An analysis of the impact of embryo transfer difficulty on live birth rates, using a standardised grading system

Abstract STUDY QUESTION What is the inter-observer agreement among embryologists for decision to freeze blastocysts of borderline morphology and can it be improved with a modified grading system? SUMMARY ANSWER The inter-observer agreement among embryologists deciding whether to freeze blastocysts of marginal morphology was low and was not improved by a modified grading system. WHAT IS KNOWN ALREADY While previous research on inter-observer variability on the decision of which embryo to transfer from a cohort of blastocysts is good, the impact of grading variability regarding decision to freeze borderline blastocysts has not been investigated. Agreement for inner cell mass (ICM) and trophectoderm (TE) grade is only fair, factors which contribute to the grade that influences decision to freeze. STUDY DESIGN, SIZE, DURATION This was a prospective study involving 18 embryologists working at four different IVF clinics within a single organisation between January 2019 and July 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS All embryologists currently practicing blastocyst grading at a multi-site organisation were invited to participate. The survey was comprised of blastocyst images in three planes and asked (i) the likelihood of freezing and (ii) whether the blastocyst would be frozen based on visual assessment. Blastocysts varied by quality and were categorised as either top (n = 20), borderline (n = 60) or non-viable/degenerate quality (n = 20). A total of 1800 freeze decisions were assessed. To assess the impact of grading criteria on inter-observer agreement for decision to freeze, the survey was taken once when the embryologists used the Gardner criteria and again 6 months after transitioning to a modified Gardner criterion with four grades for ICM and TE. The fourth grade was introduced with the aim to promote higher levels of agreement for the clinical usability decision when the blastocyst was of marginal quality. MAIN RESULTS AND THE ROLE OF CHANCE The inter-observer agreement for decision to freeze was near perfect (kappa 1.0) for top and non-viable/degenerate quality blastocysts, and this was not affected by the blastocysts grading criteria used (top quality; P = 0.330 and non-viable/degenerate quality; P = 0.18). In contrast, the cohort of borderline blastocysts received a mixed freeze rate (average 52.7%) during the first survey, indicative of blastocysts that showed uncertain viability and promoting significant disagreement for decision to freeze among the embryologists (kappa 0.304). After transitioning to a modified Gardner criteria with an additional grading tier, the average freeze rate increased (64.8%; P < 0.0001); however, the inter-observer agreement for decision to freeze was unchanged (kappa 0.301). Therefore, significant disagreement for decision to freeze among embryologists is an ongoing issue not resolved by the two grading criteria assessed here. LIMITATIONS, REASONS FOR CAUTION Blastocyst assessment was performed from time-lapse images in three planes, rather than with a microscope in the laboratory. The inter-observer agreement for decision to freeze may be lower for embryologists working in different clinics with different grading protocols. WIDER IMPLICATIONS OF THE FINDINGS The decision to freeze a blastocyst with borderline morphology is a common clinical issue that has the potential to arise for any patient during blastocyst culture. Disagreement for decision to freeze these blastocysts, and therefore clinical usability in frozen embryo transfer cycles, affects consistency in patient care due to a potential impact on cumulative live birth rates, as well as financial, emotional and time costs associated with the frozen embryo transfer cycles. We demonstrate significant disagreement for decision to freeze borderline blastocysts among embryologists using the same grading scheme within a large multisite organisation, a phenomenon which was not improved with a modified grading system. Decision-making around borderline embryos is an area requiring further research, especially as studies continue to demonstrate the reduced but modest live birth rates for low quality blastocysts (Grade C). These results provide support for emerging technology for embryo assessment, such as artificial intelligence. STUDY FUNDING/COMPETING INTEREST(S) None declared. TRIAL REGISTRATION NUMBER Not applicable.

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P–237 The good, the fast and the slow: which is better? Live birth rate following single blastocyst frozen embryo transfer

Human Reproduction ◽

10.1093/humrep/deab130.236 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

P Sokol ◽

E Clu. Obradó ◽

M Sol Inarejos ◽

M Parrieg. Beltrán ◽

F Martíne. Sa. Andrés ◽

...

