A Transcript from our Andrology/Embryology Forum on 3 Day Transfers vs Blastocyst Transfers

Dr. T. Timothy Smith

Lauren asks:
You said that you only/prefer to transfer embryos from ICSI in the blast stage. I am 36 and had three grade 2 (1 being best), 10 cell, day three embroys implanted (still waiting for results). My other 4 fertilized eggs did not make it to blast for freezing. This is our first IVF attempt. Would you have risked the ones that were transferred to try to get them to blast? I was even bummed they didn't freeze the other four on day three b/c I can't see risking any embroys given I didn't have a lot and I am 36.

The point of growing embryos to the blastocyst stage in the laboratory is to deliberately weed out the embryos that do not have the genetic potential for continued growth. The "risk" you speak of doesn't really exist. If they're gonna make it, they do. If they don't, they don't. Of course, there's always the "risk" that no embryos make it to the blastocyst stage in the laboratory, but (because the problem is related to the genetics of the embryo, not culture conditions in the laboratory) they wouldn't have made in the uterus either.

I hope this clears things up. Good luck. I hope things work out for you.

Lauren asks:
Thanks so much for your reply. So I guess you are saying that the only successful pregancies with IVF are with those embryos that would make it to blast. It also makes sense that your better off growing embies in a good lab that can mimic tubes. But then, if that's the case then why not grow every embryo to blast and then transfer those that make it. It seems to me that most transfers today are with three day embryos.
I also read that most ICSI embies don't make it to blast but I also know that ICSI rates are similar to IVF w/o ICSI. (I think I already mentioned this)

Then us anxious chicks would not have to wait and wonder if our embryos are implanting and growing!

Again, I look forward to your reply

Dr Smith replies:
You are correct that only the embryos that make it to the blastocyst stage (and beyond) can generate a succesful IVF pregnancy. In my lab, and many others, all embryos are grown to the blastocyst stage and only well developed blastocyst stage embryos are transferred to the uterus on day 5 or 6. Extra embryos are cryopreserved at the blastocyst stage.

Why aren't all programs doing this? There are numerous reasons for continuing to perform day three transfers: its cheaper, its less work for the lab, lower liability because the lab has the embryos for a shorter period of time, everybody makes it to transfer, if the cycle doesn't result in a pregnancy, the program can still look good, etc. You'll notice I didn't say anything about a day 3 transfer improving your chances of getting pregnant - it doesn't. The reason programs continue to transfer day 3 embryos is because its more convenient for the lab and the docs.

However, growing the embryos to the blastocyst stage prior to transfer does not automatically result in a pregnancy. Because the embryos have reached the blastocyst stage prior to transfer, its reasonable to assume the embryos a capable of implantation. BUT the embryos are transferred to the uterine cavity and they still must attached to the uterine wall (endometrium) and continue the implantation process for 10 ten days before a "pregnancy" is established. The attachement and implantation processes are currently beyond our control and these represent the crap-shoot in all of this.

At least with blastocyst stage embryo transfer you know the embryos are capable of implantation. When day 3 transfers are performed, its completely uncertain as to whether or not the embryos made it to the blastocyst stage (unless there's a pregnancy). If you don't become pregnant, you're left hanging. What went wrong? Were my embryos O.K.? Should I do this again??? Of course, your doc's answer will likely be "Yes" since that keeps him in business. As you can see, there's a potential sinister side to day 3 transfers...

Success rates with ICSI can be deceiving. Programs vary in their criteria for performing ICSI. Some perform ICSI on everybody (probably so that they can charge for it), some perform ICSI when there is the slightest indication of a problem with the sperm while others (like mine) only perform ICSI when there is a serious problem with the sperm. When ICSI is performed when there is no problem with the sperm, the success rate is almost as good as that following conventional IVF insemination. However, if ICSI is performed for severe sperm problems, the success rate is quite low - even when the embryos are grown to the blastocyst stage prior to transfer. Its not the ICSI per se, severe sperm problems impact embryo growth before and after the blastocyst stage of development.

Hang in there. Hopefully at least one of your embryos toughed it out and you'll get good news soon.

Lauren asks:
Thanks so much for all the information you have provided to me. I still have a question regarding the prevailing practices on when to transfer.

After reading your last response to my question, I did MORE research. It seems like clinics able to grow embryos to blast do so based on basically # and quality of embryos and age of female. They will not risk loosing embryos if they don't feel they will grow to blast in the lab. If there is doubt as to whether the embryos will make it to blast, they feel the body can handle growing the embryos versus the lab.

This is my clinics approach. They put the best three in me and left the rest to grow to blast. I was not given details on the quality of my remaining 4 embryos (which actually really bothers me and I plan to get that information.)

