Endometriosis Foundation of America
Endometriosis 2013 / Egg Freezing as an Option for Endometriosis Patients
Jamie Grifo, MD
Thank you Avner. I am not sure where the Newt Gingrich thing came in at. There are very few people in Washington who are my favorites and he is not particularly at the top of the list.
I am going to talk today about egg freezing as we all seem to be talking about. But I think it is a very important topic, especially for women who have chronic disease and whose chronic disease will affect their fertility. The indications for egg freezing initially developed as a treatment for patients with cancer who were going to lose their ovaries from surgery or lose their ovaries because of chemotherapy. The idea is that you have some eggs in the freezer or ovarian tissue in the freezer and you could then, after they have been cured of their disease, be able to treat the infertility that would be a side effect of that treatment. I think the controversy around that is pretty minimal; most people are very supportive of that type of endeavor. We have been highly criticized, however, for the concept of electively freezing, which allows a young woman who is choosing a switch that Avner was talking about, to not have a baby at a younger age and to freeze their eggs for future use. While the American Society of Reproductive Medicine has declared that egg freeing is no longer experimental, it still does not agree with us offering elective egg freezing for women choosing it for that reason.
Endometriosis is kind of in-between. It really is a medical indication for offering egg freezing, perhaps not as similar as cancer but there are similarities in terms of what one can expect with endometriosis, hence treatment that diminished ovarian reserves. In a certain sense the biological clock ticks a little faster for patients who have this chronic disease, who have multiple surgeries and whose ovarian reserve does diminish at an earlier age. IEF preserving fertility in these patients by freezing eggs has become an option that is being talked about, maybe not condoned, but certainly not condemned but there are critics of us in this field.
This is a slide you have probably seen four times already. It is the per cycle baby rate of an IVF cycle, which first of all is never 100 percent. But you can see there is a dramatic change with age that, oh around 38, you can see a blip. But at 30 it is about, in our program, this is 90 years of data - the baby rate. Not the pregnancy rate because pregnancy rates are different from baby rates and much higher, by the way. The baby rate is about 60 percent. At 40 it is 27 percent and every two years it drops half at 40, over 44 it is two percent. Not very good and many women in New York are delaying child bearing. Sometimes surgery gets in the way and endometriosis gets in the way and delays child bearing. While an egg donor can give you that pregnancy rate that you get at age 30 because the eggs are that age, most people prefer to be their own egg donor and have their own eggs. That is why I think egg freezing has taken off as a field. While the pill has revolutionized women's health care the thing about the pill is that it is somewhat affordable for most people and unfortunately egg freezing has yet to be affordable for most people. It is incredibly expensive, it is highly technical and that is one of the reasons why it may not have quite the same impact on women until it becomes more affordable. But that is a long way away as far as I can tell.
Freezing eggs is really not a new thing. I guess Avner said that it was 2006, but really the first baby from egg freezing was born in 1986. It really was not much of a specialty because we were not very good at it but we were not very good at IVF back then. We had miserable pregnancy rates. When we were fellows at Yale a 10 percent pregnancy rate was something to be very proud of and now I do not think a clinic would survive very long with that kind of pregnancy rate, and I am talking about young patients. It took us about 25 years to get really efficient at egg freezing.
Part of the reason actually is another example, I guess, of Avner's Newt Gingrich comment, which strikes a chord in me because when politicians practice medicine the outcome is never good. It is like practicing medicine without a license. The Italian legislators practiced medicine for years. They require fertility specialists, like myself, to not fertilize more than three eggs. Therefore, my Italian counterparts had all these extra eggs in their labs not knowing what to do with them. They started to freeze them and they actually started to make babies from frozen thawed eggs. In the late 1990s they started recording this and everyone got interested. Maybe we really can make egg freezing a specialty where we have some success. The problem with that type of legislation is it really guaranteed Italian patients inferior care in infertility by only allowing doctors to fertilize three eggs and dramatically reducing the chance of success. However an unintended happy consequence was it actually promoted egg freezing. So you can actually say that the pope was the reason egg freezing got so good. Can you imagine me saying that at the Vatican! I do not think I would last very long.
