icsi and blastocyst development
9 Replies
wrenster - December 3

Hello

I posted a couple of weeks ago about success with icsi and pesa/tesa etc and since your reply I have had a follow up appt with my clinic, and I have done some of my own research.

You are very much of the view that in vitro development of embryos to blastocyst stage is no different to in utero development, the advantage being better embryo selection at blastocyst stage.

I did discuss this with the doctor briefly at my follow up and he said that with icsi this is a contraversial area and that they might do better in utero in this case - hence need for day 3 replacement.

By chance I was searching through clinical papers on a database at work and had printed off some to read. One of them (In Human Reproduction I think) was a study looking at blastocyst development with icsi and ivf. It compared sibling oocytes by dividing them up with some for icsi and some for IVF and looking at blast development. The IVF ones achieved double the number of blastcysts vs the icsi ones. The paper then went on to say that implantation rates have been shown to be the same for icsi and IVF in many previous studies with day 2/3 transfers . Thus it concluded that icsi embryos may not develop as well in vitro as they do in utero.

I think this might have been what my doc was thinking of when he said it was contraversial. What are your views on this? I am trying to make sense of the best way to proceed in our next icsi. I am now not sure if proceeeding to blast would be the best option for us.

Regards
Wrenster

 

Dr Smith - December 5

I agree with your doc. The whole in vitro versus in vivo thing is controversial. I think it is, to some degree, lab dependent. Culturing embryos to the blastocyst stage requires a higher degree of control of lab conditions and an attention to detail above and beyond that of Day 3 transfers. Some labs struggle with this - especially high volume labs.

When interpreting studies that compare blastocyst development following ICSI or IVF (or, for that matter, any comparison involving blastocyst development) it is important to consider the blastocyst development rate. Overall, in a good lab, about 40-70% of the embryos should develop to the blastocyst stage. Studies that report blastocyst development rates significantly below this are using suboptimal culture methods. In those studies, in vivo development may very well be superior to in vitro development. At the very least, it is not a valid comparision.

There are many reports suggesting that blastocyst development is lower if ICSI is used (my study included). However, there are two factors to consider. In most programs, ICSI is performed when there is a problem with the sperm. The effect of poor sperm quality has to be considered. This is particularly relevant when TESA and PESA sperm are used. This brings up the question of genetic normalacy of testicular or epididymal sperm. The one thing that in vitro or in vivo culture cannot change is the genetics of the embryo.

The other factor to consider, all things being equal, is the ICSI procedure itself. There is at least one study that I'm aware of that concluded that if ICSI is performed when there is no problem with the sperm, the blastocyst development rate is significantly lower than conventional IVF insemination in sibling oocytes. However, since TESA and PESA sperm require ICSI to achieve fertilization, the point is moot.

 

BekyVice - December 6

I'm interested in what you just said, about a study finding ICSI to significantly lower the blastocyst development rate than conventional IVF, when used with normal sperm.

Two questions:
1) Is it a common procedure to take 1/2 the eggs retrieved and perform ICSI and the other half leave in the petri dish to see if "ships meet in the night"? Has this ever been requested of your clinic? (My DH has low morph, mot, count... but not absent. We retrieved 15 eggs last time, all fertilized, day 3 all great, but downhill on day 4 and day 5 only 1 good blast to transfer and nothing to freeze.)

2) Speaking of studies... is there anything known about any "harm" done to eggs by putting them through assisted hatching? I know the "standard" is to AH any >40 y.o. maternal eggs, but wonder if we can try some AH and some not.

 

Dr Smith - December 6

Some clinics will split eggs and ICSI one half and use conventional IVF insemination on the other half. This is performed in cases of "unexplained infertility" because the cause for the infertility may be failed fertilization (although quite rare). So, they don't take any chances and ICSI half. The vast majority of the time, failed fertilization can be avoided by performing a thorough semen analysis (including strict morphology) on the day of the egg retrieval. A small percentage of the time, everything can look fine from the sperm side of the equation and failed fertilization is a result of a defect in the eggs that prevent sperm penetration.

