How are embryos tested and how many should you transfer in IVF?
I guess you could say that a few factors led me to look into the topic of embryos.
For one, we're don't feel very informed on what it really goes into determining how many embryos will make to a quality high enough for transfer, from those that do make it, how you and your doctor determine how many will be transferred. This is important for us because we're trying to consider how many tries we think we would need at IVF in order to be successful. We're also not sure how much my having only one ovary and PCOS factors in. And of course there's the topic of the new octuplets who were just born and the question of why her doctor would have ever transferred that many embryos in the first place.
Disclaimer - Please note that the information below is my personal synopsis of the free online radio program hosted by Kim Haun, founder of Conceive Magazine, with guest Dr. Peter Ahlering, an ob/gyn and medical director of the Sher Institutes for Reproductive Medicine in St. Louis. It is in no way meant to quote the either of the parties mentioned above.
Listen for Yourself
Scroll down in the archive to:
Date: 7/24/08
Title: "How Many Embryos to Transfer in IVF".
Embryo Fertilization and Selection
The selection of many embryos is made for you by nature because so many eggs and embryos are abnormal and don't survive past a certain stage. With medications, you can get a woman to produce a lot of eggs but can't get them all to fertilize. If you had someone who had 20 eggs, why wouldn't you want to put to use ICSI with every egg to get them all to fertilize? Even if you do this, you can't always get them all to fertilize because there maybe be chromosomal abnormalities with the egg or problems with the sperm, but you can't often tell by looking at them. Certain people do ICSI on every patient. SHER uses ICSI with every In Vitro Fertilization (IVF) patient and the results are just better in order to optimize fertilization. If you fail at that, you're out at the get-go. This concept has been around for years and SHER believes this is better, even when there's no evident male factor. By doing ICSI, the percentage of eggs fertilized is better (under high magnification) - choosing the ones with minimal abnormalities, and thus has better potential to fertilize and make a higher quality embryo, which translates to more ongoing pregnancy. SHER has been doing 100% ICSI has been doing this for at least 10 years. Not every clinic does this.
If there is a male factor (qualitative or quantitative abnormalities of sperm), the only option you have is to do ICSI. The selection process is really very key.
Women get excited when they get scanned and have a lot of follicles, but get disappointed when very few become fertilized. While ICSI helps, the fact is, the majority of eggs are not going to make a baby. Starting with more eggs will be to a patients advantage to some degree because you will have more that make it through the fertilization stage, then to day 3 and 5, but nature weeds out the abnormal ones as the process goes on. The goal is to maximize the process and attempt to make sure a good egg will make it - thus doing ICSI.
When to Transfer Embryos in IVF - Day 3 or Day 5?
Are physicians and doctors still transferring at day 3, or are they waiting until day 5? The overall thought is if an embryo is going to make a baby, then it will, regardless of the day. However, as technology has advanced, you can take the embryo to a farther stage to allow (the blastocyst stage) you to select embryos that will have a better chance. Before, technology wouldn't allow you do this. The problem is you are trying to reduce the number of multiple pregnancies. Day 5 is the best way to go these days. For example, if you have 10 embryos on day 3, that all look good and the same under the microscope, you pretty much know that only half will make it do day 5. Your chance of picking the wrong ones increases when you have so many embryos. So a patient who only has 3 on day 3, it doesn't matter when you put them in (if you wait until day 5 or not), but it does increase higher multiples. So between day 3 and 5, you let them natural deselect.
Grading Embryos?
How do you compare at day 3 to see what will be the best? Two easiest and cheapest to help select embryos:
1) Natural Deselection - letting nature choose
2) Morphological Appearance at a microscopic level (chance for implantation, checking for fragmentation, etc. This is where experience of an embryologist comes into play). A high number of good quality embryos on day 3 makes it more difficult. Is there any medical reason to transfer on day 3, rather than day 5? No. The only reason is if the patient wants the doctor to (perhaps the belief that they are better on the inside than the outside). If you only have 2 or 3 good embryos on day 3, you should still wait it out.
Do you think that day 5 will be the max for how long you can grow and embryo in a dish? There are reports of people doing day 7, but it all comes back to when fertilization takes place. Going to day 6 isn't unusual, but it's more like 5.5 for Dr. Ahlering's clinic. The embryo has to hatch and once it hatches it has to attach to an endometrial lining and begin the process of implantation. Going beyond day 6, practically speaking, it probably isn't happening. It will need to be cryopreserved or transferred at that point because it will die off if it can't implant after it hatches.
