P–164 Mulitcentre derived time lapse algorithms developed using 6228 transferred embryos with known birth outcome incorporating novel morphological and morphokinetic markers

Abstract Study question Can incorporation of novel markers of morphology with known temporal events successfully rank embryos to enable prediction of propensity for live birth? Summary answer Incorporation of variables for trophectoderm and morula grading demonstrably enhanced the model to rank embryos in order of potential for live birth. What is known already Models built using morphokinetic markers of development are widely used to rank embryos within a cohort. Such models include defined temporal parameters which are closely related to morphological grade. However, morphological grading by an embryologist is subjective and is not strongly correlated to outcome. Combining with defined kinetic events has been suggested to improve prediction of outcome. Study design, size, duration Data from 6228 known live birth outcome embryos from 8 UK clinics between 2011 – 2018 were investigated using an exploratory approach to identify novel markers of development. Participants/materials, setting, methods Five significant variables were defined, a derivative of time to start of blastulation; a derivative of trophectoderm grade; a kinetic variable utilising t3, t4, t5 and t8; an interval variable of tB-tSB and a variable based on novel morula classification. To maximise the output, a proxy value was derived for missing datapoints. The model was built using logistical regression and validated using fivefold cross validation with the data split as 80% training and 20% test. Main results and the role of chance An algorithm was developed including the five significant variables identified with an AUC of 0.685 demonstrating reliable prediction of live birth. Without morphological variables, the AUC was 0.674 demonstrating the improvement in the prediction value by including the derivative of the trophectoderm and morula grade. This resulted in ten classes of algorithm scores, 1–10, giving a live birth rate from 2% to 46%, irrespective of patient variables, for chance of live birth. Limitations, reasons for caution Successful application of the algorithm is reliant on stringent quality assurance for maintenance of accurate annotation and grading, and may not be transferable between laboratories with different SOPs. Wider implications of the findings: The addition of a trophectoderm and morula grade in combination with morphokinetic parameters, increases the predictive value of the algorithm in relation to live birth outcome. Using proxy values allows maximization of data for model generation, and allows the model to be applied when missing values are present. Trial registration number Not applicable

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Impact of time-lapse and reduced oxygen culture on live birth rate and its correlation with infertility diagnosis

Fertility and Sterility ◽

10.1016/j.fertnstert.2015.07.294 ◽

2015 ◽

Vol 104 (3) ◽

pp. e95 ◽

Cited By ~ 1

Author(s):

N. Zaninovic ◽

Q. Zhan ◽

R. Clarke ◽

Z. Ye ◽

N. Pereira ◽

...

Keyword(s):

Live Birth ◽

Birth Rate ◽

Live Birth Rate ◽

Time Lapse

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Embryo incubation and assessment by time-lapse system versus conventional incubators in Chinese women with diminished ovarian re serve undergoing IVF/ICSI : a study protocol for a randomized controlled trial

10.21203/rs.2.24758/v1 ◽

2020 ◽

Author(s):

Miaoxin Chen ◽

Yuanyuan Wu ◽

Xin Huang ◽

Wentao Li ◽

Chunyan Sun ◽

...

Keyword(s):

Clinical Trial ◽

Live Birth ◽

Embryo Culture ◽

Birth Rate ◽

Live Birth Rate ◽

Time Lapse ◽

Absolute Difference ◽

Cumulative Live Birth Rate ◽

Randomized Controlled ◽

Cumulative Live Birth

Abstract Background: Time-lapse imaging system (TLS) is a newly developed non-invasive embryo assessment system. Compared with conventional incubators, it provides stable culture condition and consistent observation of embryo development, thereby improving embryo quality and selection. In theory, these benefits could improve clinical outcomes of in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). Although this system has been routinely used in many IVF centers globally, it remains unclear if the TLS results in higher cumulative live birth rate and high-quality evidence is warranted. The purpose of this study is to compare the effectiveness of the TLS with conventional incubators in infertile diminished ovarian reserve (DOR) patients. Methods: This study is a double-blind randomized controlled clinical trial (1:1 treatment ratio of TLS vs. conventional incubator). A total of 730 DOR patients undergoing the first or second cycle of IVF or ICSI will be enrolled and randomized into two parallel groups. Participants in group A will undergo embryo culture and selection in the TLS, and participants in group B will undergo embryo culture in the conventional incubators and embryo selection by the morphological characteristics. The primary outcome is the cumulative live birth rate of the trial IVF/ICSI cycle within 12 months after randomization. This study is powered to detect an absolute difference of 10% (35% vs 25%) at the significance level of 0.05 and 80% statistical power based on a two-sided test. Discussion: The results of this study will provide evidence for the efficacy and safety of time-lapse system compared with conventional incubators in patients with DOR undergoing IVF/ICSI. Trial registration: Chinese Clinical Trial Registry, ChiCTR1900027746. Registered on 24 Nov 2019.

