Sustained Implantation Rate Research Articles

Parental Balanced Translocation Carriers do not have Decreased Usable Blastulation Rates or Live Birth Rates Compared to Infertile Controls.

To determine if translocation carriers have a reduced number of usable blastocysts compared to infertile controls. Retrospective cohort study. All cycles of balanced translocation carriers undergoing IVF with preimplantation genetic testing (PGT-SR) for structural rearrangements at a single infertility center compared to an age-matched control cycles of infertile patients undergoing preimplantation genetic testing for aneuploidy (PGT-A) from January 2012-August 2022. Balanced translocation carriers. Primary outcome measures were blastulation rate, usable blastulation rates and live birth rate. Secondary outcome measures were sustained implantation rate, fertilization rate, number of oocytes retrieved, number of metaphase II oocytes, total blastulation failure, number of 2 pronuclear embryos, and number of euploid embryos. Outcome measures were compared between male translocation carriers and controls, female translocation carriers and controls, and Robertsonian versus reciprocal translocation carriers. A total of 1,291 retrieval cycles from 993 patients were included, of which 255 patients were translocation carriers, while 738 were controls. Of those with translocations, 30 (11.5%) were Robertsonian and 231 (88.5%) were reciprocal carriers. There was a statistically significant difference in the blastulation rate between carriers and controls (59.5% versus 62.1%; p-value = 0.01). However, usable blastulation rates (47.2% versus 50.0%) were equivalent between groups. There were no differences in number of oocytes retrieved (18.5 versus 18.3), number of 2 pronuclear embryos (13.4 versus 12.5), sustained implantation rate (71.4% versus 75.1%) or live birth rate (63.0% versus 66.1%) between translocation carriers and controls. In both male and female translocation carriers versus controls, there were no differences in usable blastulation rates or live birth rates. When comparing Robertsonian with reciprocal translocation carriers, rates of blastulation, usable blastulation, sustained implantation, and live birth rate were equivalent. Despite fewer euploid embryos, there were no differences in rates of usable blastulation or live birth rates in balanced translocation carriers, regardless of sex of affected partner or type of rearrangement, compared to controls. Routine karyotyping for blastulation failure may not be necessary based on these findings.

P-801 Sub-endometrial administration of angiogenic precursor cells and growth factors effectively optimizes endometrial thickness (EMT) and pregnancy outcomes in women with refractory thin endometrium

Abstract Study question Can hysteroscopic instillation of autologous blood derived progenitor cells combined with platelet derived growth factor concentrate into subendometrial region help patient with thin endometrium conceive? Summary answer Hysteroscopic subendometrial administration of stem cells represents a safe effective alternative method for patients recommended surrogacy, fail to improve despite using all possible treatment options What is known already Chronically thin endometrium is a challenge in ART, results in repeated expensive IVF cycles, cycle cancellations, unplanned cryopreservation of embryos and, surrogacy. Many studies have successfully used stem cells or platelet derivatives to rejuvenate reproductive tissues. When these growth-promoting cells and growth factors from platelets are delivered into basal layer which is origin of endometrial cells quality of the endometrium can be improved. While bone marrow is excellent source for obtaining stem cells main challenge is invasiveness of collection. This forms the basis for collecting mobilized endothelial progenitor cells from bone marrow into circulation for easy collection Study design, size, duration This study is to evaluate effect angiogenic precursor cells and growth factors derived from peripheral blood and bone marrow in improving endometrial quality and pregnancy outcomes. In the present pilot study involving 87 patients with persistent refractory thin endometrium were included and underwent frozen embryo transfer from April 2021-January 2024 at A4 fertility center, Chennai. All patients were treated with peripheral blood derived progenitor cells and platelet derived growth factors. Participants/materials, setting, methods 87 patients with EMT<7mm and >2 cancelled/failed cycles included. Two doses of SC-G-CSF were given on Menstrual Cycle Day 3&4, followed by venous blood aspiration on MCD-5. Seragen’s selective enrichment protocol was used to prepare circulating endothelial progenitor cells and growth factors concentrate. With 2.9mm hysteroscope and single lumen ovum pickup needle harvested cells and growth factors were injected on all four walls of cavity. Main results and the role of chance In this cohort, all patients presented refractory thin endometrium during hormone replacement therapy (HRT), despite exhaustive prior medication attempts. Subendometrial injection was employed, resulting in a significant increase in endometrial thickness (EMT) post peripheral blood cell injection (6.0 ± 0.71 vs. 7.80 ± 0.8; P = 0.0001), averaging a substantial improvement of 1.80mm. An optimal response, defined as EMT≥ 7mm, was observed in 47.2% (53) of cases. Patients with improved thickness underwent embryo transfer in the subsequent cycle, displaying a significant enhancement in endometrial thickness. Out of 53 patients, 47.2% (25) tested positive for β-HCG, while 45.3% (24) tested negative. Miscarriage occurred in 9.4% (5) of patients, with 8.8% (3) delivering healthy full-term babies. Notably, 28.3% (15) sustained uneventful pregnancies, accounting for a 34% sustained implantation rate. Comparatively, when benchmarked against subendometrial platelet-rich plasma (PRP) studies, primary and secondary outcomes in our study demonstrated superiority. This favorable outcome is attributed to the combined utilization of mobilized progenitor cells and growth factors. Prior research has established that the endometrium derives its stem cell content from the bone marrow, underscoring the efficacy of this novel approach. Limitations, reasons for caution Future research should explore avenues for women with refractory thin endometrium, offering conception options without resorting to surrogacy. Clinician expertise in patientselection, personalized dosage, and administration is crucial. While our study offers promising insights, its limitations include small sample size and lack of randomization, emphasizing need for larger, controlled trials. Wider implications of the findings Our study reveals that combine use of growth factors progenitor cells enhances endometrial thickness and improves pregnancy and live birth rates. Re-evaluating need for surrogacy in nonresponsive thin endometrium may be warranted. Insights from hematopoietic stem cell research offer reliable strategy for routine use in IVF clinical practice. Trial registration number Not applicable

Best quality vs. sex selection – an analysis of embryo selection preferences for patients undergoing preimplantation genetic testing for aneuploidy over a 10-year period

