An investigation into the effect of potential confounding patient and treatment parameters on human embryo morphokinetics.

OBJECTIVE: To determine the effect of patient and treatment parameters on 19 embryo morphokinetic parameters using pronuclear fading as time zero. DESIGN: Single-site, retrospective cohort analysis. SETTING: Fertility treatment center. PATIENTS(S): Patients undergoing treatment between September 2014 and January 2016 (n = 639) whose embryos were cultured in the EmbryoScope for 6 days (n = 2,376). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Multiple regression analysis of body mass index; maternal age; infertility diagnosis; treatment type; suppression protocol on time to each cellular division (tn): t2, t3, t4, t5, t6, t7, t8, t9, time to start of compaction (tM), start of blastulation (tSB), full blastocyst (tB); and interval measurements: s2, s3, cc2, cc3, cc4, t9-tM, tM-tSB, and tSB-tB. Beta coefficients were analyzed to quantify any significant effects. RESULT(S): Embryos appeared to be subtly affected by patient and treatment parameters, exhibiting complex relationships between various morphokinetic parameters and specific patient and treatment factors, rather than a systemic effect. CONCLUSION(S): These findings outline the need for the consideration of confounding factors when assessing an embryo's ability to achieve implantation. Although morphokinetic parameters have been related to embryo viability, it is likely that this will vary depending on the embryo's origin.

Can embryo morphokinetic parameters predict euploid pregnancy loss?

OBJECTIVE: To use time-lapse imaging to compare embryo morphokinetic parameters between embryos resulting in euploid pregnancy loss and euploid embryos resulting in live birth. DESIGN: Retrospective cohort study. SETTING: Single academic fertility center. PATIENT(S): All euploid single embryo transfers between October 2015 and January 2018. INTERVENTION(S): Collection and analysis of baseline characteristics, cycle parameters, and outcomes. MAIN OUTCOME MEASURE(S): Embryo morphokinetic measurements assessed with time-lapse imaging for time to syngamy (TPNf), time to two cells, time to three cells, time to four cells, time to eight cells, time to morula, and time to blastocyst. RESULT(S): The study included 192 euploid single-embryo transfers. Of these, the pregnancy rate was 78% (150 of 193) and the live-birth rate was 63% (121 of 193). There were 43 transfers that did not result in pregnancy, 15 biochemical pregnancy losses, 13 clinical losses, and 121 live births. There was no statistically significant difference in age, body mass index, or number of oocytes retrieved between the groups. Unadjusted and adjusted models revealed no differences in the morphokinetics of embryos resulting in euploid miscarriage compared with those resulting in live birth. CONCLUSION(S): Embryos that resulted in a euploid miscarriage did not display evidence of abnormal morphokinetics on time-lapse imaging. Euploid pregnancy loss is likely multifactorial, including both embryo and endometrial factors. Further research is needed to identify factors that can predict and prevent euploid loss.

Consistency and objectivity of automated embryo assessments using deep neural networks.

OBJECTIVE: To evaluate the consistency and objectivity of deep neural networks in embryo scoring and making disposition decisions for biopsy and cryopreservation in comparison to grading by highly trained embryologists. DESIGN: Prospective double-blind study using retrospective data. SETTING: U.S.-based large academic fertility center. PATIENTS: Not applicable. INTERVENTION(S): Embryo images (748 recorded at 70 hours postinsemination [hpi]) and 742 at 113 hpi) were used to evaluate embryologists and neural networks in embryo grading. The performance of 10 embryologists and a neural network were also evaluated in disposition decision making using 56 embryos. MAIN OUTCOME MEASURES: Coefficients of variation (%CV) and measures of consistencies were compared. RESULTS: Embryologists exhibited a high degree of variability (%CV averages: 82.84% for 70 hpi and 44.98% for 113 hpi) in grading embryo. When selecting blastocysts for biopsy or cryopreservation, embryologists had an average consistency of 52.14% and 57.68%, respectively. The neural network outperformed the embryologists in selecting blastocysts for biopsy and cryopreservation with a consistency of 83.92%. Cronbach's α analysis revealed an α coefficient of 0.60 for the embryologists and 1.00 for the network. CONCLUSIONS: The results of our study show a high degree of interembryologist and intraembryologist variability in scoring embryos, likely due to the subjective nature of traditional morphology grading. This may ultimately lead to less precise disposition decisions and discarding of viable embryos. The application of a deep neural network, as shown in our study, can introduce improved reliability and high consistency during the process of embryo selection and disposition, potentially improving outcomes in an embryology laboratory.

A Strength, Weaknesses, Opportunities and Threats analysis on time lapse.

PURPOSE OF REVIEW: The study of embryonic development through conventional microscopy has contributed significantly to the success of IVF. However, clinical pregnancy rates per transfer remain as low as 30% according to the latest records of European society if human reproduction and society if assisted reproduction. Considering the increased need to reduce the number of multiple pregnancies, the embryologist is required to improve embryo selection methods to reduce the number of embryos transferred and identify those with the highest implantation potential. This represents a big challenge considering that applying this strategy could jeopardize the overall success rates. New strategies have been proposed including the use of time-lapse systems among others. Although this technology has been used for a decade in IVF labs controversies still exist regarding its potential to substitute conventional morphology for embryo evaluation. RECENT FINDINGS: Lately, different algorithms have been developed correlating embryo kinetics to blastocyst formation, implantation potential, chromosomal content and live birth rate. Moreover, automation and the use of artificial intelligence have recently been introduced to improve this technology. SUMMARY: The present review describes the time-lapse technology and the models available, using a Strength, Weaknesses, Opportunities and Threats analysis based on the clinical experience and published data since 2010.

