Infertility Clinical Trial
Official title:
Time-Lapse Incubation for Embryo Culture - The Impact of Morphokinetics and Environmental Stability on Reproductive Outcomes
Embryo culture and selection has been a continuous challenge in evolution since the birth of
In Vitro Fertilization (IVF). Traditionally, embryo quality and its presumed suitability for
transfer were assessed based on morphologic features. However, the consensus as to the
optimal time points for embryo assessment and as to 'preferable' characteristics have been
challenging. Alongside this has been the challenge of achieving balance between multiple
points of assessment, yet stabilizing the embryo environment for growth. In standard
incubation, each new morphological assessment of embryos in culture theoretically creates an
additional disruption to culture.
Most recently, time-lapse incubators (TLI) have been introduced as a novel embryo culture
system attempting to limit culture disturbances. These incubators have been integrated with
digital imaging, allowing for a substantial limitation in embryo handling and environmental
disturbances. They have also introduced new morphokinetic parameters to embryo assessment
and to optimizing selection of embryos. Thus far, a limited number of studies have examined
the clinical outcomes and value of time lapse monitoring systems versus the more ubiquitous
incubators (e.g. multichamber) for reproductive outcomes. In particular, the isolated value
of morphokinetics in embryo assessment and of this new stable culture environment in TLI are
still in question.
The objectives of this study are to prospectively assess and compare fertility outcomes when
embryos are cultured in the TLI system versus more traditional bench incubators (BI). We
will specifically assess the added value of the closed and isolated TLI compared to BI on
reproductive outcomes, as well as the value of morphokinetic grading in IVF.
Research Objectives:
We are now reaching a new age with an opportunity to advance to theoretically better culture
environments and improvements on measures of embryo assessment.
The objectives of this research study will be to evaluate and compare the reproductive
outcomes in isolating one of two new interventions introduced by the Time-Lapse Incubator
(TLI) system. The first will be an assessment of the TLI environment compared to the
standard Bench Incubator (BI) environment. The second will be an assessment of the added
morphokinetic grading of embryos compared to the traditional morphologic grading alone.
Although the primary objective of this study will focus on clinical pregnancy rates and
fresh embryo transfers, further research using embryos frozen from this study will be
conducted to also evaluate cumulative pregnancy rates per oocyte pick-up (OPU) cycle in the
future.
Methods The current study will be a prospective randomized and double-blinded study using
three patient arms. The first arm will include patients randomized to embryo culture in a
tri-gas bench incubator (Miri, Benchtop Multi-room incubator). These embryos will undergo
multiple evaluations using light microscopy and traditional morphologic assessment according
to accepted criteria. The second arm will include patients randomized to embryo culture in a
time-lapse incubator (Miri TL, Time-Lapse Incubator). These embryos will remain in the TLI
and undergo both morphologic and morphokinetic evaluation and grading according to a
multivariable scoring model. They will not be removed from incubation for the duration of
culture. The third arm will include patients also randomized to embryo culture in a
time-lapse incubator (Miri TL, Time-Lapse Incubator). These embryos will remain in the TLI
and undergo only traditional morphologic assessment according to accepted criteria with no
additional imaging. They will also not be removed from incubation for the duration of
culture. The time points and evaluated parameters will be identical to those in arm 1 of the
study.
Patients will be assessed for suitability, inclusion and exclusion criteria by the physician
and nursing team prior to initiation of an IVF/ICSI cycle at our centre. Once the patient is
deemed eligible, a member of the care team will discuss details of the study with the
patient.
Approved study subjects will undergo standard controlled ovarian hyperstimulation (COH).
Protocols and their corresponding medications will be decided upon at the discretion of the
treating physician. These may include long gonadotropin-releasing hormone (GnRH) agonist
protocol and GnRH antagonist protocol. Follicular aspiration will be performed in the IVF
unit via transvaginal needle aspiration. Endometrial preparation and luteal phase support
will be recommended as per our departmental protocol. The number of embryos for transfer
will be defined prior to cycle initiation, according to The Israel Society of Obstetrics &
Gynecology.
Patient randomization will occur after Human Chorionic Gonadotropin (hCG) administration has
already been ensured, prior to Intracytoplasmic Sperm Injection (ICSI). The randomization
procedure will be accomplished using computer-generated randomization.
After follicular aspiration and transfer to the laboratory, the follicular fluid will be
examined for presence of oocytes. Oocytes will then be scored for maturity and any
morphologically abnormal features. ICSI will then be performed using fresh sperm from the
corresponding partner.
Embryos will then be placed in culture media. The embryos within culture media will then be
placed in either the Miri Benchtop or Miri Timelapse incubator according to their
corresponding group of randomization. Note that the environment of the Miri benchtop and
Miri TL incubators will be considered identical. oxygen concentration and carbon dioxide
concentrations set at 5% and 5.5% respectively.
Embryos in arm 1 of the study (Miri Benchtop incubator) will be morphologically assessed by
light microscopy at pre-defined time points and according to accepted criteria by one of the
trained laboratory embryologists. The time points for evaluation will be at 16 - 20 hours
post-ICSI (for normal fertilization), at 44 - 48 hours (day 2) post-ICSI, and then at 64 -
72 hours (day 3) post-ICSI. Evaluated parameters will include cell number, cell size, cell
symmetry, and percent fragmentation. Any gross abnormalities will be noted. Embryos will
then be graded on day 3 according to these evaluated parameters and transferred according to
preferential grading. If embryo transfer has been predetermined for day 5, additional
assessment will take place at approximately 116 hours.
Embryos in arm 2 of the study (Miri TL incubator) will be morphologically and
morphokinetically assessed by the same laboratory embryologists using digital images
generated by the incubator's integrated time-lapse imaging system. Assessment and scoring
will be performed as per our scoring classification system. Morphological screening of
embryos will initially be performed in order to discard or exclude those clearly not viable
for transfer. Morphokinetic parameters will then be used in order to rank remaining embryos
score categories from a maximum of 4.0 to a minimum of -2.0, in order of hypothesized
decreasing implantation potential.
Embryos in arm 3 of the study (Miri TL incubator) will be morphologically assessed by the
embryologists using digital images generated by the incubator's integrated time-lapse
imaging system. As noted above, the time points and evaluated parameters will be identical
to those in arm 1 of the study. Decisions on embryos for transfer will also be identical.
For each patient, embryos will be selected for transfer based on their morphologic scoring
alone (Arm 1 and 3) or by the morphokinetic decision tree scoring (Arm 2). The number of
embryos for transfer will have been pre-determined (as noted above).
Those embryos not selected and deemed appropriate for future transfer will undergo
cryopreservation by vitrification.
Blinding of the current study will be ensured at multiple points. The gynecologists
performing oocyte retrieval and embryo transfer will be blinded to the predefined and
randomized patient group. Patients will be unaware of their group of randomization.
Statisticians will also be blinded to the group of randomization in calculating pregnancy
outcomes. It will unfortunately not be possible to ensure blinding of those embryologists
performing the morphologic and morphokinetic assessments.
Sample Size calculation:
The pregnancy rate in our IVF Unit in the sub-group of patients with demographic and
clinical characteristics similar to those included in the study, is about 40%. Assuming that
in the TLI group pregnancy rate will increase by 10%, the sample size required per group is
124 patients per arm, with an alpha risk of 5% and a power of 80%.
Statistics:
The statistical analysis will be done by intention to treat.
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