generalized linear models after adjustment for relevant confounders. The cumulative live birth rate decreased significantly with increasing BMI from 32.6% in normal-weight women to 29.4% in overweight women, 27.0% in women in obesity class I, 21.8% in women in obesity class II, and 7.6% in women in obesity class III. The risk of hypertensive disorders of pregnancy increased significantly and progressively with increasing BMI, from 4.6% in normal-weight women to 7.8% in overweight women and 12.5%, 17.9%, and 20.3% in women in obesity classes I, II, and III. The risk of preterm birth followed a similar pattern, from 6.3% in normal-weight women to 7.5% in overweight women and 8.9%, 9.9%, and 15.3% in women in obesity classes I, II, and III. The risks of other perinatal complications, such as perinatal death, showed an even more pronounced increase. Using a large and complete national cohort of women undergoing IVF, we demonstrate a dose-dependent decrease in live birth rate and a substantial increase in maternal and perinatal complications with increasing BMI. Strategies to improve this situation are warranted.

Season at the time of oocyte collection and frozen embryo transfer outcomes.

Does the meteorological season at the time of oocyte retrieval affect live birth rates in subsequent frozen embryo transfers? Frozen embryo transfers resulting from oocytes retrieved in summer have 30% increased odds of live birth compared to frozen embryo transfers resulting from oocytes retrieved in autumn, regardless of the season at the time of embryo transfer. Season at the time of frozen embryo transfer does not appear to be associated with live birth rate. One study in the northern hemisphere found increased odds of live birth with frozen embryo transfer resulting from oocytes collected in summer when compared to those collected in winter. Retrospective cohort study including all frozen embryo transfers performed by a single clinic over eight years, from January 2013 to December 2021. There were 3659 frozen embryo transfers with embryos generated from 2155 IVF cycles in 1835 patients. Outcome data were missing for two embryo transfers, which were excluded from analysis. Outcomes were analysed by the season, temperatures, and measured duration of sunshine at the time of oocyte collection and at the time of frozen embryo transfer. There were no significant differences between patients with oocyte collection or embryo transfers in different seasons. Meteorological conditions on the day of oocyte collection and the day of frozen embryo transfer, and in the preceding 14- and 28-day periods, were collected including mean, minimum, and maximum temperatures, and recorded duration of sunshine hours. Clinical and embryological outcomes were analysed for their association with seasons, temperatures, and duration of sunshine with correction for repeated cycles per participant, age at the time of oocyte retrieval, and quadratic age. Compared to frozen embryo transfers with oocyte retrieval dates in autumn, transfers with oocyte retrieval dates in summer had 30% increased odds of live birth (odds ratio (OR): 1.30, 95% CI: 1.04-1.62) which remained consistent after adjustment for season at the time of embryo transfer. A high duration of sunshine hours (in the top tertile) on the day of oocyte retrieval was associated with a 28% increase in odds of live birth compared to duration of sunshine hours in the lowest tertile (OR 1.28, 95% CI: 1.06-1.53). Temperature on the day of oocyte retrieval did not independently affect the odds of live birth. The odds of live birth were decreased by 18% when the minimum temperature on the day of embryo transfer was high, compared with low (OR: 0.82, 95% CI: 0.69-0.99), which was consistent after correction for the conditions at the time of oocyte retrieval. This was a retrospective cohort study, however, all patients during the study period were included and data was missing for only two patients. Given the retrospective nature, causation is not proven and there are other factors that may affect live birth rates and for which we did not have data and were unable to adjust, including pollutants and behavioural factors. We were also not able to stratify results based on specific patient populations (such as poor- or hyper-responders) nor report the cumulative live birth rate per commenced cycle. These findings may be particularly relevant for patients planning oocyte or embryo cryopreservation. Given the increasing utilization of cryopreservation, identification of factors that influence outcomes in subsequent frozen embryo transfers has implications for future therapeutic and management options. Further studies to clarify the physiology underlying the influence of sunshine hours or season on subsequent frozen embryo transfer outcomes are required, including identification of specific populations that may benefit from these factors. No funding was provided for this study. S.L. has received educational travel assistance from Besins, Merck and Organon outside the submitted work. R.H. is National Medical Director of City Fertility and Medical Director of Fertility Specialists of Western Australia, has received honoraria from MSD, Merck Serono, Origio and Ferring outside the submitted work, and has equity interests in CHA SMG. C.R., M.W., and E.N. declare that they have no conflicts of interest. N/A.