New Techniques for Selecting Embryos
Day 3 objective techniques to select if you have more than 4 or 5 encourages better pregnancy rates. If you don't have a good number of embryos on day 3, you simply put them in and let nature decide. If you do have a good number, you can use these new techniques on day 3:
1) PGT or CGH - which assess the chromosomal abnormalities. The number one reason an embryo fails to implant and make a baby is due to chromosomal issues, so accessing the status is very helpful.
2) HLAG Testing - A protein marker that can be tested on day 2 to access the presence of HLAG in the culture medium of the embryo. This involves taking out the fluid that has been nurturing the embryo and testing the fluid, and leaving the embryo untouched. If there is the presence of HLAG in certain amounts, it suggest it will have better developmental potential, thus reducing the number of embryos you have to put back in. So if you choose 1 or 2 embryos which test HLAG positive, you increase the likelihood that you will will have as good or better pregnancy rate. This is a non-invasive procedure because the embryo itself is untouched - only really using about 50 micro liters, a very small amount, to test with.
Keep in mind, one of the main reasons any of the above is done is to prevent the need to put back in a large amount of embryos, thus keeping the higher multiple probability down.
How many Frozen Embryos to Transfer?
Is there a typical number of embryos transferred in a frozen cycle? Factors which will help determine this are:
1) Age
2) The day the embroys were transferred on
3) What happened with the previous fresh cycle and some of the medical issues that might factor in - successful pregnancy? Date of transfer?
General guidelines, assuming it was blastocysts that were cryopreserved, the big question - does cryoproservation negatively affect the potential of any given embroy? The answer - yes, it can probably affect the embroys viabliltity depending on how it was frozen. For example, using a process called vitrification, vs. the old-school cryopreservation. So assuming they were vitrified as blastocysts, let's use a 34 year old as an example. You would thaw and culture let, meaning you them set for 4 hours to see if they survive. Most will survive the immediate thaw, but sometimes one or two will drop out which is why you culture them - then you put in what remains. In the case where you have a lot of embryos you can use a combined approach - culture 4 and if you have only 0 or 1 that makes it thorough the culture process, you might do a quick thaw and add in 1 or 2 embryos to get a total of 3 and then do the transfer.
It definitely gets more tricky with a frozen cycle, which is why you need to work closely with your doctor to decide which strategy to take. However, using a strategy like this you can optimize the per transfer outcome and minimize the number of transfers to go through all of the embryos - thus being better on the patient and ultimately keeping costs down. You are thus optimizing the chance for an ongoing pregnancy per transfer. In summary you can afford to be more aggressive in the number that are transferred, factoring in the fact that cryopreservation can degrade somewhat. However, if you are freezing normal-grade embryos, you are probably working with a very similar playing field, however, not all embryos are tested before they are frozen.
In the example of a 34 year old, Dr. Ahlering comments he doesn't recommend putting in more than 4 cryopreserved blastocysts, because you increase the odds of having a higher order multiple. If you are comfortable putting that many in, its all in how you go about getting those 4, as mentioned in the previous techniques.
Ultimately, Dr. Ahlering likes to ask his patients how many they want to put in. The patient typically ask him how many he recommends, and he then factors in their entire situation and makes a suggestion.
After knowing what I know now, I find it very hard to believe that a doctor would ever find it ethical to transfer 8 embryos with today's technology. The fact that so much testing can be done now days prior to the transfer would indicate that you would have no need to "increase the odds" by way of putting in more than enough. With new technology, we have come so far in the last decade even that the increasing the odds method just doesn't seem to make sense after a certain point. For most people it would seem that "point" is 2-3 and anything above that (4 to perhaps 6 max) is a very rare occasion.
I know I said in a previous post that I would leave the technical medical debate about the octuplet situation up to doctors, and while I still agree to that, I have now formed enough of an educated opinion that I find it hard to be OK with what she requested and what her doctor ultimately executed. I hope most people recognize that this isn't the norm, nor the accepted standard for this part of the medical community, and that infertility isn't given a bad name going forward. Most everyone involved, including myself, wants a happy healthy baby to be conceived and born under the best circumstances possible. It's not simply about what the patient wants but also, and most of all, it's about the new life that is being brought into the world thanks to these treatments.