PurposeInvestigate patient preferences in embryo selection for transfer regarding quality versus sex in IVF/ICSI cycles with PGT-A and assess associated clinical implications.MethodsRetrospective cohort study at a university fertility practice from January 2012 to December 2021. Included were patients undergoing single frozen euploid transfers with at least one embryo of each sex available. Primary outcomes were preference for embryo selection (quality vs. sex) and sex preference (male vs. female). Trends over 10 years were evaluated and clinical outcomes, including clinical pregnancy rate (CPR), sustained implantation rate (SIR), and live birth rate (LBR), were compared.ResultsA total of 5,145 embryo transfer cycles were included; 54.5% chose the best-quality embryo, while 45.5% selected based on sex. Among those choosing based on sex, 56.5% chose male embryos and 43.5% chose female. Preference for quality remained consistent over the decade (p = 0.30), while male embryos were consistently favored (p = 0.64). Best-quality embryos had higher grades (p < 0.001). Clinical outcomes were similar between groups (CPR: 74.4% vs. 71.9%, p = 0.05; SIR: 64.9% vs. 63.4%, p = 0.26; LBR: 58.8% vs. 56.7%, p = 0.13), and between male and female embryo selections.ConclusionsSex selection remains common, with 45.5% selecting embryos based on sex, predominantly favoring males. This trend persisted over 10 years, with comparable clinical outcomes regardless of selection criteria.

Leukocytospermia does not negatively impact outcomes in in vitro fertilization cycles with intracytoplasmic sperm injection and preimplantation genetic testing for aneuploidy: findings from 5435 cycles

PurposeTo investigate whether leukocytospermia (defined as the presence of ≥ 1 × 106 white blood cells/mL) affects clinical and embryologic outcomes in in vitro fertilization (IVF) cycles with intracytoplasmic sperm injection (ICSI) and preimplantation genetic testing for aneuploidy (PGT-A).MethodsThis was a retrospective cohort study including 5425 cycles between January 2012 to December 2021 at a single large university-affiliated fertility clinic. The primary outcome was live birth rate (LBR).ResultsThe prevalence of leukocytospermia was 33.9% (n = 1843). Baseline characteristics including female age, BMI, AMH, Day 3 FSH, and male partner’s age were similar in cycles with and without leukocytospermia. The LBR after the first euploid embryo transfer was similar in those with and without leukocytospermia (62.3% vs. 63% p = 0.625). Secondary outcomes including clinical pregnancy rate (CPR), sustained implantation rate (SIR), fertilization (2PN) rate, blastulation rate, and aneuploidy rate were also evaluated. The CPR (73.3% vs 74.9%, p = 0.213) and SIR (64.6% vs. 66%, p = 0.305) were similar in both groups. The 2PN rate was also similar in both groups (85.7% vs. 85.8%, p = 0.791), as was the blastulation rate per 2PN (56.7% vs. 57.5%, p = 0.116). The aneuploidy rate was not significantly different between groups (25.7% vs 24.4%, p = 0.053). A generalized estimation equation with logistic regression demonstrated that the presence leukocytospermia did not influence the LBR (adjusted OR 0.878; 95% CI, 0.680–1.138).ConclusionLeukocytospermia diagnosed just prior to an IVF cycle with PGT-A does not negatively impact clinical or embryologic outcomes.

A pilot study to investigate the clinically predictive values of copy number variations detected by next-generation sequencing of cell-free deoxyribonucleic acid in spent culture media

To investigate the positive predictive value and false positive risk of copy number variations (CNV's) detected in cell free deoxyribonucleic acid (DNA) from spent culture media for nonviable or aneuploid embryos. Diagnostic/prognostic accuracy study. Patients aged 35 and younger with an indication for IVF-ICSI and elective single frozen embryo transfer at a single, private IVF center. Embryo selection was performed according to the conventional grading, blinded to noninvasive preimplantation genetic testing for aneuploidy (niPGT-A) results. After clinical outcomes were established, spent culture media samples were analyzed. Prognostic accuracy of CNVs according to niPGT-A results to predict nonviability or clinical aneuploidy. One hundred twenty patients completed the study. Interpretations of next-generation sequencing (NGS) profiles were as follows: 7.5% (n = 9) failed quality control; 62.5% (n = 75) no CNVs detected; and 30% (n = 36) abnormal copy number detected. Stratification of abnormal NGS profiles was as follows: 15% (n = 18) whole chromosome and 15% (n = 18) uncertain reproductive potential. An intermediate CNV was evident in 27.8% (n = 5) of the whole chromosome abnormalities. The negative predictive value for samples with no detected abnormality was 57.3% (43/75). Whole chromosome abnormality was associated with a positive predictive value of 94.4% (17/18), lower sustained implantation rate (5.6%, 1/18), and higher relative risk (RR) for nonviability compared with no detected abnormalities (RR 2.21, 95% CI: 1.66-2.94). No other CNVs were associated with significant differences in the sustained implantation or RRs for nonviability. Unequal sex chromosome proportions suggested that maternal contamination was not uncommon. A secondary descriptive analysis of 705 supernumerary embryos revealed proportions of NGS profile interpretations similar to the transferred cohort. Significant median absolute pairwise differences between certain subcategories of CNV abnormalities were apparent. Whole chromosome abnormalities were associated with a high positive predictive value and significant RR for nonviability. Embryos associated with other CNVs had sustained implantation rates similar to those with no abnormalities detected. Further studies are required to validate the clinical applicability of niPGT-A. clinicaltrials.gov (NCT04732013).

