Endometrial Preparation Protocols Research Articles

P-613 Natural cycles monitoring for frozen embryo transfers: is it beneficial to start immediately after ovarian stimulation?

Abstract Study question Are there more advantages in performing frozen embryo transfer (FET) immediately after ovarian stimulation or in delaying it by at least one menstruation? Summary answer In natural cycles, timing of frozen embryo transfer does not affect clinical pregnancy rates, but immediate transfer is associated with higher rates of cycle cancellation. What is known already In order to achieve a reduced time to pregnancy and avoid additional stress for the couple, some Centers initiate FETs immediately, i.e. on the first menstrual cycle after ovarian stimulation. However, the detrimental effect of hormonal stimulation on ovarian function and endometrial receptivity may persist in the following cycle and immediate FETs may increase the possibility of cycle cancellation and reduce pregnancy rate. Available evidence on this subject, mainly focused on endometrial preparation with hormonal replacement therapy (HRT), showed contrasting results. Moreover, studies on FETs performed on natural cycles are lacking. Study design, size, duration This is a retrospective study conducted at the Infertility Unit of the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico in Milan, Italy. A large amount of single FETs, performed between 2014 and 2021, was considered and was then divided in two groups according to their timing (immediate or delayed). The primary outcome was to assess the clinical pregnancy rate (CPR); secondary outcomes were live birth rate (LBR) and the cycle cancellation rate. Participants/materials, setting, methods True natural cycles (T-NC) and modified cycles with the use of triggered ovulation (M-NC) protocols for endometrial preparation were pursued in women with regular menses; otherwise, HRT was used. Immediate FET was defined when performed on the first menstruation following ovarian stimulation (i.e. withdrawal bleeding occurring after ovarian stimulation or after a failed fresh embryo transfer). Delayed FETs included those performed after at least two menstruations. Only the first transfer after ovarian stimulation was considered. Main results and the role of chance A total of 5,765 FET cycles were included in the study. FET cycles were achieved through T-NC in 4,477 cases (78% of all FETs), of which 364 were immediate and 4,113 were delayed. M-NC cycles accounted for 1% of the total amount of FETs and HRT protocols were pursued in 11% of cases. The analysis showed no impact of FET timing on CPR both in the whole cohort and in the subgroups based on different endometrial preparation protocols. Focusing on T-NC cycles, the CPR in the immediate group was comparable to that of the postponed group (29 vs. 32% respectively, OR 0.90 [95% CI 0.71 - 1.14]). On the other hand, LBR in T-NC cycles was significantly lower in the immediate group than in the delayed group (20% vs. 25% respectively, OR 0.74 [95% CI 0.56 - 0.96]). Consequently, immediate FETs resulted to be associated with a significantly higher rate of pregnancy loss (31% vs. 21% respectively, p = 0.03). Furthermore, cycle cancellation occurred more frequently in the immediate T-NC group, compared with the delayed group (18% vs. 12% respectively, p = 0.003). Similar results were observed in HRT cycles (15% in immediate FETs vs. 7% in delayed FETs, p = 0.08). Limitations, reasons for caution The retrospective nature of this study involves a risk of selection bias. Moreover, the reason for cycle cancellation was not always available; thus, these data were not included in the analysis. Lastly, these outcomes are only applicable to a similar cohort, that is Centers following a non-elective freeze-all policy. Wider implications of the findings This is the largest investigation on T-NC FETs and is among the very few studies providing separate results on different endometrial preparation protocols. Evidence from this study is in line with some previous retrospective analyses and in contrast with others. Thus, randomized controlled trials are needed to confirm these results. Trial registration number not applicable

P-410 A modified artificial cycle-frozen embryo transfer(mAC-FET) protocol with evidence of corpus luteum(CL) formation as determined by serum relaxin-2 in early pregnancy :a prospective proof-of-concept study

Abstract Study question Can a mAC-FET protocol for endometrial preparation in ovulatory patients lead to formation of a CL as evidenced by serum relaxin-2 in the pregnant patients? Summary answer CL forms in the mAC-FET protocol as serum relaxin-2 in early pregnancy was comparable to that in spontaneous conception.Late luteal rise of relaxin-2 wasn’t demonstrated. What is known already Clinical evidence points to increased incidence of preeclampsia in pregnancies by AC-FET cycles compared to ovulatory FET cycles-natural cycle(NC) and mNC. The absence of CL and it’s secretory products like relaxin-2 is a contributing factor. FET protocols for endometrial preparation in ovulatory patients need to be optimised. NC/mNC-FET protocols need frequent monitoring. Also there is a temporal variability between LH/hCG and progesterone levels. We studied a mAC-FET protocol in ovulatory patients with a delayed start(day3-5 of the cycle),low dose transdermal 17β estradiol gel to see the formation of CL as elucidated by the presence of serum relaxin-2 in early pregnancy. Study design, size, duration A proof-of- concept prospective study was conducted at a tertiary centre (July2023-Dec2023). Serum relaxin-2(R&D/Quantikine/ELISA) was determined in 4 groups of patients- Group-A. mAC-FET(n = 34) 1.On the day of start of progesterone 2.Post-ET day5-9 (along with serum progesterone) 3.In pregnancy(6-9 weeks of gestation) Group-B. AC-FET(n = 8) 1.On the day of start of progesterone 2.In pregnancy(6-9 weeks) Group-C. Spontaneous conception (n = 9) 1.In pregnancy(6-9 weeks) Group-D. Infertility patients ( n = 24) 1.Preovulatory. All patients were ≤40 years with a BMI ≤30kg/m2. Participants/materials, setting, methods In the AC-FET cohort-oral estradiol 6mg/day was started from day1/2 of the cycle. When endometrial thickness was>7mm,progesterone<1ng/ ml then intramuscular progesterone was started- 50mg/day-3 days,100mg on day4-the day of ET(Day-3 embryos) and continued every alternate day.Progesterone gel was added post-ET. In the mAC-FET cohort-17β transdermal estradiol gel(0.06%) 3mg/day was started from day3-5,rest of the protocol was similar. Statistical analysis was performed using appropriate non-parametric tests.Pearson coefficient(r) was used to assess linear-relationship.Two-tailed P<.05 indicated statistical significance. Main results and the role of chance Mean age and BMI of the patients with mAC-FET was 33.3±4.7 years and 24.4±3.7 kg/ m2 which was comparable across all groups (P=.14,P=.52 respectively). Clinical pregnancy rate in the mAC-FET group was 52.94%(18/34). 3 patients had an early abortion. Baseline relaxin-2 levels, median[Interquartile range(IQR)] were comparable- AC-FET cohort-9.1pg/mL(8.6-16.8), mAC-FET cohort-11.5pg/mL(9.6-13.7) and the infertility cohort-10.9pg/mL(8.4-14.5) (P=0.74) The primary outcome was the comparable levels of serum relaxin-2, in early pregnancy in the mAC-FET group and spontaneous conception group - median (IQR) 449.8pg/mL(73.1-492.3) and 487.9pg/mL(419.1-497.8) respectively (P=.12) The relaxin-2 levels, in early pregnancy in the mAC-FET group were significantly higher than the AC-FET group median(IQR) 449.8pg/mL(73.1-492.3) and 7.9pg/mL(7.8-9.5) respectively (P=.0005). As secondary outcomes, we studied the late luteal rise of relaxin-2 in the mAC-FET group and the relationship of late luteal progesterone with relaxin-2 in early pregnancies in the mAC-FET cohort. A late luteal rise of relaxin-2 was not demonstrated in the mAC-FET cohort. The serum relaxin-2, on the day of start of progesterone and on day5-9 post ET- median(IQR) 11.5pg/mL(9.6-13.7) and 11.4pg/mL(9.0-18.5), respectively was comparable (P=.18). The relationship between serum relaxin-2 in early pregnancy and the progesterone levels on day5-9 post ET in the mAC-FET cohort was not significant r = -.059 (P=.07) Limitations, reasons for caution This was a small proof- of-concept single centre study. Due to the limited numbers and short duration of the study, we could not compare efficacy, cancellation rates and pregnancy outcomes of the mAC-FET protocol with other FET protocols. Wider implications of the findings The mAC-FET protocol studied for endometrial preparation was similar to the AC -FET protocol regarding monitoring,flexibility and consistent progesterone exposure with the added advantage of the presence of the CL.This may decrease the risk of maternal/neonatal complications. Larger studies are needed to confirm it’s efficacy and impact on pregnancy outcomes. Trial registration number Not Applicable

