Research: Aneuploidy by Age, Day, and Grade

 It's been a while since I've done a good research-related post. Shame on me, that's what happens when life gets too busy! I have a few that I'd like to share. They're basically a chronical of my neuroses, so take this for what it's worth.

Today's topic is aneuploidy by day and grade. Where possible, age is also factored in. My one euploid blast is a day 7 4AA, so I looked for data on grade to set expectations.

Looking at day 5 and 6 embryos, by age and by grade, this 2014 study from Human Genetics & Embryology is probably my favorite, because it shows some of the highest euploidy rates for my age group! It's around 45% of day 5 embryos from 40-42 year old eggs. It also shows AA embryos, regardless of day, having an aneuploidy rate of just over 50%. I cling to this one for hope.

Article text:  https://www.omicsonline.org/open-access-pdfs/morphological-and-kinetic-embryological-criteria-and-correlation-withaneuploidy-rates-how-might-they-be-used-to-choose-the-best-iv-2161-0436-1000129.pdf 

This is another awesome resource, from 2019. It splits out euploidy rates by day and grade, and includes day 7 embryos. Mean maternal age was 37, and in keeping with my own results, it finds that AA blasts, regardless of day, have the highest euploidy rate, including 58.5% of day 5, 50% of day 6, and 63% of day 7. The article also mentions pregnancy outcomes for transfers, and notes that the live birth rate for day 5 euploids is 77%, while the live birth rate for day 7 euploids is 43.8%. 

Article text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364279/

This 2016 article is more somber, showing a 90%+ aneuploidy rate for day 7 embryos in the 40+ age range. It also lists out pregnancy outcomes by transfer of embryos. The caveat with this one is that the sample is extremely small.  

Article text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832487/

Meanwhile, here's 2019 Human Reproduction article looking at aneuploidy by day and age. The researchers included embryos with C quality, which might explain their much lower euploidy rates in the 41-42 year old range (25% day 5, 23% day 6, 18% day 7). This also had a lower live birth rate for euploid embryos, ranging from 56% for day 5 embryos, to 45.8% for day 6 embryos, to only 21.5% for day 7 embryos. The split out live birth rates for day 7 embryos by embryo quality, however they lump everything 4BB and greater into the same "good quality" bucket, which sees a 26% live birth rate. 

Article text: https://www.rmany.com/content/2-our-team/1-physicians/dr-eric-flisser/what-is-the-reproductive-potential-of-day-7-euploid-embryos.pdf

So there you have it. If you're wondering what the probability of aneuploidy is for your embryos, based on day, grade, and age of the eggs, here are some of the top research articles. There are more articles available, although most older ones relied on day 3 blastomere biopsies, and therefore produce a different picture than day 5/6/7 blastocyst biopsy.

Dear Embryologist

 Dear Embryologist,

When you called me with my day 6 update on Saturday, you refused to share the grade of my blast with me. You told me I had to wait for my regroup, in 3 weeks after my CCS results are back. You refused even when I, truthfully, told you that I'd specifically asked Dr. B if I could get grades at the time of biopsy, since I'm banking, and she expressly agreed. 

I know that this is a job for you. Sharing grades with me would slow you down and you were already calling late on a weekend. (Although, to be fair, you were calling me with my egg sheet in front of you, and that egg sheet contained the lone embryo's grade, so simply reading the words "It's a day 6 3bb" wouldn't have taken very long.) You were certainly right in telling me that grade is not a perfect predictor of aneuploidy, although I was also right in mentioning that higher grades are correlated with higher aneuploidy.

I vaguely understand your hesitation. Please allow me to articulate why this was important to me.

Having a child is the single most life-changing activity out there. Sure, your career impacts your life, but you can always change careers. Your choice of spouse or partner can change your life, but you can also change spouses or partners. Having a kid though, fundamentally alters every moment of every day for decades, if not longer. 

Here I am, working on the single biggest event in my life, and because of infertility, I have almost zero control over it. How crazy is that? You control your career choice. You control your partner choice. But in my case, infertility, the most control I have is writing a very large check, taking my medications as instructed, and keeping my body as healthy as possible to maximize my chances. In other words, I have very little control. 

Information isn't control. But information is about as close to control as I can get. Information lets me plan my next steps. It lets me prepare for the most probable outcomes. Information is pretty much the only panacea for the pain that comes from the lack of control of something so fundamentally important.

In the course of a single breath, you have the opportunity to share information that can help. Information that can reduce the pain and anxiety. That ten second inconvenience for you will dramatically reduce days of anxiety for me.

I know that this is a job for you, but it's life changing for me. Please reconsider your response and your actions in the future, and think about how some empathy and kindness could make a world of difference to someone who is hurting.

Regards,

Me

Hello There, Yet

 Two weeks ago I noted that my cycle was going amazingly well, but I was waiting for the proverbial other shoe to drop. 