O-297 Contribution of Frozen Embryo Transfer Cycles to ICSI Clinical Outcomes in Male Factor Infertility

Abstract Study question What is the benefit of adding frozen embryo transfer (FET) cycles to ICSI clinical outcomes in male factor infertility? Summary answer FET carried out on spare embryos that reached blastocyst stage remarkably contributed to additional clinical pregnancies in ICSI cycles for male factor infertility. What is known already Current trends in reproductive medicine lean toward full-preimplantation development and eventually to PGT-A to select a single euploid embryo for transfer. The utilization of this approach, while beneficial in most couples, is not ideal for male factor infertility due to the tendency of being characterized by impaired embryo development. So, we wonder if the utilization in FET cycles of leftover embryos that reached to blastocyst stage or those that eventually reached day 5 for aneuploidy testing contributed to the clinical outcomes. Study design, size, duration In the past 7 years, we included 22,289 couples who underwent ICSI while the large majority (84.8%) received a fresh embryo transfer, of which 70.9% were transferred at day 3. Leftover embryos, together with those euploid after PGT-A at blastocyst stage, were replaced in subsequent FET cycles. The clinical outcomes including clinical pregnancy rate (CPR) and deliveries were compared between the fresh embryo transfer and those after FET in total and after PGT-A. Participants/materials, setting, methods Couples with male factor underwent ICSI in standard fashion using exclusively ejaculated sample. For fresh embryo transfer cycles, embryos were transferred either at day 3 or at day 5. For FET cycles, embryos were cultured up to exclusively blastocyst stage and cryopreserved by vitrification. For aneuploidy, NGS was carried out for PGT-A. FET was carried out in natural or programmed cycles. Main results and the role of chance In the cohort underwent fresh embryo transfer, 18,896 couples underwent 37,751 ICSI cycles, where 322,916 oocytes were injected and 243,768 (75.5%) fertilized. Additionally, 3,393 patients received 4,712 FET in total with a fertilization of 69.8% (46,163/66,171) that did not differ from the fresh transfer group. The number of average embryos transferred in fresh cycles was 2.4±2 while FET was carried out exclusively on single embryo. Fresh transfer yielded 37.3% (14,087/37,751) CPR, while overall FET cycles achieved a higher CPR at 52.2% (2,462/4,712, P&amp;lt;0.0001). Similarly, the delivery rate in fresh cycles was 31.8% (12004/37751) and became 45.5% (2145/4712) in the FET (P&amp;lt;0.0001). To identify the advantage of selecting a single euploidy embryo, we compared FET on leftover unscreened blastocyst to those that were planned for PGT-A. Spare embryo transfers involved 1774 patients in 2282 cycles with a fertilization rate of 67.7% (18,905/27,937). For the PGT-A cycles, 1619 couples in 2430 cycles achieved a comparable fertilization rate of 71.3% (27,258/38,234), In this comparison, the FET on spare unscreened embryos achieved a CPR at 47.0% (1,072/2,282) while in the PGT-A group reached CPR at 57.2% (1390/2430, P&amp;lt;0.0001). Similarly, the delivery rate was 37.6% (857/2,282) in the FET and PGT-A was 53.0% (1,288/2,430) (P&amp;lt;0.0001). Limitations, reasons for caution The comparison is retrospective and is carried out on male factor infertility where day 3 embryo transfer were performed almost exclusively on fresh cycle to overcome poor embryo development. Nonetheless, those spare embryos that reached blastocyst stage and those that electively underwent aneuploidy testing significantly contributed to enhance clinical outcomes. Wider implications of the findings ICSI can overcome most of male infertility; however, the risk of impaired embryo development proposes a transfer at cleavage stage. The advanced embryo culture condition together with time-lapse allowed us to monitor embryos up to the blastocyst stage that once transferred, improving clinical outcomes, especially for embryos with confirmed euploidy. Trial registration number N/A

A balancing act: sex selection after pre-implantation genetic testing for aneuploidy for first versus second baby.

How often do patients undergoing frozen embryo transfer (FET) after preimplantation genetic testing for aneuploidy (PGT-A) choose to select for sex and do sex selection rates differ before and after successful delivery of a first baby? When a choice was available between male and female embryos, patients selected the sex more frequently when trying to conceive the second child (62%) as compared to the first child (32.4%) and most commonly selected for the opposite sex of the first child. Sex selection is widely available in US fertility clinics. However, the rate of sex selection for patients undergoing FET after PGT-A is unknown. This is a retrospective cohort study of 585 patients that took place between January 2013 and February 2021. The study took place at a single, urban academic fertility center in the USA. Patients were included if they had a live birth after single euploid FET and returned for at least one subsequent euploid FET. The primary outcomes were the rates of sex selection for first versus second baby. Secondary outcomes were rate of selection for same versus opposite sex as first live birth and overall rate of selection for males versus females. Five hundred and eighty-five patients underwent a total of 1560 single euploid FETs resulting in either one or two live births. A choice between male and female euploid embryos was available for 919 FETs (first child: 67.5% (519/769) versus second child: 50.6% (400/791), P < 0.01). When a choice was available, patients selected the sex more frequently when trying to conceive the second child (first child: 32.4% (168/519) versus second child: 62.0% (248/400), P < 0.01). When sex was selected after first live birth, the opposite sex of the first child was selected 81.8% (203/248 FETs) of the time. Of transfers that involved sex selection, rates of male and female selection were similar for the first child, but selection for females was greater for the second child (first child: 51.2% (86/168) male versus 48.9% (82/168) female, second child: 41.1% (102/248) male versus 58.9% (146/248) female, P < 0.04). The study was performed at one urban academic medical center in the Northeastern US, which may limit generalizability to other settings where PGT-A may be performed less frequently, or sex selection may be limited or not permitted. In addition, we could not reliably account for whether patients or their partners had prior children and if so, of what sex. Patients undergoing PGT-A with both male and female euploid embryos were more likely to select for sex when attempting a second child and usually selected for the opposite sex of their first child. These findings highlight the potential for family balancing for patients who undergo PGT-A in settings where sex selection is permitted. This study received no funding. The authors have no conflicts of interest to declare. N/A.

