Preimplantation Genetic Testing -Barriers to its use and development

March 21, 2014Carole 11 Comments »

Amy Klein, who writes the Fertility Diary column at the New York Times and blogs at In Vitro. wrote a provocative Slate article, Embryo Testing Should Not be Controversial:Fears of designer babies,eugenics, and abortion are inhibiting research and medicine .which takes up some of the barriers to societal acceptance and full technical optimization of embryo testing to benefit patients.

Amy interviewed me for the piece which was, I will admit, flattering and scary at the same time. In my experience, reporters don’t always get it right but she quoted me fairly. I am also troubled by the way PGD and PGS are portrayed by the media because the popular press often obscures the facts because facts are boring and designer babies are thrilling in a dark scarey way. I get it but I don’t like it.

For those of you who’d like a dose of science, you might enjoy this  journal club in which scientists from various IVF groups discuss recent advances and best methods in PGS. It was broadcast live by the Pacific Coast Reproductive Society earlier in the week and included embryologists from as far away as India but can be accessed anytime through this link.

For those of you who are embryologists, you really need to hear this because it illustrates the various ways to “skin the cat” regarding PGS and that the ART field is still evolving and trying to determine the best way to proceed for patients to get the most benefit. They also poll centers during the presentation to get an idea of the popularity of different approaches.  The technology for the live webinar, like PGS, is also evolving so you will have to patient with imperfect  audio connections at times.  The last couple of minutes included free chat among some of the participants until someone said, “Hey, I think we’re still live”. Yes, the  technology of webinars and PGS are both still in development.

Some of the questions that are discussed –and debated —in the journal club were:

  • Best biopsy methods: Should we sample polar body cells vs. day 3 cleavage cells vs. later stage embryos (morula, early blatocyst, expanded blastocyst or hatched blastocyst).
  • Best patient candidates for embryo biopsy: minimum number of embryos? Is it worth $5,000 to only biopsy one embryo if that is all they have? Should biopsy/testing be routine for all IVF patients?
  • Best testing methods: FISH vs. Microarray vs both.
  • Possibility of sampling the fluid from inside the embryo (the blastocoel) instead of sacrificing a cell for testing.
  • The contribution of the male sperm to embryo aneuploidy. Should all IVF patients  where the male has male factor have the embryos tested for aneuploidy? What percentage of aneuploidy errors come from the male (about 10%).
  • What is the better approach: Transfer fresh embryos or freeze embryos followed by later transfer?

These live journal clubs will be ongoing through this new Fertility and Sterility Journal webinar initiative with at least 24 future webinars on both male and female infertility topics on a monthly basis.

© 2014, Carole. All rights reserved.

11 Responses to this entry

  • Julie Says:

    My husband and I recently have to decide whether we want to spend $5000 to perform PGS on one embryo if that is all we have left on day 5/6 (we started out with only 5 embryos). We decided that we would do it so that we could save ourselves some agony from disappointments and heartbreaks. Also, we do not want to have to make the tough decision as to whether to terminate the pregnancy at a later date.

  • Carole Says:

    Thanks for sharing your experience. I wish you MUCH GOOD LUCK going forward! Carole

  • Julie Says:

    Hi Carole, there is a recent systematic study that claims that PGS actually hurt women’s chance of achieving pregnancy:
    http://www.rbej.com/content/12/1/22
    It claims that many embryos do not make it in vitro to day 5 that might survive in vivo. Can you weigh in on this?

  • Carole Says:

    Hi Julie,
    Very interesting paper. Thanks for sharing. I think that I would agree with the fact that IVF does not have good clinical trials. It is difficult to expect a patient to allow themselves to be sorted into two possible treatments, only one expected to be better, when they are paying the bill.

    But I don’t see how you could prove that any single embryo that demised on day 5 would have implanted if only you’d transferred it on day 3. You can take a group of embryos from the same patient (to keep genetic influences similar but not identical) , transfer some on day 3 and see whether the rest go on or die, but that still doesn’t prove that the embryo you transferred would have died. You would have to take one embryo- split it into two, transfer one-half and grow one-half but that is probably impossible, almost certainly unethical. Most of the clinics that argue for day 3 transfer either can’t grow embryos to day 5 or are very concerned about the potential risk of imprinting errors with prolonged culture. The imprinting issue is still not resolved because we don’t have long term data yet and some of the concerns wouldn’t manifest until middle age.

    I do agree with the authors that the use of PGS is problematic –especially when it is used for everyone, at every lab(even those with poor technique) , for all kinds of patients. Older patients should in theory benefit but if they make few embryos, they are most likely to not have a transfer at all, which makes patients unhappy. It is also possible, but has not been proven, that some populations of patients may have less robust embryos that are less able to survive the rigors of biopsy and extended culture, but if those populations exist, we don’t know how to identify them.

    PGS can reduce a woman’s chance of pregnancy if her embryos can’t survive the added manipulations or if the technical manipulations are performed poorly. I can easily believe that these two factors can easily account for much if not all the reduced pregnancy rates observed with PGS. My two cents.

    Because of the dissatisfaction with PGS, some providers are becoming very excited about the potential for real time continuous embry imaging coupled with algorithms to detect the embryos whose growth rate is most consistent with high probability of implantation.

  • Em Says:

    Great blog. I was hoping to get your feedback on my current situation regarding genetic testing, if possible.

    I am about to undergo a frozen embryo cycle. I have one child after a successful IVF cycle back in 2012 (my first successful one after 2 failed fresh, a failed frozen, and 2 cancelled cycles.) My issue did not appear to be my embryos which made it to day 5 or 6 blasts but instead my thin lining and recurrent fluid in my uterus.

