A study of the effects of a novel ovarian stimulation regimen on embryo aneuploidy rates in IVF, and the impact of aneuploidy on implantation, as assessed in an in vitro model.

By limiting the number of embryos transferred to the uterus to only a single
embryo, the risk of multiple gestation can be reduced. In order to improve the
effectiveness of single embryo transfer, the ability to select the embryo with
the highest potential to develop into a healthy child is of vital importance.
While embryos rated as high quality by standardized morphological assessment
are associated with higher implantation and pregnancy rates, it is still not
possible to predict with certainty which embryo will implant and has the
highest potential to develop into a healthy child. An increasing body of
evidence indicates that the incidence of chromosomal abnormalities in embryos
is extremely high and good embryo morphology does not necessarily exclude an
abnormal chromosomal constitution. Since aneuploidies are considered the main
cause of embryonic wastage and loss, this phenomenon may be primarily
responsible for the relatively poor pregnancy rates reported after IVF.
The introduction of fluorescent in-situ hybridization (FISH) techniques for
preimplantation genetic diagnosis has enabled screening of embryos for
chromosomal aneuploidies before transfer. Preimplantation genetic screening
(PGS) is now applied clinically in numerous IVF laboratories throughout the
world. However, a recent meta-analysis has shown that PGS is yet to have a
significant impact on IVF outcomes. This may partly be explained by the fact
that most aneuploidies observed at this stage originate during the first
mitotic divisions of early preimplantation development, resulting in
chromosomally mosaic embryos. If a chromosomally mosaic embryo is biopsied,
this cell may not be representative for the remaining embryo.
Our group recently completed the first prospectively designed, randomized
trial, comparing embryo aneuploidy rates following two ovarian hyperstimulation
regimens in a group of 111 IVF patients. Milder stimulation was associated with
a reduction in the number of oocytes retrieved and embryos generated. However,
the proportion of chromosomally normal embryos was significantly increased.
These results showed for the first time a direct correlation between the
ovarian stimulation protocol and the incidence of chromosome abnormalities in
the embryo. The observation that mild stimulation in some patients still
resulted in a high oocyte yield and concurring higher proportions of abnormal
embryos , underscores the need of further development of minimal stimulation
approaches.

In this study we aim to compare the effect of two different ovarian stimulation
protocols on embryo quality in a group of women of 39 years or younger, in a
prospectively randomized controlled trial. PGS will be performed to assess
chromosomal competence of the resulting embryos, as we have previously shown
this to reflect embryo quality. Embryos diagnosed as chromosomally normal will
be transferred or cryopreserved. Embryos diagnosed as aneuploid or mosaic will
be investigated for their implantation and developmental potential, by
transferring them to an in vitro implantation model. After an extended culture
period, implantation behaviour will be assessed and the entire embryo is
reanalysed to detect the proportion of chromosomally abnormal cells. The
implantation behaviour will be correlated to the type of abnormality and the
chromosome(s) involved.

Prospectively randomized, clinical study in 110 women undergoing IVF treatment

There is an ongoing debate as to whether biopsy of embryos may decrease the
implantation potential of the embryo. To date, this has not been directly
investigated. It is likely that any decreased developmental potential is
counteracted by the effect of not transferring aneuploid embryos. The biopsy of
two cells may have more impact on development, but has also been shown to
increase the accuracy of the diagnosis.
As the in vitro implantation procedure will use only embryos diagnosed as
abnormal or mosaic after PGS analysis which would otherwise be discarded, there
is no additional risk involved. This model will, however, yield unique data on
the significance of chromosomal mosaicism for the implantation potential of the
embryo.