The reproductive potential of vitrified-warmed euploid embryos declines following repeated uterine transfers

BackgroundRecurrent implantation failure (RIF) represents a vague clinical condition with an unclear diagnostic challenge that lacks solid scientific underpinning. Although euploid embryos have demonstrated consistent implantation capabilities across various age groups, a unanimous agreement regarding the advantages of preimplantation genetic testing for aneuploidy (PGT-A) in managing RIF is absent. The ongoing discussion about whether chromosomal aneuploidy in embryos significantly contributes to recurrent implantation failure remains unsettled. Despite active discussions in recent times, a universally accepted characterization of recurrent implantation failure remains elusive. We aimed in this study to measure the reproductive performance of vitrified-warmed euploid embryos transferred to the uterus in successive cycles.MethodsThis observational cohort study included women (n = 387) with an anatomically normal uterus who underwent oocyte retrieval for PGT-A treatment with at least one biopsied blastocyst, between January 2017 and December 2021 at a university-affiliated public fertility center. The procedures involved in this study included ICSI, blastocyst culture, trophectoderm biopsy and comprehensive 24-chromosome analysis of preimplantation embryos using Next Generation Sequencing (NGS). Women, who failed a vitrified-warmed euploid embryo transfer, had successive blastocyst transfer cycles (FET) for a total of three using remaining cryopreserved euploid blastocysts from the same oocyte retrieval cycle. The primary endpoints were sustained implantation rate (SIR) and live birth rate (LBR) per vitrified-warmed single euploid embryo. The secondary endpoints were mean euploidy rate (m-ER) per cohort of biopsied blastocysts from each patient, as well as pregnancy and miscarriage rates.ResultsThe mean age of the patient population was 33.4 years (95% CI 32.8–33.9). A total of 1,641 embryos derived from the first oocyte retrieval cycle were biopsied and screened. We found no associations between the m-ER and the number of previous failed IVF cycles among different ranges of maternal age at oocyte retrieval (P = 0.45). Pairwise comparisons showed a significant decrease in the sustained implantation rate (44.7% vs. 30%; P = 0.01) and the livebirth rate per single euploid blastocyst (37.1% vs. 25%; P = 0.02) between the 1st and 3rd FET. The cumulative SIR and LBR after up to three successive single embryo transfers were 77.1% and 68.8%, respectively. We found that the live birth rate of the first vitrified-warmed euploid blastocyst transferred decreased significantly with the increasing number of previously failed IVF attempts by categories (45.3% vs. 35.8% vs. 27.6%; P = 0.04). A comparable decrease in sustained implantation rate was also observed but did not reach statistical significance (50% vs. 44.2 vs. 37.9%; P = NS). Using a logistic regression model, we confirmed the presence of a negative association between the number of previous IVF failed attempts and the live birth rate per embryo transfer cycle (OR = 0.76; 95% CI 0.62–0.94; P = 0.01).ConclusionsThese findings are vital for enhancing patient counseling and refining management strategies for individuals facing recurrent implantation failure. By tailoring interventions based on age and ovarian reserve, healthcare professionals can offer more personalized guidance, potentially improving the overall success rates and patient experiences in fertility treatments.Trial registration numberN/A.

Recurrent Implantation Failure: Reality or a Statistical Mirage?: Consensus Statement From the July 1, 2022 Lugano Workshop on Recurrent Implantation Failure

ABSTRACT Despite advancements in assisted reproductive technologies over the past few decades, a 35% failure rate is still observed for unexplained reasons when transferring euploid embryos to an anatomically normal uterus. Recurrent implantation failure (RIF) is defined based on cumulative ART cycles failing; however, there is an absence in consensus on the diagnostic criteria, which leads to the risk of overdiagnosing and overtreating the condition. This consensus statement by the Lugano RIF Workshop aimed to merge variation in the clinical concept and management of RIF, focusing primarily on euploid blastocyst transfers in hormone replacement-primed cycles. The workshop comprised a panel of 27 international experts selected on the basis of overall research activities and publications on the subject. A literature search as conducted for all relevant titles and abstracts published between January 2015 and May 2022 for review. Consensus conclusions were based on the literature search and expert opinions. Consideration of an RIF diagnosis was determined to focus on failure to achieve sustained implantation (defined as a gestational sac identified on ultrasound). Historically, RIF was defined as the failed transfer of &gt;10 embryos; however, today, a common number used is 3, which is also similar to the rate of failure based on a 95% confidence interval. Based on large clinical data sets, approximately 2%–5% of patients pursuing ART treatment may have RIF, and the decline in future implantation rate with each cycle fits more to an exponential delay curve than a linear decrease. The diagnosis of RIF should not be considered based on a single cohort of embryos, but rather on the number of euploid blastocyst transferred adjusted to patient’s age. In the absence of abnormal uterine bleeding and normal uterine size, further evaluation of asymptomatic adenomyosis is not warranted. Testing for biomarkers of endometrial receptivity and the endometrial microbiome have not been validated using RCTs and should not be used. The role of chronic inflammation in RIF remains unclear, but evidence suggests chronic endometritis does not directly play a role in ART outcome as assessed by sustained implantation rate after euploid embryo transfer. Substantial evidence exists that is low progesterone on the day of embryo transfer results in worse ART outcomes, and that IM progesterone may be superior to vaginal progesterone. There are no effective treatments for RIF currently, and immunomodulatory treatments that may be offered including glucocorticoids, IVIG, and GCSF have a lack of comprehensive data. This consensus document finds that RIF is likely present in fewer than 5% of patients undergoing ART and has been overdiagnosed and overtreated without sufficient critical evaluation of the presumed condition. It also highlights areas where future research is needed, both in the pathophysiologic cause of RIF and hypothetical treatment modalities.

O-290 Clinical utility of putative mosaicism detected using concurrent copy-number and genotyping PGT method: outcomes from multisite, prospective, non-selection study including 9828 single embryo transfer cycles