The effect of gonadotropin-releasing hormone agonist downregulation in conjunction with hormone replacement therapy on endometrial preparation in patients for frozen–thawed embryo transfer

ObjectiveTo investigate the effects of combining gonadotropin-releasing hormone agonist (GnRHa) downregulation with hormone replacement therapy (HRT, GnRHa-HRT) on the clinical outcomes of patients undergoing frozen–thawed embryo transfer (FET).MethodsIn this retrospective study, we included patients who had FET between January 2018 and December 2022. They were categorized into HRT and GnRHa-HRT groups based on the endometrial preparation protocol. The study compared the clinical outcomes of patients in two groups. Possible factors affecting clinical outcomes were analyzed using univariate analysis. To analyze the impact of two endometrial preparation methods on clinical outcomes, multifactorial logistic regression was performed.ResultsThe rates of clinical pregnancy (47.31% vs. 59.60%), embryo implantation (37.58% vs. 49.65%), biochemical pregnancy (52.36% vs. 64.31%), and early abortion (7.07% vs. 10.77%) were statistically different between the two groups (p < 0.05). Analysis using multifactorial logistic regression showed that there was a 1.65-fold increase in clinical pregnancy rates (OR = 1.65, 95% CI: 1.29–2.12, p < 0.001) and a 1.55-fold increase in embryo implantation rates (OR = 1.55, 95% CI: 1.27–1.90, p < 0.001) in the GnRHa-HRT group when compared to the HRT group. For blastocyst transfer, the clinical pregnancy and implantation rates of the GnRHa-HRT group were significantly higher than those of the HRT group (OR = 1.75, 95% CI: 1.30–2.37, p < 0.001; OR = 1.73, 95% CI: 1.35–2.21, p < 0.001).ConclusionIn FET cycles, leuprorelin (as a GnRHa) downregulation combined with HRT may improve the clinical outcome of patients compared to the HRT cycle, especially for the clinical pregnancy and embryo implantation rates of patients with blastocyst transfer.

P-780 Bone health in Danish children aged 7-10 years born after assisted reproductive technology with frozen and fresh embryo transfer

Abstract Study question Is bone health in children conceived after frozen embryo transfer (FET) different from children conceived after fresh embryo transfer (fresh-ET) and natural conception (NC)? Summary answer FET-children had higher bone mineral density (BMD) and bone mineral content (BMC) compared to fresh-ET-children. Insulin-like-growth-factor-I (IGF-I) levels and lean bodymass were similar between groups. What is known already Children conceived after assisted reproductive technology (ART) with FET have a higher average birthweight (BW) and increased risk of being born large-for-gestational-age (LGA) while children born after fresh-ET are more often born small-for-gestational-age (SGA). In general, BW is a determinant of BMD and BMC in childhood with LGA being associated with higher BMD and BMC compared to children born appropriate-for-gestational-age. The relationship between BW and BMD and BMC may be mediated by IGF-I levels and lean bodymass as IGF-I is an important regulator of muscle and bone development. Bone health in children born after ART is scarcely explored. Study design, size, duration This study was part of the large Danish cohort study “Health in Childhood following Assisted Reproductive Technology” (HiCART) which included 606 singletons (292 boys) born in Denmark between 2009 and 2013. The children were conceived after FET (n = 200), fresh-ET (n = 203) and NC (n = 203) and matched for birth year and sex. The study examinations were performed from January 2019 to September 2021. Participants/materials, setting, methods The children underwent a clinical examination at 7-10 years of age with anthropometric measurements, pubertal staging, a fasting blood sample and a whole-body dual-energy x-ray absorptiometry-scan (DXA). Anthropometric measurements and circulating growth factors were converted to standard deviation scores (SDS) using Danish reference material. The study groups were compared pairwise using univariate linear regression and multiple linear regression adjusting for relevant confounders including sex, age, puberty, maternal pregestational BMI, breastfeeding and BW (SDS). Main results and the role of chance Children conceived after FET had significantly higher BW (SDS) (mean, SD: 0.20 SDS, 1.09) compared to children conceived after fresh-ET (-0.22 SDS, 1.00), mean difference: 0.42 SDS (95% CI: 0.21; 0.62) and NC (-0.16 SDS, 1.09), mean difference: 0.35 SDS (95% CI: 0.14; 0.57). In the adjusted model, children born after FET had significantly higher total BMD (g/cm2) (mean difference 0.01, 95% CI: 0.00; 0.03) and size-adjusted BMC (BMC/height, g/m) (mean difference 0.21, 95% CI: 0.01; 0.40) compared to children born after fresh-ET. There was no significant difference in total BMD or BMC/height when comparing FET and fresh-ET to NC children, respectively. There was a trend towards higher lean bodymass (g) in children born after FET and lower lean bodymass in children born after fresh-ET compared to NC children, however this did not reach the level of significance. IGF-I (SDS), IGF-binding-protein-3 (SDS) and serum calcium (mmol/L) levels were comparable between the groups. In the entire cohort, there was a significantly positive correlation between BW (SDS) and size-adjusted BMC (BMC/height, g/m) (b: 0.21, 95% CI: 0.14; 0.27) and total lean bodymass (g) (b: 755, 95% CI: 531; 978), while a significantly negative correlation with IGF-I (SDS) (b: -0.07, 95% CI: -0.13; -0.01). Limitations, reasons for caution The study was powered to detect a clinically relevant difference in BMI (SDS), the primary outcome. Hence, secondary analyses are exploratory by nature. We have no information regarding endometrial preparation protocol in the FET-cycles which may bias the results. Multiple testing may increase our risk of type I errors. Wider implications of the findings Reassuringly, BMD and size-adjusted BMC in children born after ART with FET and fresh-ET were comparable to NC children. Potential determinants of BMD and BMC (IGF-I and lean bodymass) were also similar. Increased BMD and size-adjusted BMC in FET compared to fresh-ET suggests that the different BW-profiles play a role. Trial registration number NCT03719703

P-405 Effects of intrauterine perfusion of autologous platelet-rich plasma on recurrent implantation failure in frozen-thawed embryo transfer: a meta-analysis of randomized controlled trials