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Impact of time-lapse imaging incubators with single-step culture medium on cumulative live birth rate in IVF cycles: a retrospective cohort study

10.22541/au.162048004.43720005/v1 ◽

2021 ◽

Author(s):

Mariano Mascarenhas ◽

Sarah J Owen ◽

Emily French ◽

Karen Thompson ◽

Adam H Balen

Keyword(s):

Live Birth ◽

Retrospective Cohort ◽

Birth Rate ◽

Culture Medium ◽

Live Birth Rate ◽

Time Lapse ◽

Single Step ◽

Cumulative Live Birth Rate ◽

Cumulative Live Birth ◽

Time Lapse Imaging

Objective To compare the cumulative live birth rate per egg retrieval between time lapse imaging (TLI) incubators and standard culture (SC) incubators both using a single-step culture medium Design Retrospective cohort study Setting A tertiary level fertility-centre Population Women undergoing an IVF cycle between November 2015 and December 2017 Methods Comparison was done between 1219 IVF cycles using TLI and 1039 cycles using SC after accounting for confounding factors such as age and number of oocytes retrieved. Main outcome measure Cumulative live birth rate per egg retrieval Results The live birth rate per egg retrieval following fresh embryo transfer was noted to be higher for TLI cycles (TLI 39.87% vs SC 38.02%, aOR 1.20, 95% CI 1.01 to 1.44). More embryos were available for cryopreservation in the TLI arm (MD 0.08 embryos, 95% CI 0.10 to 0.41). The live birth rate per frozen embryo transfer was not significantly different. The cumulative live birth rate per egg retrieval was significantly higher in the TLI arm (TLI 50.29% vs SC 46.78%, aOR 1.24, 95% CI 1.04 to 1.48) Conclusions With the use of single step medium, there appears to be a greater benefit of TLI through a reduced interruption in embryo culture conditions, resulting in a higher number of embryos available for cryostorage which in turn appears to improve the cumulative live birth rate. Funding No funding was obtained for this study Keywords Time lapse imaging, cumulative live birth rate, single step culture medium, embryo utilization rate

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O-219 Detailed morpho-kinetic analysis of the first cleavage can help in evaluating the viability of direct-cleaved human zygotes

Human Reproduction ◽

10.1093/humrep/deab128.043 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

T Shimura ◽

K Yumoto ◽

M Sugishima ◽

Y Mio

Keyword(s):