Abstract Study question What is the clinical utility and associated outcomes of mosaic whole chromosome or segmental aneuploidies detected using concurrent copy-number and genotyping analysis in PGT-A cycles? Summary answer Although high-level whole-chromosome mosaicism is linked to reduced sustained implantation, it has limited clinical significance in PGT-A cycles when co-evaluated with other clinical/ embryological factors What is known already NGS-based PGT-A can detect intermediate chromosomal copy number (CN), commonly interpreted as mosaic chromosomal aneuploidies in embryos. A prospective non-selection approach is the most effective way to assess the clinical utility of reporting putative mosaicism findings in PGT-A, wherein the presence of mosaicism is not disclosed and does not influence embryo selection. Conflicting results have been reported previously, possibly due to technological limitations in mosaicism assessment or retrospective analysis methods. This study reports the results of the largest multisite prospective non-selection clinical study examining the predictive value of whole-chromosome and segmental mosaicism, assessed through combined CN and genotyping data analysis. Study design, size, duration A multisite study involving seven IVF clinics was conducted from Feb 2020 to Oct 2022, including 6951 patients and 9828 single embryo transfers. The study involved a prospective non-selection approach, where embryos suspected of having whole chromosomal or segmental mosaicism were reported as negative for non-mosaic aneuploidies. Embryos were chosen for transfer based solely on standard morphological features. The primary outcome was sustained implantation rate (SIR) defined as pregnancy continuing beyond 8 weeks of gestation. Participants/materials, setting, methods In this study, the trophectoderm biopsies were analyzed using a custom, targeted NGS assay that examined approximately 5000 loci across the genome, providing genotyping information to support aneuploidy classification. Mosaicism was identified by any copy number deviation from the expected two copies (LogR plots) and confirmed by corresponding SNP B-allele frequency (BAF) patterns. Confounding factors, such as clinical and embryological variables, were controlled for in the multivariate analysis. Main results and the role of chance The average female age in this cohort was 34.9 years (SD = 4.1), with aneuploidy rate of 30% in embryos and SIR of 61.2%. Of the embryos transferred, 6.5% (636/9828) were whole chromosomal mosaic (WCM) only; 9.6% (947/9828) were segmental mosaic (SM) only and 1% (83/9829) were a combination of WCM and SM. The rate of putative mosaicism ranged from 15%-89%. The SIR of embryos in the control group (non-mosaic), SM and WCM were 62% (5190/8328; 95%CI), 58% (549/947;95%CI) and 50.3% (320/636; 95%CI P &amp;lt; 0.01) respectively. A logistic model found that the level of WCM was associated to SIR, along with other embryological and clinical factors. In particular, WCM with a CN difference &amp;gt;50% as well as poor embryo morphology were associated with lower SIR (OR = 0.5; 95% CI:0.32-0.76), but low-level (&amp;lt;50%) mosaicism was not significant (NS). Notably, female age (OR = 0.98; 95% CI:0.97-0.99 per year), BMI (0.98; 95% CI:0.98-0.99) and previous ET failures (OR = 0.58; 95% CI:0.5-0.68) were strongly associated with SIR. A predictive model, taking into account all relevant variables, yielded a significant stratification of SIR, from 43% to 68%. Given the low incidence of WCM in our clinical setting, the multivariate SIR prediction (AUC) was 0.580 without WCM and 0.585 with mosaicism included. Limitations, reasons for caution This study did not have prenatal and post-natal data available at the time of the abstract's writing, hence conclusions about these outcomes wasn’t possible. Despite the large sample size, chromosome specific analysis was not feasible. Furthermore, this study’s data is platform-specific and cannot be translated to other PGT-A assays. Wider implications of the findings In this non-selection study, WCM of &amp;gt; 50% variation was associated with lower SIR. However, high-level WCM has a minimal overall impact on SIR when co-evaluating with other clinical/ embryological parameters. Decisions on reporting criteria for these findings must weigh the risk of discarding potentially viable embryos with substantial reproductive potential. Trial registration number Not applicable

O-138 Covid-19 vaccine does not affect sustained implantation rates after single euploid embryo transfer, a retrospective study with 4868 cases

Study questionIs sustained implantation rate (SIR) of covid-19 vaccinated women diminished in assisted reproduction treatments due to endometrial receptivity harm?Summary answerSIR of euploid embryos remains constant regardless vaccination and doses applied, but impact of interval last dose-embryo transfer needs to be further evaluated.What is known alreadyLittle is known about the effects of both covid infection and vaccines on endometrial receptivity of women attempting motherhood.There is a generalized concern about potential secondary effects of covid vaccine on many health areas, and assisted reproduction is not an exception. Then, it is mandatory on the current epidemic context to evaluate if either infection or its preventive treatment may interfere reproductive physiology of infertile patients.ART offers a robust model to study this problem by controlling oocyte and embryo quality with the use of PGT-A, then enabling the study of endometrial independent contribution to reproductive success.Study design, size, durationRetrospective study analyzing two cohorts, historical cohort of PGT-A cases using own oocytes one year pre-pandemia, and post vaccination initiation from women already having received one or two doses.Patients undergoing single embryo transfers (ET) after PGT-A were included, to be able to discern purely endometrial factors of sustained implantation. Means and proportions with their corresponding 95%CI (within brackets) were calculated, and crude/adjusted odds ratios calculated for the main outcomes, SIR and clinical pregnancy rate (CPR)Participants/materials, setting, methodsA total of 4868 ET were included on this study, 3272 for the control, non vaccinated group, vs 890 from women already vaccinated with at last one dose at the time of ET.The main outcomes were CPR per embryo transfer (presence of a sac by ultrasonography on week 7th), and SIR (fetal heartbeat at week 12th). Crude and adjusted odds ratio were calculated, using logistic regression models to control for potentially confounding variables.Main results and the role of chanceMean age was 38.3 years 95%CI(38.2-38.4), BMI, 23.2kg/m2 95%CI(23.1 23.4), fresh oocytes on 80%, mixed 16.4% and vitrified on 3.6% of cases. Donor sperm used on 12.8% of treatments, and testicular retrieved sperm on 2.5% of them. Day of embryo transfer was D5 on 71.3% and D6 on 28.6% cases.CPR per ET was 70.6% 95%CI(69.3-71.9) in the control group and 70.4%95%CI(67.4-73.4) on vaccinated, OR 0.994 95%CI(0.849-1.163), and after adjustment by patient’s age, oocyte age, source of sperm, donor sperm use, day of ET, use of vitrified oocytes and BMI, AdjOR 1.039 95%CI(0.876-1.233), while SIR in the controls was 64.3% 95%CI(62.7-66.0) vs. 62.6% 95%CI(58.8-66.4) on vaccinated, with OR 0.929 95%CI(0.777-1.110) and AdjOR 0.981 95%CI(0.807-1.192), p > 0.05.Those patients having received only one dose or two doses by the time of ET, showed comparable results, on both CPR and SIR.Concerning data categorized per time quartiles (from vaccine to ET), while CPR was comparable, SIR, on the first quartile (Q1) was 66.5%, while Q2 was 68.0%, Q3 66.3%, and Q4 50.4%, and using Q1 as reference, ORQ2-Q1 1.073 95%CI(0.680-1.693), ORQ3-Q1 0.869 95%CI(0.545-1.385) and OR Q4-Q1 0.512 95%CI(0.321-0.818), p = 0.009 while after adjustment AdjORQ2-Q1 0.965 95%CI(0.585-1.594), AdjORQ3-Q1 0.834 95%CI(0.492-1.413) and AdjORQ4-Q1 0.533 95%CI(0.316-0.899), p = 0.018.Limitations, reasons for cautionThis is a retrospective study, and although controlled statistically, possible biases due to the nature of the work remain possible, and a cause-effect link cannot be purely drawn from it. Further prospective studies on the potential effect of covid vaccines on reproductive outcomes are still needed.Wider implications of the findingsOur results send a message of reassurance to patients in the process of assisted reproductive treatment regarding the potential negative impact of the vaccine on endometrial receptivity and reproductive outcomes. Aiming motherhood is no reason for delaying vaccination against covid-19.Trial registration numberNot applicable