Keyword(s):

Logistic Regression ◽

Embryo Transfer ◽

Live Birth ◽

Embryo Quality ◽

Frozen Embryo Transfer ◽

Birth Rates ◽

Live Birth Rates ◽

Actual Effect ◽

Blastocyst Quality ◽

The Impact

Abstract Study question Are embryo quality and day of vitrification (Day 5, 6 or 7) associated with live birth rates (LBR) following single blastocyst transfer (SBT) in frozen embryo transfer cycle (FET)? Summary answer Both blastocyst quality and day of vitrification are significantly associated with LBRs, with very low LBR when poor quality embryos are frozen on day 6. What is known already Evidence suggests that chromosomal status (ploidy) is strongly associated with blastocyst morphology and good quality embryos are more likely to be euploid. Furthermore, previous studies have shown a relationship between the time that embryos need to reach blastocyst stage and their euploidy rate with slowly developing blastocysts showing higher rate of aneuploidy. Nonetheless, despite all this evidence little is known about the actual effect of the combination of blastocyst quality and day of its vitrification. The scope of this study was to quantify the actual effect of the embryo quality and day of vitrification on live birth rates following FET. Study design, size, duration Retrospective analysis of 1546 FET cycles with SBT conducted between 2017 and 2019 in the university-affiliated private clinic. The embryos used for FET were obtained from IVF/ICSI: with PGT (FET-PGT) or without PGT (FET0) or from donated oocytes (FET-DON). Participants/materials, setting, methods FET with natural, natural-modified and completely medicated cycles to prepare endometrial lining were included. Blastocysts were classified according to Spanish Association for the Study of Reproductive Biology (ASEBIR) classification, ranging from A (the highest) to D (the lowest). The impact on LBR of different subgroups, formed within FET-PGT, FET0, FET-DON groups due to different day of vitrification and blastocyst quality, was assessed, using logistic regression after adjusting for age, day of vitrification and embryo quality. Main results and the role of chance We included 1546 FET cycles. Of those, 543 (35%) corresponded to FET-PGT; 648 (42%) to FET0 and 355 (23%) to FET-DON cycles. Overall, 1051 (68%) embryos were frozen on day 5(D5), 472 (30.5%) on day 6(D6) and 23 (1.5%) on day 7(D7). As far as embryo quality was concerned, 215 (13.9%) grade A; 957 (61.9%) B; 371(24%) C and 3(0.2%) D blastocysts were transferred. LBRs were significantly different between different embryos frozen on D5 44.3%; on D6 28.8% and on D7 8.7%, p < 0.001. When blastocyst quality was considered, LBR were 48.4% for grade A; 42.5% for B; 25.1% for C and 0% for D, p < 0.001. After applying logistic regression analysis, the odds ratio (OR) for transferring D6-blastocyst was 1.08, 95% CI[0.45; 2.62] and blastocyst with grade B and C; 0.71, 95% CI[0.51; 1.00]; 0.57,95% CI[0.36; 0.88] respectively. However, after transferring D6-blastocyst graded as C, the OR was 0.33, 95% CI[0.12; 0.90]. Our predictive model showed that the impact of the embryo quality on LBR was sustained across three groups. Transfer of D5/D6 grade A blastocyst resulted in the highest, while D6-C in the lowest LBR in all the groups. In the latter case vitrification on D6 impaired additionally the outcome. Limitations, reasons for caution The study should be interpreted with caution due to its retrospective character and the assessment of blastocyst quality on the day of vitrification and not on the day its transfer. Wider implications of the findings: Our robust findings could be considered a useful tool for counselling couples who seek advice regarding their expected success rates in the setting of FET with SBT. The very low livebirth rates in low quality (C) slow developing (D6) embryos should be communicated to patients prior to planning a FET. Trial registration number Not applicable

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The impact of difficult embryo transfer on implantation, clinical pregnancy and live birth rates following single blastocyst replacement

10.26226/morressier.5912d9ead462b802923861eb ◽

2017 ◽

Author(s):

Edward Coats

Keyword(s):

Embryo Transfer ◽

Live Birth ◽

Clinical Pregnancy ◽

Birth Rates ◽

Live Birth Rates ◽

The Impact

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Assessment of the impact of asynchronous syngamy by time-lapse imaging on early human embryo development, implantation and live birth rates