TRANSFER OF PREVIOUSLY VITRIFIED EUPLOID EMBRYOS IN UNSTIMULATED MENSTRUAL CYCLES YIELDS HIGHER LIVE BIRTH RATES AND A LOWER INCIDENCE OF HYPERTENSIVE COMPLICATIONS COMPARED TO HORMONE REPLACEMENT CYCLES

There has been a trend favoring freeze-all IVF cycles with subsequent frozen embryo transfer (FET) due to increased utilization of PGT, OHSS prevention, and reports of improved outcome with FET for some patients. FET may be performed in either a natural, unstimulated menstrual cycle or in a programmed cycle using hormone replacement therapy. Although several prior publications have demonstrated similar pregnancy rates between protocols, direct comparisons may be confounded due to heterogeneity within patient populations, particularly embryo quality and recipient age at oocyte retrieval.

Multicentre study on rates and reasons for treatment discontinuation in patients with remaining cryopreserved embryos

Research questionWhat is the discontinuation rate among patients with remaining cryopreserved embryos in Belgium and what are the reasons for discontinuation? DesignMulticentre, cross-sectional study across 11 Belgian fertility clinics. Patients were eligible (n = 1917) if they had previously undergone an unsuccessful fresh embryo transfer (fresh group) or frozen embryo transfer (FET) (in-between group) and did not start a subsequent FET cycle within 1 year despite having remaining cryopreserved embryos. The denominator was all patients with embryos cryopreserved during the same period (2012–2017) (n = 21,329). Data were collected through an online anonymous questionnaire. ResultsThe discontinuation rate for patients with remaining cryopreserved embryos was 9% (1917/21329). For the final analysis, 304 completed questionnaires were included. The most important reasons for discontinuing FET cycles were psychological (50%) and physical (43%) burden, effect on work (29%), woman's age (25%) and effect on the relationship (25%). In 69% of cases, the patient themselves made the decision to delay FET treatment. In 16% of respondents, the decision to delay FET was determined by external factors: treating physician (9%), social environment (4%), close family (3%) and society (3%). Suggested improvements were psychological support before (41%), during (51%) and after (51%) treatment, as well as lifestyle counselling (44%) and receiving digital information (43%). ConclusionsThe discontinuation rate is remarkably high in patients with remaining cryopreserved embryos who have a good prognosis. Respondents stressed the need to improve the integration of psychological and patient-tailored care into daily assisted reproductive technology practice.

P-424 Endometrial receptivity as determined by Endometrial Receptivity Analysis (ERA) can change after a successful live birth from a frozen embryo transfer (FET)

Abstract Study question Endometrial receptivity as determined by Endometrial Receptivity Analysis (ERA) can change after a successful live birth from a frozen a frozen embryo transfer (FET) Summary answer 27 of 33 patients with a previous live birth from FET had an altered endometrial receptivity profile by ERA after a subsequent unsuccessful FET. What is known already The endometrial window of implantation is approximately 24 hours wide with a complex interaction of autocrine, paracrine, and endocrine factors. Successful embryo implantation involves a 3-step process of apposition, adhesion, and invasion of an embryo into a receptive endometrium. The ERA was developed using the expression profile of 248 genes using Next Generation Sequencing to determine if the endometrium is receptive, early receptive, late receptive, pre-receptive or post-receptive to objectively determine the optimal timing of progesterone exposure prior to embryo transfer. Some studies have shown statistically significant improvements in live birth rates while other studies have shown no difference. Study design, size, duration Case series of 33 patients with successful live birth following euploid FET using 5 days of progesterone (P + 5) with subsequent unsuccessful FET using the same protocol from January 2018 – December 2020. 27 of 33 patients who repeated their ERA were found to be non-receptive using P + 5. The new ERA profile results were used for their next FET. Implantation and live birth rates were calculated. Participants/materials, setting, methods A single private practice fertility clinic performed 340 ERA cycles from January 2018 – December 2020 with 276 subsequent FET cycles. An observational study of 33 patients with a previous live birth using P + 5 elected to repeat their ERA cycle after an unsuccessful FET. Implantation and live birth rates were calculated for their subsequent FET after completing the repeat ERA. Main results and the role of chance Repeat ERA result for patients with a previous live birth using P + 5 revealed that 6 patients still needed P + 5 (18.2%) for a receptive endometrial profile, 8 patients (24.2%) needed an extra 12 hours (P + 5.5), 18 patients (54.5%) needed an extra 24 hours (P + 6) and only one patient (3.0%) needed an extra 48 hours (P + 7). No patient that repeated their ERA after a previous live birth had a post-receptive profile (P + 4 or P + 4.5) and one patient had successful live births after using 3 different ERA profiles (P + 5, P + 6 and P + 7). All patients except one had repeat ERA results that were pre-receptive with only one patient changing from P + 6 to P + 5. FET cycles using P + 5 and P + 7 had a 100% implantation and pregnancy rate, while patients using P + 5.5 had the lowest implantation rate (62.5%) and live birth rate (37.5%). Patients with an ERA profile of P + 6 had an implantation rate of 94.1% and live birth rate of 88.2%. The small number of patients in this case series make a type I error possible because of the low number of patients in each ERA profile category with insufficient power to reach statistical significance. Limitations, reasons for caution Implantation rate for the clinic during the study period was 75% and live birth rate of 68% using euploid embryos. Our high baseline implantation and live birth rates, coupled with low numbers of patients in this observational study, make these results less generalizable to the IVF population at large. Wider implications of the findings It is widely accepted that ERA results are reproducible and do not change during a woman’s reproductive life. These results suggest that some women may have an altered window of receptivity after both successful and unsuccessful FET cycles. It may be reasonable to repeat ERA cycles for carefully selected patients. Trial registration number N/A

