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Embryo Banking

Good Day to All,

Today I’d like to talk about embryo banking, which means storing as many embryos as you can for later use. It’s a topic that comes up every day in my practice and on the surface it makes sense, just as egg freezing makes sense for the young and unattached.   The typical scenario is of a woman who is committed to a partner or has identified a donor, who wants to become pregnant now, but is concerned, due to her age, that she will not be able to become pregnant again when she wishes a second or even a third. She may be also concerned that if she does become pregnant and has a miscarriage, she will be similarly be placed at a disadvantage due to the loss of time and the advancement of age.   She therefore packs away as many embryos as she can, possibly after preimplantation genetic screening, and is limited only by her tolerance to the IVF process and, of course, finances.

Does this sound like a good idea? Yes, it’s an outstanding idea; it’s proactive, realistic and optimistic. But, it comes with a number of down sides. Is it really worth the trouble? All of us fertility doctors have charts and graphs blaring out the chances of pregnancy based on age, but those are just averages. We can’t know for sure who will and will not have a baby now or 2 years down the road. And what about all women over 35 who are thinking of becoming pregnant on their own, should I seek them out on First Avenue and scream, “Wait, you’re making a big mistake, come in and bank your embryos!”?

While I consider IVF to be one of the true miracles of modern medicine, its effects on a patients psyche is one of medicine’s scourges. On average, things seem to work out wonderfully for most involved, but individually it can be frustrating, disappointing, exhausting; the list goes on. Some who intend to bank are confronted with low egg production or poor embryo development or genetically abnormal embryos or a combination of these all leaving nothing to save. Granted, some would rather know these things sooner rather than later, and are strong enough to consider other options and move on, but some do not appreciate being thrust into a hole, left with uncertainty in their ability to even naturally conceive.

And then there is the cost; embarking on such a process without insurance coverage is a considerable commitment; having coverage is an enviable luxury.

Summarizing, banking could be a smart play. However for many, the negatives may outweigh the positives.  

Dr. Licciardi

Important Final Words on Pre-Implantation Genetic Diagnosis

These past few blogs covering PGD raise a few important issues. There are some well-know fertility centers that are really pushing TE biopsy. The feeling is that the technology has finally become accurate and safe enough.  It may be that doing IVF with PGD leads to a higher pregnancy rate and a lower miscarriage rate.  Plus, if you know you are getting a normal embryo, we can transfer fewer embryos, lowering the rates of twins and triplets.

This all sounds good, however, I think we need just a little more time, but maybe not much more.  In a good center, the pregnancy rate for a woman under 37 years of age is 40-50% without PGD.  PGD adds an invasive procedure. The shell of then embryo has to be opened, usually by a laser beam, then some of the embryo, even if it’s a small piece, has to be chopped away.  We make it sound simple, and so far it seems safe, but no one should promise you all of the safety data is in.  Not to mention the additional costs, which could vary from program to program, but $6,000 is a safe estimate.

In theory, ideally, PGD will be the way to go and everyone doing IVF will have their embryos tested, the pregnancy rates will go up, miscarriage rates will go down and we will say goodbye to IVF twins.   And if the system works really well, in the end this will save money because people will need fewer IVF cycles for success (not to mention the drug cost savings if fewer cycles are needed).

Encouraging news concerning PGD is coming out of the data on miscarriage. Good PGD does decrease the rate of miscarriage. A very high percentage of miscarriages are caused by aneuploidy, which means an abnormality in the number of chromosomes present in the embryo. Just one example of aneuploidy is Down’s syndrome, which is the result of an extra chromosome 21 (also called trisomy 21).  The bulk of PGD is performed looking for aneuploidy.

The reduction of miscarriage rates after PGD has 2 important implications. One is that preventing a woman from having a miscarriage is obviously a welcome idea, as the emotional toll of pregnancy loss is significant. The second is that miscarriage takes time.  While many miscarriages occur early, many women do not suffer their loss until 7-10 weeks, later if the fetus survives to the CVS (10 weeks) or amnio (17 weeks).  When you add in the recovery time of 1-2 months before a woman can try again post-miscarriage, the total time lost could be 2-4 months. This is especially difficult in an older woman whose reproductive time is already limited.

One shortcoming of this technology is that this new method of testing requires a blastocyst. Many IVF programs are still not comfortable growing their embryos to blastocyst; they prefer transferring their embryos on day 3.  These programs will not be able to provide these new services until they become very good a growing embryos out to day 5, which for some clinics could take a very long time.

Lastly, not everyone who wants PGD is a candidate for PGD.  The group that may benefit the best from a PGD cycle is those who are above the average age for reproduction. However in this group, egg production is lower, as is the rate of good (biopsyable) blastocyst formation. So there may be the intention for PGD at cycle start, but if the egg number or embryos quality is low, the option for PGD in that cycle may be lost. Straight IVF may or may not still be a viable option, but at times even those are not possible.  I try to be positive to the end, but it is always necessary to cover all eventualities.