COVID-19 mRNA vaccines have no effect on endometrial receptivity after euploid embryo transfer

Research questionDoes the COVID-19 vaccination affect endometrial receptivity after single euploid embryo transfer, measured by sustained implantation rate? DesignA retrospective cohort study analysing two groups of single euploid embryo transfers using own oocytes: one historical cohort of 3272 transfers 1 year before the pandemic; and one comprising 890 transfers in women previously vaccinated with mRNA vaccines against severe acute respiratory syndrome coronavirus 2. The main outcomes were clinical pregnancy rate (CPR) and sustained implantation rate (SIR) per embryo transfer. These outcomes were compared between non-vaccinated and vaccinated women, and women who had received one and two doses. Lastly, vaccinated women were divided into quartiles according to the time from last dose to embryo transfer. ResultsSimilar CPR and SIR were found between non-vaccinated and vaccinated women, and the odds ratio for both outcomes was not statistically significant after being controlled for potential confounders (OR 0.937, 95% CI 0.695 to 1.265 and OR 0.910, 95% CI 0.648 to 1.227 respectively). Within the vaccinated group, women who had received one or two doses also had similar outcomes. In addition, no differences were found according to the time interval from vaccination to embryo transfer. ConclusionThe administration of mRNA vaccines against COVID-19 had no effect on endometrial receptivity and embryo implantation, regardless of the number of doses and time interval from vaccination to embryo transfer. The potential negative effect of the vaccine on endometrial receptivity and reproductive outcomes is reassuring for patients in the process of undergoing assisted reproductive treatment.

EXPOSURE OF OVARIES TO COVID-19 VACCINATION DOES NOT IMPAIR FERTILITY

Misinformation regarding Covid vaccination has contributed to vaccine hesitancy. Initially, there were claims that immune cross reactivity between the SARS CoV-2 spike protein and syncytin-1 would prevent embryo implantation. We previously demonstrated no difference in implantation and sustained implantation rates between previously vaccinated or infected women compared to other women.1 More recently, misinterpretation of vaccine biodistribution data has led to a second claim that mRNA containing lipid nanoparticles are concentrated in the ovaries and spike protein produced there would also cause infertility. The purpose of this study is to determine whether prior in vivo ovarian exposure to lipid nanoparticle-mRNA vaccination against SARS-CoV2 spike protein reduces subsequent fertility in women. This is an ongoing observational study of women undergoing frozen embryo transfer with a single expanded blastocyst. This is an interim report (n =128) encompassing transfers between Jan 1 and Jul 02. All patients had serum analyzed prior to starting stimulation for egg retrieval to quantitatively determine the level of Anti-SARS-CoV-2 Spike IgG. Reactive (antibody positive) patients were questioned to determine a history of vaccination or infection. Patients were divided into three groups based on their status. Women who were vaccinated (n = 26); women who had previous infection with SARS-CoV-2 (n=11) and women without a history of either vaccination or infection (n=91). Only patients receiving the mRNA vaccines from BioNTech / Pfizer (BNT162b2) and Moderna (mRNA-1273) were analyzed. Outcome measure for the three groups were initial implantation rate (serum hCG level > 5 mIU/mL obtained 8 days after embryo transfer followed by a rising level two to three days later), sustained implantation rate (transvaginal ultrasound documented positive FHTs at two time points at least one week apart) and miscarriage rate (the difference between initial and sustained implantation rates). Baseline characteristics were analyzed using ANOVA. Chi square analysis was used to compare pregnancy rates. Tabled 1Non-reactiveVaccinationInfectionP ValueTotal transfers912611Implantation rate86.8% (n=79)84.6% (n=22)90.9% (n=10)0.19Sustained implantation rate63.7% (n=58)61.5% (n=16)54.6% (n=6)0.10Miscarriage rate23.1%23.1%36.3%0.15 Open table in a new tab Embryos produced from oocytes exposed in vivo to lipid nanoparticles containing mRNA for the SARS CoV-2 spike protein are not less likely to produce pregnancy or more likely to miscarry.

Effect of age and morphology on sustained implantation rate after euploid blastocyst transfer

Research questionWhat impact does maternal age and embryo morphology have on sustained implantation rates of euploid blastocysts? DesignThis was a retrospective analysis of sustained implantation rates of euploid blastocysts stratified by maternal age and morphology. The primary analysis included 208 embryo transfers with a total of 229 embryos transferred from January 2017 through August 2020. ResultsFor all ages the sustained implantation rates for day 5 good quality blastocysts were higher than for day 5 fair, day 5 poor and day 6 blastocysts. At a maternal age of 36 years the best-fit sustained implantation rates were 86% for day 5 good quality blastocysts, 64% for day 5 fair, 63% for day 5 poor, and 51% for all day 6 blastocysts analysed as one group. When controlling for morphology and day of biopsy, there were higher sustained implantation rates for euploid embryos of younger patients compared with older patients. The best-fit sustained implantation rates for age 33 compared to age 39 years were 86% versus 80% for day 5 good, 71% versus 62% for day 5 fair, 59% versus 55% for day 5 poor, and 81% versus 46% for all day 6. ConclusionsThere was a clinically significant higher sustained implantation rate at all ages for euploid day 5 good quality embryos compared with day 5 fair, day 5 poor and day 6 embryos.