P-527 Comparison of implantation rate and preimplantation genetic testing between hatching and hatched blastocysts

Abstract Study question Does embryo stage, hatching versus hatched blastocyst, affect ploidy status and implantation rates (IR)? Summary answer The embryo stage may influence ploidy status, but no correlation was made between embryo stage and IR. What is known already It is generally accepted that hatched embryos present increased vulnerability when handled and are often selected against. The literature on this varies with some reporting that the transfer of hatched blastocysts resulted in lower pregnancy rates compared to hatching or expanded blastocysts. Other studies have found no difference in clinical outcome with the transfer of hatched blastocysts compared to other stages. Reports defining the relationship between hatched or hatching blastocysts and ploidy rates are limited. Study design, size, duration Retrospective analysis of IR of 224 transferred euploid embryos and ploidy rate (P-Rt) of 1431 embryos produced in two IVF labs in the United States between 2019-2021. Embryos underwent assisted hatching on Day 3 and were subjected to preimplantation genetic testing (PGT) on Day 5 or Day 6 followed by vitrification. IR was defined as the presence of an intrauterine implantation sac with the detection of a fetal heartbeat on ultrasound. Participants/materials, setting, methods Trophectoderm biopsies were evaluated by NextGen Sequencing at the same genetics laboratory (Ovation Genetics, Nashville, TN). P-Rt included the following categories: Normal (N) or euploid, Abnormal (ABN) or aneuploid, Low-Mosaic (LM), and High-Mosaic (HM). Euploid embryos were transferred in subsequent frozen embryo transfer (FET) cycles and monitored by clinical ultrasound. Chi-square statistical analysis was performed to identify potential differences (p &amp;lt; 0.05). Main results and the role of chance No significant difference was observed in IR after transferring euploid hatched blastocysts compared to euploid hatching blastocysts. The IR of hatched blastocysts was 40.3% compared to 50.3% for hatching blastocysts (p = 0.21). A significant difference in ABN and HM embryos was observed according to embryo stage (p = 0.02). The ABN rate was 21.2% for hatched blastocysts compared to 28.0% for hatching blastocyst and the HM rate of hatched blastocysts was 10.3% versus hatching blastocyst at 7.5%. No significant difference in Normal and LM ploidy rates were observed according to embryo stage. The N ploidy rate of hatched blastocysts was 58.1% versus 54.4% in hatching blastocysts, and LM rate for hatched blastocysts was 10.3% compared to 10.1% in hatching blastocysts. Limitations, reasons for caution The limited data set did not include fresh embryo transfers or the transfer of untested embryos. The inclusion of increased embryo numbers could strengthen the power of the evaluation and allow for more robust statistical analysis. Wider implications of the findings Embryo selection is a multifactorial process consisting of a wide range of parameters. Numerous advances in embryo production and evaluation have resulted in the need for an algorithm or guide to rank embryos for transfer. Further investigation is warranted to elucidate comprehensive recommendations for embryo selection. Trial registration number not applicable

Adaptive data-driven models to best predict the likelihood of live birth as the IVF cycle moves on and for each embryo transfer

PurposeTo dynamically assess the evolution of live birth predictive factors’ impact throughout the in vitro fertilization (IVF) process, for each fresh and subsequent frozen embryo transfers.MethodsIn this multicentric study, data from 13,574 fresh IVF cycles and 6,770 subsequent frozen embryo transfers were retrospectively analyzed. Fifty-seven descriptive parameters were included and split into four categories: (1) demographic (couple’s baseline characteristics), (2) ovarian stimulation, (3) laboratory data, and (4) embryo transfer (fresh and frozen). All these parameters were used to develop four successive predictive models with the outcome being a live birth event.ResultsEight parameters were predictive of live birth in the first step after the first consultation, 9 in the second step after the stimulation, 11 in the third step with laboratory data, and 13 in the 4th step at the transfer stage. The predictive performance of the models increased at each step. Certain parameters remained predictive in all 4 models while others were predictive only in the first models and no longer in the subsequent ones when including new parameters. Moreover, some parameters were predictive in fresh transfers but not in frozen transfers.ConclusionThis work evaluates the chances of live birth for each embryo transfer individually and not the cumulative outcome after multiple IVF attempts. The different predictive models allow to determine which parameters should be taken into account or not at each step of an IVF cycle, and especially at the time of each embryo transfer, fresh or frozen.