As a follow up to my previous post, the first study below concludes that the ICSI procedure itself may be detrimental, the second two studies refute the first study. Even after all these years in use, ICSI is still controversial.

Hum Reprod. 2000 Jul;15(7):1592-6.
Embryonic development in vitro is compromised by the ICSI procedure. Griffiths TA, et al.

Fertil Steril. 2005 May;83(5):1397-403.
Blastocyst formation in in vitro fertilization versus intracytoplasmic sperm injection cycles: influence of the fertilization procedure. Van Landuyt L, et al.

J Assist Reprod Genet. 2003 Mar;20(3):113-6.
Effect of ICSI on subsequent blastocyst development and pregnancy rates.Westphal LM, et al.

When there is a moderate/severe probelm(s) with the sperm ( and, accordingly ICSI is performed), we have observed that a significant number of embryos arrest between 8-cell and compacted morula stage (the stage immediately preceeding the blastocyst stage). This underscores the rationale for waiting to the blastocyst stage for transfer - everything looked "great" on Day 3...

Hum Reprod. 2001 May;16(5):918-24.
The effect of intracytoplasmic sperm injection and semen parameters on blastocyst development in vitro. Miller JE, Smith TT.

When performed by an experienced embryologist, AH does no harm the embryo. Several studies have shown AH on Day 3 to be helpful, while just as many studies have concluded that it doesn't make a difference. The effectiveness of performing AH on Day 3 is still controversial. However, everybody seems to agree that it can't do any harm and it may help in certain patient populations (i.e. >40). Assisted hatching is performed immediately prior to transfer and it would be unusual to perform AH on one embryo and not on the other. AH is approached as an all-or-none.

 

BekyVice - December 6

You are, of course, wonderfully thorough and helpful.
Thank you for your time.

 

wrenster - December 7

Hello and thanks for your reply to my question about blast development. One of the papers you listed above was the paper I referred to originally where ICSI and IVF were compared using sibling oocytes and the same (healthy) sperm. The last 2 you listed (including yours) were ones I had not seen before and have now read - thanks!

I'm trying to get things straight in my head to help me make decisions about my next treatment.

The evidence seems to suggest that having ICSI (even if with healthy sperm) means blast development is compromised vs IVF. However there is also evidence that suggests IVF and ICSI success rates are similar (with healthy sperm at day 2/3 transfer) wrt implantation. Thus the conclusion I am coming to is that in vitro blast development may not be as effective as in vivo and implies that it would in fact be better to replace icsi embryos at day 2 or 3.

However at the same time your study shows that many embryos arrest at day 3/4 with icsi often even if they looked good at day 3.

So this leaves me unclear about which should is the optimal route to take with my next treatment.

In my last situation I had 5 'average quality' grade 2-3 embryos (scale 1-5 where 1 is best) and the embryologist said that there were 2 that were slighltly better than the others at day 3. These were subsequently replaced. I did not see the other embryos but I did ask if it was possible to leave them to develop to blastocyst and I was told that they had no hope of developing. In your experience, from your study, do you think that this is correct - or could any of the less good embies have gone on to form a blastocyst? Did your study simply conclude that not all good quality embryos make it to blastocyst stage, or did you observe poorer quality ones making a 'comeback' on day 4 or 5?

Would you have advised the same thing if it were in your clinic?





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Dr Smith - December 7

Another cautionary note when evaluating studies that compare Day 2/3 transfers with blastocyst transfers (whether they are looking at ICSI or not) is that the same number of embryos are transferred in both arms of the study. It is often the case that more embryos (often up to twice the number) are transferred on Day 2/3 than on Day 5. Thus, they are not comparing apples with apples.

