Study: Common test to assess viability of IVF embryos may be flawed

A test deployed in many fertility clinics to assess the viability of embryos for use in IVF is likely to overestimate the number of embryos with abnormalities, suggests a study published today.

Using a new technique for imaging embryos in real time, a team led by scientists at the Loke Centre for Trophoblast Research, University of Cambridge, showed that abnormalities can arise at a later stage of embryo development than previously thought. This means that the tests used in some clinics may be finding errors in cells that will go on to develop into the placenta – and abnormalities in placental cells are less likely to affect the health of the fetus.

When an egg has been fertilized by a sperm, it is known as a zygote. This then divides, each new cell taking a copy of each parent's DNA. Each of these cells itself divides and copies, and this process occurs repeatedly, developing into a hollow ball of cells, a stage of the embryo known as a blastocyst.

Around six days after fertilization, the blastocyst implants itself into the lining of the uterus. Its outer cells develop into the placenta, a temporary organ that ensures the embryo – and the fetus into which it develops – receives the correct levels of nutrition and hormones necessary for its growth.

Assisted conception technologies are increasingly widespread due to a range of factors. These technologies involve fertilizing eggs in the clinic and transferring the blastocyst into the uterus. However, before transfer, many clinics test the embryos for aneuploidy, where some cells in the embryo have the wrong number of chromosomes. When abnormalities are detected, the embryo may be deemed inviable and discarded, meaning patients may need to go through another cycle of treatment, which can prove costly.

So-called pre-implantation genetic testing for aneuploidy is a treatment 'add on' that may be offered to older women and those with a history of recurrent miscarriages or multiple IVF failures.

Researchers at the Loke Centre for Trophoblast Research, Cambridge, are interested in how early human embryos develop before implantation in the womb. This is because in assisted conceived, as many as nine in ten embryos fail to develop to a stage where they can be transferred to the womb.

Having a baby through assisted conception can be very challenging. Most embryos fail to develop or to implant, and even those that are good quality may not be transferred. Much more basic research is needed to inform future clinical practice and improve rates of assisted conception."

Professor Kathy Niakan, Director of the Loke Centre for Trophoblast Research and Co-Chair of Cambridge Reproduction

To help understand development of the embryo at this early stage, Professor Niakan and colleagues, in collaboration with researchers at the Francis Crick Institute, developed a new, state-of-the-art method for watching embryos live in high resolution. The details are published today in Nature Biotechnology.

The new imaging technique involves tagging DNA inside the cell nucleus with a fluorescent protein, making it visible under a microscope. The researchers then use an imaging technique known as light-sheet microscopy to observe the embryos in 3D as they developed without damaging them.

First author Dr Ahmed Abdelbaki, a postdoctoral researcher at the Loke Centre for Trophoblast Research, said: "This is the first time that this very gentle method, with much higher resolution, has been used. It meant that we could watch the embryos as they developed over a two-day period, the longest continuous time that this process has been observed."

Co-author Professor Ben Steventon from the Department of Genetics at the University of Cambridge said: "The unique design of the microscope allows for multiple precious embryos to be watched simultaneously, and from both sides. This has allowed the team to catch events that have previously been missed. It's a proof of the power of direct observation to uncover unexpected findings in human biology."

The technique led to a very unexpected finding.

Professor Niakan, the study's senior author, said: "We were extremely surprised to discover that abnormal cell divisions can happen from scratch at a very late stage of human development. It was only by using a new imaging technique that it was possible to see this happening."

Of the 13 embryos analysed by the team, 10% of the cells contained chromosomal abnormalities. These arose from problems when DNA is being copied between cells, for example when chromosomes did not move properly during division or when a cell divides into three, rather than two.

Because these abnormalities arise at a relatively late stage of the embryo's development, they appear in the outer layer of the blastocyst, which develops into the placenta – and it is from this layer that biopsies are taken for pre-genetic testing for aneuploidy.

Professor Niakan's team is now studying cells in the inner layer to see whether such spontaneous abnormalities can also arise there.

The embryos used in this study were donated by families who had had successful pregnancies. The families were treated at Bourn Hall Clinic and Create Fertility.

The research was supported by Wellcome, the Francis Crick Institute (which receives core funding from Cancer Research UK, the Medical Research Council and Wellcome) and the Engineering and Physical Sciences Research Council.