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Thank you so much for your informative reply, Dr. Smith. I guess only time will tell. I won't get my hopes up too much at this point. I'll let you know the outcome in a couple of weeks.

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Dr. Smith,
You replied to a question I posted earlier, and I really appreciated your response.
Yesterday I had the retrieval of my 4th IVF. My RE, it seems, finally found the right protocol for me, and I stimmed very well on Menopure and Cetrotide. From our experience, my eggs need time to mature and are found to be best in the larger follicles. So I stimmed for 14 days with the largest follicles reaching 28-30mm. Of a total of 24 follicles, 14 eggs were retrieved - my best yield yet. 7 were mature and looked very good. They were all ICSId (there's no sperm problem, but after 3 previous failed attempts our RE decided to take all measures).
Today (day 1) our RE called and said none of the eggs fertilized. He was in shock. They're still following them to see if maybe there was late fertilization, but I know the chances for that are close to zero. Our clinic and RE are very reputable. It seems like everything went so well this cycle. Do you have any thoughts on what could be the problem and whether it can be dealt with?
(I'm 34, day 3 FSH 4.7, LH 2.2, E2<30)

thanks, allison

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Fragmentation usually shows up early, in the first couple of days. The fact that the embryo reached the 4-cell stage without exhibiting framentation indicates that what you saw on Day 4 were true cells, not fragments. The cells get pretty smal by the time the embryo reaches the morula stage and can be confused with fragments if you don't know how much fragmentation was present at the earlier developmental stages (confusing even for embryologists). I would be more confident if the embryo had initiated the compaction process prior to transfer, but as such, a morula on Day 4 is considered developmentally "on time".

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Allison:

Every once in a while we get thrown a curve ball. I do not have a good explanation for what specifically went wrong. When ICSI fails to activate the eggs (assuming the ICSI was performed properly by an experienced embryologist), the problem lies with the cytoplasm of the eggs. This can usually be explained by inadequate cytoplasmic maturation caused by not waiting until the follicles are large enough or cutting the stimulation too short. Neither of these conditions apply to your cycle. So, I'm sorry to say, I'm left scratching my head too. Curve ball.

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Thanks for the answer. We consulted another RE who seems confidant that the stimulation was way too long and that the eggs must have been post-mature. He doesn't think that it is right that my follicles need to be so big for the eggs to maure. Do you think this could be the case? Would this type of result -- no fertilization at all (7 eggs) with ICSI be consistent with eggs that are post-mature?

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Yes to both questions, but hindsight is 20/20. Failed fertilization due to post-maturity usually occurs with conventional IVF insemination, not with ICSI. That's why I didn't menion it in my previous post, but it is possible.

Also, be aware that whenever you go for a second opinion, the new doc will find fault with the old doc. These guys are highly competitive amongst themselves and sometimes patients get caught in the crossfire. You mentioned that you did better on previous cycles when the follicles were left to grow a little bigger. O.K., so maybe this time the doc went a little too far to try to maximize the number of good, mature eggs, but a shorter stimulation is worse than a longer one. Beware of docs that promote themselves by criticizing others. There's no absolute right or absolute wrong way to do this. Ovarian stimulation is not an exact sceince.

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I have just finished my 5th round of IVF however this time they also included PGS (Pre Genetic Screening). I am 34 years of age however due to operations have blocked tubes. My issue has always been the growth rate of the embryos they only ever seem to become 4 cell on day 3. This time round they carried out a biopsy on 4 embryos on day 3 however they were only 4 cells. So by removing one cell from each embryo they could check the chromosomes (genetic make up). On day 4 they result came back as normal however they had only gone on to the 6 cell stage 2 have been put back & I now have the dreaded 2 week wait....Can anybody offer any advice or even maybe some encouragement I don't know If i can go through it again.

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Dr. Doom-n-Gloom here. I know you are looking for encouragement, but I play the part of a realist on this board. If you're emotionally up to it, let me know. I'll give you the objective, scientific point of view. If you're not emotionally up to it, that's O.K. too. Waiting for the pregnancy test can be the worst part of the whole process. I understand. I don't want to contribute to your woes by giving you cold facts when you need warm feelings. Best of luck.