The Appraisal of Body Content (ABC) trial: Increased male or female adiposity does not significantly impact in vitro fertilization laboratory or clinical outcomes

To investigate the impact of obesity as determined by bioelectric impedance analysis (BIA) and body mass index (BMI) on invitro fertilization (IVF) laboratory and clinical outcomes. Prospective cohort study. Academic-affiliated private practice. A total of 1,889 infertile couples undergoing IVF from June 2016 to January2019. Female patients and male partners underwent BIA and BMI measurement at the time of oocyte retrieval. Embryology and clinical outcomes were prospectively tracked with comparison groups determined by percentage of body fat (%BF) and BMI categories. Fertilization rate, blastocyst formation rate, euploidy rate, miscarriage rate, sustained implantation rate, live birth rate, rates of low birth weight/very low birth weight, prematurity rates. Fertilization rates and euploidy rates were equivalent among all women. Blastocyst formation rates were slightly higher (55%) in women with an obese %BF compared with all other %BF categories (51%); however, this trend was not noted in women defined as obese by BMI. Miscarriage rates, sustained implantation rates, and live birth rates were equivalent among all women. The rate of very low birth weight was low but increased in obese women (3%) versus underweight, normal-weight, and overweight counterparts (0%-1.3%) as determined by %BF and BMI. Obesity in men did not significantly affect any embryologic or clinical outcomes. Although maternal obesity imposes a small but increased risk of very low birth weight infants, most embryology and pregnancy outcomes are equivalent to normal weight patients. Paternal obesity does not appear to affect IVF, pregnancy, or delivery outcomes.

Rate of true recurrent implantation failure is low: results of three successive frozen euploid single embryo transfers

To study the true prevalence of recurrent implantation failure. Retrospective cohort study. A private assisted reproductive technology center. Women (n = 4,429) with anatomically normal uterus who underwent up to three consecutive frozen euploid single embryo transfers (FE-SETs) were included in the study. Cycles with donor eggs or gestational carriers were excluded. None. Cumulative outcomes from these cycles were analyzed. A logistic regression model was used to assess the differences of outcomes between first, second, and third FE-SET and a Kaplan-Meier curve as used to analyze cumulative implantation rate. The mean age of the patients included in the study was of 35.4 years. The sustained implantation rates of the first, second, and third FE-SET were 69.9%, 59.8%, and 60.3% per transfer, respectively. The cumulative sustained implantation rate after up to three consecutive FE-SET was 95.2%. The live birth rates after the first, second, and third FE-SET were 64.8%, 54.4%, and 54.1% per transfer, respectively. The cumulative live birth rate after up to three consecutive FE-SET was 92.6%. The miscarriage rate after observing a positive heartbeat was not different between the first (7.2%), second (8.8%), and third (12.7%) FE-SET. Our findings suggest that true recurrent implantation failure is rare. For those patients with the ability to make euploid blastocysts, <5% would fail to achieve a clinical pregnancy with three embryos transferred. It remains to be further investigated whether this threshold identifies a truly recalcitrant group or simply a statistical certainty based on random variation.

Embryo’s Natural Motion (enMotion): a paired randomized controlled trial evaluating a dynamic embryo culture system

To determine if a dynamic embryo culture system affects the reproductive potential of human embryos resulting from invitro fertilization (IVF). Paired randomized controlled trial (RCT). IVF center. IVF patients with normal ovarian reserve eligible for two-embryo transfer. IVF care was routine until fertilization was confirmed. Two-pronuclear embryos (2PNs) were then randomized: One-half of each patient's 2PNs were cultured in dynamic culture and one-half in static culture. Preimplantation genetic testing for embryonic aneuploidy was used to control for aneuploidy and allow for DNA fingerprinting. The best euploid blastocyst from each culture system was selected and patients underwent a frozen two-embryo transfer. If a singleton gestation resulted, DNA-fingerprinting was used to determine which of the two blastocysts implanted. The dynamic platform used was the NSSB-300 (Nepagene). The primary outcome was the proportion of usable blastocysts obtained. The secondary outcome was sustained implantation rate (SIR). One hundred participants completed oocyte retrieval and blastocyst vitrification for frozen-thawed embryo transfer; 609 dynamic 2PNs and 615 static 2PNs were followed; and 304 blastocysts developed in dynamic culture and 333 blastocysts developed in static culture. In the paired analysis, the rate of usable blastulation was similar between dynamic and static culture (58.3% vs. 57.1%). In addition, there was no difference in the rate of aneuploidy (20.0% vs. 33.3%) or SIR (67.1% vs. 63.1%) between groups. In this paired RCT, dynamic culture did not improve usable blastulation rate or SIR. NCT02467725.

Erratum. Worth the wait? Day 7 blastocysts have lower euploidy rates but similar sustained implantation rates as Day 5 and Day 6 blastocysts.