 

Well, that’s quite a bit about PGD. Thanks very much for reading.

Don’t forget to read the disclaimer from 5.17.06.

Dr. Licciardi

References:

  • Braude P. Preimplantation diagnosis for genetic susceptibility. N Engl J Med 2006; 355(6):541-3.
  • Gutiérrez-Mateo C., Colls P., Sánchez-García J., Escudero T., Prates R., Wells D., Munné S. Validation of microarray comparative genomic hybridization for comprehensive chromosome analysis of embryos. Fertil Steril. 2011; 95: 953-958.
  • Twisk M, Mastenbroek S, van Wely M, Heineman MJ, Van der Veen F, Repping S. Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilization or intracytoplasmic sperm injection. Cochrane Database Syst Rev 2006; 25(1):CD005291.
  • Munne S, Fischer J, Warner A, Chen S, Zouves C, Cohen J, Referring Centers PGD Group. Preimplantation genetic diagnosis significantly reduces pregnancy loss in infertile couples: a multicenter study. Fertil Steril. 2006; 85(2):326-32.

 

 

The New Phase of Embryo Biopsy and PGD

Hello to all!

Welcome to this latest blog, which will discuss embryo biopsy and pre-implantation genetic diagnosis (PGD).While many of you may feel that theses processes do not apply to you, the science is progressing to the point that more and more people are becoming candidates. We can’t completely tell yet, but it is possible that in the future almost all IVF cycles will involve PGD. Plus more people may become IVF candidates because of PGD. We’ll see.

In the meantime, I would like to bring you up to speed with some newer information about the treatment. This is the first of a 2 part series. The first will discuss the reasons why PGD took a while to become potentially helpful.

This one is a bit technical, so if you’re really not biased towards technical things, you can wait for the next blog, which has a little more practical information. Here we go. PGD has been around for 2 decades. In fact, one of my partners, Dr. Grifo, was the first doctor in the US to successfully perform the procedure. 20 years is a long time in the world of medicine, but interestingly, the progression of PGD and its usefulness had stalled.

The early techniques were important and useful, however limitations it their reliability kept PGD from being used to it’s potential. The early problems were four-fold. One, the embryos needed to be biopsied on day 3 because we could not at first grow embryos 5 days in the lab. A day 3 embryo has progressed to 8 cells ideally, however, on day 3 many embryos are 5,6,or 7 cells. Of course we do see embryos that are 2-4 cells on day 3, but we usually do not consider them viable enough for a biopsy. The biopsy is performed by opening the shell of the embryo, as is done in hatching, and then plucking off one cell to be tested.

One cell from a 6 cell embryo means that a big percentage (1/6supth/sup, or 17%) of the embryo is removed. Embryos may not like to have a big chunk of them pulled away and may not grow as well as an embryo that is undisturbed. In addition, some of the early cells are destined to be part of the embryo itself and others the placenta. At that stage we can’t tell which cells are which so we just take one at random. If we remove one of the few embryonic cells, the fetus may not develop, we think. These percentage issues led to the second problem, which is that usually only one cell could be removed for testing. If we could routinely take 2 cells we would have get twice as much DNA and therefore be much more accurate with our diagnosis.

There are cases where a second cell has been removed; if for instance, if the first cell was damaged in the extraction process. Some IVF clinics have routinely removed two cells to enhance the accuracy of the testing process, however it was shown that removing 2 cells is too harmful to the embryo. And this leads to the third problem, the biochemistry of the analysis. It’s the DNA of the cell that is tested. I will not go into the gory details of DNA analysis here but I will touch on a couple of things. Early on, a good but flawed method of analyzing the DNA was used. This involved making chemicals that latched on to the single chromosome, and theses chemicals were of different colors. Because each chromosome is very different, you could have one chemical that only stuck to an area on the 21supst supchromosome.

This chemical for instance, would be green. Other chemicals of different colors would stick to the other chromosomes, such that chromosome 15 could be yellow, chromosome 18 could be red, etc. The cell would be treated with these ”probes,” and under the microscope one could look at the cell and count up the colors. Two of the same was the goal. 3 greens, as an example, would indicate the embryo had 3 chromosome 21s, therefore meaning the embryo had trisomy 21, or Down’s syndrome. This technique also worked well, but not well enough to be near perfect, and in medicine, near perfect is the minimally acceptable result. Here is a picture (Munne).

