Monday, January 12, 2009

More About Embryos

The questions: at the time of this writing there were 84 questions to answer. I will read through them and get to most, but probably not all. I am sure this is most difficult for those who write about the here and now, i.e. questions about a cycle in progress. Many of you have commented that the topics are more helpful than the questions, so I want to continue with the embryo blogs, and then go to more questions. I do like answering the questions.


The egg is one cell, the fertilized egg is one cell, and then the egg divides, becoming 2 cells. The 2 cells are smaller than the one big one, and with each division, the cells become smaller. After 2 they become 4. Actually many times they become 3. Both the 2 cells may not divide at the same time. That’s why an embryo can be a 3, 4, 5, 6, 7, 8 or other cell number. It does not need to be an even number.


So here are pictures of 2 cell, cell 4 cell and 8 cell embryos.






The overall size of the embryo does not change. The zonna pellucida stays the same size, so the cells need to fit inside. Just like a developing chick can’t be bigger than the egg, till the end.
These are pictures of perfect looking embryos. Most embryos do not look like these, and that’s ok. These are the typical embryos you see on web sites.
Most of the questions about embryo development we cannot answer. Why do some embryos look prettier than others? Why are some embryos slower than others? Why are some embryos fragmented? We are not close to understanding these questions. We prefer if an embryo looks “better”, meaning the cells are dividing at the right rate and there is minimal fragmentation.
How quickly should an embryo grow? 1 day after the retrieval, they are still one cell, but the next day division should take place. A 4 cell may be the best, but a 2 or 3 may be ok. And of course, they have to keep growing, so that the next day, day 3, they should be 5-8 cells. A 4 cell on day 3 is really slow. Certainly, as with many other slow embryos, a baby is possible with a 4 cell on day 3, but it’s better to have an embryo that is more advanced. The closer you get to 8 the better, 6 is the minimum “good” number”.
Most clinics have their own classification system for grading embryos. Some labs call their best embryos A’s. Some 1’s, some 5’s. There is a reason for this. IVF is a relatively new science and many of the lab directors who started 10-20 years ago had little human IVF experience. There just were not a large group of scientists who previously worked in IVF labs. They had backgrounds in brain science, animal science and all sorts of other areas. Some of them turned into great lab directors (hats off to our lab director, Dr. Krey), but there was not grading system that the whole country followed. Each program just made up its own system for grading day 3 embryos. We could all get on the same page, but now it’s too hard to go back.
It would be really difficult for each program to go back through 20 years of charts and change the numbers assigned to each embryo. Plus if we all change now to a new system, it’s hard have some embryos graded one way and some another, especially for research purposes. So things will stay as they are. It just makes it a little difficult when you talk to your friends to compare embryos. To jump ahead a little, there is a system most of us follow for day 5 embryos.

What is fragmentation? Fragments are little pieces of the cell that break off as the embryo divides. A little bit of fragmentation is normal. As the degree of fragmentation increase, the odds of implantation go down.
Let’s look at some day 3 embryos to see varying amounts of fragmentation.
This close up shows the normal larger cells, and some smaller round “fragments”.


Here is a group of embryos from the same woman. The embryo far right is the best. It has very few fragments. The top embryo looks good too. The bottom middle looks ok, but is a bit more fragmented.


This embryo has a high degree of fragmentation (compare to the nice embryos at the begining).











In this picture, the far right embryo is full of fragments.

We frequently assign a fragmentation score by estimating the percentage of the embryo volume that is replaced by fragments. 0% is actually rare, some fragments are expected. 0% is ok, but it does not happen much. We consider up to about 10% to still be very good. 10-20% is still OK, not quite as good. More than 20% is more abnormal, we consider the embryo to be of poorer quality. Pregnancy can occur with a fragmented embryo, but the odds are lower.
Sometimes fragments are removed from an embryo in the lab, by making a small hole in the shell and sucking out the fragments on day 3. This is done at the time of hatching since the hole is the same. The embryo can look much better, but we do not know if it means the embryo is really in better shape.

Can we reduce a woman’s chance of producing fragmented embryos? We try, but we never know if our efforts helped, or things improved as a result of chance. We add lupron, remove lupron, add LH, remove LH, lower doses, increase doses, give few days or more days of stimulation, etc etc.

So what’s worse, a slow embryo or a fragmented embryo? Of course it depends on how slow or how fragmented, but basically, it’s a tie
An important issue here is that if you have done 1-2 cycles of IVF, and you make eggs and embryos and have fragmented embryos, donor eggs may still not be necessary. Get a second opinion at the best program possible. Maybe DE is the best thing for you, but maybe another try under different conditions will do the trick.

Thanks for reading, and please read disclaimer 5/17/06.
Dr. Licciardi

14 Comments:

Anonymous Lisa said...