10.26226/morressier.573c1511d462b80296c9836b ◽

2016 ◽

Author(s):

Shabana Sayed

Keyword(s):

Embryo Development ◽

Live Birth ◽

Human Embryo ◽

Time Lapse ◽

Birth Rates ◽

Live Birth Rates ◽

Human Embryo Development ◽

Time Lapse Imaging ◽

The Impact ◽

Early Human

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02 / Single and double embryo transfer provide similar live birth rates in frozen cycles

10.26226/morressier.5af300b3738ab10027aa9aba ◽

2018 ◽

Author(s):

Racca Annalisa ◽

Panagiotis Drakopoulos ◽

Samuel dos Santos Ribeiro ◽

Christophe Blockeel

Keyword(s):

Embryo Transfer ◽

Live Birth ◽

Birth Rates ◽

Live Birth Rates ◽

Double Embryo Transfer

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The effects of the day of trophectoderm biopsy and blastocyst grade on the clinical and neonatal outcomes of preimplantation genetic testing–frozen embryo transfer cycles

Zygote ◽

10.1017/s0967199421000435 ◽

2021 ◽

pp. 1-6

Author(s):

Linjun Chen ◽

Zhenyu Diao ◽

Jie Wang ◽

Zhipeng Xu ◽

Ningyuan Zhang ◽

...

Keyword(s):

Birth Weight ◽

Genetic Testing ◽

Embryo Transfer ◽

Live Birth ◽

Frozen Embryo Transfer ◽

Neonatal Outcomes ◽

Miscarriage Rate ◽

Birth Rates ◽

Preimplantation Genetic Testing ◽

Live Birth Rates

Summary This study analyzed the effects of the day of trophectoderm (TE) biopsy and blastocyst grade on clinical and neonatal outcomes. The results showed that the implantation and live birth rates of day 5 (D5) TE biopsy were significantly higher compared with those of D6 TE biopsy. The miscarriage rate of the former was lower than that of the latter, but there was no statistically significant difference. Higher quality blastocysts can achieve better implantation and live birth rates. Among good quality blastocysts, the implantation and live birth rates of D5 and D6 TE biopsy were not significantly different. Among fair quality and poor quality blastocysts, the implantation and live birth rates of D5 TE biopsy were significantly higher compared with those of D6 TE biopsy. Neither blastocyst grade nor the day of TE biopsy significantly affected the miscarriage rate. Neonatal outcomes, including newborn sex, gestational age, preterm birth, birth weight and low birth weight in the D5 and D6 TE biopsies were not significantly different. Both blastocyst grade and the day of TE biopsy must be considered at the same time when performing preimplantation genetic testing–frozen embryo transfer.

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Sperm Selection by Magnetic-Activated Cell Sorting Before Microinjection of Autologous Oocytes Increases Cumulative Live Birth Rates with Limited Clinical Impact: A Retrospective Study in Unselected Males

Biology ◽

10.3390/biology10050430 ◽

2021 ◽

Vol 10 (5) ◽

pp. 430

Author(s):

María Gil Juliá ◽

Irene Hervás ◽

Ana Navarro-Gómez Lechón ◽

Fernando Quintana ◽

David Amorós ◽

...

Keyword(s):

Live Birth ◽

Clinical Impact ◽

Sperm Selection ◽

Reproductive Outcomes ◽

Birth Rates ◽

Multicenter Observational Study ◽

Live Birth Rates ◽

Cumulative Live Birth ◽

The Impact ◽

Autologous Oocytes

The application of MACS non-apoptotic sperm selection in infertility clinics is controversial since the published literature does not agree on its effect on reproductive outcomes. Therefore, it is not part of the routine clinical practice. Classical measures of reproductive success (pregnancy or live birth rates per ovarian stimulation) introduce a bias in the evaluation of a technique’s effect, since only the best embryo is transferred. This retrospective, multicenter, observational study evaluated the impact of MACS on reproductive outcomes, measuring results in classical parameters and cumulative live birth rates (CLBR). Data from ICSI cycles using autologous oocyte in Spanish IVIRMA fertility clinics from January 2008 to February 2020 were divided into two groups according to their semen processing: standard practice (reference: 46,807 patients) versus an added MACS sperm selection (1779 patients). Only when measured as CLBR per embryo transferred and per MII oocyte used was the difference between groups statistically significant. There were no significant differences between MACS and reference groups on pregnancy and live birth rates. In conclusion, results suggest that non-apoptotic sperm selection by MACS on unselected males prior to ICSI with autologous oocytes has limited clinical impact, showing a subtle increase in CLBR per embryo transferred.

