Time Lapse Embryo Imaging: How it may change IVF.

October 28, 2012Carole No Comments »

I have been going to the annual American Society for Reproductive Meeting (ASRM) for years and frankly, some years it felt like the field was stagnating but this year was different. I will be writing a series of posts on what I thought was especially interesting from this year’s meeting. Here’s the first.

I have long supported day 5 culture and have written about the usefulness of growing embryos out to blastocyst stage to select the one or two embryos that have the most potential for implantation. Because anything more than a singleton pregnancy poses additional risk to both mother and baby, responsible IVF programs have recognized the need to work toward  the goal of elective single embryo transfer for IVF patients.

Time-lapse embryo imaging may offer an effective non-invasive morphological analysis method for embryo selection. In time-lapse photography, the embryos are photographed every 5 minutes around the clock and the resultant images are put together for the ultimate home movie. Software imposed over the shifting images can calculate whether the embryos are hitting milestones on time.

At least three companies, Auxogyn, Fertilitech and CryoInnovation are all developing various time-lapse systems for continuous monitoring of embryos as they grow in culture.  Auxogyn’s  Early Embryo Viability Assessment System (Eeva) and Cryo Innovations PrimoVision evo system both work by placing microscopes with digital output inside the IVF center’s existing embryo incubators. Fertilitech’s Embryoscope takes a different approach with a new incubator design that has a  built-in embryo “drawer” with  time-lapse photography capability.  The advantages of all these designs is that embryos are minimally disturbed once they go into culture. Depending on the media used, media changes may be very infrequent and hazardous time outside the incubator to evaluate morphology simply isn’t happening so the embryo experiences a more normal growth environment with stable temperature and pH.

Why is continuous monitoring of embryo growth useful?  Early research using these systems has revealed that embryos have pretty precise developmental milestones that they usually hit on time if they are going to be viable and produce implantation-capable blastocysts. For instance, Dr. Renee A Reijo Pera, Director of the Center for Human Embryonic Stem Cell Research and Education at the  Institute for Stem Cell Biology and Regenerative Medicine reviewed recent research showing that human embryos have at least three distinct checkpoints that occur before day 3 of culture which have the potential to identify viable vs. non-viable embryos.

  1. Time to complete first cell division: 15 minutes (range 10-20 minutes). Once the fertilized egg starts to “pinch in” at opposite ends to the time in which two complete cells are formed takes about 15 minutes in the normal embryo.
  2. The  appearance of a third cell takes about 11 hours (range 9-15 hours).
  3. The 3rd and 4th cell should appear within one hour of each other in the viable embryo.

Analysis of  time-lapse images suggest that ninety-three percent of the embryos that hit these checkpoints on time are viable and continue to blastocyst stage. This means that embryologists might be able to use non-invasive time-lapse data to predict on day 3 which cleavage stage cells have the potential to go the distance, removing the main justification for extended culture. This new method for embryo evaluation may bypass some of the  concerns that persist regarding prolonged culture that have appeared in the literature periodically and seem to persist as real effects. For instance, some studies have suggested that the normal epigenetic modification of the embryo’s genes that occurs in the Fallopian tube environment is modified as a result of artificial culture conditions. Some studies suggest that these abnormal epigenetic effects may result in the persistent lower average birth weight  of IVF infants, even when other factors are controlled for.

Conversely, in domestic animals, epigenetic issues from in vitro maturation of oocytes appear to result in a higher than normal  birthweight (large offspring syndrome) discussed in an earlier post.  If we could know on day 3, which embryos are viable, they can be selected and transferred routinely on day 3 of culture, minimizing the opportunity for abnormal epigenetic changes. Although it is not clear how significant these cultural effects on imprinting are, fewer days in culture should, in theory,  reduce these effects.

These time points can’t be found without continuous embryo monitoring.  Proprietary software is available for each system that tracks each embryo as it develops and allows the embryologist to “review” the tape to look for transient abnormalities that appear and disappear, that otherwise would be missed by periodic evaluation.  Time lapse photography has revealed that individual embryo cells can spit out pieces of cytoplasm (fragments) which sometimes contain chromosomes, only to be reabsorbed by the same cell later (chromosome number unchanged) or more troubling by an adjacent cell, causing aneuploidy (an abnormal number of chromosomes).

Some researchers even propose that these profiles of normal embryos obtained through time-lapse may even provide a non-invasive means of identifying those embryos that are more likely to be aneuploid, although confirmation of aneuploidy requires direct genetic testing of a cell. Some correlations of time lapse events with embryo quality are:

  • Aneuploidy affects the timing of first cytokinesis.
  • An immature egg may have a prolonged time for appearance of the third cell.
  • Synchronous development is associated with good cell symmetry, traditionally a marker of good morphology- used to discriminate among embryos for selection.

Although the promise of time-lapse photography analysis is not fully proven and the implementation may be slow because these devices are expensive, it offers an exciting new predictive power for evaluating viable embryos –and may allow patients to benefit from fewer days in culture before transfer.

 

 

 

 

 

 

© 2012, Carole. All rights reserved.

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