So what do you think? Do you in your lab do any day three transfers?

I hope this will be my last question and again I look forward to your reply.

Dr Smith replies:
I am thoroughly enjoying our dialog as it gives me an opportunity to get on my soapbox about day 3 transfers. Thanks for the chance to vent

You're right that many programs will transfer the embryos on day 3 when they are concerned that the embryos may not develop to the blastocyst stage. HOWEVER, its not because they feel the embryos will do better in the uterus. They know there's no scientific evidence to back up this assumption. It is because they do not want to face the patient and infom them their embryos failed to reach the blastocyst stage. They are afraid that you will think the embryos failed to grow because of suboptimal lab conditions. As I explained, the embryos fail to reach the blastocyst stage because they are genetically incapable of doing so, not because anything anybody did or didn't do. In our program, we attempt to grow ALL embryos to the blastocyst stage. We have at least 1 blastocyst stage embryo for transfer 96% of the time.

You'll notice in your research into the pactices of other programs that no programs claim that their pregnancy rates improve when failing embryos are transferred to the uterus on day 3. The rationale for a day 3 transfer is to get out from under the "blame" for the failing embryos. By transferring failing embryos on day 3, the program also transfers the responsibility for the subsequent failed cycle to the patient. It is a subtle manipulation of the patient's emotions. Here's the scenario: "We're so sorry the cycle didn't work, but you know the embryos were still growing when we transferred them. We don't know what you did to them afterwords. Wanna try again?" Using this pyschological manipulation, it becomes the patient's fault the cycle didn't work, not the programs's. See how it works?

I am not implying that they transferred your embryos on day 3 because they were failing. They were fine. So when I talk about this manipulation, it doesn't really apply to you. I'm writing this for the benefit of other patients who have been manipulated.

Lauren asks:
I too have enjoyed our discourse and I am printing out everything so I have it as ammunition and information for the future. For now, I had a beta today (ten days after transferring three, three day old embryos). It came back 103. I am extremely relieved and cautiously excited.

But back to your information. After much research, I absolutely agree with your point of view. I am a very logical, analytical person and what you are saying makes the most sense in all this hocus pocus of fertilty. Before I found out about our success (to date) I was ready to head to NYC and see you!

The key is finding a clinic that can bring those embryos to blast. For now I am going to think we won't have to worry about this for a while!

Are there other clinics that you know of that are bringing all embryos to blast?

Wow, what would I do without the internet?!!!
As an aside, how far do you think the IVF community is from getting to where your clinic is? I realize I said no more questions but. . .

Thanks again and for now, you have successfully answered my questions and made me a informed patient.

Dr Smith replies:
CONGRATULATIONS!!!!!
I am very for you and your dh. Your beta hCG is in a good range for the number of days post transfer. Cautious optimism is in order, but things look good so far.

In my posts I was trying to debunk the hocus pocus. We're no magicians. We're just folks doing our job (and what a great job it is!). After many years in the IVF lab, my attitude is to do the very best job I can and then whatever happens, happens. So much of this is beyond our control. If I know I did my best, then I can sleep well at night.

As far as the number of programs who attempt to grow all embryos to the blastocyst stage, there are several thoughout the country. Many of the large programs have attempted blastocyst culture, but returned to day 3 transfers because they had trouble getting the embryos to grow the the blastocyst stage. Growing the embryos to the blastocyst stage requires great attention to detail - a luxury not afforded in a big program performing dozens of procedures a day. Programs performing less than 200 cycles per year have had the best luck with blastocyst culture and transfer with reported (but unverified) pregnancy rates in the 50-70% range for younger patients and egg donor cycles.

I am extremely fortunate to work with an RE (Dr. Jane Miller - shameless plug!) who believes in attempting to grow the embryos to the blastocyst stage prior to transfer. We both realize the importance of patient education in all of this. We spend a lot of time speaking with patients before an IVF cycle so that they understand what the lab can and cannot do. From these discussions, they have realistic expectations and experience less stress during the cycle. Unfortunately, many RE's have way too much ego tied up in their work and will do anything to make themselves look good to the patients (including day 3 transfers). Until RE's decide to accept the fact that the outcome of much of what they do is outside of their control, they will continue to take credit for the successes and shift blame elsewhere for the failures.

There, I've said my peace.

I hope our online discussions will benefit others and give them the information they need to ask the right questions of their doctor.

