Can novel early non-invasive biomarkers of embryo quality be identified with time-lapse imaging to predict live birth?

Abstract

STUDY QUESTION Can time-lapse imaging systems make it possible to identify novel early non-invasive biomarkers to predict live birth? SUMMARY ANSWER From mostly high-grade embryos, out of 35 morphometric, morphologic and morphokinetic variables, only pronuclei (PN) position at time of PN juxtaposition and the absence of multinucleated blastomeres at the 2-cell stage (MNB2cell), were potentially associated with live birth. WHAT IS KNOWN ALREADY Previous studies indicate that some kinetic markers may be predictive of blastocyst development and embryonic implantation. Certain teams have suggested including some of them in decisional algorithms for embryo transfers. STUDY DESIGN, SIZE, DURATION Using a time-lapse incubator (EmbryoScope, Unisense FertiliTech), we retrospectively explored the associations between the morphometric, morphologic and morphokinetic parameters of oocytes, zygotes and embryos, and their associations with live birth. This study assessed 232 embryos from single embryo transfers after ICSI cycles performed between January 2014 and December 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS The morphometric, morphologic and morphokinetic parameters (18, 4 and 13, respectively) of oocytes, zygotes and early embryos were studied retrospectively. The associations between these parameters were examined using a Spearman’s correlation, Mann–Whitney or chi-squared test as appropriate. We examined whether these parameters were associated with outcomes in univariate and multivariate logistic regression analyses. MAIN RESULTS AND THE ROLE OF CHANCE Central PN juxtaposition was associated with a 2-fold increase in the odds of live birth (OR = 2.20; 95% CI, [1.26–3.89]; P = 0.006), while the presence of MNB2cell was associated with half the odds of live birth (OR = 0.51; 95% CI, [0.27–0.95]; P = 0.035). These two parameters were independent of embryo kinetics. The 33 remaining parameters had no significant association with the capacity of transferred embryos to develop to term. LIMITATIONS, REASONS FOR CAUTION Even though the population size was relatively small, our analyses were based on homogeneous cycles, i.e. young women whose transferred embryos were found to be high-grade according to conventional morphology evaluation. In addition, our conclusions were established from a specific, highly selected population, so other study populations, such as women in an older age bracket, may yield different results. Finally, because we assessed day 2/3 transfers, our findings cannot be generalized to embryos cultured up to the blastocyst stage. WIDER IMPLICATIONS OF THE FINDINGS It would be interesting to explore, prospectively, whether PN localisation is a relevant measure to predict embryo development when added into further algorithms and whether this parameter could be suitable for use in other IVF clinics. Further studies are needed, notably to explore the added value of timing evaluation in cohorts of embryos with low or intermediate morphology grade, as well as in other maternal populations (i.e. older women). STUDY FUNDING/COMPETING INTEREST(S) No external funding was used for this study. P. Sagot received funding from the following commercial companies: Merck Serono, Finox Biotech, Ferring, MSD France SAS, Teva Sante ́ SAS, Allergan France, Gedeon Richter France, Effik S.A., Karl Storz Endoscopie France, GE Medical Systems SCS, Laboratoires Genevrier, H.A.C. Pharma and Ipsen. All the authors confirm that none of this funding was used to support the research in this study. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the journal policies on sharing data and materials.

Scanning Probe Microscopies: Imaging and Biomechanics in Reproductive Medicine Research

“…In ARTs, trained embryologists select oocytes to fertilize or the embryo to transfer, mainly by visual inspection via bright field optical microscopy, subjecting the selection to personal interpretation. To improve this selection method, several non-invasive methodologies based on optical imaging techniques have been proposed [ 6 , 52 , 53 ]. Some of them have considered morphometric and morphokinetic parameters, but their relevance is still debated [ 52 , 53 ].…”

“…To improve this selection method, several non-invasive methodologies based on optical imaging techniques have been proposed [ 6 , 52 , 53 ]. Some of them have considered morphometric and morphokinetic parameters, but their relevance is still debated [ 52 , 53 ]. Another one, based on the detection of the mitotic spindle by polarized light microscopy, shows that visualization of the mitotic spindle can improve the prediction of oocyte quality.…”

“…Like for oocytes, there are significant efforts to improve embryo selection, and many of the optical and AI approaches proposed for oocytes are also considered valid for this choice [ 52 , 53 , 55 ]. The mechanical properties of embryos can represent a parameter helpful for identifying viable, high-quality embryos to implant.…”

Evaluating the value of day 0 of an ICSI cycle on indicating laboratory outcome

“…Numerous studies from embryo morphology to novel biomarkers have been introduced as the next holy grail in efficient embryo selection. The majority of the studies focus principally on the events that follow successful fertilization of the oocyte both in terms of morphology and morphokinetics 1 , 2 . Morphological evaluation of zygotes, cleavage stage embryos and blastocysts has been thoroughly investigated and a consensus was achieved for each of these stages in 2010 according to SART and 2011 according to ESHRE 3 , 4 .…”

“…The formation and morphological characteristics of the resulting zygote appear to be of importance regarding the developmental potential of the preimplantation embryo. Interestingly, recent studies revisiting the zygote score (Z-Score) scenario encompassed in TLM practice have indicated the importance of zygotes’ scoring, both in terms of the time of pronuclei (PN) formation 26 , PN disappearance 27 , 28 as well as the juxtaposition area of the PNs 2 . A good quality zygote seems to be unanimously acknowledged to result to an optimal IVF outcome 3 .…”