Abstract Study question We aimed to evaluate the effect of the platelet-rich plasma （PRP) on pregnancy outcomes in patients with RIF undergoing frozen-thawed embryo transfer (FET). Summary answer Intrauterine infusion of PRP might have more beneficial effects on pregnancy outcomes in RIF patients undergoing FET. What is known already Immunological therapies are of great interest to specialists in reproductive medicine. The immune therapies use intrauterine infusion (i.e., PRP, PBMC, G-CSF, and hCG) for endometrial immunomodulation. Despite the limited number of publications available, the results are encouraging. In the network meta-analysis, PRP, PBMC, C-GCSF, and hCG administration all significantly increased embryo implantation and clinical pregnancy compared to controls. Additionally, PRP administration resulted in a higher live birth rate than the control. This year, more research has focused on PRP as an innovative method to treat RIF. Study design, size, duration Medline, Embase, and Cochrane Controlled Register of Trials (CENTRAL) were searched from inception to July 29, 2023. The randomized controlled trials (RCTs) reporting on pregnancy outcomes of women with RIF who were administered PRP undergoing FET were included. We conducted a meta-analysis where possible using a fixed effects model. The Cochrane Handbook was used to assess the risk of bias for RCTs. Binary outcomes were pooled using risk ratio (RR) with 95% confidence intervals (CIs). Participants/materials, setting, methods Seven RCTs were included with 1,014 RIF women. The final number of women analyzed was 508 with intrauterine infusion PRP and 506 without it. Main results and the role of chance Meta-analysis showed that compared to the controls, the women who received PRP had a significantly higher embryo implantation rate (n = 2, risk ratio (RR) 2.34, 95% CI 1.65 to 3.32; P < 0.00001, I2 = 0%), biochemical pregnancy rate (n = 5, RR 1.94, 95% CI 1.60 to 2.36; P < 0.00001, I2 = 0%), clinical pregnancy rate (n = 7, RR 2.31, 95% CI 1.89 to 2.82; P < 0.00001, I2 = 0%), ongoing pregnancy rate (n = 3, RR 2.70, 95% CI 1.79 to 4.05, P = 0.0004, I2 = 31%), and multiple pregnancy rate (n = 3, RR 2.67, 95% CI 1.07 to 6.68, P = 0.04, I2 = 0%). However, PRP was not attributable to reduce the miscarriage rate (n = 3, RR 1.15, 95% CI 0.40 to 3.35; P = 0.80, I2 = 0%). Limitations, reasons for caution The proportion of small-sample studies included has to some extent affected the validity of the results. There were some variations regarding the PRP preparation process, which may result in a variable composition and concentrations of its different contents. Wider implications of the findings Intrauterine infusion PRP in patients with RIF who underwent FET may improve the pregnancy outcomes assessed in RCTs, including clinical pregnancy and ongoing pregnancy. Therefore, we suggest that PRP be included in endometrial preparation protocols. Trial registration number not applicable

P-318 Reproductive ageing: the seed, the soil, or both?

Abstract Study question Is it all about the embryo? Can a single euploid blastocyst transfer sustain reproductive outcomes in women with advanced reproductive age? Summary answer Despite euploid embryo transfer, endometrial senescence appears to play a crucial role in determining reproductive success, particularly in older patients undergoing in vitro fertilization (IVF). What is known already Advanced reproductive age significantly impairs oocyte and embryo quality. Effective crosstalk and synchronization between embryo and endometrium are pivotal for successful pregnancies, both in vivo and in vitro. Implantation failure remains a persistent challenge in IVF, exacerbated by delayed family planning trends. The transfer of euploid blastocysts through preimplantation genetic testing for aneuploidy (PGT-A) is a potential strategy to address implantation issues, decrease miscarriages, and shorten time-to-pregnancy. However, a significant proportion of IVF treatments remain unsuccessful, suggesting critical factors beyond the embryo. Study design, size, duration This retrospective study analyzed 457 single euploid blastocyst transfers performed by two doctors at a private IVF center from January to November 2023. Inclusion criteria encompassed cases with PGT-A indications (advanced maternal age, repeated implantation failure, recurrent pregnancy loss, etc.) or cases where embryo biopsy was patient-requested. The primary outcome was ongoing pregnancy rate (OPR), with secondary outcomes including pregnancy rate (PR) and clinical pregnancy rate (CPR). Participants/materials, setting, methods Participants were categorized into four groups: Group 1 (< 35 years old; N = 100), Group 2 (35-37 years old; N = 102), Group 3 (38-40 years old; N = 118), and Group 4 (> 41 years old; N = 87). A control group (oocyte donation; N = 50) with single euploid embryo transfers showed a mean recipient age of 43 years. Donors were always less than 32 years old. Endometrial preparation protocols were consistent across all groups. Chi-square test was used to compare groups. Main results and the role of chance Among the 457 transfers analyzed, with a mean female age of 37 years, the overall PR was 71.3%, CPR was 64.8%, and OPR was 60.2%. Groups showed no differences in demographic variables and cycle parameters. Group 1 demonstrated higher PR (83.3%), CPR (78.4%), and OPR (73.5%) compared to Group 2 (PR 70.9%, p = 0.034; CPR 66%, p = 0.047; OPR 62.1%, p = 0.081), Group 3 (PR 68.2%, p = 0.009; CPR 61.2%, p = 0.005; OPR 56.6%, p = 0.008), and Group 4 (PR 65%, p = 0.002; CPR 56.1%, p < 0.001; OPR 51.2%, p = 0.001). Furthermore, the control group (oocyte recipients) showed significantly lower PR (68%, p = 0.031), CPR (54%, p = 0.002), and OPR (46%, p < 0.001) compared to Group 1, but not with the other groups. These findings demonstrate that even with euploid embryos originating from young donors, older women exhibited lower pregnancy rates than young women transferring single euploid blastocysts from their own oocytes and similar rates compared to those with advanced reproductive age transferring their own euploid blastocysts, implying that endometrial ageing may disproportionately influence IVF treatment outcomes. Limitations, reasons for caution The retrospective design introduces inherent bias, notably selection bias and unmeasured confounders. This preliminary data did not account for male infertility factors and their impact on embryo quality. Wider implications of the findings Reproductive aging appears to be influenced by factors beyond the embryo itself, especially in women above 35 years. Further research is warranted to elucidate the causes and impact of reproductive aging on implantation potential, aiming to refine clinical practices and enhance the success of IVF treatments. Trial registration number not applicable

O-293 Mastering consistency: a similar training allows to standardize embryo transfer performance, but experience does not involve further improvements

Abstract Study question Is there any variation in the live birth rate (LBR) per vitrified-warmed single euploid blastocyst transfer (SEBT) among clinicians trained at the same IVF center? Summary answer The LBR per SEBT (overall: 53%) remained consistent among equally trained transfer operators (range: 48%-60%) regardless of the number of prior procedures performed. What is known already The number of ART treatments and practitioners has increased over the years. To ensure high standards, an efficient quality control system should monitor and standardize operators’ performance by leveraging statistically-sound key-performance-indicators (KPIs). The embryo transfer procedure is a clinically relevant step, particularly susceptible to variations among clinicians, irrespective of their experience. However, the outcome of “LBR per transfer” is influenced by various confounders, such as embryo stage, morphology, reproductive history, uterine conditions, and others. Our objective was to assess potential differences among transfer practitioners who underwent the same training at a single IVF center in the least biased scenario possible. Study design, size, duration Retrospective single center study. Out of 8663 transfers performed by 4 operators (all trained by operator-1) between 2013 and 2021, we selected 421 first vitrified-warmed transfers with day5 euploid blastocysts whose morphology was >Gardner’s BB-grade in non-obese women, thereby excluding all main confounders on our primary outcome (= LBR per SEBT across different operators). The study was powered to exclude a 18%-decrease (β = 0.8, α = 0.05) in the LBR versus operator-1 (ratio comparator:control=1:2). Participants/materials, setting, methods We conducted ICSI, blastocyst biopsy without day3 zona-drilling, and aneuploidy testing to exclude full-chromosome uniform aneuploidies. All blastocysts were transferred ∼2 hours after warming. Uterine assessment was conducted to exclude putative conditions associated with lower LBR. Endometrial preparation protocol (modified-natural cycle versus hormone-replacement-therapy), maternal age at transfer, experience of prior implantation(s) (yes/no), the embryologists involved in the transfer procedure, were assessed as putative further confounders. All significant differences were confirmed through regression analyses. Main results and the role of chance The overall LBR per vitrified-warmed SEBT was 53.4% (N = 225/421). Operator-1 conducted 3960 transfer procedures during the study period, with 167 eligible for this study, achieving a 55.7% LBR (N = 93/167). Operator-2,-3, and -4 respectively conducted 2533, 1087, and 1083 procedures during the study period, with 134, 62, and 58 eligible for this study. Their LBRs were 50% (N = 67/134, p-value versus operator-1=0.2), 48.4% (N = 30/62, p-value=0.2), and 60.3% (N = 35/58, p-value=0.3). Multivariate logistic regression analysis, adjusted for endometrial preparation protocol and embryologists involved in the transfer procedure, confirmed the absence of an association (Operator-2 vs. 1 multivariate-OR: 0.83, 95%CI 0.5-1.39, adjusted-p=0.49; Operator-3 vs. 1 multivariate-OR: 0.75, 95%CI 0.40-1.40, adjusted-p=0.37; Operator-4 vs. 1 multivariate-OR: 1.40, 95%CI 0.72-2.70, adjusted-p=0.32). Importantly, the number of prior transfer procedures conducted by each clinician during the study period also showed no association with the primary outcome (OR = 1.0, p-value=0.82). From an IVF center perspective, the LBR per SEBT remained stable across the 9-year study period, showing minimal non-significant fluctuations. These outcomes describe an IVF center where equally-trained clinicians adopt the same standard-operating-procedures to manage vitrified-warmed embryo transfers. In this context, the LBR per SEBT represents an ideal KPI to assess the learning curve of operators in training. Limitations, reasons for caution Over 2500 SEBTs are required to rule out a 5%-decrease in the LBR. Yet, such a substantial number is better suited for comparing centers’ rather than practitioners’ performance. It would be intriguing to investigate potential differences among operators who underwent different training regimens but operate within the same clinic. Wider implications of the findings No correlation exists between the number of prior embryo transfer procedures conducted and further improvements, therefore initial operators’ training is crucial for standardizing their performance. LBR per SEBT is a strong KPI, though poorly-actionable in the short-term. It’s better suited for center comparisons, prompting internal procedure reviews when differences arise. Trial registration number not applicable

