Wednesday, August 29, 2012

All about CGH microarray- part II

A continuation from my previous post, this discusses the pros and cons of CGH microarray. If there is anything I have missed out, please bring it up here.

2 kinds of embryo biopsies:
First a little background, and its going to get technical. You can biopsy a developing embryo at 2 points- around day 3, where you pull out a single blastomere, and on day 5-6, after the blastocyst has begun hatching- here you can get out multiple cells. The latter is called a trophectoderm biopsy.

A blastomere biopsy on day 3 is more harmful to the embryo, because "removal of one or two cells from a six- to eight-cell embryo on day 3 depletes the embryonic mass by 12.5%–25% or more, risking the inadvertent removal of critical cells from the embryo, especially if attempting to improve diagnostic certainty by taking more than one cell for testing." Also, with a single cell biopsy on day 3, you have a significant chance on missing out on mosaicism, a condition where chromosomal errors can be introduced during cell division after fertilization, at any point. The earlier the mosaicism is introduced, obviously, the greater impact it would have.  

A trophectoderm biopsy on day 6 appears to have 2 advantages over a blastomere biopsy on day 3-- a) it is potentially less damaging to the embryo (you remove a much lower percentage of the total number of cells, and one lab, who had done this a gazillion times and were now expert at this, clearly, reported that "after allowing for blastocele reconstitution" the majority of their embryos survived their freeze-thaw) and b) It has a  much higher chance (but is not a 100% reliable obviously), of catching out on mosaicism.

Ok- those technicalities being explained,  my RE wisely chose a trophectoderm biopsy, so lets move on to the pros and cons of that, with CGH micrroarray thrown in.

Cons

Damage to the embryo during biopsy: The more the lack of experience of the tech doing this, the higher the possibility of damage, or so i think--correct me if I'm wrong, it does not seem like a simple procedure, no idea what the learning curve is like. Additionally, there are different options of herniating the zona pellucida(?) prior to biopsy, and some may be safer than others, it depends on available technology.

Obviously, as stated above a trophoectoderm biopsy is better than a blastomere biopsy, because you take less from the embryo. But the risk remains that you can damage the embryo, worst case, none of your chromosomal normals might survive the thaw. Or they might be able to survive, but might have a lower chance of implanting. My mother had a unique worry: that there would be flawed development of the baby due to embryo biopsy.  Nothing I've read shows any indication of abnormalities in any children resulting from biopsy (there have been 700 children born from blastomere biopsy worldwide in 2005, apparently). There are plenty of logical reasons to think it decreases your chances of having viable embryos in itself, and based on the hardiness of the embryo and the skill/experience of the tech doing this delicate procedure, may even result in your IVF cycle producing zero clinical pregnancies. That, I think is the worst case scenario, and its one I've considered.I think my final decision will be made after considering the experience my clinic has had with this procedure. If I'm one the first people they try it with, I'll be aware before I decide, one way or the other. 

It does not eliminate the possibility of mosaicism: Obviously, a trophectoderm biopsy is your best chance of detecting this, while it is not foolproof. Again, it comes down to the luck of the draw and about overall risk reduction of pregnancy loss. My goal is to eliminate as many aneuploids as possible. I know that I may not be able to get them all.

Limitations of the technique itself:  My RE bought this one up- its a new-ish procedure, with limitations. In the very best hands with the very best luck, its limits of detection are possibly microdeletions/microinsertions. Still room for things to go wrong. But right now, I'm considering it only for its core ability- the ability to detect gross aneuploidy. Good enough for me.

Practical issues: I'm doing this in India, where CGH microarray is not offered as a procedure (I hope some enterprising individual comes across this and decides to start this as a business venture, sometime soon, though its not going to happen for me). So we are doing it in a clinic where this is not usually done (and I am deeply and utterly grateful for their willingness to take this on), then will be attempting to ship DNA across continents (So much can go wrong there), then I have to find a lab willing to do this, who accepts extracted, amplified DNA from another country as raw material for this procedure (anybody who has had this done, can you tell me the name of your lab?) CCRM girls, this is done in house (right?)
Right now, I just know of  24suretest (in England) and CCRM.