STUDY QUESTION Does the reproductive potential of embryos change when blastocyst development takes longer than the traditionally accepted 5 days when accounting for aneuploidy and endometrial-embryo asynchrony? SUMMARY ANSWER Aneuploidy increases with increasing duration of blastulation, but if blastocyst morphologic quality and endometrial-embryo asynchrony are controlled for, euploid Day 7 embryos have similar sustained implantation as compared to Days 5 and 6 euploid blastocysts. WHAT IS KNOWN ALREADY The relative contributions of diminished embryo quality versus endometrial and embryo asynchrony to poor outcomes associated with embryos cultured past Day 6 are not clear. Asynchrony can be eliminated by embryo vitrification with transfer in a subsequent month after retrieval. STUDY DESIGN, SIZE, DURATION Retrospective cohort study of patients from a single center attempting conception through ICSI and utilizing preimplantation genetic testing for aneuploidy screening (PGT-A) from January 2017 to September 2018. Cycles were excluded if they utilized surgical sperm or preimplantation genetic testing for monogenetic/single gene defects. ICSI cycle outcomes from 2586 patients were evaluated for ploidy status of embryos. PARTICIPANTS/MATERIALS, SETTING, METHODS Only patients undergoing single, euploid frozen embryo transfer were included when analyzing cycle outcomes by day of blastocyst expansion of the transferred embryo (n = 2130). Ploidy rates by the day upon which an embryo was considered to be usable (denoted, 'usable blastulation day') were determined so as to assess the contribution of aneuploidy to slow embryo development. Outcomes of euploid frozen single embryo transfers (SET) of Day 7 embryos were evaluated to assess the reproductive potential associated with embryos that were slowly developing for reasons other than aneuploidy. Analyses were adjusted by maternal age and blastocyst morphology. MAIN RESULTS AND THE ROLE OF CHANCE Overall, 67.7% (n = 3508) of usable Day 5 blastocysts were euploid, 52.1% (n = 5560) of usable Day 6 blastocysts were euploid and 43.1% (n = 229) of usable Day 7 embryos were euploid (Day 5 versus Day 6: odds ratio (OR) 0.7 (95% CI, 0.64-0.76), P < 0.001; Day 5 versus Day 7: OR 0.56 (95% CI, 0.46-0.69), P < 0.001; Day 6 versus Day 7: OR 0.81 (95% CI, 0.67-0.99), P = 0.036). Stratified by Society for Assisted Reproductive Technology maternal age groups, a reduction in the prevalence of euploidy by increasing time to embryo blastulation was still seen. The sustained implantation rate (SIR) was similar after euploid SET of Days 5 and 6 embryos (overall, 68.9% (95% CI, 66.0-71.6) and 66.8% (95% CI, 63.8-69.7), respectively; P = 0.81). SIR after euploid Day 7 SET appeared slightly lower than that of Days 5 and 6 embryos (52.6% (95% CI, 35.8-69.0); (Day 5 versus Day 7: OR, 0.67 (95% CI, 0.32-1.41), P = 0.29; Day 6 versus Day 7: OR 0.58 (95% CI, 0.28-1.2), P = 0.14)) but did not achieve statistical significance. LIMITATIONS, REASONS FOR CAUTION The primary limitation is the low number of Day 7 blastocyst transfers that limits statistical power. Additionally, the retrospective nature of this study may prevent full elucidation of potential biases with respect to culture, morphologic assessment and selection of Day 7 embryos for transfer. WIDER IMPLICATIONS OF THE FINDINGS Routine culture through Day 7 may successfully increase the pool of transferrable embryos for patients who would otherwise have no usable embryos if culture terminated on Day 6. This is particularly true for older patients (i.e. greater than 35 years of age), whose embryos take longer to blastulate and, therefore, are more susceptible to cycle cancelation. Additionally, as evidenced by an adequate overall SIR of 52.6% after euploid SET of Day 7 blastocysts, embryos developing to a usable blastocyst on Day 7 are likely within the 'window of blastulation.' STUDY FUNDING/COMPETING INTEREST(S) None.

Worth the wait? Day 7 blastocysts have lower euploidy rates but similar sustained implantation rates as Day 5 and Day 6 blastocysts

Does the reproductive potential of embryos change when blastocyst development takes longer than the traditionally accepted 5 days when accounting for aneuploidy and endometrial-embryo asynchrony? Aneuploidy increases with increasing duration of blastulation, but if blastocyst morphologic quality and endometrial-embryo asynchrony are controlled for, euploid Day 7 embryos have similar sustained implantation as compared to Days 5 and 6 euploid blastocysts. The relative contributions of diminished embryo quality versus endometrial and embryo asynchrony to poor outcomes associated with embryos cultured past Day 6 are not clear. Asynchrony can be eliminated by embryo vitrification with transfer in a subsequent month after retrieval. Retrospective cohort study of patients from a single center attempting conception through ICSI and utilizing preimplantation genetic testing for aneuploidy screening (PGT-A) from January 2017 to September 2018. Cycles were excluded if they utilized surgical sperm or preimplantation genetic testing for monogenetic/single gene defects. ICSI cycle outcomes from 2586 patients were evaluated for ploidy status of embryos. Only patients undergoing single, euploid frozen embryo transfer were included when analyzing cycle outcomes by day of blastocyst expansion of the transferred embryo (n = 2130). Ploidy rates by the day upon which an embryo was considered to be usable (denoted, 'usable blastulation day') were determined so as to assess the contribution of aneuploidy to slow embryo development. Outcomes of euploid frozen single embryo transfers (SET) of Day 7 embryos were evaluated to assess the reproductive potential associated with embryos that were slowly developing for reasons other than aneuploidy. Analyses were adjusted by maternal age and blastocyst morphology. Overall, 67.7% (n = 3508) of usable Day 5 blastocysts were euploid, 52.1% (n =5560) of usable Day 6 blastocysts were euploid and 43.1% (n =229) of usable Day 7 embryos were euploid (Day 5 versus Day 6: odds ratio (OR) 0.7 (95% CI, 0.64-0.76), P < 0.001; Day 5 versus Day 7: OR 0.56 (95% CI, 0.46-0.69), P < 0.001; Day 6 versus Day 7: OR 0.81 (95% CI, 0.67-0.99), P = 0.036). Stratified by Society for Assisted Reproductive Technology maternal age groups, a reduction in the prevalence of euploidy by increasing time to embryo blastulation was still seen. The sustained implantation rate (SIR) was similar after euploid SET of Days 5 and 6 embryos (overall, 68.9% (95% CI, 66.0-71.6) and 66.8% (95% CI, 63.8-69.7), respectively; P = 0.81). SIR after euploid Day 7 SET appeared slightly lower than that of Days 5 and 6 embryos (52.6% (95% CI, 35.8-69.0); (Day 5 versus Day 7: OR, 0.67 (95% CI, 0.32-1.41), P = 0.29; Day 6 versus Day 7: OR 0.58 (95% CI, 0.28-1.2), P = 0.14)) but did not achieve statistical significance. The primary limitation is the low number of Day 7 blastocyst transfers that limits statistical power. Additionally, the retrospective nature of this study may prevent full elucidation of potential biases with respect to culture, morphologic assessment and selection of Day 7 embryos for transfer. Routine culture through Day 7 may successfully increase the pool of transferrable embryos for patients who would otherwise have no usable embryos if culture terminated on Day 6. This is particularly true for older patients (i.e. greater than 35years of age), whose embryos take longer to blastulate and, therefore, are more susceptible to cycle cancelation. Additionally, as evidenced by an adequate overall SIR of 52.6% after euploid SET of Day 7 blastocysts, embryos developing to a usable blastocyst on Day 7 are likely within the 'window of blastulation.' None.