Thank you for your always-informative blog. I am done pursuing IVF with my eggs, but I did three cycles. Two at 42 and one just after turning 43. The first one yielded 0 eggs, so no embryos to talk about. But with a protocol change I got pregnant with both subsequent cycles and lost both after seeing the heartbeat due, we presume, to age-related chromosomal issues. What I'm still trying to reconcile is the fact that our embryos looked "perfect" at face value. (We did not do PGD for fear of doing more harm than good.) In one cycle we transferred 4 best-quality 8-celled embryos (85% fert rate); in the other we transferred 3 best-quality 8-celled embryos (100% fert rate). This part haunts me. Why did they all look so good? And what does this say about the relevance or true predictive value of anyone's grading system? It just seems that if all my eggs/embryos are doomed to fail due to my age that we'd at least see poor fertilization rates, and/or so-called poor-quality embryos, and no pregnancies to begin with (which is of course what we got without ART). Or does age make all other criteria moot?

Also, is it possible that there were any "actual" good embryos that just didn't implant for some reason? I'm guessing the answer to that is "Maybe." But the assumption is always that it's the good ones that do . . . so is it reasonable to assume that the ones that stuck for me, for a while anyway, were the best of the bunch?

4:02 PM  
Anonymous MJ said...

I have heard recently that a better predictor of embryo implantation success is the oxygen consumption of the embryo. Are the big labs like yours doing this now? Plan to do this soon?

This is an excerpt from a Dec 2008 article on the subject: In fertility treatment, doctors decide which fertilized eggs are best for use by judging the shape and condition of the eggs using a microscope. However, this method lacks precision as it relies only on physical observations, and the rate of pregnancy using such eggs for the procedures is only 20 percent to 30 percent. [...]

However, fertilized eggs also consume oxygen, and Takafumi Utsunomiya, director of St. Luke Clinic in Oita, measured the amount of oxygen eggs breathe by measuring subtle changes in oxygen concentration in a culture solution surrounding the egg. The technique was developed by Tohoku University and Yamagata University.

7:58 AM  
Blogger Lisa said...

Thank Dr. L!!

7:52 AM  
Blogger Suzanne said...

I'm almost 39 years old and have had 2 failed cycles: 1 fresh, 1 frozen. The fresh cycle went very well with 16 eggs, 11 fertilized and 5 blastocysts. My RE is very hopeful that we'll have a successful cycle.

I also have Hashimoto's thyroiditis and my last TSH level was at 3.4. In your opinion, what is an optimal TSH level for a successful pregnancy? We're getting ready to start another fresh cycle and I'm hopeful we'll have just as many blasts this time. The last thing I want is to finally get pregnant and then miscarry.

5:00 PM  
Anonymous Anonymous said...

Dr. L-
I just found your blog and I'm hoping you can answer a question that I'm having a tough time finding any information about.

I am 38 (almost 39) and have been TTC since October 07. I've been under an RE's care for about 6 months and my FSH has always come back on day 2 at 10 or below. I was about to start my first IVF cycle and surprisingly my FSH was 16 (so we didn't go forward). The only thing that was different was that I started taking a very low dose of Zoloft one week before the test (I'm gotten very depressed trying to conceive). Could this have any effect on my FSH levels? No one seems to know for sure..

Please help -
Thank you very much.

P.S - I looked for a link to e-mail you privately but didn't find one - sorry if this is the wrong place for this question.

5:13 PM  
Anonymous Anonymous said...

MW - I am 35 years old and have done 1 fresh ivf cycle. I produced 12 eggs, 8 fertilized. I had a day 4 transfer of 4 grade 1 embryos (top rating) that resulted in a 6 week miscarriage. A gestational sac was seen, but no heartbeat. My doctor said chromosomal abnormality was the problem, but I am wondering if assisted hatching can increase the likely hood of miscarriage.

10:37 AM  
Anonymous Faith said...

Hello. Unsure if this is the correct place for questions or not...
I am 33yo, been being treated by fertility specialist since 1996 when was diagnosed as Unexplained Infertility. Two ectopics resulting in loss of both tubes. One fresh IVF cycle and 2 frozen cycles...none resulting in pregnancy.
My cycle is completely normal, my uterus is healthy, my hormone levels are all acceptable. All IVF cycles, I took Lupron as well as PIO shots, with suppositories added day of transfer.
My question is if it is possible that this is too much progesterone? Is that a possibility? If all else is normal, could this be causing too thick of a lining and preventing implantation?
I am at a loss. My DR says no, this wouldn't have been the reason. But, he has no reason why I am unable to conceive with IVF, just that I haven't.
Was just wondering what your opinion was.
Thank you.

2:57 PM  
Anonymous JenDennis said...

This is such a great blog, thank you so much!!! I'm only 25 years old but I was diagnosed with stage 4 endometriosis. I never experienced any symptoms or pain, I switched to a new gynecologist, he felt the massess and sent me to an RE. I've had two surgeries to remove endometriomas in my ovaries, both about the size of a softball. I was told that everything after my last surgery looked good and was fuctioning properly. My husband had a vasectomy and we planned to have that reversed but we're told our only option is ivf and not to bother with a vasectomy reversal. Is ivf really my only option? My last lupron injection is wearing off and we need to make a decision.

