Infertility Clinical Trial
Official title:
Morphometrics and Morphokinetics of Thawed Oocytes and Embryos
The aim of this observational study is to describe for the first time a complete set of
morphometric and morphokinetic parameters of frozen-thawed human embryos in order to select
the embryo with the highest implantation potential. These parameters will be correlated with
(1) data of the fresh embryos and their subsequent survival, the evolution of the contact
surfaces between surviving blastomeres and the resumption of mitosis; (2) patient
characteristics and clinical outcome of frozen-thawed embryos and (3) a comparison between
embryos cryopreserved with vitrification or the slow method regarding these parameters will
be performed.
This project aims to introduce new evaluation criteria of the frozen-thawed embryos to
improve success rate of FET cycles. By establishing new precise, reliable and non-invasive
measurable parameters, we aim to (1) select which supernumerary embryos are at chance to
survive the freezing/thawing procedures, (2) establish cut off parameters for the survival
rate of the embryo, (3) assess implantation, pregnancy and live birth rates depending on the
developmental characteristics after thawing and after 24h of culture.
Our strategy for improving the outcome of FET cycles is based on the study of morphometric
and morphokinetic parameters in frozen-thawed embryos and the correlation with
embryological, clinical and cycle parameters. Transferring a well-defined thawed embryo with
a high implantation potential may lead towards an increase in the implantation and life
birth rate and an increase in the cumulative live birth rate with a reduction of the IVF
costs in order to optimize the health-economic situation of reproductive medicine.
Cryopreservation of supernumerary embryos is an essential part of Assisted Reproduction
Techniques (ART) and is nowadays a standard routine procedure in the IVF laboratory. Its
clinical application consists in (1) the possibility of increasing cumulative delivery rates
per cycle and (2) the reduction of the number of transferable embryos in both fresh and
successive frozen thawed embryo transfer cycles (FET) decreasing the risk of multiple
pregnancies.
Two different techniques to cryopreserve embryos are commonly used: slow freezing and
vitrification. During slow freezing, the embryo is exposed to subzero temperatures in a
controlled rate with the use of low concentration of cryoprotectant. Alternatively, using
vitrification the embryo rapidly enters into a glass-like state with the use of high
concentrations of cryoprotectant and rapid cooling rates. Several studies comparing
cryopreservation of human embryos by vitrification or slow freezing are available and
meta-analyses have been published. Although vitrification has been found to have
significantly higher survival rates than slow freezing, results on implantation rate,
clinical pregnancy rate and live birth rate remain unclear, mostly due to a paucity of
well-designed and powered prospective randomized controlled studies assessing live birth
rates.
Embryo evaluation to select the embryo(s) with the highest implantation potential is
routinely based on embryo developmental and morphological characteristics using light
microscopy. The embryo parameters usually correlated to the implantation capacity of an
embryo in a fresh cycle are the number of blastomeres, their symmetry and the percentage
cytoplasmic fragmentation. For the evaluation of frozen-thawed embryos, the percentage of
blastomeres that survive the freezing-thawing process and their developmental capacity after
overnight culture have to be added to these factors.
Current research in the development of non-invasive methods for scoring embryos and ranking
them according to their ability to implant and give rise to a healthy birth include both
morphometrics and morphokinetics.
Morphometrics Multilevel computerized images enable assessment over an unlimited time period
and allow a detailed evaluation of the embryo. Several morphometric studies of human fresh
oocytes and embryos with embryo implantation and development have been published.
Morphometric studies using multilevel images combined with a computer-assisted scoring
system (CASS) may be superior compared to standard scoring system (SSS) to predict
implantation and/or live birth based on the number and size of blastomeres on day 3.
Semi-automated morphometric analysis also revealed correlations between total embryo volume
and clinical pregnancy. Another study evaluating morphometric characteristics including the
absolute volumes, coefficients of form and the coefficient of diversity of human embryos
and/or oocytes showed a higher coefficient of diversity between sister blastomeres in
embryos that successfully implanted and progressed to birth. Morphometric characteristics
including the external and internal diameter of the zona pellucida, the thickness of the
zona pellucida and the embryo cell mass diameter were described. They stated that image
analysis could be used to predict the criteria needed for more efficient embryo assessment
before transfer. The mean blastomere size was correlated with the degree of fragmentation
and multinucleation in a study using computer-controlled multilevel analyses with 232
embryos. However, until now, no morphometric studies in human frozen thawed embryos have
been described.
Morphokinetics Time-lapse imaging allows documentation of early growth without disturbing
the culture environment. At this moment, no prospective randomized trial data are available
showing that embryos selected from time-lapse imaging have significantly improved
implantation rates compared with embryos selected with conventional morphological
evaluation.
However, time lapse imaging of embryos have revealed a correlation between first cleavage
time, time between cleavages, blastomere size and multinucleation and implantation potential
of human embryos. A correlation between the times of each embryo cleavage between 2 to 8
cell stage, the ability to become a blastocyst and implantation potential. Moreover,
morphokinetic studies have demonstrated that direct cleavage from 2 cells to 3 cells has
been correlated with a low implantation and ongoing pregnancy rate. According to time-lapse
recording in 38 oocytes, embryo quality was related to fertilization events and periodicity
of the cyctoplasmic wave: good quality embryos arose from oocytes that had more uniform
timing from injection to pronuclear abuttal and longer cytoplasmic wave. Furthermore,
cellular fragments in human embryos can disappear during in vitro culture.
Only a few studies on morphokinetics in human cryopreserved embryos have been published.
Using videocinematography on respectively 50 and 103 frozen-thawed embryos, it was shown
that the occurrence of smooth membranes and the cell-cell adherence were predictive for the
implantation capacity of frozen-cleaved embryos. Wong et al. followed the development of 242
supernumerary frozen d1-old embryos in a study combining time lapse microscopy and gene
expression profiling: success in progression to the blastocyst stage could be predicted by
measuring three dynamic, noninvasive imaging parameters by day 2 after fertilization before
embryonic genome activation: (1) duration of the first cytokinesis, (2) time interval
between the end of the first mitosis and the initiation of the second and (3) the time
interval between the second and third mitoses.
This observational study aims to describe morphometric and morphokinetic parameters of
thawed human embryos after freezing (slow freezing or vitrification). The study will focus
on the evolution of the blastomere volume, the evolution of the contact surfaces between
surviving blastomeres and the development of the embryo using time lapse imaging. Embryo
morphometric and morphokinetic parameters will be analyzed together with patient
characteristics and clinical parameters using cluster analysis techniques. The correlation
between morphometrics/morphokinetics and the implantation potential of frozen-thawed embryos
will be studied in cycles with single embryo transfer and in cycles with dual implantation
after double embryo transfer.
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Observational Model: Cohort, Time Perspective: Retrospective
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