For one, we're don't feel very informed on what it really goes into determining how many embryos will make to a quality high enough for transfer, from those that do make it, how you and your doctor determine how many will be transferred. This is important for us because we're trying to consider how many tries we think we would need at IVF in order to be successful. We're also not sure how much my having only one ovary and PCOS factors in. And of course there's the topic of the new octuplets who were just born and the question of why her doctor would have ever transferred that many embryos in the first place.
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Disclaimer - Please note that the information below is my personal synopsis of the free online radio program hosted by Kim Haun, founder of Conceive Magazine, with guest Dr. Peter Ahlering, an ob/gyn and medical director of the Sher Institutes for Reproductive Medicine in St. Louis. It is in no way meant to quote the either of the parties mentioned above.
Listen for Yourself
Scroll down in the archive to:
Date: 7/24/08
Title: "How Many Embryos to Transfer in IVF".
Embryo Fertilization and Selection
The selection of many embryos is made for you by nature because so many eggs and embryos are abnormal and don't survive past a certain stage. With medications, you can get a woman to produce a lot of eggs but can't get them all to fertilize. If you had someone who had 20 eggs, why wouldn't you want to put to use ICSI with every egg to get them all to fertilize? Even if you do this, you can't always get them all to fertilize because there maybe be chromosomal abnormalities with the egg or problems with the sperm, but you can't often tell by looking at them. Certain people do ICSI on every patient. SHER uses ICSI with every In Vitro Fertilization (IVF) patient and the results are just better in order to optimize fertilization. If you fail at that, you're out at the get-go. This concept has been around for years and SHER believes this is better, even when there's no evident male factor. By doing ICSI, the percentage of eggs fertilized is better (under high magnification) - choosing the ones with minimal abnormalities, and thus has better potential to fertilize and make a higher quality embryo, which translates to more ongoing pregnancy. SHER has been doing 100% ICSI has been doing this for at least 10 years. Not every clinic does this.
If there is a male factor (qualitative or quantitative abnormalities of sperm), the only option you have is to do ICSI. The selection process is really very key.
Women get excited when they get scanned and have a lot of follicles, but get disappointed when very few become fertilized. While ICSI helps, the fact is, the majority of eggs are not going to make a baby. Starting with more eggs will be to a patients advantage to some degree because you will have more that make it through the fertilization stage, then to day 3 and 5, but nature weeds out the abnormal ones as the process goes on. The goal is to maximize the process and attempt to make sure a good egg will make it - thus doing ICSI.
When to Transfer Embryos in IVF - Day 3 or Day 5?
Are physicians and doctors still transferring at day 3, or are they waiting until day 5? The overall thought is if an embryo is going to make a baby, then it will, regardless of the day. However, as technology has advanced, you can take the embryo to a farther stage to allow (the blastocyst stage) you to select embryos that will have a better chance. Before, technology wouldn't allow you do this. The problem is you are trying to reduce the number of multiple pregnancies. Day 5 is the best way to go these days. For example, if you have 10 embryos on day 3, that all look good and the same under the microscope, you pretty much know that only half will make it do day 5. Your chance of picking the wrong ones increases when you have so many embryos. So a patient who only has 3 on day 3, it doesn't matter when you put them in (if you wait until day 5 or not), but it does increase higher multiples. So between day 3 and 5, you let them natural deselect.
Grading Embryos?
How do you compare at day 3 to see what will be the best? Two easiest and cheapest to help select embryos:
1) Natural Deselection - letting nature choose
2) Morphological Appearance at a microscopic level (chance for implantation, checking for fragmentation, etc. This is where experience of an embryologist comes into play). A high number of good quality embryos on day 3 makes it more difficult. Is there any medical reason to transfer on day 3, rather than day 5? No. The only reason is if the patient wants the doctor to (perhaps the belief that they are better on the inside than the outside). If you only have 2 or 3 good embryos on day 3, you should still wait it out.
Do you think that day 5 will be the max for how long you can grow and embryo in a dish? There are reports of people doing day 7, but it all comes back to when fertilization takes place. Going to day 6 isn't unusual, but it's more like 5.5 for Dr. Ahlering's clinic. The embryo has to hatch and once it hatches it has to attach to an endometrial lining and begin the process of implantation. Going beyond day 6, practically speaking, it probably isn't happening. It will need to be cryopreserved or transferred at that point because it will die off if it can't implant after it hatches.