Many of the older studies comparing Day 2/3 v. Day 5 (ICSI or not) were performed using culture systems that are now obsolete. The relatively recent (last 5-6 years) incorporation of FDA-approved sequential culture media systems and more stringent laboratory conditions (i.e. pH control, 02 reduction, removal of airborne contaminants, etc.) have resulted in much more "healthy" blastocysts with significantly improved developmental potential. We are much closer to the "in vivo' environment today than we were 7 years ago. I would say a critical factor in deciding in vitro or in vivo embryo culture (whether ICSI'd or not) is to determine the experience and degree of success your particular lab has with blastocyst culture. Unfortunately, there is still considerable variability between labs with respect to blastocyst culture. You are as unclear as the rest of us and I don't think there is an absolute "right" answer in your case. I know, I know, not much comfort am I?

With regard to the "comeback kids". On several occasions I have observed embryos deemed to have marginal or poor developmental potential on Day 3 make a comeback and reach the blastocyst stage, usually on Day 6. However, not all blastocysts are created equal. The number of stems in the inner cell mass of the blastocyst is of critical importance for future development. It is often the case that these marginal embryos develop to the blastocyst stage, BUT do not contain an adequate number of stem cells for term development. These blastocyst stage embryos, if transferred, often result in "chemical" pregnancies or early miscarriages.

In that particular study, we were really interested in the impact of crappy sperm on blastocyst development, not the effect of ICSI per se. ICSI was more of a complicating variable in our study rather than a separate variable to be evaluated. Crappy sperm mandated the use of ICSI. We did not ICSI with "normal" sperm. Those studies had already been done with ambiguous results (as you found out). What we found (and had suspected) was that when crappy sperm was used for IVF (mandating the use of ICSI), fewer embryos that looked good on Day 3 (as well as those that didn't look good) made it to the blastocyst stage. Those that did make it to the blastocyst stage were of poorer quality (i.e. fewer stem cells) than those embryos derived from conventionally inseminated eggs with "good" sperm. Thus, we determined that just performing ICSI does not "cure" male infertility, although it does improve fertilization markedly in cases with severe sperm problems. Up until then, ICSI was being toted as the "magic bullet" for male inferitilty. All things being equal on the egg side, crappy sperm leads to crappy embryos. We and Denny Sakkas published on the same topic within a few months of each (although we didn't know the other was working on the say track). He found very simmilar results, which was comforting.

 

BekyVice - December 7

Reading all of your above thoughts... my question is:

If we should try ICSI with a donor egg program (assuming at 42 that my eggs have no hope), would chances be great, then? Or just as iffy.

[Background: DH has low count and morph and motility, when we retrieved 15 good eggs from me, 13 fertilized, but at day 4 things went downhill and only one made it to blast, but it was grade, the highest. Chemical pregnancy resulted.]

My clinic has a 59% success rate with donor eggs, but they don't post the ages of the recipients. What factors would make young (proven good) eggs + ICSI not work? Each time I went for blood tests during my ICSI IVF cycle with own eggs, they came back "great." Lining was "great." All doctors and nurses gave us high hopes of it working, but it didn't.

Is this a case where PGD would make sense? (I don't know about PGD process... does this hurt the embryo and give it less of a chance?)

 

wrenster - December 8

Thanks very much for clarifying things and taking the trouble to search out clinical paper references etc. Its all so fascinating!! I guess the best thing I can do is find a clinic where everything is as optimal as possible and where they have good blastocyst development rates, then hope for the best! I think that could be quite difficult here (UK) as most places seem to do day 2/3 routinely and blastocyst development is the exception.

Regards

Wrenster.

 

Dr Smith - December 9

Not sure why Day 2/3 transfers are so popular in the UK, but they are. Maybe insurance re-imbursement is so low they don't what to take a lot of extra time to develop the embryos to Day 5. I guess they think its better if your uterus does that for free. Same here in the US for programs that accept only insurance.

 

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