    During my successful cycle, I transferred 3 blasts, (1 day 5, 2 day 6s) and after a vanishing twin, gave birth to one healthy child. I was 32 at the time.

    I am now ready to try for a second child (and still need to use IVF as my tubes have been removed.)

    I have 2 embryos frozen at day 6 blasts and 6 frozen at the 2PN stage. I just found out that my insurance covers CGH testing so I am considering using it before going through my FET. Although I didn’t believe embryo quality to be a problem in the past, it is concerning to me that of the 3 embryos I put back, 2 did not attach making me fear they were abnormal.

    My RE suggested that if I want to do CGH testing, I only do it on the 2PNs…by aging them and biopsying any that make it to blast.

    My fear is that this will be damaging to the embryos since they will be thawed, biopsied, and refrozen…to later be thawed again for a transfer.

    My questions?
    Would you recommend I pursue CGH testing if it is not a financial burden?

    What are the risks to the embryos? Potential of losing them/damaging them? Risk of consistently thawing and refreezing?

    *I am afraid I will use them all up, or lose them and have to undergo a fresh cycle at 35:(

    I’d welcome feedback from a neutral 3rd party.

    Thanks!

    Em

  • Carole Says:

    Dear Em,
    Every intervention with the embryo creates another opportunity for things to go wrong. However, any issues with biopsy are either catstrophic- the entire embryo demises or nothing happens. I am unaware of any congenital abnormalities related to biopsy; if damage is severe, the embryo will not implant. You don’t mention your age but if you are under 35, you have a lower risk of aneuploidy (abnormal chromosome number) which is what you are looking for in the CGH testing most of the time. (I am assuming that you (and your partner) are not known to carry a genetic condition. Freezing and rethawing is not ideal; but embryos are surprisingly resilient and Usually tolerate this if the technical piece is done well. Thawing at the 2PN stage and culturing to biopsy is the way I would do it too, if you were to decide to go ahead. Good Luck! Carole

  • CC Says:

    Hi Carole
    Thanks for writing this great blog. We are considering PGD as I’m 43- IVF 1 (at 43) led to 10 eggs, 6 Blasts (2 of which were not suitable for freezing). 2 x fresh transfer led to singleton pregnancy with MMC at 8 weeks and FET to twin pregnancy with vanishing twin at 8 weeks and MC of aneuploidy fetus at 14 weeks.
    We want one more try using my eggs with PGD but I’ve been reading about self correction of aneuploidy at day 3 and a suggestion that it could also correct even at day 5. As I understand it, the aneuploidy cells would be pushed out to form part of the placenta as the normal cells take over to form a healthy fetus. Is it really possible for corrections at this stage or later in development ie could there be a correction at day 6 or 7 or would it be safe to say that there are too many cells at this point for a correction?
    I hope this makes sense.

    Thanks CC

  • Carole Says:

    Hi CC,
    I think you can have some self correction also in later embryonic stages – one mechanism may be to divert these abnormal cells to the trophectoderm which makes the placenta, but not the baby- as you mention above. However, this phenomenon is not very well understood and I wouldn’t rely on self-correction to “repair” an abnormal embryo after transfer. I also think no physician would knowingly transfer an abnormal embryo in the hope that it might self-correct. You will probably only be given the option of transferring any normal embryo based on PGD testing on day 5 (so any self-correction from day 3 would have already occurred). Even with PGD, the probability of a live birth from an IVF cycle attempt is low–4% or 4 in 100 women age 43-44. National CDC summary here http://nccd.cdc.gov/DRH_ART/Apps/NationalSummaryReport.aspx Using donor eggs increases your chances dramatically but there are lots of social, emotional issues to consider with using donor eggs, so I appreciate that it is not for everyone. Yes, I would definitely use PGD/PGS to check for aneuploidy in embryos you are considering for transfer. I would definitely be thinking about other options if the IVF doesn’t work this time. I would not suggest you do many more rounds of IVF- results don’t improve as you age with IVF. Frankly, I am surprised that your doctor advised IVF without PGS screening at your age. Hopefully, he discussed the expectations for success at the front end. Whatever you decide, I hope that you are one of the lucky ones and I wish you MUCH GOOD LUCK in whatever you decide!! Carole

  • CC Says:

    Thanks for clarifying that Carole and thanks for the wishes- I need them! I’m from Ireland and we have no PG testing here at all bar one clinic and with them the samples have to be sent to the UK for analysis. We can do embryo imaging but that’s it really in terms of monitoring (I was told I didn’t need it). This time we will be going abroad- far from ideal but that’s life. We are really hoping we get lucky but if not I have a lovely younger sister that has offered us her eggs.

    Can I ask one last question for advanced maternal age testing- should we do a CGH 24 chromosome analysis (PGS) alone or in combination with some single gene mutations testing (PGD) ie are there single gene mutations that you find become more common with advanced age?
    Thanks Carole

  • Carole Says:

    Hi CC,
    I think the CGH 24 is the standard of care. It will pick up all aneuploidies- including Trisomy 21 which results in Down’s syndrome. As far as single gene mutations, that is a question for a genetic counselor who could better advise you regarding any specific risks based on your and your partner’s family history and -in some cases- genetic pre-screening of your genome using cells (often cheek cells) is possible. I would recommend that you see a genetic counselor for specific single gene mutation risk analysis and recommendations. Genesis Genetics (see website here http://genesisgenetics.org/) is a lab specializing in pre-implantation genetic testing (actually one of the pioneer labs in the US) – has a lot of good patient information on this topic. Good Luck!! Carole

  • Progenesis Says:

    I appreciate your preimplantation genetic testing barriers article ans a big thumbs up for this entry.

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