O-010 The One-and-Done Approach: does higher dosing of gonadotropins in predicted high and low responders increase the incidence of multiple live births from one ART-stimulation cycle?

Abstract Study question Does higher gonadotropin dosing in predicted high and low responders lead to a higher reproductive potential from one ART-cycle? Summary answer Higher gonadotropin dosing may double the incidence of more than one child birth from one ART-stimulation cycle in predicted high responders. What is known already Several studies have been conducted to address individualization of the gonadotropin starting dose, one of them being the OPTIMIST-trial. This trial investigated whether an individualized gonadotropin starting dose improved cumulative live birth rates (cLBR) and treatment safety. There was no difference in cLBR between the standard and adjusted starting dose groups, yet a statistically significant decrease in the occurrence of ovarian hyper-stimulation syndrome (OHSS) in predicted high responders. The discussion arose if the higher dosed patients that achieved a live birth (LB) could have had supernumerary useable frozen embryos left, potentially resulting in multiple live births from one stimulation cycle. Study design, size, duration Predicted high and low responders (based on AFC) that achieved a LB in the OPTIMIST trial were included. Predicted high responders received either the standard (150 IU) or a reduced dosage gonadotropins (100 IU). Predicted low responders received a higher dose (225/450 IU) or the standard gonadotropin dose (150 IU). All known subsequent frozen embryo transfers after the 1st LB were analyzed for the chance of a second live birth from the same stimulation cycle. Participants/materials, setting, methods 527 women had a LB in the OPTIMIST trial during the study period or thereafter from embryos obtained from the last stimulation cycle during the study period. Except for 23 women, data was collected regarding the return of these patients for a renewed child wish. Multiple imputation was performed (10 imputations, 20 iterations). Odds ratio (OR) with 95% confidence interval (CI) were calculated and adjusted for confounders if necessary. Main results and the role of chance Of the 504 women, 340 women had remaining frozen embryos. The incidence of at least two live births from one stimulation cycle was twice as high in the standard dosage arm (150 IU) of the predicted high responder group (21,5% versus 10,8%, OR 2.27 [95% CI, 1.19 – 4.31]. The incidence of at least two live births in the predicted low responder group did not differ (7,1% versus 6,2% for the higher versus the standard dosed group respectively, OR 1.04 [95% CI, 0.31 – 3.46]). After excluding 149 women with frozen embryos that did not return for their renewed child wish (resulting in a total of 355 women), the comparison showed that the incidence of at least two live births from one stimulation was 30.1% versus 15.0% for the 150 IU versus 100 IU high responder groups, OR 2.43 [95% CI, 1.25 - 4.74]. In the low responder group, 11,8% versus 9,0% had a second live birth in the 225/450 IU versus the 150 IU group (OR 1.60 [95% CI 0.43– 5.98]). More information on the number of embryos used for a second child and gonadotropin dose adjustments is currently obtained. Limitations, reasons for caution Not all women had returned for or used all their frozen embryos, which may lead to selection bias. The potential benefit of the one-and-done strategy needs to be balanced against higher safety risks and the clinical relevance should be interpreted with caution. Wider implications of the findings To date, no study investigated the total number of live births from one IVF/ICSI stimulation cycle in relation to the FSH dosage administered. These results stress the need for additional research to advice the clinician on choosing an appropriate starting dose which balances the reproductive potential and treatment safety risks. Trial registration number not applicable

P-781 Elective single cleavage-stage embryo transfer in IVF patients with suboptimal ovarian response is not detrimental to cumulative pregnancy and reduces multiple pregnancy rates