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Dr. Smith,
I posted previously and wanted to let you know that as expected my first IVF was unsuccessful (I had plently of fertilized eggs, but none that made it to 8 cells by day 3). I met with my RE and he wants my husband to do a thorough sperm analysis (FISH) w/genetic testing (personally I think it's a waste) and for me to try another IVF with PCG and a 3dt. I suggested your recommendation to do a 5dt and he thought since I've had a previous miscarriage, a PGD with a 3dt (if applicable) would be a better route to take. I've heard PGD can be expensive and am wondering if I should strongly request a 5dt and take my chances that they will make it to 5 days. What do you think? Do you have any idea as to why my eggs would stop developing after everything else went so well? I know they were genetically abnormal, but do you think another IVF with my own eggs is a waste of time and $? Or is there a chance that I just had a bad batch and next time the result could be better?

I am just at a loss here and would greatly appreciate your honest opinion. Thanks, Sam

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A paternal DNA problem doesn't really explain what you observed, since abnormal paternal DNA usually causes arrested embryo development later on (i.e. Day 4-5, or later during the first trimester of pregnancy). So I agree with you that a comprehensive genetic analysis of the sperm may not be worthwhile. Of course, it can't hurt either (except your wallet).

If PGD is performed on Day 3 (as it usually is), then the embryos would not be transferred until Day 4 at the earliest because it takes 24 hours to get the PGD results back from the genetics lab. What would be the harm in waiting one more day to be sure they reach the blastocyst stage? Hmmm, your doctor's recommendation doesn't quite make sense. The miscarriage has nothing to do with the choice to go to Day 5 or not. Obviously the embryo that resulted in the miscarriage made it past Day 5. And a single miscarriage is not a justification for PGD. Recurrent miscarriage is a justification, but that means 3 or more successive miscarriages. That's not your situation. PGD is expensive and will add approximately $3K to the final price. I think your doc is grasping at straws trying to explain the failure (which may very well fall within the "sh** happens" category) and trying to give you something different to look forward to on the next cycle. Personally, I'm not so gung-ho about the PGD at this point.

I think you should try again. Every batch of eggs is genetically different and there may be a good one in the next batch. Did your doc suggest a change in your stimulation protocol? That could have been a problem too and could explain (to some degree) the high embryonic arrest you observed. If the cytoplasm of the eggs had not had an adequate amount of time to mature (short stimulation, small follicles), it can cause arrested development (although your situation is a bit extreme for that explanation).

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Dr. Smith, thank you so much for your thorough reply. I honestly don’t think there is a problem with the sperm, but his reasoning was that since they can’t genetically test the eggs (other than from the PGD), it would show where the genetic abnormality came from by ommission or confirmation and it’s a pretty easy test to do, so why not, but my feeling is why if it’s not necessary.

I don’t know what the harm in waiting one more day for the 5 day transfer would be either, but he seemed to think if we waited until day 5, we wouldn’t have anything to transfer (not very encouraging). I think he mentioned the miscarriage because he was proving his point that although the embryo made it past the blastcyst stage, obviously there was something genetically wrong with it and if he did the PGD he’d know what was worth and not worth transfering. I guess.

My RE doesn’t want to change the protocol because he said he was pleased by how I responded to the meds, but obviously it didn’t work, so I was hoping to try something different. I had my retrieval on CD14, which seemed a little early. I really like your recommendations and am now wondering if I should see someone else or at least see if he’s open to longer stimulation and 5 day transfer. Is my situation common, where you get a lot of fertilized eggs that don’t make it to 8 cells on day 3? Do you think it would be a good idea to meet with another RE? I am Newport Beach, CA so I am lucky to have a lot to choose from nearby. I apologize for so many questions, but greatly appreciate your feedback.

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PGD is a very superficial genetic analysis. Of the 23 pairs of chromosomes, PGD can evalauate a maximum of 9 to determine if there's one extra or one short. That leaves 14 other chromosome pairs that could make trouble. In addition, the number of chromosomes in a embryo is only the tip of the iceberg from a genetic point of view. Subtle genetic defects (like single gene mutations) can lead to miscarriage and these cannot be identified with PGD at present. I think that PGD is being over-pitched by the ART community. It has become the "next big thing" in assisted reproductive technology, but in actuality, it is a very crude tool to determine the genetic normalicy of an embryo. Although PGD can reduce the chance of miscarriage in women with recurrent miscarriage, PGD does not prevent miscarriages altogether (not by a long shot). Beware the PGD sales pitch.