Inner cell mass and trophectoderm morphology impact the likelihood of achieving sustained implantation among expanded, euploid blastocysts

Preimplantation for genetic testing for aneuploidy (PGT-A) has been prospectively demonstrated to increase implantation rates over morphologic assessment alone. However, it is unclear whether morphology retains additional predictive power once an embryo is diagnosed as euploid with PGT-A. We sought to evaluate the influence of morphologic assessment by comparing pregnancy outcomes among expanded, euploid blastocysts (blasts). Retrospective cohort. All autologous IVF cycles between 2012-2016 were reviewed for inclusion. Only transfer of expanded blasts were performed during this time period (at least Grade 4 by Gardner criteria) and only single embryo transfers were included. The subjects were separated into 3 groups (good, fair, poor) based on the morphology of the inner cell mass (ICM) and trophectoderm (TE). Good quality blasts were defined as having any combination of A or B grades for both ICM and TE. Fair quality blasts were those with only 1 C grade assigned to either ICM or TE grade. Blasts with C grades in both ICM and TE were categorized as poor. The primary outcome was sustained implantation rate (SIR), defined as presence of fetal cardiac activity at 8 weeks. Logistic regression was performed to control for female age, size of the blast cohort, and day of transfer (5 or 6). Secondary outcome included pregnancy loss rate following a positive serum beta human chorionic gonadotropin (bHCG). A total of 2949 transfers were included. Blasts graded as good, fair, and poor quality demonstrated SIR of 70.5%, 56.9%, and 47.5%, respectively. Compared to the good quality cohort, and after controlling for age, cohort size, and day of transfer, the adjusted odds of sustained implantation were significantly reduced for the fair (aOR 0.56, 95% CI 0.44-0.71, p<0.001) and the poor-quality group (aOR 0.35, 95% 0.22-0.55) (p<0.001). Pregnancy loss rate was significantly lower among good quality blasts (p<0.001). Even among fully expanded, euploid blasts, ICM and TE morphology influence the likelihood of achieving a sustained implantation. The letter C grade in either or both ICM and TE is also associated with an increased risk of miscarriage. These data indicate that morphologic assessments should be considered when counseling patients on anticipated success - even among euploid blasts. This information may be particularly useful to patients who are planning to bank multiple euploid embryos to achieve their desired family size.Tabled 1Study CharacteristicsGoodFairPoorP-valueN251235780Age35.8 +/- 2.436.7 +/- 2.936.7 +/- 2.80.14AMH3.4 (2.1-5.7)2.6 (1.8-5.3)2.4 (0.9-4.1)<0.01Initial serum beta-HCG179.5 (140-202)117.4 (103-186)100.2 (93-163)<0.001% Serum Positive beta-HCG83.4% (2094/2512)79% (282/357)70% (56/80)<0.01Sustained Implantation Rate70.5% (1772/2512)56.9% (203/557)47.5% (38/80)<0.001Pregnancy Loss Rate after Positive beta-HCG15.4% (322/2094)38.9% (79/203)32.1% (18/56)<0.001 Open table in a new tab

Sustained implantation rate is not impacted by increasing fragile X premutation allele size

Fragile X (FX) premutation carrier patients are at risk for premature ovarian insufficiency (POI), which hinder the effects of IVF. Recent work demonstrated that FX associated embryology is comparable to controls. The questions that remain are 1) how many patients that present for FX PGD have at least one embryo suitable for transfer, and 2) is the sustained implantation rate (SIR) lower for embryos created from a FX premutation carrier? Retrospective Observational Study. Patients from March 2011 to April 2017 from a single IVF center who underwent PGD for FX (with concurrent qPCR-based aneuploidy screening) were included. PGD was performed by a single laboratory that utilized qPCR-based SNP genotyping for linkage analysis. This method determines which embryos inherited the FX-positive maternal chromosome, but cannot determine the size of the CGG repeat in the embryo. Patient characteristics, PGD results, and clinical outcomes including SIR (defined as presence of fetal cardiac activity at 8 weeks of pregnancy/ the number of embryos transferred) were analyzed. Embryos were considered available for transfer if they were euploid and negative for the FX affected haplotype. 28 patients had probes developed for FX PGD and underwent a total of 49 attempted IVF cycles were included. The mean patient age was 31.7±4.8 years. The average CGG repeat size was 100.3 repeats, including 1 full mutation. Due to poor response, 1 patient did not proceed; resulting in 27 patients undergoing a retrieval. 24 patients produced viable blastocysts to undergo PGD. 21 patients had 68 embryos available for transfer, with only 3 patients not producing normal blastocysts. While 4 patients are awaiting their transfer cycles, 17 patients underwent a single embryo transfer. A total of 21 embryos were transferred. 15 patients experienced a successful implantation, yielding 18 ongoing pregnancies. The median number of cycles that a patient underwent was 1.7 cycles. 12 patients only needed 1 cycle to have a successful transfer. The euploid rate per cycle was 68.9%, as expected in this young patient cohort. The SIR for a patient’s first transfer was 88.2%, and overall the SIR was 85.7%. These numbers also suggest that the SIR does not negatively correlate with an increasing maternal premutation allele size, although more patients are needed to fully investigate.Tabled 1Maternal CGG Repeat Size45-5556-7980-99≥100Number of patients who started at least one IVF cycle21286% Patients with at least one usable embryo100% (2/2)82% (9/11)100% (5/5)83% (5/6)Average sustained implantation rate (%)100% (1/1)63% (5/8)100% (4/4)100% (4/4) Open table in a new tab Nearly all patients presenting for PGD for FX were successful in achieving at least one sustained pregnancy. To our knowledge these data are the largest cohort to date of patients undergoing PGD for FX that includes clinical outcomes.

Is there a difference in sustained implantation rate (SIR) in patients who elect a gender preference versus those who select the best quality embryo for transfer when utilizing preimplantation genetic screening (PGS)?

Is there a difference in sustained implantation rate (SIR) in patients who elect a gender preference versus those who select the best quality embryo for transfer when utilizing preimplantation genetic screening (PGS)?