You can see that the colors are sometimes faint. One problem occurred when 2 color spots were very close to each other making accurate reading difficult. One shortcoming of this technology was that only 14 probes were available (fewer earlier on), and we have 23 pairs of chromosomes. Therefore, if an embryo had an extra chromosome 20 and there were no probes for chromosome 20, we would have to say it’s probably normal and do the transfer and hope for the best. This could lead to pregnancy failure or miscarriage. This probe technique is sometimes still used, however newer tests are better for most things.Other tests, which are sometimes still used, do not use colors and probes. They involve instead making millions of copies of a small specific area in the cell’s DNA. This test is more used when looking for subtle genetic defects, as in sickle cell disease. Having millions of copies lets us confirm that our results are correct. We can actually see the piece of DNA we are looking for. Here is a picture. Don’t try to figure it out, it’s just an example. Each dark line is millions of copies of DNA (Girardet et al).

In an attempt to make al of those copies, things can go wrong, resulting in the wrong diagnosis or no diagnosis at all. This system is actually a good system, but when using a single cell, the amount of starting material is so small, problems and errors can occur.The fourth problem was mosaicism. We were all taught that after the egg divides, all of the new cells have the same DNA and are identical. What we have learned from embryo DNA testing is that some cells are different than others. In about 30% of the cases, the embryo is made up of 2 cell types. This is called mosiacism. This is problem when trying to get a picture of the whole embryo based on the DNA extracted from only one cell. If we take off cell that we test as normal, but the rest of the embryo is abnormal, we will transfer that abnormal embryo leading to no pregnancy or miscarriage. The opposite issue of discarding and “abnormal” embryo that is really mostly normal also can happen.Next time we will talk about the newer developments that may make PGD more acceptable.

Thanks for reading and don’t forget the disclaimer 5.17.06. Dr. Licciardi

References:

  • Braude P. Preimplantation diagnosis for genetic susceptibility. N Engl J Med 2006; 355(6):541-3.
  • Gutiérrez-Mateo C., Colls P., Sánchez-García J., Escudero T., Prates R., Wells D., Munné S. Validation of microarray comparative genomic hybridization for comprehensive chromosome analysis of embryos. Fertil Steril. 2011; 95: 953-958.
  • Twisk M, Mastenbroek S, van Wely M, Heineman MJ, Van der Veen F, Repping S. Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilization or intracytoplasmic sperm injection. Cochrane Database Syst Rev 2006; 25(1):CD005291.
  • Munne S, Fischer J, Warner A, Chen S, Zouves C, Cohen J, Referring Centers PGD Group. Preimplantation genetic diagnosis significantly reduces pregnancy loss in infertile couples: a multicenter study. Fertil Steril. 2006; 85(2):326-32.

More About PGD

So should you have PGD? Well, this is between you and your doctor. Hopefully this blog will help you in your discussion with him/her. Let me start by saying that there is a place for PGD. There are some patients that are clearly candidates, and many children have been born as a result. I am very happy for those of you who have had PGD successfully. The problem is in saying that if it’s good for some, it’s good for all.
We already said that PGD is not all it’s cracked up to be. How could that be? Isn’t IVF science cutting edge? Yes it is, but it’s not perfected and here are some of the pitfalls.

Mosaicism. In basic biology it is taught that the cells of the early embryo are identical. Since it all starts from the DNA of the fertilized egg, as the cells divide they all have the same DNA. Well, this is usually the case, but often enough, there is mosaicism, meaning that some cells have one type of DNA and other cells have different DNA. For example, in an 8 cell embryo, it’s possible to have some cells that cause Down’s Syndrome (this is an extra chromosome 21) and some cells can be normal. Just to back up, almost all of us have 23 pairs of chromosomes, for a total of 46. If an embryo is missing at least one, or had an extra 1, we generally call this aneuploidy. Aueuploidy is the genetic problem related to aging. Down’s is an extra chromosome 21, but any of the chromosomes affected in the same way, either an extra or missing. Getting back to PGD, if the embryo has 2 normal cells, and 6 abnormal cells, and the biopsy plucks off a normal cell, this mostly abnormal embryo will be transferred, probably producing no pregnancy. If the embryo is mostly normal and an abnormal cell is tested, that embryo will not get transferred, yet it may have produced a normal child.

Embryo Damage. This is very hard to quantitate, but embryo biopsy is a rather invasive procedure. So it may be that removing 1/8 of the embryo reduces its viability.

Testing Error. Even when done correctly in experienced hands, error happens. Meaning the lab says the cell is normal when it is abnormal, and visa versa. The error rate is low, but if many embryos are tested the chance of an error per case increases.