Live Birth ◽

Birth Rate ◽

Live Birth Rate ◽

Time Lapse ◽

Cell Group ◽

Group 3 ◽

Group 2 ◽

Time Lapse Imaging ◽

Human Zygotes ◽

Group 1

Abstract Study question Why do some direct-cleaved human zygotes still lead to a live birth? Summary answer Direct-cleaved zygotes which have undergone the 2-cell stage can lead to a live birth, while zygotes cleaved from 1-cell to ≥ 3-cell do not. What is known already In recent years, zygotes that develop from 2-cell to 3-cell within 5 hours after the first cleavage have been evaluated as “direct-cleaved” zygotes, because normal cleavage takes approximately 12 hours to complete. It was reported that their implantation rate was significantly lower than zygotes with normal cleavage pattern, and eliminating direct-cleaved zygotes from transfer could improve the implantation rate. However, some direct-cleaved zygotes at the first cleavage could still lead to a live birth. Few reports have examined the difference between a cleavage from 1-cell to ≥ 3-cell and 2-cell to ≥ 3-cell within 5 hours after the first cleavage. Study design, size, duration A retrospective study involving 2,077 cycles of IVF/ICSI between July 2012 and July 2019. A total of 5,991 normally fertilized zygotes (2PN/2PB) were included. Of those, 3,508 were evaluated as usable good/fair quality embryos on Day2/3, and the rest (n = 2,483) were evaluated as poor quality and rejected from transfer or cryopreservation after 7 days of culture. Of 3,508 usable embryos, 884 were selected based on the availability of results of live birth for this study. Participants/materials, setting, methods Time-lapse imaging (5 slices along Z-axis every 10 minutes) was performed in EmbryoScopeTM. Zygotes were morphokinetically analyzed in detail and classified into four groups by their cleavage patterns: Group1 (1-cell→2-cell); Group 2 (1-cell→3-cell); Group 3 (1-cell→2-cell→≥3-cell within 5 hours after the first cleavage); and Group 4 (1-cell→2-cell→≥5-cell). The proportion, mean maternal age and live birth rate of each group were examined. Main results and the role of chance The proportion of Groups 1-4 was 83.6% (n = 739), 3.8% (n = 34), 5.9% (n = 52), and 6.7% (n = 59), respectively. 0f 884 zygotes examined in this study, the mean maternal age was significantly higher in Group 2 and 4 than in Group 1 (P < 0.05; 37.4±4.9 in Group1, 39.1±5.2 in Group 2, 38.6±6.0 in Group 3, and 38.7±5.1 in Group 4). The rate of confirmed gestational sac was significantly lower in Group 2 and 4 than in Group 1 [P < 0.01; 36.3% (n = 268/739), 0% (n = 0/34), 25.0% (n = 13/52), and 18.6% (n = 11/59) in Groups 1-4, respectively]. Furthermore, the live birth rate was significantly higher in Group 1 than in Groups 2, 3 and 4 [P < 0.01; 28.4% (n = 210/739), 0% (n = 0/34), 13.5% (n = 7/52), and 15.3% (n = 9/59) in Groups 1-4, respectively]. Above all, while zygotes in Group 2 showed no pregnancy and live birth at all, zygotes in Group 3 showed a live birth rate of 13.5%. However, they had a significantly higher miscarriage rate (42.9%, n = 6) compared to zygotes in Group 1 (19.5%, n = 55). Limitations, reasons for caution It is very difficult to capture cleavage patterns by routine observations because the timings of developmental events are different between embryos. A time-lapse imaging and culturing system is essential to solve this problem, however, it cannot visualize the distribution of chromosomes, and no chromosomal analysis was conducted in this study. Wider implications of the findings This study revealed that zygotes previously classified as “direct-cleaved” and eliminated from transfer included viable zygotes which could lead to a live birth. Therefore, it is crucial to optimize the use of time-lapse imaging of human zygotes in order to precisely evaluate the first cleavage. Trial registration number not applicable

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Early embryo morphokinetics is a better predictor of post-ICSI live birth than embryo morphology: speed is more important than beauty at the cleavage stage

Zygote ◽

10.1017/s0967199421000253 ◽

2021 ◽

pp. 1-8

Author(s):

Alessandro Bartolacci ◽

Mariabeatrice Dal Canto ◽

Maria Cristina Guglielmo ◽

Laura Mura ◽

Claudio Brigante ◽

...

Keyword(s):

Multivariate Analysis ◽

Live Birth ◽

Live Birth Rate ◽

Roc Curves ◽

Time Lapse ◽

Early Embryo ◽

Developmental Competence ◽

Embryo Morphology ◽

Roc Curve Analysis ◽

Morphokinetic Parameters

Abstract Given the importance of embryo developmental competence assessment in reproductive medicine and biology, the aim of this study was to compare the performance of fertilization and cleavage morphokinetics with embryo morphology to predict post-ICSI live birth. Data from embryos cultured in a time-lapse microscopy (TLM) incubator and with known live birth outcomes (LB: embryos achieving live birth, n = 168; NLB: embryos not achieving live birth, n = 1633) were used to generate receiver operating characteristic (ROC) curves based on morphokinetic or morphological scores, and the respective areas under the curve (AUC) were compared. The association between live birth and 12 combinations of four morphokinetic quality degrees (A–D) with three morphological quality degrees (A–C) was assessed using multivariate analysis. Morphokinetic parameters from tPNa to t8 were reached earlier in LB compared with NLB embryos. The ROC curve analysis indicated that morphokinetic information is more accurate than conventional morphology to predict live birth [AUC = 0.64 (95% CI 0.58–0.70) versus AUC = 0.58 (95% CI 0.51–0.65)]. The multivariate analysis was in line with AUCs, revealing that embryos with poor morphokinetics, independently of their morphology, provide lower live birth rates (P < 0.001). A considerable percentage of embryos with top morphology presented poor morphokinetics (20.10%), accompanied by a severely reduced live birth rate in comparison with embryos with top morphology and morphokinetics (P < 0.001). In conclusion, TLM-derived early morphokinetic parameters were more predictive of live-birth achievement following ICSI than conventional morphology.