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P–590 Women with hypothalamic hypogonadism have lower live birth rates following frozen embryo transfer

Human Reproduction ◽

10.1093/humrep/deab130.589 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

R Heidenberg ◽

A Lanes ◽

E Ginsburg ◽

C Gordon

Keyword(s):

Embryo Transfer ◽

Live Birth ◽

Polycystic Ovary ◽

Frozen Embryo Transfer ◽

Fresh Embryo Transfer ◽

Ovary Syndrome ◽

Birth Rates ◽

Live Birth Rates ◽

Tubal Factor Infertility ◽

Tubal Factor

Abstract Study question How do live birth rates differ in anovulatory women with polycystic ovary syndrome and hypothalamic hypogonadism compared to normo-ovulatory women undergoing fresh or frozen embryo transfer? Summary answer Live birth rates are similar among all groups undergoing fresh embryo transfer but are significantly lower in women with hypothalamic hypogonadism undergoing frozen embryo transfer. What is known already Conflicting data exist regarding pregnancy outcomes in patients with tubal factor infertility versus polycystic ovary syndrome (PCOS). Some studies demonstrate higher pregnancy and live birth rates for women with PCOS undergoing fresh embryo transfer, but other studies demonstrate no difference. Women with PCOS have higher live birth rates than those with tubal factor infertility when undergoing frozen embryo transfer. Fewer data are available regarding IVF outcomes in women with hypothalamic hypogonadism (HH) and tubal factor infertility. Several studies report comparable live birth rates with fresh embryo transfer, but there are no data on frozen embryo transfer outcomes. Study design, size, duration Retrospective cohort study of all fresh and frozen autologous embryo transfers performed for patients with oligo-anovulation (PCOS, n = 380 and HH, n = 39) and normo-ovulation (tubal factor infertility, n = 315) from 1/1/2012 to 6/30/2019. A total of 734 transfers from 653 patients were analyzed. Participants/materials, setting, methods Transfer outcomes, including implantation, miscarriage, clinical pregnancy and live birth rates, were assessed in fresh and frozen embryo transfer cycles. Adjusted relative risks (RR) and 95% confidence intervals (CI) were calculated adjusting for age, BMI, stimulation protocol, number of embryos transferred, embryo quality, endometrial stripe thickness and day of transfer. Poisson regression was used for counts and with an offset for ratios. Generalized estimating equations were used to account for patients contributing multiple cycles. Main results and the role of chance For fresh embryo transfer cycles, live birth rates are similar among patients with tubal factor infertility, PCOS and HH (29.5% vs. 37.9% vs. 35.9%, respectively, aRR 1.15 95% CI: 0.91–1.44 and aRR 1.23 95% CI: 0.81–2.00, respectively). When evaluating frozen embryo transfer cycles, patients with HH have lower live birth rates than patients with tubal factor infertility (26.5% vs. 42.6%, aRR 0.54 95% CI: 0.33–0.88) and patients with PCOS (26.5% vs. 46.7%, aRR 0.55 95% CI: 0.34–0.88). Additionally, patients with HH have higher chemical pregnancy rates and miscarriage rates than patients with tubal factor infertility (26.5% vs. 13.0% and 17.7% vs. 6.5%, respectively, RR 2.71 95% CI: 1.27–5.77 and RR 2.03 95% CI: 1.05–3.80, respectively). Point biserial correlation showed no significant correlation between live birth and endometrial stripe thickness in HH patients undergoing frozen embryo transfer (r = 0.028, p-value 0.876). Limitations, reasons for caution This study is limited by its retrospective nature and the small sample size of women with hypothalamic hypogonadism. Additionally, these data represent outcomes from a single academic center, so generalizability of our findings may be limited. Wider implications of the findings: Lower live birth rates for HH patients undergoing frozen embryo transfer cycles are not correlated with endometrial stripe thickness. This may be due to absent gonadotropin signaling on endometrial receptors. A prospective randomized trial of HH patients to modified natural versus programmed frozen embryo transfer would best support this hypothesis. Trial registration number Not applicable