These pitfalls get magnified when a woman produces few eggs. The biggest risk here is that the one good embryo gets damaged or is misdiagnosed as abnormal.
So the most important question you have to ask is, “will PGD increase my chances of having a baby?” If your doctor says, “Yes, absolutely”, or “most of our patients are getting PGD”, get another opinion.
The bottom line is that the medical community is not so sure yet if PGD increases pregnancy rates. Theoretically it should, but in practice nothing has been proven yet. It is possible that PGD will reduce the chance of miscarriage, and there are some studies to show this is the case, but there is other research showing it may not.
And what about the cost? My partner Dr. Berkeley brought up a great point. For the extra cost of 2 PGDs, you can pay for another IVF cycle.
Just to repeat, I have patients who do PGD, but they make the choice after getting whatever information I can give them.
Please read disclaimer 5/17/06.
Dr. Licciardi

p.s. I have recently heard of programs that freeze the embryos of poor responding patients over a few cycles to get a batch big enough to biopsy all at once. It sounds a little extreme to me, but I can’t really comment until I see the results published. Just remember, a frozen embryo is not a good as a fresh.

References:

  • Braude P. Preimplantation diagnosis for genetic susceptibility. N Engl J Med 2006; 355(6):541-3.
  • Gutiérrez-Mateo C., Colls P., Sánchez-García J., Escudero T., Prates R., Wells D., Munné S., 2011. Validation of microarray comparative genomic hybridization for comprehensive chromosome analysis of embryos. Fertil Steril 95: 953-958.
  • Twisk M, Mastenbroek S, van Wely M, Heineman MJ, Van der Veen F, Repping S. Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in-vitro fertilization or intracytoplasmic sperm injection. Cochrane Database Syst Rev 2006; 25(1):CD005291.
  • Munne S, Fischer J, Warner A, Chen S, Zouves C, Cohen J, Referring Centers PGD Group. Preimplantation genetic diagnosis significantly reduces pregnancy loss in infertile couples: a multicenter study. Fertil Steril 2006; 85(2):326-32.

The PGD Paradox

The next couple of blogs will be about the downside of PGD.

PGD: Pre-Implantation Genetic Diagnosis, otherwise known as Embryo Biopsy.

A day 3 embryo is ideally 8 cells. One of the cells can be removed and the DNA in the cell can be analyzed. If the cell is normal, we can transfer the embryo into the woman’s uterus. If it is abnormal it will not get transferred. Now it can be a little more complicated. Some centers are biopsying polar bodies, and some talk of testing blastocysts; but the great majority of the biopsies are done on day 3.
PGD is mostly performed for 2 indications. One is to look for genetic diseases. Here, one or both parents carry genes that will lead to illness in the child, so they undergo PGD to identify the embryos without the abnormal gene or genes.
The second is to look for aneuploidy, which means an abnormal number of chromosomes. This is the problem that occurs with age related infertility and miscarriage. You’ve heard of Down’s syndrome, which is when the child has an extra chromosome 21. But we have 23 pairs of chromosomes, so if an embryo gets one too few or one to many of any of the chromosomes, the embryo may be abnormal. In these cases, the embryo may just not implant, or it could grow early on and miscarry, or in rare cases it could turn into an abnormal baby.
Aneuploidy testing is the most common indication for PGD, and for good reason. Women who want to increase their chances of becoming pregnant, or want to reduce their chance of miscarrying an abnormal fetus, can do in vitro fertilization, get their embryos tested using PGD, and transfer the good embryos.
The problem is that PGD for aneuploidy has not been as helpful in improving pregnancy rates and reducing miscarriage as we had hoped, thus the paradox. If you were a patient undergoing IVF, had a good stimulation, normal uterus, nice embryos and no pregnancy, what explanation would you get from your doctor? He or she would probably tell you that although they looked good, your embryos were probably genetically abnormal. This tells me that if you were to do PGD, and had only the normal embryos transferred, you should expect a very very high pregnancy rate. Unfortunately, this is not the case. I’ll talk about possible reasons why next time. As usual, please read disclaimer 5/17/06.
Dr. Licciardi

References:

  • Braude P. Preimplantation diagnosis for genetic susceptibility. N Engl J Med 2006; 355(6):541-3.
  • Gutiérrez-Mateo C., Colls P., Sánchez-García J., Escudero T., Prates R., Wells D., Munné S., 2011. Validation of microarray comparative genomic hybridization for comprehensive chromosome analysis of embryos. Fertil Steril 95: 953-958.
  • Twisk M, Mastenbroek S, van Wely M, Heineman MJ, Van der Veen F, Repping S. Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in-vitro fertilization or intracytoplasmic sperm injection. Cochrane Database Syst Rev 2006; 25(1):CD005291.
  • Munne S, Fischer J, Warner A, Chen S, Zouves C, Cohen J, Referring Centers PGD Group. Preimplantation genetic diagnosis significantly reduces pregnancy loss in infertile couples: a multicenter study. Fertil Steril 2006; 85(2):326-32.