P-643 Menopause should not be considered a confounding factor in endometrial preparation protocol’s comparative clinical trials: a retrospective cohort study with 1.109 euploid single embryo transfers

Abstract Study question Does menopause have an impact on obstetric and perinatal outcomes when performing elective euploid single-blastocyst transfers (eeSBT) in a hormonal replacement treatment (HRT) protocol? Summary answer eeSBT in a non-menopause elective HRT group(eHRT) did not show higher success rates nor better obstetric and perinatal outcomes compared to a menopause HRT group(mHRT). What is known already Menopause has been suggested to be a confounding factor in clinical trials when comparing the results and success rates for endometrial preparation in modified natural cycle (mNC) Vs HRT: including menopause patients could lead to selection bias seen that they can never be included in the mNC group. Few data are available on eeSBT ≥3BB (Gardner score) cryotransfers comparing obstetric and perinatal results between eHRT and mHRT, to have the opportunity to include them all in further comparative trials, with a low bias risk. Study design, size, duration Retrospective single-centre comparative study, including 1.109 eeSBT (≥3BB, Gardner score) between Jan-2018 and Dec-2022: 1.025 (92,4%) in eHRT and 84 (7,6%) in mHRT. The eHRT and mHRT groups were homogeneous for egg donor’s age (29,1±5,9 yo Vs 25,8±4,1 yo) recipient’s age (41,4±4,9 yo Vs 44,9±4,7 yo), body mass index (22,6±4,7 Vs 22,6±5,3) severe male factor (3,5% Vs 3,6%), the need for sperm donation (30,0% Vs 35,7%), and the average throphoectoderm embryo quality (A = 32,5% Vs A = 29,8%). Participants/materials, setting, methods We studied the clinical, obstetric and perinatal outcomes of the 1.109 eeSBT, comparing eHRT and mHRT groups for: pregnancy rate, miscarriage rate, live birth rate, twin pregnancy rate, severe preeclampsia, preterm birth rate (<37, <35, <32 and <28 weeks) and neonatal weight. We used Chi-square test and T-Test to compare groups (p < 0,05). Main results and the role of chance There were no statistically significant differences between eHRT and mHRT groups when comparing pregnancy rates (63,7% Vs 64,3%, p = 0,92), miscarriage rates (15,6% Vs 11,1%, p = 0,053) and live birth rates (44,3% Vs 48,8%, p = 0,42); no significant differences were found in the severe preeclampsia rate(2,0 Vs 1,2, p = 0,84), nor in the twin pregnancy rate (0,9 Vs 2,4, p = 0,34) even if it almost tripled in the mHRT group. Preterm, major and extreme preterm birth rates were comprable between eHRT and mHRT groups: <37 weeks (9,9% Vs 4,9%, p = 0,29) < 35 weeks (3,3% Vs 0, p = 0,23) <32 weeks (1,3% Vs 0, p = 0,46) <28 weeks (0,2% Vs 0, p = 0,76). There were no significant differences in neonatal weight (3292 + 481g Vs 3.135 + 419g, p = 0,052). Limitations, reasons for caution In a preliminary study, we compared and additional 245 eeSBT in mNC with the HRT group, and no significant differences in obstetric or perinatal outcomes were reported when including or excluding the mHRT sub-group. Wider implications of the findings In eeSBT, the eHRT group did not report better obstetric nor perinatal results compared to the mHRT group; further prospective clinical trials comparing mNC Vs HRT should not consider menopause as a major confouding factor, when using eeSBT. Trial registration number Not Applicable

O-151 Endometrial preparation using CONCEIVF algorithm with intrauterine and sub-endometrial endosera administration for enhanced pregnancy rates in women with thin endometrium

Abstract Study question Could personalized regenerative medicine based strategies promote endometrial growth and receptivity in women with refractory thin endometrium resulting in successful implantation and live births? Summary answer Personalized regenerative medicine based strategies remarkably promote endometrial growth and receptivity in women with refractory thin endometrium resulting in successful implantation and live births What is known already Thin endometrium (<7mm) is considered sub-optimal for embryo transfer and associated with reduced pregnancy chances. Regenerative medicine based strategies utilizing stem cells, growth factors alone or in combination for endometrial regeneration have been proposed as futuristic clinical therapies. Data-intensive biomedical technologies in research studies reveals that humans vary widely at genetic, biochemical, physiological, exposure and behavioral levels, especially with respect to disease processes and treatment responsiveness. Hence there is a need to deeply ‘personalize,’ interventional strategies at clinical and dosage level for individual patients. Study design, size, duration In this self- controlled study, 60 women with history of more than 3 failed IVF cycles due to persistent refractory thin endometrium (<7mm) were enrolled between July 21-December 23. 42 women were treated with intrauterine administration of Endosera and 18 patients were treated with sub-endometrial administration of Endosera as suggested by CONCEIVF - Proprietary Algorithm from Seragen.. Endosera is Autologous platelet derived implantation friendly anti-inflammatory cytokines and concentrated growth factors and progenitor cells. Participants/materials, setting, methods CONCEIVF-Algorithm classifies patients (High, Moderate, Poor responders) based on age, BMI, clinical history, guiding standardized dosage routines for proliferative, secretory, implantation phases including CD 33/CD34 cells minimal threshold, are specified. Intrauterine Endosera administration, 2 or 3 times from menstrual cycle day 5 during FET, precedes embryo transfer. Sub-endometrial administration involves Endosera with endothelial progenitor cell support on cycle days 5-7, followed by embryo transfer two days after the final Endosera infusion in the subsequent cycle. Main results and the role of chance Clinical pregnancy rate was 77%(46/60), no pregnancy in 10 patients accounting for 17%. 50% (30/60) delivered healthy babies and 17%(10/60) of uneventful pregnancies are progressing. 3 patients (5%) had miscarriage between 6-8 weeks. Improvement in endometrium thickness (EMT) was 90% with mean difference of 1.9mm improvement in 54 patients. No adverse effects reported. 33 patients out of 42 conceived and 6 out of 42 patients did not conceive and 3 out of 42 patients are yet to undergo embryo transfer in the intra-uterine group. 13 patients out of 18 conceived and 4 out of 18 patients did not conceive and 1 out of 18 patient is yet to undergo embryo transfer in the sub-endometrial group. Live birth rate and on-going pregnancies are indicators of overall endometrial quality (thickness and receptivity) improvement and validates that personalization helps to achieve maximum success rate. 15 out of 60 patients who were referred to surrogacy have conceived. In women with a history of cycle cancellations due to thin endometrium, CONCEIVF algorithm recommended personalized Endosera dosages resulted in improved endometrial thickness, clinical pregnancy and live birth. Personalization holds the key for precision because now two patients are alike! Limitations, reasons for caution This prospective self-control study, contains small sample size and lacks randomized controlgroup. Our results are encouraging but large cohort of patients is needed to establish efficacy. of protocols and positive patient predictors score to strengthen Conceivf personalized recommendations. Wider implications of the findings Despite global rise in FET for diverse indications, ongoing efforts to find the optimal endometrial preparation protocol persist. Our personalized approach achieved cumulative 74% pregnancy rate (40/54 ETs done), inspiring planned randomized trials to validate results and help women with resistant thin endometrium to conceive without surrogacy. Trial registration number Not applicable