Pros:

It would definitely improve the chances of success. One study reported that after taking into account aneuploidy and mosaicism, over 50 % of the generated embryos of 'young women'  were chromosomally abnormal.  Clearly, age does not protect you fully.  And I'm young (in that I appear to have plenty of eggs left, with excellent FSH, AMH, estradiol and AFC--similar to that of any egg donor), and I make eggs capable of fertilization and implantation, and 2 out of my 3 eggs may have been chromosomally abnormal.

If 40 % of the embryos generated through IVF are aneuploid (and embryo grade is not much of an indicator of whether am embryo is euploid or not!) then I would need some serious luck to avoid having a surrogate go through loss. Both my RE and my mother were of the thought process that, if my surrogate went through one loss, or more, it would be something easily borne, because it is not me going through the pregnancy. I think everybody was startled when I burst into tears at the very thought of my surrogate losing the pregnancy--and the 20 week amnio time point was under discussion here. I think women who have lost babies will completely understand my horrified reaction, while others would think--- its not your body, so what is the matter? To that, I'm going to say, its still your child. So you will be devastated each and every time it happens, especially if you get to the point of 20 weeks, where your hopes have really been built up. For people having gone through the process of using a surrogate, if you could address how you felt at the thought of anything happening to the surrogate pregnancy in the comments section, that would be very useful.

It would potentially decrease time required for success: Lets start with the assumption that around 40% of my embryos will be aneuploid. I line up one surrogate. Transfer one embryo (I refuse to do multiple embryo transfers to one surrogate).  If its aneuploid, best case, we lose around 3 months.Worst case, its something that we don't detect for 20 weeks (again, bloody scary prospect for the mother, while the general audience thinks this is not a big deal). Then, we repeat the process again. If we get unlucky, it would really be a while before we hit on a winning combination. I want to stay in India around 3-4 years maximally. I also want any children I have to spend atleast the first formative 2 years of their lives around my family---which means, for my 2 plans to mesh, this has to work quickly. While IVF with PGS does not guarantee this---I could totally lose a chromosomally normal embryo, at 5 months, for multiple reasons, it reduces the overall risk of pregnancy loss.

A valuable learning experience: If we embark on this road, everybody involved could learn a lot, even if no pregnancy results from this IVF cycle.  I could learn more about the nature of my embryos. The person doing this should get valuable laboratory experience at this technique. If this entire IVF fails, the only commodity that would be definitively lost is money and time. The time would smart, but the money? We spend money on so many things, so many of them relatively inconsequential that I'm not going to feel bad about spending money on this, even if it fails utterly. My mom wants to get me a diamond set worth around a million rupees for the wedding. The possibility of a baby is definitely something priceless, and this venture may set us back around 1/5th of that price, so I'm not going to quibble about it.

This is a post utterly open to lively comment and debate. I hope there is some of that, and more importantly feedback on available facilities (in the US, or anywhere else) that do this routinely and are willing to accept samples and my $$$.  I know a lot of people, from everywhere, read this blog. I hope that will come in useful here!

11 comments:

  1. I wish I had something to add. I am intently listening to the feedback. I feel like you are making a good choice for you. Avoiding another loss is worth pursuing at great cost. Even facing a 50/50 chance is unbearable at times. Thanks for the rundown on these. I learned a lot.

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  2. Wow - this is a lot of very good information.  I have no help to add, but I'm fascinated to see the responses.  Glad you're getting some answers!

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  3. Our Day 3 blastomere biopsy was sent to Reprogenetics in Livington, NJ (from our California IVF clinic).
    I know SIRM in Vegas does the Day 5 biopsy - not sure who they use as we never got that far with our cycle there.

    We were also willing to throw money at the problem and felt it was worth the cost to reduce the time and emotional distress of future miscarriages. That said, we transferred three genetically normal embryos, one at a time, from our donor cycle, and the first two didn't implant. So it doesn't fix everything, but I much preferred a BFN to a positive test that ended in another miscarriage 8-10 weeks later.

    With our 27 year old donor, we had 5 genetically normal of 12 embryos, and 3 were physically good enough to use/freeze.