Tangeroo asks:
I have read with great interest the dialogue with Lauren on this issue. I am presently trying to decide what to do for my second ivf attempt (more about that later). I have been scouring the 'net for as much info as I can get on the pros and cons. One article I was able to get through my RE was called "To Blast or Not to Blast?" recently published, one of authors is from Boston ivf. That article suggested that it was not that clear cut that 3 day embies that don't make it to blast would not have continued to grow and implant if transferred earlier. Other articles I have read state that the real benefit to blast is just avoiding high order multiples, not any difference in pg rates. I also read an article suggesting that sequential transfer (both 3 day and 5 day on the same patient) could have some benefits with the 3 day'ers somehow paving the way for the blasts -- something about cytokines (sounded suspect to me though).
Back to me now, my first ivf we got 25 eggs, 21 fertilized, 12 looked really good on day 3, so we decided to blast. On day 5, we transferred 2 great looking blasts and ended up with 5 to freeze (4 on day 5, 1 on day 6). Still, no success. My RE was surprised that it didn't work because everything looked indicative of a high chance of success. I just turned 37, have pco, normal range fsh (5.5).

For this next cycle (assuming similar fert etc results), my RE is giving me the choice to go 3 day or 5. She suggested we could try 3 with or without AH just for the sake of trying something different. That for some patients day 3 seems to work after day 5 did not. (She admits this is not scientific).

At this point, I am leaning toward another day 5 try, but if this doesn't work, on the 3rd cycle go try day 3.

In addition to any comments you may have on the articles I have read, my questions to you are, in your experience doing almost all day 5 transfers, have you had any patients who had good looking but ultimately failed day 5 transfers then switch to day 3 and have success?

Also, if I can slip in a question about AH, is there any benefit to be gained from doing it if it is not obviously necessary? i.e. if the zona doesn't visually appear to be too thick.

I will be looking forward to any thoughts you have.

Dr Smith replies:
You're right that it can never be "scientifically proven" that embryos which failed to develop in vitro might have continued in vivo (in the uteus). However, when embryos that failed to develop in vitro are analyzed for genetic abnormalities, a very high percentage had gross genetic abnormalities strongly suggesting that they were of limited devlopmental potential.
With regard to the article from Boston IVF, they same author recently gave a lecture on this subject to our local ART group (New York Society for Reproductive Medicine) and concluded that since their lab (performing in excess of 2000 cycles per year) had difficulty in growing embryos to the blastocyst stage AND since insurance reimbursement was the same for day 3 and day 5 culture of embryos, its better and more profitable to transfer on day 3. He also mentioned that you usually have some embryos to freeze on day 3, so you could charge for that too. Get the picture

Avoiding high order multiple pregnancies is a real benefit of blastocyst transfer. However, you are correct that the jury is still out as to whether or not pregnancy rates are higher with blastocyst stage embryo transfer. Pregnancy rates depend on many things besides the stage at which the embryos are transferred (i.e. the skill of the RE in perfroming the embryo transfer). What is VERY clear is that the implantation rate for blastocysts is 2-3x higher than day 3 embryos. I believe that in time, as more physicians get used to the idea of culturing embros to the blastocyst stage prior to transfer, blastocyst transfers will become routine. You see, I remember in the early nineties there was a great hullabalu associated with extending embryo culture from 2 days to 3 days. When the benefits became well known and accepted, day 3 transfers became the norm. I think the same will happen again with day 5 transfers.

The paper on sequential embrtyo transfer (day 3 followed by day 5) is BS. You were right to be skeptical.

For your upcoming cycle, I believe that you should stick with day 5. HOWEVER, I'm a firm believer in assisted hatching (for everyone) and think this might be the key in your case. I perform assisted hatching on all blastocyst stage embryos a few hours prior to transfer. This is a tricky protocol that few people know or perform, so have the embryologist at your program e-mail me for the protocol. We saw a jump in our pregnancy rate when I started hatching blastocysts prior to transfer, so I know it works. I also hatch all frozen-thawed blastocyst stage embryos prior to transfer.

I realized that I didn't answer one of your questions.
We've never had a patient attain a successful pregnancy with a day 3 transfer after failing a day 5 transfer. However, once we changed to blastocyst transfers 2+ years ago, we have never performed a day 3 transfer. For us, blastocyst culture and transfer has worked out great. See below for mid-year 2001 stats for our program:

88% of our patients make it to retieval and of those that do, 94% make it to transfer.

<36 yr old 52% ongoin preg per retrieval
36-39 yr old 48% ongoing preg per retrieval
40+ yr old 4/8 ongoing preg (50%, but not so reliable because number of patients is low.)
Donor egg 88% ongoing preg per retrieval

Last years stats weren't quite as high, (36-44% ongoing or live birth for patients <40 yr old, 63% for donor egg) but that's before I was hatching the blastocysts. Hatching made a difference.

I don't see any programs using day 3 transfers with these kinds of stats, so I think we're doing something right.