P-286 Comparative study of frozen-thawed embryo transfer with modified natural cycle versus HRT cycle in previously cancelled true natural cycle patients

Abstract Study question Is there any difference in outcome of frozen embryo transfer(FET) between hormone replacement therapy(HRT) and modified natural cycle(MNC) in previously cancelled true natural cycle patients Summary answer In patients with previous history of cancelled true natural cycle, MNC results in higher clinical pregnancy rates after FET, when compared to HRT cycle What is known already Preparation of endometrium lays down the foundation for conception and subsequent successful pregnancy.There has been a plethora of endometrial preparation protocols described in the literature. The established protocols are true natural cycle,MNC with or without luteal phase support(LPS) and HRT cycle with or without gonadotrophin releasing hormone agonist(GnRha) suppression. Nevertheless,there is no consensus on protocol which may provide the best outcome in patients who have had cancelled true natural cycle.In such situations,HRT cycle may be considered as an easy option as the cancellation rate is low.However,HRT treatment is known for higher early pregnancy and obstetric complications,compared to MNC Study design, size, duration Prospective observational study,where 155 patients undergoing FET who had minimum one true natural cycle cancellation were recruited.They were divided into group A undergoing HRT cycle(n = 77) and group B for MNC cycle(n = 78).The study was conducted in a fertility unit over six months from June-November 2023.Primary outcome measures were serum betaHCG estimation and ultrasonographic documentation of intrauterine pregnancy.Results were analysed using statistical software SPSS version25 and p value of less than 0.05 was considered statistically significant Participants/materials, setting, methods HRT patients received injectable GnRha 3.75 mg on day21 of previous cycle.Oral estradiol valerate 6mg daily started on day2 of menses. When ET was minimum 7mm, luteal phase support(LPS) was started with daily oral and vaginal progesterone(30mg and 600mcg respectively),followed by FET. MNC patients received Letrozole 5mg daily from day 2-6 of menstruation.rhCG 250mcg was given subcutaneously,when ET was at least 7mm,dominant follicle 16-18mm and progesterone(P4) less than 1ng/ml.LPS(vaginal progesterone600mcg) was started 36hours after rHCG,followed by FET Main results and the role of chance Mean ET in MNC group was 8.92mm ± SD1.38, which was higher than HRT group (8.31 mm ± SD0.89). This difference was statistically significant with a p value of 0.014.Serum beta HCG estimation was done 2weeks after FET. In HRT group beta HCG was positive in 41 out of 77(53.25%) and in MNC group positivity was higher being 48 out of 78(61.54%). However, this difference was not statistically significant. Transvaginal ultrasonography(TVS) was done to confirm intrauterine pregnancy 2weeks after beta HCG assay. Clinical pregnancy rate(CPR) was higher in MNC group with 32 out of 78(41.03%),compared to 18 out of 77(23.38%) in HRT group. This difference is statistically significant with p value of 0.019 Limitations, reasons for caution Relatively small population in this study may be the reason for caution to interpret the statistical data. Study with higher numbers may bring about more robust conclusions Wider implications of the findings Patients with failed true natural cycles may be considered for modified natural cycle(MNC) stimulation for FET, without attempt of another true natural cycle stimulation Trial registration number NOT APPLICABLE

O-206 Natural, modified natural or artificial endometrial preparation strategies for frozen embryo transfer in ovulatory women (MONART): a randomized controlled trial

Abstract Study question Are live birth rates after natural (NC), modified natural (mNC) endometrial preparation superior to artificial cycle (AC) strategies for ovulatory women undergoing frozen embryo transfer? Summary answer Live birth rates were comparable between NC, mNC, and AC. However, NC and mNC resulted in a significantly higher cycle cancellation rate. What is known already The number of frozen embryo transfer (FET) cycles has increased dramatically. In ovulatory women undergoing FET, three common strategies can be used for endometrial preparation: NC, mNC (NC + human chorionic gonadotropin trigger), and AC protocols. Previous studies comparing the effectiveness of these strategies had several drawbacks, including small sample size, lack of consistency between studies in the assessment and reporting of outcomes, and the retrospective origin, which introduced potential biases. Therefore, there is a lack of consensus on the optimal endometrial preparation protocol for FET. Study design, size, duration This single-center, open-label, randomized controlled trial was conducted at IVFMD, My Duc Hospital in Ho Chi Minh City, Vietnam. From March 2021 to March 2022, a total number of 1,428 participants were randomized (476 per group). The primary outcome of the study was live birth after one FET. Secondary outcomes were fertility outcomes, early pregnancy complications, obstetrical outcomes, perinatal and neonatal complications, and endometrial preparation cycle cancellation rates. Participants/materials, setting, methods Eligible participants were ovulatory women aged 18–45 with FET treatment, underwent no more than three IVF/intracytoplasmic sperm injection-FET cycles, had no more than two day-3 or one blastocyst transferred. Women with menopause/anovulation, contraindications for hormonal administration, uterine abnormalities who underwent in-vitro maturation, pre-implantation genetic testing, oocyte donation cycles were excluded. The FET strategies included FET after the first endometrial preparation cycles with AC, mNC, or NC, as per randomization, and the second with AC. Main results and the role of chance A total of 4,779 participants were screened, of whom 1,428 eligible individuals (476 per group) were randomized after written informed consent. The live birth rate after one FET was 36.6% (174/476) in the natural cycle strategy group, 33.4% (159/476) in the modified natural cycle strategy group, and 34.0% (162/476) in the artificial cycle strategy group (relative risk [95% confidence interval] for natural versus artificial cycle strategy: 1.07 [0.87–1.33] and for modified natural versus artificial cycle strategy: 0.98 [0.79–1.22]). Maternal and neonatal outcomes were comparable between groups, in particular,hypertensive disorders in pregnancy. For both natural and modified cycle groups, 20.08% (99/476) of the first FET cycles were canceled before subsequent successful ET versus none in the artificial cycle group. Limitations, reasons for caution Due to the nature of the intervention, blinding was not possible. The study was conducted in ovulatory women in a single center in Vietnam, which may limit the generalisability of the findings. Wider implications of the findings Live birth rates and obstetric/neonatal outcomes after the natural cycle, modified natural cycle, or artificial cycle strategies for ovulatory women undergoing FET are comparable, with higher cancellation rates in both the natural cycle and the modified natural cycle groups. Trial registration number NCT04804020

Оцінка впливу гінекологічної патології на шанси живонародження серед жінок із повторними невдачами імплантації