    In our second cycle with her, we had 11 genetically normal of 18 embryos, and 8 were physically good enough to freeze.

    More detail, and sample report at: http://bravingivf.blogspot.com/2011/11/what-cgh-results-look-like.html

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  4. This is a lot of good information. I had a question, you mention finding out at 20 weeks with amnio, will not a CVS test find that sort of chromosomal stuff sooner? My understanding is the CVS is an earlier test....maybe you you can clarify?

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  5. Yes, you totally can do a CVS as well- that is around 12 weeks, I think.. I have to talk to a Doctor here who apparently is really good at these- that was the other side of the equation for me, whether we could get somebody truly skilled, who has done 100s-1000s of these procedures, to do this. Apparently, there are people like that here.

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  6. Thanks for sharing your story. I read the comment on your post about the woman who transferred 2 chromosomal normals and had a 6 weeks loss, but there is the other side of the equation.

    The numbers you post are scary, 7 out of 18 abnormal from a 27 year old donor, which fits in nearly 50 %  statistic and with a 3 day biopsy, you are not even taking into account mosaicism.

    I'm so, so glad things have worked out for you!!

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  7. Sue - IVF TravelerAugust 31, 2012 at 9:06 PM

    You may want to check with Gennet in Prague, I think they do CGH testing in house. There is also a clinic in Turkey that I have heard of. You may also want to check out Natera/Gene Security Network in California they do a full chromosome testing that some doctors feel has some additional advantages.

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  8. "For people having gone through the process of using a surrogate, if you could address how you felt at the thought of anything happening to the surrogate pregnancy in the comments section, that would be very useful."

    My husband have gone through 2 transfers to a gestational surrogate.....and 2 miscarriages.  Two for two.  Both losses were chromosomally normal babies.  Though I have never lost one of my babies while it was gestating in my own body (a pregnancy is literally impossible for me, thus the use of a surrogate), I can tell you that the grief is just as tremendous.  Our first loss occurred on December 11th...second loss on June 14th.  Just this afternoon, I laid in my bed and bawled for my babies.  The despair is relentless.  

    I'm not sure how much you've researched (or "believe in") DQ-alpha compatibility as a cause of RPL, but I firmly believe this is what we were up against with our surrogate.  Our (her's, my husband's and my) DQ-alpha compatibility was SHOCKINGLY bad (we discovered this after our first loss).  We threw Intralipids, Lovenox, Dexamethasone, etc. at the problem, only to face another loss.  Needless to say, we're moving on with a new surrogate (who we've had tested for her DQ-alpha numbers before moving forward).  Surrogacy is not the "easy" route, by an means.

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  9.  Thank you for sharing your story. I really, really hope that finding a surrogate with an appropriate MHC haplotype fixes things for you. I don't honestly know what to think on the DQ alpha story.

    Theoretically, there is a most definitely a basis for loss with NK cell activation and attack due to expression of different MHC molecules,  but biology is difficult to gauge, one way or the other.

    Questions (out of academic curiosity)--when did the losses happen? Also, Had the first surrogate you had used carried to term previously?

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  10. Our first loss was discovered at the 7 week ultrasound.  With the second loss we saw an acceptable heartbeat at 7 weeks, only to lose it at 8 weeks 4 days.  Our past surrogate has one daughter of her own and has also given birth to a little girl as a Traditional Surrogate, and a little boy as a Gestational Surrogate.  

    Our DQ-alpha numbers were as follows:
    -My husband: 4.1, 4.1 (the dreaded 4.1!)
    -Me: 1.1, 1.1
    -Surrogate: 1.1, 4.1
    i.e. each embryo we transferred to her was an exact DQ-alpha match

    Before our second transfer, it was discovered that her cytokines were elevated, and she also tested positive for an APA antibody (thus the Intralipids and Lovenox).  Our current surrogate's DQ-alpha numbers are 2.1, 3.1 so we're crossing our fingers (just transferred a top-grade blastocyst to her yesterday!).

    Wishing you much luck as you embark on your surrogacy journey!

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  11. Please check out Natera for SNP aneuploidy testing - http://www.natera.com/aneuploidy-pgd-overview.html.

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