A Bridge Too Far or the Holy Grail?

Author: Gary Harton, PhD Market Development Leader, Genetics, PerkinElmer

Here I am, a woman undergoing IVF to try and have the child that my partner and I so desperately want to have, and I find out that the majority of my embryos from each IVF cycle do not have the correct number of chromosomes!  How is this possible?  I mean, I’m not ‘old’!  Maybe I’m not young anymore but am I really that ‘reproductively old’???

Turns out the answer is probably yes. By the time a woman hits 35 years of age, about half of her good quality (i.e. ‘pretty’) embryos are genetically abnormal and will not create a healthy live birth!  I’ll go get a cup of coffee while that one sinks in…

I’m not just saying this is going to be the case, there is plenty of data to back me up on this one 1,2.  And while I could put a number of charts or facts and figures here to prove the above point, I’m going to assume that you trust me enough to not make me do that here.  It’s one thing to be told your age may impact your fertility however it’s entirely another to see a fancy color-coded line chart doing a dramatic nose dive to prove this point!

What I am going to say is that there is plenty of good data out there to support the fact that as women age, the aneuploidy rate in their IVF embryos rises significantly from about age 35 and up.  Since the average age of a woman undergoing IVF in the US is about 38 years old, you can see why this might be an issue!  So, what to do about it?  Well, there is a way to have a look at which embryos are aneuploid (wrong number of chromosomes) and which embryos are euploid (correct number of chromosomes) during an IVF cycle but before embryo transfer.  Selectively choosing euploid embryos is the process known as preimplantation genetic testing for aneuploidy (PGT-A for short). PGT-A has been shown in a number of studies to help get women pregnant faster, as well as help them stay pregnant (reduction of miscarriage)3,4.  That sounds perfect, right?  Of course it isn’t perfect, and there are plenty of arguments around this topic which we are NOT going to go into here.  My opinion is that PGT-A is a good choice for many women undergoing IVF but it isn’t for everyone and not for every cycle.

The question today is what could we do to make PGT-A better?  Or safer?  Or more attractive to the couple?  Again, I don’t want to get into the argument here of whether PGT-A works or doesn’t work.  I also don’t want to discuss the more recent debate around mosaic embryos and their impact on outcomes, enough has been written about that already!  One of the main ‘hurdles’ for growing the number of PGT-A cycles globally is the fact that to perform conventional PGT-A, you have to work with an IVF center that has a highly skilled team of embryologists on staff that can perform one of the most amazing lab tasks you’ve ever seen… embryo biopsy.  Go ahead, go on YouTube and look up ‘blastocyst biopsy’ and, you’ll be amazed at what you find and will probably sit there for an hour or two watching video after video.  It is truly a gift to have so many great embryologists in the world that can remove a few cells from a developing embryo and leave the embryo healthy enough to be frozen and warmed (thawed) later for embryo transfer!

However, not every country has enough embryologists with the skill to perform embryo biopsy.  In addition, embryo biopsy is illegal in some countries and territories around the world.  This means that there are many places in the world where women undergo IVF cycles and the only assessment of embryo quality that is received is looking down the microscope a few times and saying ‘this one looks good’.  As mentioned earlier, 50 % of IVF embryos or MORE are genetically abnormal so looking down the microscope just isn’t good enough in 2020.  When it comes to transferring embryos, you don’t want to just know they are attractive, you want to know they are chromosomally healthy.  After your baby is born is when you can debate how aesthetically pleasing they are if you’d like.

Non-Invasive PGT

Are you ready for the good news?

IVF and genetics groups around the world are starting to look at non-invasive methods of assessing the embryos genetic make-up ahead of transfer.  The idea here is that growing embryos living in their little drop of media in the dark incubator are actually very busy.  The cells are differentiating, the cells are moving around getting ready for the next stage of development, and, it seems, some cells are dying, which is a natural growth process and great news for us.  It is these dead and dying cells that are releasing their DNA into the middle of the growing embryo in a cavity called the blastocoel, and also releasing their DNA into the culture media that surrounds the embryo while it grows.  So, now we have access to DNA from the embryo that can tell us something about the genetic make-up of the embryo without actually ever biopsying the embryo.  The media that the embryo lives in is typically discarded… but what if it wasn’t trash?  What if it contained enough DNA to allow for genetic testing?  What if, even in a country where no one had ever done embryo biopsy, an embryologist could sample the media before discarding it and this little media sample had everything we needed to be able to offer PGT-A?  That would be pretty awesome wouldn’t it?  Well, as a geneticist interested in reproductive genetics, I think so.  In fact, I think that non-invasive PGT-A will be a large part of the future of IVF treatment.

Now that I’ve gotten you excited about this new reproductive technology (go with me on this), it is my job to also tell you the other side of the story!  Non-invasive PGT is still in its infancy and we have a lot to learn before this technology becomes part of everyday life in the IVF/Genetics center.  We have to worry about contamination of the media from many sources; the manufacturer (they don’t really think about human or other species of DNA when they think about contamination in their media), the IVF lab staff who handle the dishes and media routinely, and the genetics staff who handle the samples.  Lastly, there is one other surprising ‘culprit’ of contamination. PLOT TWIST! It’s, the embryo itself (or more realistically the egg and/or sperm from the couple).

The egg is delivered with a large number of maternal cells called cumulus cells.  If these cells are not removed and the embryo is not washed repeatedly to ensure they are gone, they will confound the diagnosis of the embryo.  Likewise, sperm DNA can also contaminate the media causing an errant result.  This is one of the main reasons that non-invasive PGT isn’t quite as popular as Instagram or Tik Tok videos.  It isn’t as accurate as performing an invasive biopsy…… yet.  In the most recent data sets I’ve seen, some labs are able to achieve fairly high concordance rates between biopsy and non-invasive PGT, in the high 80-90 % range.  However, other groups have published concordance rates below 50%!  No test is going to work with a false positive or false negative rate that high!

So, today we are at the precipice of a fantastic new technology in the IVF space.  A technology that may change the game again when it comes to embryo selection.  And one that will undoubtedly be better for the embryo and may allow more people to have access to genetic testing of their embryos before they transfer them back into the uterus.  Ideally we’d partner non-invasive PGT analysis of embryo chromosome status with other non-invasive methods, for instance time-lapse, to begin to hone in on the absolute ‘best’ embryo to transfer first, leading to more pregnant women and more babies delivered through the IVF process.

Whether you’re an embryologist/geneticist or not, if you’re interested in building your family through IVF or you’re simply interested in being in the know when it comes to cutting edge reproductive techniques, this is one to watch. Not only could this knowledge make you more fun at parties (pro tip: as soon as your host brings out the Deviled Eggs, that’s your cue!) but it can also be a less invasive and healthy way to build your family.

  1. Harton GL, Munné S, Surrey M, et al. Diminished effect of maternal age on implantation after preimplantation genetic diagnosis with array comparative genomic hybridization. Fertil Steril 2013.
  2. Forman et al. In vitro fertilization with single euploid blastocyst transfer: a randomized controlled trial. Fertility & Sterility 2013.
  3. C Rubio, J Bellver, L Rodrigo, et al. In vitro fertilization with preimplantation genetic diagnosis for aneuploidies in advanced maternal age: a randomized, controlled study.  Fertil Steril 2017.
  4. Yang Z, Liu J, Collins GS, et al. Selection of single blastocysts for fresh transfer via standard morphology assessment alone and with array CGH for good prognosis IVF patients: Results from a randomized pilot study. Mol Cytogenet 2012.

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