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4. Time-Lapse Imaging: An Inside View of Human Embryos

Time-Lapse Imaging: An Inside View of Human Embryos

This imaging system takes pictures of embryos at set intervals during culture and stitches them together to make a time-lapse video that shows clearly how each embryo has developed for up to 5 days in culture. These pictures and videos are fascinating to review as they have opened up a whole new world to embryologists.

Catching critical errors
We can now observe subtle but critical developmental errors that occur during culture and use this information to help us make better choices about which embryo to transfer. For example, each cell in an early embryo should divide into 2 daughter cells about every 12 to 16 hours. With time-lapse imaging, we are seeing that in about 10 percent of embryos, a cell will divide into not 2, but 3, daughter cells, generating an erroneous and likely fatal chromosome complement in those cells. Some embryos can recover from this catastrophe but, overall, implantation rates are lower than in embryos where such an error does not occur (1). These "phenotypic" abnormalities are almost impossible to catch without time-lapse technology.

Additionally, embryos make "developmental" errors that can be caught on camera, and even identified by a computer before an embryologist reviews a video. By necessity, embryos must develop along a certain timeline in order to be at the right stage of development for implantation when the uterus is ready. Embryos developing too quickly or too slowly may miss the implantation window, which closes about 7 days after ovulation (or egg retrieval, in the case of IVF patients). A groundbreaking research paper (2) published in Nature Biotechnology in 2010 showed, for the first time, that the first few cell divisions in the embryo are critical predictors of future potential, and that it is possible to accurately identify as soon as 48 hours after fertilization embryos that are likely to arrest before implantation.

Making better choices
These are critical findings. Noninvasive objective measures of embryo viability will allow us to better choose embryos for transfer and freezing for individual patients, while maintaining a safe and uninterrupted culture environment for the embryos. It also allows us to limit the number of embryos we transfer, therefore reducing the incidence of multiple pregnancies. This advances our goal of one healthy baby at a time for each of our patients. We consider multiple pregnancies a risky and undesirable outcome after IVF treatment.

PFC's role in the research
With the hope of improving outcomes for all our patients, PFC has been participating in trials of time-lapse technology for almost 2 years. The initial trials were focused on establishing that the technology was safe, determining if the findings from the research studies (2) would hold up in the clinical environment with embryos that were being transferred, and on further refining the computer automated predictions that were based on cell division timings.

All of these aims have been achieved, and the technology is so promising that we have already been invited to present results at the American Society for Reproductive Medicine (ASRM), The Fertility Society of Australia (FSA), The Association of Clinical Embryologists (ACE) and The British Fertility Society (BFS) in the UK, and the European Society for Human Reproduction and Embryology (ESHRE).

Our work so far has been in collaboration with Auxogyn, Inc, a Menlo Park company working on time-lapse imaging and software to help embryologists identify viable embryos in a cohort. Their system uses a novel dark-field illumination microscope to track embryos. It only exposes them to about 5 percent of the light that would be needed if the embryos were assessed using a conventional inverted microscope outside the incubator. Since embryos would ordinarily not be exposed to light in the body, we like the idea of minimal light exposure in the lab.

Additionally, the software actually predicts which embryos are likely to continue developing, and automatically generates this prediction as soon as an embryo has reached the 4-cell stage of development. Early indications are that the computer prediction can be used in conjunction with the embryologist’s traditional observations of the embryos to identify viable embryos early in the process. This too is significant as it could allow us to put embryos back into the uterus earlier, thus minimizing their exposure to the artificial environment in the laboratory.

These studies are exciting and ongoing. Patients receiving IVF treatment at PFC in 2013 and beyond may have the opportunity to participate in the next round of studies where we will be using traditional embryo assessment methods together with time-lapse imaging to identify embryos for transfer. In most cases, we will be able to provide copies of the embryo videos to patients, opening up our world to you. Feel free to ask your physician about opportunities to have your embryos imaged, and we will report back on our latest findings in the near future.

Time-lapse technology allows us to watch embryos develop inside the culture incubator and see key indicators of viability. We can look at individual snapshots, like the pictures here, one taken on each day of development. Or we can run the pictures together into a movie and watch how each embryo has progressed over the 5 days in the laboratory.

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