Aim - to study the prognostic impact of the presence of gynecological pathology on live birth in women with multiple negative implantation attempts in the context of the proposed methods of examination and treatment, such as preimplantation genetic diagnosis of embryos and individualization of the endometrial preparation protocol, taking into account the results of the assessment of the implantation window. Materials and methods. The prospective cohort study included 93 women with infertility treated by in vitro fertilization (IVF). Patients had repeated failed implantation attempts and were divided into three groups: the Group 1 - patients who were treated with genetically untested embryos according to a standard fixed stimulation protocol, the Group 2 - patients who were treated with euploid embryos after preimplantation genetic screening according to a standard fixed protocol; the Group 3 - patients treated with euploid embryos after preimplantation genetic screening and determination of the implantation window with subsequent modification of the stimulation protocol, according to the results of the endometrial examination. The implantation window was determined by three-time aspiration biopsy of the endometrium during the luteal phase of the menstrual cycle. The samples were analyzed by scanning electron microscopy. Based on the results, the endometrial preparation protocol was individualized for the next IVF attempt. Preimplantation diagnostics of embryos was performed using the next generation method. Statistical analysis was performed using IBM SPSS V25.0 for Windows software. Results. According to the results obtained, the presence of genital pathology reduced the chance of live birth by 30% in patients with repeated failed implantation attempts. Pathologies such as endometriosis, including endometrioid ovarian cysts, benign breast disease and Asherman syndrome have a negative effect on the chance of live birth among patients who have undergone infertility treatment with IVF. Conclusions. The presence of gynecologic pathology reduces the chances of live birth in patients with repeated failed implantation attempts undergoing IVF treatment. The study was conducted in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee for all participants. Informed consent was obtained from the patients. No conflict of interests was declared by the authors.

Assessment of the implantation window and embryonic factor impact to the treatment of recurrent implantation failure (RIF). A prospective study

The aim: to study of the prognostic value of endometrial receptivity and preimplantation genetic diagnosis of embryos, and their influence on the effectiveness of in vitro fertilization (IVF) programs. We also evaluate the importance of this factor in comparison with other potential causes of infertility. Materials and methods: This prospective cohort study included 123 infertile women who underwent in vitro fertilization (IVF) treatment. 93 patients had repeated unsuccessful implantation attempts and were divided into three groups: group 1 - patients who were treated using genetically untested embryos according to a standard fixed stimulation protocol, group 2 - patients who were treated using euploid embryos after preimplantation genetic screening according to standard fixed protocol; group 3 - patients who underwent treatment using euploid embryos after pre-implantation genetic screening and determination of the implantation window with subsequent modification of the stimulation protocol, according to the endometrial examination result. 30 patients had a first attempt at IVF, which was carried out using genetically untested embryos, according to a standard fixed protocol, and made up the control group (CG). Determination of the window of implantation was carried out by triple aspiration biopsy of the endometrium during the luteal phase of the menstrual cycle since the endometrium is most susceptible to implantation during this period. Samples were analyzed using scanning electron microscopy. Based on the results obtained, the endometrial preparation protocol was individualized for the next attempt. preimplantation genetic testing (PGT) of embryos was carried out by the next generation (NGS) method. Statistical analysis was performed using IBM SPSS V25.0 for Windows software. Results: According to the obtained results, patient characteristics, screening rates, IVF cycle characteristics, and the number, quality, and stage of transferred embryos were compared between groups. The rate of clinical pregnancy was 46.7 % among patients of group 1.70 % among patients of group 2, 82.8 % among patients of group 3 and 50.0 % of the control group and statistically significantly different between groups (χ2=10.955, p= 0.012). The rate of live birth was 43.3 % among patients of group 1, 53.3 % among patients of group 2, 72.4 % among patients of group 3 and 43.3 % - of the control group, however, it did not differ statistically significantly between groups (χ2=6,639, р=0,084) Conclusions: The unique window of implantation and the embryonic factor are among the main reasons for multiple failed implantation attempts. Personalization of the endometrial preparation protocol and preimplantation embryo diagnosis are effective methods to improve IVF outcomes

Natural proliferative phase frozen embryo transfer-a new approach which may facilitate scheduling without hindering pregnancy outcomes.

How does a natural proliferative phase (NPP) strategy for frozen embryo transfer (FET) compare with the conventional artificial (AC) and natural (NC) endometrial preparation protocols in terms of live birth rates (LBR)? This study supports the hypothesis that, just as for NC, NPP-FET may be a superior alternative to AC in terms of LBR. Although FETs are increasing worldwide, the optimal FET protocol is still largely controversial. Despite recent evidence supporting a possibly higher efficacy and safety of NC FETs, their widespread use is limited by the difficulties encountered during cycle monitoring and scheduling. In this single center retrospective cohort study, we describe the NPP-FET protocol, in which vaginal progesterone is initiated during the proliferative phase as soon as an endometrium with a thickness of at least 7 mm is identified and ovulation is ruled out, regardless of mean diameter of the dominant follicle. For comparison, we considered all blastocyst stage FET cycles preformed at a private infertility center between January 2010 and June 2022, subdivided according to the following subgroups of endometrial preparation: AC, NPP, and NC. We performed multivariable generalized estimating equations regression analysis to account for the following potential confounding variables: oocyte age at retrieval, oocyte source (autologous without preimplantation genetic testing for aneuploidies (PGT-A) versus autologous with PGT-A versus donated), number of oocytes retrieved/donated, embryo developmental stage (Day 5 versus Day 6), number of embryos transferred, quality of the best embryo transferred, and year of treatment. The main outcome measure was LBR. The secondary outcomes included hCG positive, clinical pregnancy and miscarriage rates, and the following perinatal outcomes: first trimester bleeding, second/third trimester bleeding, preterm rupture of membranes, gestational diabetes, gestational hypertensive disorders (GHD), and gestational age at delivery. A total of 5791 FET cycles were included in this analysis (2226 AC, 349 NPP, and 3216 NC). The LBR for FET was lower in the AC subgroup when compared to the NPP and NC (38.4%, 49.1%, and 45.2%, respectively; P < 0.01 AC versus NPP and AC versus NC). The rates of miscarriage were also lower in the NPP and NC subgroups when compared to AC (19.7%, 25.0%, and 34.9%, respectively; P < 0.01 NPP versus AC and NC versus AC). Considering perinatal outcomes, NPP-FET and NC were associated with a significantly lower first trimester bleeding compared to AC (17.3%, 14.7%, and 37.6%, respectively; P < 0.01 NPP versus AC and NC versus AC). Additionally, NC was associated with a lower rate of GHD when compared with AC (8.6% versus 14.5%, P < 0.01), while the rate following NPP-FET was 9.4%. This study is limited by its retrospective design. Moreover, there was also a low number of patients in the NPP subgroup, which may have led the study to be underpowered to detect clinically relevant differences between the subgroups. Our study posits that the NPP-FET protocol may be an effective and safe alternative to both NC and AC, while still allowing for enhanced practicality in patient follow-up and FET scheduling. Further investigation on NPP-FET is warranted, with prospective studies including a larger and more homogeneous subsets of patients. This research was supported by the IVI-RMA-Lisbon (2008-LIS-053-CG). The authors did not receive any funding for this study. The authors have no competing interests. Not applicable.

Does recurrent implantation failure exist? Prevalence and outcomes of five consecutive euploid blastocyst transfers in 123987 patients.