5:50 PM  
Blogger Springroll said...

Hello, Dr. Licciardi -
First off, thank you so much for giving us the information and the opportunity to learn more and ask questions. I am 37 yrs old, originally diagnosed with unexplained infertility, slight male factor (inconsistent morphology). However, I have gone through two failed IVF cycles - the first one was converted to an IUI due to lack of response (5 follicles, all slow to grow). In the second cycle, I had 6 follicles, all showing much better growth. With six eggs retrieved, only one fertilized with ICSI. This one embryo was 10 celled on the morning of Day 3 transfer, and the embryologist guessed that by the time of transfer (2pm) it had likely split into a 12 celled embryo. The RE indicated that while it was okay, it wasn't ideal. Unfortunately, we did not become pregnant. In my estimation, the fact that the embryo divided that quickly would be a positive, wouldn't it? I know that slow division is not ideal, but why would fast division also be a problem?
As well, the embryologist indicated that I have a "serious egg issue..." Any advice on where to go from here? I have a follow-up appt with the RE on the 11th of February.
Thanks in advance...
-Springroll

3:21 PM  
Blogger Mo and Will said...

Thank you for the additional info. This is so helpful, and an incredible service to infertile couples. I would love to know even more about fragmentation - e.g., for the pics you showed, how much fragmentation is there in each one?

Would love to know your take also on fragment removal - do your embryologists do it as a matter of course even though it is unclear if it helps?

Thank you again!

11:47 AM  
Anonymous Anonymous said...

It seems to me that there is no way to predict which embryo will take and which one will fail to implant, especially on day 3. And yet all over the blogs and boards I often see the term "poor egg quality". There are so many protocols and each one can affect the IVF cycle significantly. It's as if the RE shrugs his shoulders and all too often concedes defeat by irrevocably diagnosing the patient with "bad egg quality".
What exactly is the definition of "poor egg quality"? And when is it advisable to try donor eggs?

10:22 AM  
Anonymous Emotional said...

I'm so glad I found this blog. I thought I read the entire internet on fertility but your blog is so informative.

I am 28 years old and was on birth control for 8 years for mentstrual pain. My second month off of the pill last summer, my husband and I got pregnant naturally. At 6 weeks 3 days I had to have surgery for an ectopic pregnancy and they removed my left tube. During the surgery they noticed that my right tube looked "deformed" and tested it with dye and determined it was completely blocked. About two months later I started my first IVF cycle. I had the office hysteroscopy and my uterus looked fine. My lining was thin (5mm) at the time of retrieval and transfer and I didn't get pregnant. After my bleed my period was about 10 days late.

In January I started estrogen to prepare for an FET and at day 10 my lining was even thinner (4.6mm) so they checked again two days later and cancelled my cycle. They said that next time they will try without the estrogen b/c my lining might be responding "negatively" to the hormones, since the hysteroscopy was fine but during the fresh cycle and estrogen cycle the lining was thin.

My question is aren't the chances of a successful FET less than a fresh cycle to begin with, and a "natural" FET cycle even lower? Could my body really be reacting opposite of what the estrogen should be doing?

I started acupuncture a few weeks ago hoping that it would help stimulate blood flow. I'm still waiting for my period, though... I'm on day 36.

3:35 PM  
Blogger Shelley said...

I just found this blog as I am feeling a bit of the 'infertile blues' and was googling. It was great to see the pics of the embryos. I have 4 yo twins - courtesy of ICSI - when they transferred I saw the 2 (of 4) that were transferred - one reminded me a bit of a 'shaggy dog' compared with the other that looked more like the text book pic they showed me (I didn't know about fragmentation - until today in your post). My question is: one of my twins has Trisomy 21 (Down Syndrome) is it likely that she was the more fragmented embryo? BTW - I have to say that she is adorable - so I am not complaining - just curious. Thanks

12:41 AM  
Blogger Wordgirl said...

Dr. Licciardi,

My husband and I recently underwent our first IVF cycle. I am 36, nearly 37, and we'd been trying for a number of years before pursuing and failing at a number of IUI's -- until finally I went to an RE here in the Twin Cities and I was diagnosed as having 'pcos-like' ovaries. My husband had a mild male factor and so our doctors suggested icsi and a fairly standard protocol of bcp, lupron, menapur and follistim.

We retrieved 9 eggs, all of which were mature and 100% which fertilized. They called me two days later to tell me 8 were developing "wonderfully" and again on the fourth day after the ER. On the transfer date the doctor showed us the picture (of 2 blasts) stating that they were nearly perfect, and gave us a rating by his system that was just below what is considered perfect, which, he said, was rare.

When we asked if we had ones left to freeze he said that we had one, two, three, four blasts...and two which were morulas -- and then he said "which is practically unheard of."

I don't know this doctor well, he's the partner of the woman I've dealt with mostly -- and I didn't get to ask the questions I wanted which was:

Does this answer questions about my egg quality at all?

Best,

P/Wordgirl

9:22 PM  

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