Abstract Study question To compare elective single embryo transfer (eSET) with double embryo transfer (DET) in patients with suboptimal response to ovarian stimulation in terms of pregnancy rates. Summary answer Elective single embryo transfer in patients with suboptimal response to ovarian stimulation is not detrimental to cumulative pregnancy and delivery rates. What is known already Even though higher-order pregnancies in in vitro fertilization (IVF) programs have dropped significantly in recent years, the incidence of twin pregnancies is currently not negligible. The greatest efforts to promote eSET have been made in the IVF population with a good prognosis but results obtained in this population can hardly be extrapolated to patients with lower chances of success, such as those with low oocyte yield. Although still under discussion, it has been suggested that in patients with poor or suboptimal response to ovarian stimulation, eSET could achieve acceptable cumulative live birth rates with negligible risk of twin pregnancy. Study design, size, duration A matched case-control pre and post intervention study including IVF patients with poor or sub-optimal response to ovarian stimulation (≤9 oocytes) receiving a double embryo transfer (2016-2018) or elective single embryo transfer (2018-2020). Matching was performed 1:1 for female age (±18 months), AMH ≥1.2 or &amp;lt; 1.2 ng/ml and number of previous cycles. A sample size of 215 patients per group was foreseen to obtain ±5% variability of the main outcome (clinical pregnancy rate per cycle). Participants/materials, setting, methods A strict policy regarding single embryo transfer was introduced in our clinic from September 2018 to reduce twin pregnancy rates independently from ovarian response or embryo quality. Couples undergoing standard IVF or ICSI with ≤9 oocytes and at least 2 viable embryos were divided in two groups and matched for main variables known for influencing results: pre-intervention with DET (controls) and post-intervention with eSET (cases). In both groups, cryopreserved supernumerary embryos were always transferred individually. Main results and the role of chance A total of 463 patients with at least 2 viable embryos undergoing fresh embryo transfer after the recovery of 2 to 9 oocytes were retrospectively evaluated and, according to matching criteria, 212 cases (eSET) and 212 matched controls (DET) were included for data analysis. The cumulative clinical pregnancy rate per cycle was the same in the two groups (26%, 95%CI: 20-32%) with a crude OR = 1.00 (95%CI: 0.65-1.54), p = 1.00 and a mean female age of 37.4 and 38.0 years, respectively. The mean number of mature oocytes was 4 ±2 in both groups. Live birth rate was similar in cases and controls (22% and 21%, respectively) while twin pregnancies were significantly reduced in women receiving single embryo transfer (18% versus 0%, p = 0.008). Women receiving eSET were more likely to undergo a subsequent frozen embryo transfer (26% versus 14%, p = 0.002). Considering the main confounding factors, a binomial logistic model indicated that the cumulative clinical pregnancy rate was not significantly affected when a single embryo transfer was performed in women recovering up to nine oocytes. Similar results were obtained comparing cases and controls within subgroups: 2-4 or 5-9 oocytes; &amp;lt;35 or 35–39 or &amp;gt; 39 years female age). Limitations, reasons for caution This study does not have the statistical power to highlight small differences between the two groups. It was conducted on a specific population of women with 9 or less oocytes therefore results cannot be generalized to other populations, particularly those with a better or poorer prognosis. Wider implications of the findings eSET results are mainly based on good prognosis couples. Despite a trend for better success after fresh DET, cumulative results are not affected by eSET at the cleavage stage with significantly reduced incidence of twins and moderate delay in time to pregnancy also in poor/suboptimal responders. Trial registration number not applicable

Retrospective comparison of pregnancy outcomes of fresh and frozen-warmed single blastocyst transfer: a 5-year single-center experience.

To assess whether live birth rates (LBR) and maternal/neonatal complications differed following single fresh and frozen-warmed blastocyst transfer. The present retrospective observational study analyzed 4,613 single embryo transfers (SET) (646 fresh and 3,967 frozen) from January 1, 2014, to December 31, 2018. Fresh embryo transfer at blastocyst stage was considered according to the age of the patient and her prognosis. In case of the risk of ovarian hyperstimulation syndrome, premature progesterone rise, non-optimal endometrial growth, or supernumerary embryos, cryopreservation with subsequent frozen embryo transfer (FET) was indicated. No differences in LBR were recorded. Fresh embryo transfers yielded an increase both in neonatal complications OR 2.15 (95% CI 1.20-3.86, p 0.010), with a higher prevalence of singletons weighting below the 5th percentile (p 0.013) and of intrauterine growth retardation (p 0.015), as well as maternal complications, with a higher placenta previa occurrence OR 3.58 (95% CI 1.54-8.28, p 0.003), compared to FET. LBR appears not to be affected by the transfer procedure preferred. Fresh embryo transfer is associated with higher risk of neonatal complications (specifically a higher prevalence of singletons weighting below the 5th percentile and of intrauterine growth retardation) and placenta previa. Reflecting on the increased practice of ART procedures, it is imperative to understand whether a transfer procedure yields less complications than the other and if it is time to switch to a "freeze-all" procedure as standard practice. Clinical Trial Registration Number: NCT04310761. Date of registration: March 17, 2020, retrospectively registered.

Freeze-all policy for in vitro fertilization in women with normal response to ovarian stimulation.

ABSTRACTObjective To answer the question if the freeze-all strategy and subsequent frozen embryo transfer is preferable to fresh embryo transfer for patients with normal response to ovarian stimulation (4 to 15 oocytes recovered) during in vitro fertilization treatments.Methods A retrospective cohort from two human reproduction centers between 2013 and 2017. A total of 471 frozen embryo transfers from freeze-all cycles, and 3,208 fresh transfers were included.Results After propensity score matching adjustment for age and number of eggs, 467 freeze-all cycles and 934 fresh cycles were analyzed, revealing no statistically significant difference between groups in relation to clinical pregnancy rate (32.5% in the Freeze-all Group and 32.3% in the Fresh Group, p=0.936). For women aged 40 years and older, we observed a statistically significant higher clinical pregnancy rate when freeze-all strategy was used (29.3% in the Freeze-all Group and 19.8% in the Fresh Group, p=0.04).Conclusion Freeze-all strategy was not superior to fresh transfer for all patients with normal response to ovarian stimulation. However, women aged 40 years and older could benefit from this strategy. This deserves further investigation in future research, preferable in a prospective randomized study.

The Combined Impact of Female and Male Body Mass Index on Cumulative Pregnancy Outcomes After the First Ovarian Stimulation.