It's dropped. To convey my emotional journey via emoticon:

Eight retrieved! :-)

Seven mature!!! 8-)

Four fertilized. :(

One low grade, day 6 blast.  :'(

Four fertilized was only one less than the total I'd had fertilized in my last three cycles. And those cycles had produced three blasts for biopsy. Also, my lab reports a 50% blast rate. Thus I was dreaming of three blasts and realistically expecting two. In a big picture sort of way, one is certainly not that much less than two, or even three. But one isn't enough to hold onto hope, given my age. If we'd had three blasts, we'd have had a realistic hope of one euploid. With one, there's no realistic chance. To be fair, I don't actually know its grade - that's a post for another day when my blood pressure has dropped - but I don't think the refusal to share it with me bodes well. 

Mental Models

 I am trying to keep my mind in a healthy place during the wait for our day 6/7 call and the start of our last cycle. In doing so, I realized that my mind seems to have two settings: living life, and waiting for something. This is waiting in the sense of: I'm putting in serious amounts of effort with the hope and expectation that something good will come of it. My focus is primarily on the effort and the possible outcomes. 

Most of my life has been 'waiting for something.' Waiting to get into grad school. Waiting for my PhD. Waiting for my first leadership role. Waiting for a promotion. Waiting to have kids. Waiting to have enough saved to be financially independent. 

Since having the kids, though, and settling into various jobs at my current employer, I've spent more time focused on living life. That's living life in the sense of: concentrated focus on what I have today versus what I want for tomorrow.

Realizing that I'm back in waiting mode, but if I consciously shift myself to living mode my anxiety reduces, has been unexpected. I'm not sure it's really dawned on me before now the extent to which waiting mode has been detrimental. That's because even when deeply entrenched in periods of waiting, I am someone who routinely stops to appreciate the daily joys in life. I will marvel over the colors of leaves, or a hillside of fireflies. I notice and mentally celebrate every hug I get from the kids and DH. I smile every single time I see the plant my girlfriends gave me, which is miraculously still alive 4 years later! I have always assumed that those are signs that I am living my life, and if you asked me, I'd tell you my life is great. But the waiting still brings anxiety with it, even when the joys aren't overlooked. For today, I'm trying to focus on living. Yes, it's living while waiting, but if the focus is on living rather than waiting, the stress is lower. If the waiting ends with bad news, then it's good that I'm in living mode, because living mode is where I need to be once this round of waiting is over. 

Then There Were Four

To my absolute amazement, of the eight retrieved yesterday, seven were mature. Alas, even with the calcium ionphore, only 4 fertilized. To be fair, 4-5 fertilized was my dream number, since I never expected to get more than 5 mature, so I shouldn't complain. 

Fertilization at 57% is vastly better than our 1 of 5 last time, but slightly worse that the 2 of 3 I've had previously. I don't know if the calcium helped, or not, but I'm glad we did it. Now, we wait. Saturday for the day 6 update. Sunday for the day 7 update. If anyone makes it to biopsy, then another 16-ish days for CCS results. 

In the meantime, a few amazing things have happened. First, I found out that because we didn't get any embryos last time, I have an insurance credit. It will be enough to cover one FET and all meds. That's a savings of at least $7k, which is huge. My mom also offered to cover the bulk of another round of IVF. So the plan is to see if any of our four make blast. If they don't, then I feel good shutting the door on another baby, because clearly our gametes aren't up to the task. If we do make blast, then we'll roll immediately into another retrieval cycle. My numbers have gotten better and better each cycle, so there's a real benefit to charging ahead and not waiting out a cycle or two for CCS results. This is a plan I feel genuinely good about. 

Grow, my magnificent four! Grow, and make blast, and be normal. It's a lot to ask, but I'm asking it anyway. 

Eight!

 I just had to post through my retrieval stupor. My RE retrieved eight follicles! 

Sizes at trigger were 22, 16. 8.5 (left) and 20, 19, 14, 13, 5.5, 4.5 (right). Based on that I know they won't all be mature, and the fertilization call tomorrow will probably be the usual bummer. Still, for this moment I'm wildly happy with my ovaries and what they've done. 

It's Not All the Egg

 Can I rant for a minute? I guess it's my blog, so the answer must be yes.

What the heck is the deal with always placing 100% of the causality for fertility issues on the female end of things?

Look, I'm over 40. I know my eggs are not in the best shape in the world. And my uterus, well, that's not a pretty place. But our recent 20% fertilization rate is reasonably likely to be the result of sperm issues, and not just egg issues.

I asked my RE about artificial oocyte activation. Her response was that it probably wouldn't help us, because it's only for sperm issues rather than egg issues. 