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Perturbations of morphogenesis at the compaction stage affect blastocyst implantation and live birth rates

Human Reproduction ◽

10.1093/humrep/deab011 ◽

2021 ◽

Author(s):

Giovanni Coticchio ◽

Kenji Ezoe ◽

Cristina Lagalla ◽

Kiyoe Shimazaki ◽

Kazuki Ohata ◽

...

Keyword(s):

Clinical Outcomes ◽

Live Birth ◽

Birth Rate ◽

Live Birth Rate ◽

Time Lapse ◽

Ongoing Pregnancy ◽

Blastocyst Development ◽

Live Birth Rates ◽

Morphokinetic Parameters ◽

Morula Stage

Abstract STUDY QUESTION Do perturbations of embryo morphogenesis at compaction affect blastocyst development and clinical outcomes in assisted reproduction cycles? SUMMARY ANSWER Cell exclusion and extrusion, i.e. cell disposal occurring respectively before or during morula compaction, affect blastocyst yield and quality, as well as rates of pregnancy and live birth. WHAT IS KNOWN ALREADY Despite its pivotal role in morphogenesis for blastocyst organisation and cell fate determination, compaction at the morula stage has received little attention in clinical embryology. Time lapse technology (TLT) allows detailed morphokinetic analysis of this developmental stage. However, even in the vast majority of previous TLT studies, compaction was investigated without a specific focus. Recently, we reported that compaction may be affected by two clearly-distinct patterns of cell disposal, exclusion and extrusion, occurring prior to and during compaction, respectively. However, the crucial question of the specific relevance of partial compaction for embryo development and competence in ART has remained unanswered until now. STUDY DESIGN, SIZE, DURATION This study involved the assessment of laboratory and clinical outcomes of 2,059 morula stage embryos associated with 1,117 ICSI patients, who were treated with minimal stimulation and single vitrified-warmed blastocyst transfer (SVBT) from April 2017 to March 2018. Patterns of morula compaction were assessed and analyzed in relation to embryonic and clinical outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS Following ICSI, time-lapse videos were analysed to annotate morphokinetic parameters relevant to both pre- and post-compaction stages. According to their morphokinetic history, morulae were classified as: (I) fully compacted morulae (FCM); (II) partially compacted morulae (PCM), showing cells (a) excluded from the compaction process from the outset (Exc-PCM), (b) extruded from an already compacted morula (Ext-PCM), or (c) showing non-compacted cells arisen from both patterns (Exc/Ext-PCM). The number of excluded/extruded cells was also annotated. Possible correlations of compaction patterns with 13 morphokinetic parameters, abnormal cleavage, blastocyst yield and morphological grade, clinical and ongoing pregnancy rates, and live birth rate were evaluated. Other factors, such as patient and cycle characteristics, possibly associated with compaction patterns and their outcomes, were investigated. MAIN RESULTS AND THE ROLE OF CHANCE Full compaction was observed in 39.0% of all embryos. However, partially compacted morulae (PCM) showing excluded (Exc-PCM), extruded (Ext-PCM) cells, or indeed both phenotypes (Exc/Ext-PCM) were frequently detected (24.8%, 16.6%, and 19.6%, respectively) and collectively (61%) exceeded fully compacted morulae. Blastomere exclusion or extrusion affected one or several cells, in different proportions. In comparison to FCM, the developmental pace of the three PCM groups, observed at 13 developmental stages starting from pronuclear fading, was progressively slower (P < 0.0001). Developmental delay at post-compaction stages was more pronounced in the group showing both patterns of partial compaction. Blastomere exclusion and/or extrusion had a large negative impact on blastocyst development. In particular, rates of blastocyst formation and cryopreservation were very low in the Ext-PCM and Exc/Ext-PCM groups (P < 0.0001). Rates of blastocysts with ICM or TE of highest quality (Grade A) were severely affected in all PCM groups (P < 0.0001). In 1,083 SVBTs, blastocysts derived from all PCM groups produced much lower clinical pregnancy, ongoing pregnancy, and live birth rates (P < 0.0001). All three patterns of partial compaction emerged as factors independently associated with live birth rate, even after multivariate logistic regression analysis including maternal/paternal age, female BMI, and number of previous embryo transfers as possible confounding factors. LIMITATIONS, REASONS FOR CAUTION The retrospective design of the study represents a general limitation. WIDER IMPLICATIONS OF THE FINDINGS This large-scale study represents a further important demonstration of embryo plasticity and above all indicates new robust morphokinetic parameters for improved algorithms of embryo selection. STUDY FUNDING/COMPETING INTEREST(S) This study was exclusively supported by the participating institutions. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER NA.

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