Time-lapse imaging systems in IVF laboratories: a French national survey.

PURPOSE: Although the clinical value of time-lapse imaging (TLI) systems in in vitro fertilization (IVF) cycles is still debated, its prevalence worldwide seems to be expanding. The situation of TLI in the USA has been recently surveyed, but these results might not be transposable to other countries with different IVF regulation and funding such as France. This study evaluated the TLI situation in French IVF laboratories. METHODS: An anonymous online cross-sectional survey was sent by email to 210 embryologists in September and October 2017. Laboratories, demographics, TLI clinical use, purchasing plan, and embryologists' opinions were analyzed using logistic regression to calculate odds ratio. RESULTS: Of the 210 lab directors surveyed, 78 responded (37.1%), 43 (55%) working in private IVF laboratories and 35 (45%) in public hospitals. Thirty (38.5%) were TLI users. The odds of TLI possession were not statistically different according to laboratory sector or size. Most embryologists (n = 21, 70%) used TLI for unselected patients. Cost was the main reason given by non-users for not implementing TLI (n = 24, 50%). Most respondents were convinced that TLI is superior to standard morphology (n = 52, 73.2%) and that TLI improves culture conditions (n = 62, 84.9%). However, half (n = 39, 54.9%) indicated that evidence was still lacking to assert TLI clinical usefulness. CONCLUSION: The prevalence of TLI systems and embryologists' opinion in France was slightly different from the American situation. The different regulation and funding policy might account for some differences in terms of TLI use and perception.

Development by three-dimensional approaches and four-dimensional imaging: to the knowledge frontier and beyond.

Many advances have been taken on elucidating embryonic development and tissue homeostasis and repair by the use of experimental strategies that preserve the three-dimensional (3D) organization and allow quantitative analysis of images over time (four-dimensional). Ranging from the understanding about the relationship between blastomeres and the events that take place during gastrulation by the use of time-lapse imaging through 3D cultures that mimic organogenesis, the advances in this area are of critical value. The studies on embryonic development without disrupting the original architecture and the development of 3D organoid cultures pave a new avenue for unprecedented experimental advances that will positively impact the emergence of new treatments applying regenerative principles for both tissue repair and organ transplant.

Is morphokinetic analysis the answer?

Efforts aimed at improving pregnancy rates have focused on the search for additional markers of viability to supplement current criteria for embryo selection. Time-lapse technology represents a powerful tool in assisted reproduction for evaluating embryos dynamically. Whilst standard methods of embryo assessment are based on subjective morphology evaluation at discrete time points, thereby limiting the information produced for embryo selection, time-lapse recording introduces several additional morphokinetic parameters for embryo evaluation. This additional information can improve implantation rates and reproductive outcomes. This review surveys available knowledge on time-lapse imaging to provide an overview of the advantages and applications of this technology.

Morphological systems of human embryo assessment and clinical evidence.

Success rates with IVF have improved remarkably since the procedure was first established for clinical use with the first successful birth in 1978. The main goals today are to perform single-embryo transfer in order to prevent multiple pregnancies and achieve higher overall pregnancy rates. However, the ability to identify the most viable embryo in a cohort remains a challenge despite the numerous scoring systems currently in use. Clinicians still depend on developmental rate and morphological assessment using light microscopy as the first-line approach for embryo selection. Active research in the field involves developing non-invasive methods for scoring embryos and ranking them according to their ability to implant and give rise to a healthy birth. Current attention is particularly being focused on time-lapse evaluation. Available data from preliminary studies indicate that these systems are safe;prospective data now need to be collected to determine whether these methods do improve implantation rates. This review gives brief consideration to the use of morphological evaluations in assisted reproduction treatment, discusses the types of embryo scoring,digital imaging and biometric approaches currently in use and comments on future developments for embryo evaluation.

The clinical benefit and safety of current and future assisted reproductive technology.

Since the first birth by IVF was achieved in 1978, the techniques involved in assisted reproductive technology have grown at an enormous rate. However, new technology has rarely been robustly validated before clinical use and developing scientific understanding of the available techniques has done little to alter their use. Furthermore, there are inconsistencies in the available clinical studies and endpoints. The benefits of some technologies already established for routine use are currently dubious and there are clear ethical concerns with providing them to patients when their scientific basis is not clear. As the uptake of assisted reproductive technology increases and newer technologies continue to push the boundaries of science, it is important to consider the clinical benefits and safety of all assisted reproductive technologies. This review will discuss aspects of some of the more recent techniques, including sperm DNA-damage tests, intracytoplasmic morphologically selected sperm injection, amino acid and metabolomics profiling, preimplantation genetic screening and time-lapse imaging, and those that may have substantial impacts on the field of reproductive medicine in the future including artificial gametes, ovarian transplantation and gene therapy.

Time-lapse imaging of neural development: zebrafish lead the way into the fourth dimension.

Time-lapse imaging is often the only way to appreciate fully the many dynamic cell movements critical to neural development. Zebrafish possess many advantages that make them the best vertebrate model organism for live imaging of dynamic development events. This review will discuss technical considerations of time-lapse imaging experiments in zebrafish, describe selected examples of imaging studies in zebrafish that revealed new features or principles of neural development, and consider the promise and challenges of future time-lapse studies of neural development in zebrafish embryos and adults.