ObjectivesTo evaluate the combined impact of male and female BMI on cumulative pregnancy outcomes after the first ovarian stimulation.DesignRetrospective cohort study.SettingUniversity-affiliated reproductive medicine center.PatientsA total of 15,972 couples undergoing their first ovarian stimulations from June 2009 to June 2016 were included. During the follow-up period between June 2009 and June 2018, 14,182 couples underwent a complete ART cycle involving fresh embryo transfer and subsequent frozen embryo transfers (FETs) after their first ovarian stimulations. Patients with a BMI <24 kg/m2 served as the reference group. Patients with a BMI ≥ 24 kg/m2 were considered to be overweight, and those with a BMI ≥28 kg/m2 were considered to be obese.Intervention(s)None.Primary Outcome MeasureThe primary outcome was the cumulative live birth rate (CLBR), which defined as the delivery of at least one live birth in the fresh or in the subsequent FET cycles after the first ovarian stimulation.ResultsIn the analyses of females and males separately, compared with the reference group, overweight and obese females had a reduced CLBR (aOR 0.83, 95% CI 0.7.92 and aOR 0.76, 95% CI 0.64–0.90). Similarly, overweight males had a reduced CLBR (aOR 0.91, 95% CI 0.83–0.99) compared with that of the reference group. In the analyses of couples, those in which the male was in the reference or overweight group and the female was overweight or obese had a significantly lower CLBR than those in which both the male and female had a BMI <24 kg/m2.ConclusionsThe CLBR is negatively impacted by increased BMI in the female and overweight status in the male, both individually and together.

THE HYPOTHESIS OF PREFERENCIAL LOSS OF FEMALE EMBRYOS: EMBRYONIC SEX IS NOT ASSOCIATED WITH INCREASED ODDS OF EARLY PREGNANCY LOSS

The human sex ratio has long interested developmental biologists, statisticians, and other scientists. Primary Sex Ratio (PSR) in humans has been thought to be male-biased. Previously published studies about PSR have suggested this bias is due to a preferential loss of female conceptuses during the earliest stages of pregnancy1,2. To date, the dynamics of PSR from conception to birth are poorly understood. Literature about PSR is currently based on subjective estimates, extrapolations from large historical cohorts, or based on data sourced from natural conceptions3. Yet, the use of data from patients who undergo ART treatment presents an opportunity to observe embryonic sex prior to transfer through the application of PGT. This study aims to analyze whether the selection of female embryos prior to frozen embryo transfer (FET) are at higher risk of suffering early pregnancy loss as compared to the selection of male embryos. The study included patients who underwent a single euploid FET cycle from 2016-2021. Gender selection for family balancing cases were excluded from the analysis. PGT-A with NGS was performed for all cases. Cohorts were segregated into groups based on embryonic sex prior to transfer selection. Only top morphology embryos with a grade ≥4AA (Modified Gardner’s) were included in the study. Patient demographics and IVF cycle outcomes were recorded. Biochemical pregnancy loss (BPL) was defined as detectible serum ß-hCG and embryonic arrest prior to the development of a clinical pregnancy. Clinical pregnancy loss (CPL) was defined as the loss of a pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs. Comparative statistics and an adjusted mixed model with a GEE were utilized for statistical analyses. A sample size of 906 single, euploid FETs per cohort was calculated to ensure an 80% power to detect a difference of 5% on clinical pregnancy loss rates (α=0.05). 1,363 male were compared to 1,045 female FETs. No differences were found in patient’s age, BMI, AMH, endometrial thickness and other demographic variables between cohorts. Also, no differences were found in implantation, clinical pregnancy, ongoing pregnancy, BPL and CPL. After adjusting for age, BMI, AMH, day of biopsy and endometrial thickness, no association was found between embryo sex and increased odds of BPL (OR 0.50 CI95% 0.11-2.27, p=0.37); or CPL (OR 0.28 CI95% 0.07-1.16, p=0.08). By analyzing a large cohort of single euploid embryo transfers, we can observe the proportion of pregnancy losses that are not associated with aneuploidy, thus assessing the differences on early pregnancy loss rates based on embryonic sex while adjusting for other important covariates. For patients who undergo IVF with subsequent PGT-A and FET, there does not appear to be increased odds of pregnancy loss in selecting a single, euploid female embryo compared to male embryo counterparts.

CLINICAL VALUE OF HISTOLOGIC ENDOMETRIAL DATING IN WOMEN WITH INADEQUATE ENDOMETRIUM DURING FROZEN-THAWED BLASTOCYST- STAGE EMBRYO TRANSFER: A RETROSPECTIVE PILOT STUDY