What are the clinical pregnancy and live birth rates in women who underwent up to two more euploid blastocyst transfers after three failures in the absence of another known factor that affects implantation? The fourth and fifth euploid blastocyst transfers resulted in similar live birth rates of 40% and 53.3%, respectively, culminating in a cumulative live birth rate of 98.1% (95% CI = 96.5-99.6%) after five euploid blastocyst transfers. The first three euploid blastocysts have similar implantation and live birth rates and provide a cumulative live birth rate of 92.6%. An international multi-center retrospective study was conducted at 25 individual clinics. The study period spanned between January 2012 and December 2022. A total of 123987 patients with a total of 64572 euploid blastocyst transfers were screened for inclusion. Patients with a history of any embryo transfer at another clinic, history of any unscreened embryo transfer at participating clinics, parental karyotype abnormalities, the use of donor oocytes or a gestational carrier, untreated intracavitary uterine pathology (e.g. polyp, leiomyoma), congenital uterine anomalies, adenomyosis, communicating hydrosalpinx, endometrial thickness <6 mm prior to initiating of progesterone, use of testicular sperm due to non-obstructive azoospermia in the male partner, transfer of an embryo with a reported intermediate chromosome copy number (i.e. mosaic), preimplantation genetic testing cycles for monogenic disorders, or structural chromosome rearrangements were excluded. Ovarian stimulation protocols and embryology laboratory procedures including trophectoderm biopsy followed the usual practice of each center. The ploidy status of blastocysts was determined with comprehensive chromosome screening. Endometrial preparation protocols followed the usual practice of participating centers and included programmed cycles, natural or modified natural cycles. A total of 105 (0.085% of the total population) patients met the criteria and underwent at least one additional euploid blastocyst transfer after failing to achieve a positive pregnancy test with three consecutive euploid blastocyst transfers. Outcomes of the fourth and fifth euploid blastocyst transfers were similar across participating centers. Overall, the live birth rate was similar with the fourth and fifth euploid blastocysts (40% vs 53.3%, relative risk = 1.33, 95% CI = 0.93-1.9, P value = 0.14). Sensitivity analyses excluding blastocysts biopsied on Day 7 postfertilization, women with a BMI >30 kg/m2, cycles using non-ejaculate or donor sperm, double-embryo transfer cycles, and cycles in which the day of embryo transfer was modified due to endometrial receptivity assay test result yielded similar results. Where data were available, the fourth euploid blastocyst had similar live birth rate with the first one (relative risk = 0.84, 95% CI = 0.58-1.21, P = 0.29). The cumulative live birth rate after five euploid blastocyst transfers was 98.1% (95% CI = 96.5-99.6%). Retrospective design has its own inherent limitations. Patients continuing with a further euploid embryo transfer and patients dropping out from treatment after three failed euploid transfers can be systematically different, perhaps with regard to ovarian reserve or economic status. Implantation failure seems to be mainly due to embryonic factors. Given the stable and high live birth rates up to five euploid blastocysts, unexplained recurrent implantation failure should have a prevalence of <2%. Proceeding with another embryo transfer can be the best next step once a known etiology for implantation failure is ruled out. None. N/A.

Hyperlipidemia is negatively associated with pregnancy outcomes in patients following frozen-thawed embryo transfer: A retrospective study.

It is demonstrated that lipid metabolism disorders are associated with the reproductive performances of assisted reproductive technology. However, it is little known whether hyperlipidemia is associated with the endometrial receptivity and pregnancy outcomes of patients undergoing frozen-thawed embryo transfer (FET). This was a retrospective analysis involving 554 infertile women undergoing FET. The patients were divided into the hyperlipidemia group (n = 224) and control group (n = 320) based on the levels of serum lipids. The clinical and laboratory indexes between the two groups were compared. Meanwhile, the stratified analysis based on body mass index (BMI) and endometrial preparation protocols was performed. The independent samples t-test, Mann-Whitney U test, χ2 test and multiple logistic regression analysis were used to compare and analyze the data. The patients with hyperlipidemia had significantly higher serum lipids levels and BMI and lower clinical pregnancy and implantation rates than those with normal blood lipids (p < 0.05). The impact of hyperlipidemia on pregnancy outcomes was independent of BMI. The multiple logistic regression analysis showed that higher cholesterol was associated with lower pregnancy rate and implantation rate (p < 0.05). Regardless of blood lipid levels, the patients undergoing the hormone replacement therapy (HRT) protocol had higher estradiol levels and lower progesterone levels compared with the stimulated cycles (STC) (p < 0.05). Moreover, the clinical pregnancy rate and implantation rate of the HRT protocol were higher than those of the STC, although there was no significant difference between the two. Hyperlipidemia especially higher cholesterol has a negative effect on the pregnancy outcomes of the patients undergoing FET. Actively implementing lipid-lowering treatment and the HRT protocol seem more friendly for these patients.

What is the optimal means of preparing the endometrium in frozen-thawed embryo transfer cycles among anovulatory women? A retrospective cohort study

ObjectiveDifferent endometrial preparation protocols are used prior to frozen-thawed embryo transfer (FET). It is not clear whether letrozole-stimulated cycles are beneficial for anovulatory women compared to artificial cycles (AC) in anovulatory women. Our objective was to investigate whether clinical outcomes following frozen-thawed embryo transfer in letrozole-stimulated cycles differ from artificial cycles in anovulatory women.Study design: This is a retrospective cohort study conducted in a public fertility center in China comparing letrozole-stimulated and artificial cycles during FET. A total of 5,322 anovulatory women undergoing the first cycle of FET between January 2020 and December 2021. The primary outcome was the live birth rate. The secondary outcomes included biochemical pregnancy, clinical pregnancy, ongoing pregnancy, miscarriage, and ectopic pregnancy. ResultsThe live birth rates were significantly higher in the letrozole compared with AC (49.57 % vs. 45.22 %) both in the crude (odds ratio [OR] 1.19, 95 % confidence interval [CI] 1.01–1.40) and adjusted analysis (aOR 1.27, 95 %CI 1.08–1.50). After controlling for potential covariates, the adjusted probability of biochemical pregnancy (65.71 % vs. 63.25 %, aOR 1.20, 95 %CI: 1.01–1.43), clinical pregnancy (61.53 % vs. 58.79 %, aOR 1.20, 95 %CI: 1.02–1.43), and ongoing pregnancy (50.14 % vs. 45.66 %, aOR 1.28, 95 %CI: 1.08–1.51) were higher among those using letrozole-stimulated cycles than among those undergoing artificial cycles. The miscarriage rate was lower following letrozole compared with artificial cycles (aOR 0.59, 95 %CI: 0.43–0.80). The ectopic pregnancy in the letrozole group was similar to that in the artificial cycles. ConclusionsLetrozole-stimulated FET was significantly associated with higher rates of biochemical pregnancy, clinical pregnancy, ongoing pregnancy and live birth, and with a lower rate of miscarriage, compared with artificial cycles.

Is large for gestational age in singletons born after frozen embryo transfer associated with freezing technique or endometrial preparation protocol? A longitudinal national French study.