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P–513 Analysis of the extent of dropout-rates by extraction from cumulative live birth rates in IVF/ICSI: systematic review and meta-analysis

Human Reproduction ◽

10.1093/humrep/deab130.512 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

S Vereeck ◽

A Sugihara ◽

D D Neubourg

Keyword(s):

Embryo Transfer ◽

Live Birth ◽

Weighted Average ◽

Dropout Rate ◽

Dropout Rates ◽

Birth Rates ◽

Complete Cycle ◽

Live Birth Rates ◽

Cumulative Live Birth ◽

Icsi Cycle

Abstract Study question The purpose of this systematic review is to calculate dropout-rates of IVF/ICSI treatment by analysing the published cumulative live birth rates of IVF/ICSI treatment. Summary answer One out of three patients stop their treatment after their first IVF/ICSI cycle and dropout-rates tend to increase per consecutive cycle. What is known already Cumulative live birth rates (CLBRs) have created the possibility to present realistic probabilities of having a live birth after IVF/ICSI treatment. However, it is noted that a significant percentage of the patients stop their treatment before having a child (“dropout”). Possible reasons and predicting factors for dropout of treatment are already extensively investigated. However, only a few studies try to report about the incidence of dropout. Publications on CLBRs of large numbers of patients allow the extraction of dropout-rates. These rates will provide insight in the extent of the problem and could be used as a reference for interventional studies. Study design, size, duration Four databases (PubMed, The Cochrane Library, EMBASE, DoKS) were systematically searched from 1992 to December 2020. Search terms referred to “cumulative live birth” AND “ART/IVF/ICSI”. No restrictions were made on the type or language of publication. Studies were included if they reported absolute numbers of patients and live births per consecutive complete IVF/ICSI cycle or per consecutive embryo transfer cycle, starting from the first IVF/ICSI cycle for each patient. Participants/materials, setting, methods Dropout-rates per cycle were calculated in two manners: “intrinsic dropout-rate” with all patients that started the particular IVF/ICSI cycle in the denominator, and “potential dropout-rate” with all patients who did not achieve a live birth after IVF/ICSI (and potentially could have started a consecutive cycle) in the denominator. Dropout-rates were analysed for consecutive complete cycles and consecutive embryo transfer cycles, because these two manners are used in reporting CLBRs, often related to the reimbursement policy. Main results and the role of chance This review included 29 studies and almost 800,000 patients from different countries and registries. Regarding the patients who started their first IVF/ICSI cycle, trying to conceive their first child by IVF/ICSI, intrinsic dropout-rate was 33% (weighted average) after the first complete cycle, meaning they did not return for their second oocyte retrieval cycle. After the first embryo transfer cycle, intrinsic dropout-rate was 27% (weighted average), meaning those patients did not return for their next frozen-thawed embryo transfer cycle or for the next oocyte retrieval cycle. Regarding the patients who did not achieve a live birth after the first complete cycle, potential dropout-rate was 48% (weighted average), and 37% (weighted average) after the first embryo transfer cycle. Both potential and intrinsic dropout-rates for both consecutive complete and embryo transfer cycles tended to increase with cycle number. One study on second IVF/ICSI conceived children showed a potential dropout-rate after the first complete cycle of 29%. From studies on women >40 years of age, the potential dropout-rate after the first complete cycle was 45% (weighted average) and from studies with the uses of testicular sperm extraction, the potential dropout-rate after the first complete cycle was 34% (weighted average). Limitations, reasons for caution Our analysis was hampered by the different ways of reporting on CLBRs (complete cycles versus embryo transfer cycles), informative censoring, patients changing clinics and spontaneous pregnancies. Dropout-rates were potentially overestimated given that spontaneous pregnancies were not taken into account. Wider implications of the findings: The extent of dropout in IVF/ICSI treatment is substantial and has an important impact on its effectiveness. Therefore, it is a challenge for fertility centers to try to keep patients longer on board, by taking into account the patients’ preferences and managing their expectations. Trial registration number PROSPERO Registration number: CRD42020223512

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