I think a second opinion is a good idea. Have another RE review your records and see what they have to say about the stimulation protocol, the necessity of the sperm testing, the PGD option, Day 5 transfer, etc.

Lucky you in Newport Beach. We're getting 6-8 inches of snow in NYC tomorrow. Catch some rays for me California Girl.

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Thanks again Dr. Smith, I think I will get a second opinion. It definitely can't hurt. WOW -- 6-8 inches of snow! I won't even say what the weather is like here, but I'd actually rather be in NYC, I love it there! Take care.

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Perhaps you could evaluate this situation for me...

I had a 5 day transfer of one blastocyst the other day. On day 3 it was a perfect 16 cell morula that my RE classified as "best quality", which I assume means, even cell division. and little fragmentation. By day 5 the blastocyst was only 40 cells... Is the fact that the growth slowed down a bad sign?

Thanks for any comments...

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Dr Smith,

I had 3 failed IVF cycles. Unexplained Infertility. Never had a BFP. Husband's sperm is ok. Both DH and I had genetic testing.
1st Cycle @ reputable University - Gonal-F, Lupron, 17 retreived but the ones that fertilised stopped dividing at 2-4 cells, poor quality. They transfer 4 anyway on day 3. After I got the bad news, I made some lifestyle changes in terms of diet, exercies, herbs, and reducnig stress.
2nd Cycle - Gonal-F, Lupron, 21 retreived, ICSI 10 and Inseminated 10. Only 2 fertised with ICSI and 8 fertilised naturally. They said they picked the best eggs for ICSI. Embryo quality was more than 5 times better than the 1st, 6-8 cells. The embryologist was afraid to transfer more than 3 in case of multiple pregnancy. None good enough to freeze. Day 3 transfer. After negative result, I made real strict lifestyle changes. Also my hormal levels mimmicked that of a PCOS patient ONCE. So they wanted me to take Metformin. I decided to try it (one month) and when I went to a new clinic, the dr. told me to stop. I have no evidence of PCOS, just once my levels looked off.
3rd Cycle @ a new clinic - Follistim, Antagon, 24 retreived, 18 mature, 14 fertilised. By day 3, 9 fertilised correctly and were doing well, grades 1 and 2. Day 5 transfer they starting slowing down, none were blastocysts. 4 were compacted moruelas and one 8 cells by day 5. No pregnancy. February 06. .
I paid for 4 cycles up front and will get my money back if I dont acheive pregnancy/delivery. This was my first cycle at this clinic. He's one of the top doctors in the city. He doesnt thinlk I have a genetic issue. I dont know if he did Assisted Hatching. My question is, what do you make of my situation? Do you think AH would be beneficial for a day 5 transfer? Do you think diet, exercise, herbs, stress can have help make this kind of improvement? Is it weird that less eggs fertised with ICSI than without, especially since they picked the best quality eggs for ICSI?

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The major difference between cycles 1-2 and the third one is the absence of Lupron. Apparently, you respond better without Lupron. Some folks do and it looks like you're one of them. You new doctor gavit a try without Lupron and you had a better (more physiological) stimulation that resulted in better embryo development. Embryos at the compacted morula stage on Day 5 are within the expected range. When we observe this in our program, we wait until the morning of Day 6 to be sure they have reached the blastocyst stage before transferring them. They usually do, so no harm was done by transferring them on Day 5 at the compacted morula stage. However, the 8-cell had arrested, so there was no point to transferring that embryo.

It has been my experience (and that of others) that assisted hatching of blastocyst stage embryos immediately prior to transfer improves implantation rate.

The developmental potential of eggs cannot be assessed by just looking at the them. Hence, chosing the "best" eggs by their appearance is misleading. Your ICSI results make my point. The developmental potential of eggs lies in their genetic normalicy which cannot be determine by looking at them at the time of ICSI or insemination.

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