Is large for gestational age (LGA) observed in babies born after frozen embryo transfer (FET) associated with either the freezing technique or the endometrial preparation protocol? Artificial cycles are associated with a higher risk of LGA, with no difference in rate between the two freezing techniques (vitrification versus slow freezing) or embryo stage (cleaved embryo versus blastocyst). Several studies have compared neonatal outcomes after fresh embryo transfer (ET) and FET and shown that FET is associated with improved neonatal outcomes, including reduced risks of preterm birth, low birthweight, and small for gestational age (SGA), when compared with fresh ET. However, these studies also revealed an increased risk of LGA after FET. The underlying pathophysiology of this increased risk remains unclear; parental infertility, laboratory procedures (including embryo culture conditions and freezing-thawing processes), and endometrial preparation treatments might be involved. A multicentre epidemiological data study was performed through a retrospective analysis of the standardized individual clinical records of the French national register of IVF from 2014 to 2018, including single deliveries resulting from fresh ET or FET that were prospectively collected in fertility centres. Complementary data were collected from the participating fertility centres and included the vitrification media and devices, and the endometrial preparation protocols. Data were collected from 35 French ART centres, leading to the inclusion of a total of 72789 fresh ET, 10602 slow-freezing FET, and 39062 vitrification FET. Main clinical outcomes were presented according to origin of the transferred embryos (fresh, slow frozen, or vitrified embryos) and endometrial preparations for FET (ovulatory or artificial cycles), comparing five different groups (fresh, slow freezing-ovulatory cycle, slow freezing-artificial cycle, vitrification-ovulatory cycle, and vitrification-artificial cycle). Foetal growth disorders were defined in live-born singletons according to gestational age and sex-specific weight percentile distribution: SGA and LGA if <10th and ≥90th percentiles, respectively. Analyses were performed using linear mixed models with the ART centres as random effect. Transfers led to, respectively, 19006, 1798, and 9195 deliveries corresponding to delivery rates per transfer of 26.1%, 17.0%, and 23.5% after fresh ET, slow-freezing FET, and vitrification FET, respectively. FET cycles were performed in either ovulatory cycles (n = 21704) or artificial cycles (n = 34237), leading to 5910 and 10322 pregnancies, respectively, and corresponding to pregnancy rates per transfer of 31.6% and 33.3%. A significantly higher rate of spontaneous miscarriage was observed in artificial cycles when compared with ovulatory cycles (33.3% versus 21.4%, P < 0.001, in slow freezing groups and 31.6% versus 21.8%, P < 0.001 in vitrification groups). Consequently, a lower delivery rate per transfer was observed in artificial cycles compared with ovulatory cycles both in slow freezing and vitrification groups (15.5% versus 18.9%, P < 0.001 and 22.8% versus 24.9%, P < 0.001, respectively). Among a total of 26585 live-born singletons, 16413 babies were born from fresh ET, 1644 from slow-freezing FET, and 8528 from vitrification FET. Birthweight was significantly higher in the FET groups than in the fresh ET group, with no difference between the two freezing techniques. Likewise, LGA rates were higher and SGA rates were lower in the FET groups compared with the fresh ET group whatever the method used for embryo freezing. In a multivariable analysis, the risk of LGA following FET was significantly increased in artificial compared with ovulatory cycles. In contrast, the risk of LGA was not associated with either the freezing procedure (vitrification versus slow freezing) or the embryo stage (cleaved embryo versus blastocyst) at freezing. Regarding the vitrification method, the risk of LGA was not associated with either the vitrification medium used or the embryo stage. No data were available on maternal context, such as parity, BMI, infertility cause, or maternal comorbidities, in the French national database. In particular, we cannot exclude that the increased risk of LGA observed following FET with artificial cycles may, at least partially, be associated with a confounding effect of some maternal factors. No information about embryo culture and incubation conditions was available. Most of the vitrification techniques were performed using the same device and with two main vitrification media, limiting the validity of a comparison of risk for LGA according to the device or vitrification media used. Our results seem reassuring, since no potential foetal growth disorders following embryo vitrification in comparison with slow freezing were observed. Even if other factors are involved, the endometrial preparation treatment seems to have the greatest impact on LGA risk following FET. FET during ovulatory cycles could minimize the risk for foetal growth disorders. This work has received funding from the French Biomedicine Agency (Grant number: 19AMP002). None of the authors has any conflict of interest to declare. N/A.

Association between proliferative-to-secretory endometrial compaction and pregnancy outcomes after embryo transfer: a systematic review and meta-analysis.

Does the change in endometrial thickness (EMT) from the end of the follicular/estrogen phase to the day of embryo transfer (ET) determine subsequent pregnancy outcomes? Endometrial compaction from the late-proliferative to secretory phase is not associated with live birth rate (LBR) and other pregnancy outcomes. Endometrial compaction has been suggested to be indicative of endometrial responsiveness to progesterone, and its association with ET outcome has been investigated but is controversial. A systematic review with meta-analysis was carried out. PubMed, EMBASE, and Web of Science were searched to identify relevant studies from inception to 18 November 2022. The reference lists of included studies were also manually screened for any additional publications. Cohort studies comparing ET pregnancy outcomes between patients with and without endometrial compaction were included. A review of the studies for inclusion, data extraction, and quality assessment was performed by two independent reviewers. The effect size was synthesized as odds ratio (OR) with 95% CI using a random-effects model. Heterogeneity and publication bias were assessed by the I2 statistic and Egger's test, respectively. The primary outcome was LBR. Secondary outcomes included biochemical pregnancy rate (BPR), clinical pregnancy rate (CPR), miscarriage rate (MR), ongoing pregnancy rate (OPR), and ectopic pregnancy rate (EPR). Seventeen cohort studies involving 18973 ET cycles fulfilled the eligibility criteria. The pooled results revealed that there were no significant differences between endometrial compaction and non-compaction groups in LBR (crude OR (cOR) = 0.95, 95% CI 0.87-1.04; I2 = 0%; adjusted OR (aOR) = 1.02, 95% CI 0.87-1.19, I2 = 79%), BPR (cOR = 0.93, 95% CI 0.81-1.06; I2 = 0%; aOR = 0.88, 95% CI 0.75-1.03, I2 = 0%), CPR (cOR = 0.98, 95% CI 0.81-1.18; I2 = 70%; aOR = 0.86, 95% CI 0.72-1.02, I2 = 13%), MR (cOR = 1.09, 95% CI 0.90-1.32; I2 = 0%; aOR = 0.91, 95% CI 0.64-1.31; I2 = 0%), and EPR (cOR = 0.70, 95% CI 0.31-1.61; I2 = 61%). The OPR was marginally higher in crude analysis (cOR = 1.48, 95% CI 1.01-2.16; I2 = 81%) among women with compacted endometrium, but was not evident in adjusted results (aOR = 1.36, 95% CI 0.86-2.14; I2 = 84%). Consistently, the pooled estimate of LBR remained comparable in further subgroup and sensitivity analyses according to the degree of compaction (0%, 5%, 10%, 15%, or 20%), type of ET (fresh, frozen, or euploid only), and endometrial preparation protocol (natural or artificial). No publication bias was observed based on Egger's test. Although the number of included studies is sufficient, data on certain measures, such as EPR, are limited. The inherent bias and residual confounding were also inevitable owing to the observational study design. Furthermore, inconsistent definitions of pregnancy outcomes may affect the accuracy of our pooled analysis. Given the lack of prognostic value, assessing endometrial compaction or repeated EMT measurement on the day of ET may not be necessary or warranted. This work was supported by Natural Science Foundation of Jiangxi Province (20224BAB216025), National Natural Science Foundation of China (82260315), and Central Funds Guiding the Local Science and Technology Development (20221ZDG020071). The authors have no conflicts of interest to declare. CRD42022384539 (PROSPERO).

Effects of atosiban on clinical outcome in frozen-thawed embryo transfer: a propensity score matching study.

To evaluate the effects of atosiban on clinical outcomes in patients undergoing frozen-thawed embryo transfer. The clinical data of 1093 infertile patients who underwent frozen-thawed embryo transfer in our center from January 2019 to December 2020 were retrospectively analyzed (control, 418; atosiban, 675). Propensity score matching (PSM) analysis identified 400 matched pairs of patients.The implantation rate, clinical pregnancy rate, live birth rate, biochemical pregnancy rate, abortion rate, multiple pregnancy rate, and ectopic pregnancy rate between the two groups were compared. Before PSM, patients differed by infertility factors, number of transferred embryos, and endometrial preparation protocol (P < 0.05). After PSM, characteristics were similar in corresponding patients of the atosiban and control groups. After propensity score matching, we found that there was no significant difference in the implantation rate, clinical pregnancy rate, live birth rate, biochemical pregnancy rate, abortion rate, multiple pregnancy rate, and ectopic pregnancy rate in atosiban and control group (P > 0.05). Atosiban did not improve the clinical outcomes of infertile patients with frozen-thawed embryo transfer.