New Techniques for Selecting Embryos
Day 3 objective techniques to select if you have more than 4 or 5 encourages better pregnancy rates. If you don't have a good number of embryos on day 3, you simply put them in and let nature decide. If you do have a good number, you can use these new techniques on day 3:
1) PGT or CGH - which assess the chromosomal abnormalities. The number one reason an embryo fails to implant and make a baby is due to chromosomal issues, so accessing the status is very helpful.
2) HLAG Testing - A protein marker that can be tested on day 2 to access the presence of HLAG in the culture medium of the embryo. This involves taking out the fluid that has been nurturing the embryo and testing the fluid, and leaving the embryo untouched. If there is the presence of HLAG in certain amounts, it suggest it will have better developmental potential, thus reducing the number of embryos you have to put back in. So if you choose 1 or 2 embryos which test HLAG positive, you increase the likelihood that you will will have as good or better pregnancy rate. This is a non-invasive procedure because the embryo itself is untouched - only really using about 50 micro liters, a very small amount, to test with.
Keep in mind, one of the main reasons any of the above is done is to prevent the need to put back in a large amount of embryos, thus keeping the higher multiple probability down.
How many Frozen Embryos to Transfer?
Is there a typical number of embryos transferred in a frozen cycle? Factors which will help determine this are:
1) Age
2) The day the embroys were transferred on
3) What happened with the previous fresh cycle and some of the medical issues that might factor in - successful pregnancy? Date of transfer?
General guidelines, assuming it was blastocysts that were cryopreserved, the big question - does cryoproservation negatively affect the potential of any given embroy? The answer - yes, it can probably affect the embroys viabliltity depending on how it was frozen. For example, using a process called vitrification, vs. the old-school cryopreservation. So assuming they were vitrified as blastocysts, let's use a 34 year old as an example. You would thaw and culture let, meaning you them set for 4 hours to see if they survive. Most will survive the immediate thaw, but sometimes one or two will drop out which is why you culture them - then you put in what remains. In the case where you have a lot of embryos you can use a combined approach - culture 4 and if you have only 0 or 1 that makes it thorough the culture process, you might do a quick thaw and add in 1 or 2 embryos to get a total of 3 and then do the transfer.
It definitely gets more tricky with a frozen cycle, which is why you need to work closely with your doctor to decide which strategy to take. However, using a strategy like this you can optimize the per transfer outcome and minimize the number of transfers to go through all of the embryos - thus being better on the patient and ultimately keeping costs down. You are thus optimizing the chance for an ongoing pregnancy per transfer. In summary you can afford to be more aggressive in the number that are transferred, factoring in the fact that cryopreservation can degrade somewhat. However, if you are freezing normal-grade embryos, you are probably working with a very similar playing field, however, not all embryos are tested before they are frozen.
In the example of a 34 year old, Dr. Ahlering comments he doesn't recommend putting in more than 4 cryopreserved blastocysts, because you increase the odds of having a higher order multiple. If you are comfortable putting that many in, its all in how you go about getting those 4, as mentioned in the previous techniques.
Ultimately, Dr. Ahlering likes to ask his patients how many they want to put in. The patient typically ask him how many he recommends, and he then factors in their entire situation and makes a suggestion.
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Closing Thought...After knowing what I know now, I find it very hard to believe that a doctor would ever find it ethical to transfer 8 embryos with today's technology. The fact that so much testing can be done now days prior to the transfer would indicate that you would have no need to "increase the odds" by way of putting in more than enough. With new technology, we have come so far in the last decade even that the increasing the odds method just doesn't seem to make sense after a certain point. For most people it would seem that "point" is 2-3 and anything above that (4 to perhaps 6 max) is a very rare occasion.
I know I said in a previous post that I would leave the technical medical debate about the octuplet situation up to doctors, and while I still agree to that, I have now formed enough of an educated opinion that I find it hard to be OK with what she requested and what her doctor ultimately executed. I hope most people recognize that this isn't the norm, nor the accepted standard for this part of the medical community, and that infertility isn't given a bad name going forward. Most everyone involved, including myself, wants a happy healthy baby to be conceived and born under the best circumstances possible. It's not simply about what the patient wants but also, and most of all, it's about the new life that is being brought into the world thanks to these treatments.
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