Inadequate endometrium (IE) in preparation for a frozen embryo transfer (FET) is a challenging occurrence in assisted reproduction. While there is no accepted consensus on how to define IE a conservative approach is a measurement of less than or equal to 8mm. When the endometrium is inadequate, patients and physicians face a decision of whether to proceed with the embryo transfer. A recent study evaluating the impact of IE on FET reported a decline in pregnancy and live birth rates with each millimeter decline in endometrial thickness below 7mm (1). Histologic examination of the endometrium has been used to determine the adequacy of endometrial proliferation. To potentially reduce cycle cancellation, we evaluated the pregnancy outcome of FET cycles from patients with IE but “in-phase” histologic endometrial dating. This is a retrospective pilot study of patients between the years of 2014 and 2020 who underwent a standard hormonal endometrial preparation for FET that had been canceled due to IE defined as a maximum thickness ≤ 8mm following up to 35 days of estradiol supplementation. Endometrial biopsy was performed for histologic dating using the criteria of Noyes et al after 9 to 11 days of progesterone supplementation. Patient outcomes were also stratified based on the number and quality of embryos transferred. All study patients were determined to have “in-phase” endometrium who underwent FET cycle with the transfer of at least one good-quality blastocyst. Descriptive statistics and Pearson Correlation was calculated using SPSS software v23. A total of 21 women mean age was 38.2 ± 6.7 years and IE underwent an endometrial biopsy after estradiol proliferation and 9-11 days of progesterone supplementation. The mean endometrial thickness was 6.4 ± 0.5 mm. Seventeen women (81%) demonstrated endometria that were “in-phase” and underwent a subsequent FET cycle. The mean number of embryos transferred was 1.47 ± 0.6, the clinical pregnancy rate was 47% (8/17); miscarriage rate was 11.8% (2/17); and the live birth rate was 35.3% (6/17). There was no correlation between age and endometrial thickness (Pearson Correlation Coefficient R = 0.08, P = 0.7). Histologic dating in women with a prior canceled FET due to IE is a potentially reliable method to allow the opportunity for a successful FET with comparable outcomes to the National Average (SART National Summary Report for 2018). Studies with a larger sample size are necessary to corroborate this finding.

P–626 A freeze-all strategy improves clinical pregnancy rate in patients with few available embryos

Abstract Study question Is elective frozen blastocyst transfer an advantageous strategy for all patients? Summary answer A freeze-all strategy improves the outcomes in patients with few available embryos. What is known already With the aim of defining the best moment to perform embryo transfer, in recent years, relevance has been given to the understanding of the implantation window, however oocyte and embryo quality are key factors that are not to be disregarded. It has been suggested that a freeze-all strategy and subsequent frozen embryo transfers improve pregnancy rates. However, it is unclear whether this strategy benefits all kind of patients (i.e. with or without surplus embryos, etc). In this study, we aim to provide an answer on which patients may benefit of a freeze-all policy and a subsequent frozen embryo transfer. Study design, size, duration This retrospective cohort study includes infertile patients aged 21 to 44 years old, without previous history of recurrent failure of ART (including recurrent miscarriages). Enrolments took place between January 2015 and November 2019 and cycles with oocyte donation and PGT were excluded. Embryo transfers were performed in: 1) a fresh cycle (ET) or 2) a deferred cycle with surplus frozen embryos (FET) or embryos that were frozen in a freeze-all policy (FET-FA). Participants/materials, setting, methods Patients with blastocysts transfer were included. PGT cycles were excluded. The number of cycles complying with the inclusion criteria were: 617 ICSI cycles. Fresh embryo transfers (ET) were performed in 396 cycles (43 with a subsequent Frozen embryo transfer, FET). Frozen embryo transfers following a freeze-all strategy (FET-FA) were performed in 221 cycles. Clinical pregnancy rates (CPR) and Cumulative clinical pregnancy rates (CCPR) were calculated and compared among those groups. Main results and the role of chance Mean age of patients was 36.1 ± 3.7 years old (mean ± SD). In average, 1.83 ± 0.41 (mean ± SD) embryos were transferred. Following the first transfer (either ET and FET-FA), CPR was 40.4% and 58.4% (ET and FET-FA, respectively). Following the subset analysis of 2 age groups (≤38 &amp; &amp;gt;38 years-old); in the ≤38-group, CPR was 45.2% and 58.9% (ET and FET-FA, respectively), while in &amp;gt; 38-group, the rates were 30.8% and 54.8% (ET and FET-FA, respectively); p &amp;lt; 0.05. CCPR were also significantly better in the FET-FA group: 51.3% vs 66.8% and 33.8% vs 58.1% in the ≤38-group and &amp;gt;38-group, respectively. Additionally, CPR was analysed independently for patients with ≤2 usable embryos (1 attempt) or ≥ 3 usable embryos (surplus embryos after first attempt). When a single attempt was possible; in the ≤38-group, CPR was 36.1% and 56.9% (ET and FET-FA, respectively) while in the &amp;gt;38-group, the rates were 24.7% and 63.6% (ET and FET-FA, respectively); p &amp;lt; 0.05. When surplus embryos were available, no difference in CPR (or CCPR) between ET and FET-FA groups were observed. After first attempt CPR were 58.4% and 48.2% in the ≤38-group &amp; &amp;gt;38-group, respectively; while CCPR were 69.8% and 57.1% in the ≤38-group &amp; &amp;gt;38-group, respectively. Limitations, reasons for caution Although the authors consider that the patient population is of optimal size, a detailed analysis of the stimulation protocol and hormonal values (estradiol and progesterone) during treatment, and its potential relation to the outcomes, should follow. Wider implications of the findings: In our setting, the data suggests that freeze-all strategy (with subsequent frozen embryo transfer) over fresh transfer is advantageous for patients with few available embryos (1 or 2 embryos for a single attempt). This increases the chances to pregnancy in 30.3% in the ≤38-group and 77.9% in the &amp;gt;38-group. Trial registration number Not applicable