Hello?!? Not to point out the millions of tiny elephants in the room, but we're dealing with sperm that has consistently had 1% morphology. Sperm that has a DFI on the SCSA of 30%. Many, many clinics would call that male factor infertility. But no. Not here. Here it's all about the egg. 

Grrr. This makes me angry. Because if we focused on the sperm in addition to the egg, maybe there's something more we could do. Like Zymot. Or PICSI. Or AOA. 

We are going to do AOA. And maybe we'll have 0% fertilization this time, and it will prove that the issues are all about the egg! I am ready to stand corrected. But I fail to understand why, given the information we have today, we must assume that everything is an egg issue.

Yet

I work in Learning & Development at a big company. This year we've really been pushing training on growth mindset. To oversimplify, this is about the idea that learning and growth should be valued over performance and perfection. The hallmark words of a growth mindset often include "yet", as in: "I can't do astrophysics, yet." The "yet" indicates that you're aware that you can learn it and will in the future.

I had a monitoring appointment today. For me, things looked pretty promising. I still have a decent cohort of follicles growing together. In reflecting on this news during the drive home, I thought: "Well, the news isn't bad, yet." 

While it doesn't reflect a growth mindset, I really do feel like I'm just waiting for the bad news. Maybe it didn't come today. Maybe it won't come before retrieval. It's coming, though. It's odd, but I think only having one of five fertilize last cycle crushed me in a way I wasn't prepared for. I knew I wouldn't have many mature eggs. I knew any embryos would most likely be aneuploid. But a 20% fertilization rate? That I was not prepared for. To know that I actually managed to get five mature eggs. . five!. . . but it was all for nothing because four didn't fertilize, that's crushing. 

So I sit here waiting for the next crushing blow. I'd guess I'll trigger Thursday or Friday. I guess I won't give up, yet.

Last Chance

 I did my first shot for my last chance IVF cycle this morning. AFC of 8. I just need one euploid out of this, although selfishly I'd like two! I find myself pep-talking my ovaries, pleading with the universe to let us get a good embryo from this, and simultaneously not expecting anything good at all. I guess the cynical optimist has finally run out of optimism. 

I have a birthday this week. The birthday where my odds of a euploid embryo go from 38% to 29% based on my clinic's data. I've never been sad about a birthday before, but now I am. 

Monitoring on Saturday. Wish me luck? 

I am/have been pretty conflicted about this cycle. After getting 5 mature last cycle, I wanted to do MDLF again, but with artificial occyte activation (AOA) to combat the 20% fertilization rate we had. My RE insisted on another antagonist cycle, since we've gotten blasts from those. I really don't love this plan, and it's the first time that I've been truly unhappy with a plan to move forward. It doesn't feel good, especially since we've "gotten blasts" when having 2 fertilized, and once we only got one blast. So having one fertilized and not reaching blast doesn't seem unexpected. I also don't want to be on extended Clomid for a fourth time, given my lining, although I know that extended Clomid is CCRM's "thing" for poor responders.

All this messaging came via my nurse. In order to discuss with my RE, I'd have to cancel this cycle and wait for a regroup in 4-6 weeks. While I'm usually pretty patient, the thought of another 8+ weeks to cycle again, while having to maintain my diet, was enough to break me. So I'm trusting my RE and going with the antagonist cycle. 

Because I like putting things in one place, here's the history we're basing decisions on.

IVF #1: Estrogen & cetrotide priming. 300 Gonal/150 Menopur/100 Clomid/HGH/Dexamethasone. Cancelled after 13 days, only one follicle remaining.

IVF #2: Estrogen & short testosterone prime. Luteal phase stim due to triggering a lead on CD2. 300 Gonal/150 Menopur/100 Clomid/HGH/Dexamethasone. Cetrotide added around day 10. 6R/3M/2F/2B - aneuploid.

IVF#3: Estrogen & long testosterone prime. 300 Gonal/150 Menopur/100 Clomid/HGH/Dexamethasone. Cetrotide added around day 10. 4R/3M/2F/1B, day 7 euploid.

IVF#4: No priming. MDLF 20 units/2x/day. 300 Gonal/150 Menopur/HGH/Dexamethasone. 5R/5M/1F/0B.

If I include my 6 OI/TI cycles, I can assume that we always had at least one blast, because we always had a positive beta. Based on CL cysts, I always had 1-3 mature. Thus, taking the most conservative assumption, those were: No priming. 175-225 Gonal/75 Menopur/vaginal estrace during stims. 1-3M/1-2B/0-2 euploid.

This does point out that we get euploid blasts with cycles that don't use MDLF. But I should also point out that we never needed Cetrotide on our OI/TI cycles. My LH always stayed low, probably due to the vast amount of vaginal progesterone I was on. Given my cancelled antagonist primted cycle, I really wonder if the antagonist limits follicular maturation for me, despite sizes increasing.