Can a CGH-Abnormal Embryo Produce a Healthy Baby?

21 Jul
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The short answer to this question is “yes” but it depends on the stage of development that the embryo had reached at the time that it was biopsied for Comparative Genomic Hybridization (CGH) analysis. Some aneuploid advanced embryos (morulae or blastocysts) can and do propagate normal babies. While this is neither unusual nor surprising, the real determining factor as to whether the fetus will be normal or abnormal is the percentage of aneuploid cells (blastomeres) in the embryo. Unfortunately, to date no one knows precisely what that cut-off percentage is. Indeed, all advanced normal embryos do have some degree of mosaicism (some chromosomally abnormal cells among normal cells).

To recap both the egg and the sperm go through a reduction in chromosome number as they prepare for fertilization. This reduction division is referred to as Meiosis. In the absence of severe sperm dysfunction, the final chromosome make-up of the embryo is dictated by the egg and not the sperm. The more severe the male infertility the greater the likelihood that sperm aneuploidy (irregular chromosome number) can cause embryo aneuploidy and “incompetence.”

After fertilization has taken place, further division of cells (blastomeres) in the embryo occurs without a change in the number of chromosomes. This replication division is known as Mitosis. In some cases following normal meiosis, subsequent mitosis is faulty, resulting in a number of cells being rendered aneuploid. In such cases, the advanced embryo (i.e. day 4 morula- and/or day 5-6 blastocyst) will be mosaic (i.e. mitotically aneuploid).

As stated above, all advanced embryos have some mosaic cells. It is a fact, therefore, that many mosaic advanced embryos do indeed go on to propagate viable and healthy pregnancies. However, no one knows what percentage of mitotically aneuploid (mosaic) cells is lethal to an embryo. Is the cut-off 30%, 40%, 50% or even higher?? Such data is simply not available.

We have conclusively shown and have reported on the fact that in >95% of cases of non-male factor infertility, there is a linear propagation of chromosomal makeup from the pre-fertilized egg through early fertilization (the zygote) to the day 3 (4-9 cell) embryo. Thus, when an embryo is found (through single blastomere CGH) to be aneuploid on day 3, it is almost always due to a defect in meiosis (usually stemming from the egg) rather than as a result of mosaicism. We have also shown that Day-3 CGH-normal embryos progress to blastocyst in >90% of cases. In contrast, only about 13% of aneuploid day 3 embryos progress to blastocyst.

It could of course be argued that on rare occasions, the one abnormal cell in a day 3 embryo may be removed for analysis (while the remaining cells are normal), causing the test result to indicate an “incompetent” embryo, while it still has the potential to propagate a normal pregnancy. However, our research has shown the contrary to be the case, since CGH testing of all blastomeres taken from aneuploid day 3 embryos revealed all the cells to consistently be aneuploid. Thus, such embryos must have been meiotically aneuploid and therefore “incompetent.”

Finally, we have recently embarked on a study involving what we call “hindsight CGH” (H-CGH) testing. Here, we perform day 3 CGH testing but rather than wait several weeks for CGH results, we transfer the embryos fresh and then determine their competency in “hindsight”. The purpose in doing H-CGH is diagnostic, i.e., to ascertain retrospectively the cause of prior IVF failure or recurrent pregnancy loss. The study (which is still in progress) has thus far revealed that when the transferred embryo is CGH-abnormal, it either fails to propagate a pregnancy or it results in a miscarriage.

So, the above suggests that when eggs or day-3 (4-9 cell) embryos test CGH-abnormal, it is almost invariably due to meiotic rather than mitotic aneuploidy. The same cannot be said with confidence when it comes to 100+ cell embryos (morulae or blastocysts)…another good reason why I believe that performing Day-3 embryo CGH is preferable to so testing morulae or blastocysts.

10 Comments

  • Sheila says:

    Thank you for writing about this topic. There is a dearth of information available (at least on readily available searches) about this issue. Any research done seems to be only on promoting PGS and its high rate of reliability. However, some of the information seems difficult to corroborate based on the fact that there are few hindsight studies. Or I might be searching for validation that I might have a viable pregnancy. I recently participated in an IVF study for stimulation medication efficacy. The study required a fresh 5 day transfer and any other blastocysts were frozen. All had PGS completed at day 5 but they did not have the results until after the transfer was completed. I received a positive pregnancy test and was delighted. Last week, at 5 weeks pregnant, the results came back. The embryo they transferred was shown to be 45 XY -22. I was told “that many women in the study that became pregnant went on to have normal babies after further testing” and to “try to remain positive.” Given the current research, it is very difficult to understand why this might be the case. My understanding is that monosomy 22 is rarely compatible with life. Now I am 6 weeks pregnant and will have US next Tuesday. Given your research and what seems to be happening for the women in this study, does it seem possible that these embryos are self correcting or is there some other explanation for these conflicting results? If this is the case wouldn’t that mean that PGS is not as reliable as the IVF community seems to be thinking?

    • Geoffrey Sher says:

      My website has changed. The new site is at http://www.sherIVF.com where I host and populate new and updated blog articles . The blog can also be accessed directly by going to http://goo.gl/4hvjoP. I now only respond to posts on this new site.

      To find and follow updated and new blog articles and to post questions or comments, please use this new venue. I promise to respond promptly.

      In the interim, please re-post this question or comment on my new website-blog.

      Geoff Sher

  • Ricky says:

    Hi Dr. Sher,

    I know you mentioned that “no one knows what percentage of mitotically aneuploid (mosaic) cells is lethal to an embryo.” But do you know anything under 50% would be worth to give it a try? Have you heard of anyone who has healthy baby even with mild or moderate degree of mosaic embryos? Thank you!

    Ricky

    • Geoffrey Sher says:

      Because there is no way to differentiate reliably between mitotic and meiotic aneuploidy in embryos, I cannot answer this question. I can tell you that most blastocysts harbor some mitotically aneuploid cells.

      Geoff Sher

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