In the 1990s the question was how to freeze eggs. Should we use slow freeze, should we use vitrification? What medium should we use? During the late 1990s, after we got shut down by the FDA, another unintended consequence of ambitious regulators and legislators and even litigators, was that we were working on a method to fix old eggs by taking the nucleus out of an old egg and put it in the young egg and allow a woman to be her own egg donor. But we were shut down by the FDA. I am one of the few people in America who has a personal letter from the FDA telling me to stop my work but this is America. That is another talk and that is probably an hour long talk we will not get into it. But it did force on us an unintended consequence of spending our time working on eggs and like we do in all of our new fields, our new endeavors in our life, we go to the research lab first. We started freezing and thawing mass eggs and seeing how good we were and showing that it was safe and these are the spindle apparatus. That is what moves the chromosomes around in mass eggs that have been frozen and thawed. We showed that the spindle was intact. We actually showed that the chromosomes were intact and a number of chromosomes did not change and that we could have good results freezing and thawing eggs. It appeared that it did not harm the eggs in any manner.
We spent a lot of time making mouse babies and you look at those pregnancies rates in mice and you think that is not very good. But mouse IVF where you were doing...which you have to do with egg freezing, no one had really had very much success at all. It took us years to get good at it. We have never gotten it as good as human, but we were able to show that we could make mouse babies very efficiently, almost as efficiently as regular mouse IVF under similar conditions. We got to the point where we then were able to get permission from our institutional review board to do egg freezing in humans. Until you do these safety studies and show that you can have success in your lab I think that is the best way to put new technology into your life and that is what we have done for all of our new techniques and egg freezing is one of them. It requires IVF.
For an elective egg freeze someone who does not need IVF to get pregnant presumably, but in order to bank her eggs, she does. You have to be stimulated with gonadotropins. For the cancer patients you sometimes have to give them these medicines. We do not know the impact on their cancer later on having been stimulated earlier before they get treated. Those are some of the risks but it has become a field. There are lots of babies born from it and it does not require a male partner because many people who are going to preserve their fertility, endometriosis patients, do not have a partner. Banking embryos is an option but banking embryos with Mr. Wrong when Mr. Right comes along is complicated. It is much easier and safer from a sociologic perspective to have eggs in the freezer versus embryos.
We then went to our clinic and we recruited 23 patients and did three cycles of egg freezing. We did this around 2004/2005 and this is our first baby from egg freezing from one of the recruited patients in the study. We did 23 cycles of egg freezing for free where we froze all the eggs, thawed them all down the line a few months later and we were able to show that we could get the same per cycle pregnancy rate with frozen thawed eggs as we did with a fresh IVF cycle.
That paper, as you can see, is posted 2009 but we actually wrote the paper in 2006. It took six rejections from different journals before we finally got it published. What were the critics saying about this paper? Well, one of them actually rejected our paper outright because they said we were lying, which I thought was kind of an interesting peer review to get but eventually, after submitting and being persistent this was published and indeed, we are not the only ones in the world who can do this. There are many centers that have shown similar results.
If you think peer review is peer review it sometimes is peer suppression and politics does play a role in some of what gets published. We subsequently published a paper that showed whether we froze eggs or embryos or did fresh IVF we had the same pregnancy rates. So egg freezing, embryo freezing, freezing technology per se has really come of age. Actually, there are advantages now to freezing and that is a whole other talk we could get into as well, but we demonstrated that we could get good success with frozen, thawed eggs similar to IVF. Now, because of that you are really offering somebody something. Obviously guarantee is not a word because IVF does not work for everybody, but it does give people a very good chance.
While we have frozen about 1600 cycles of eggs for elected and medical egg cryopreservation we have only done about 82 thaws because not everybody who has frozen their eggs has used them, in fact, very few. But from the 82 thaws we have done, and some of these are not ideal age patients, in fact I have a 46 year old patient who is 22 weeks pregnant now who froze her eggs at 42, not a recommended age to freeze eggs. But the fact is we can get some success in older patients but they are going to be limited just like IVF success rates are limited in those patients. But we have a 33 percent delivery rate per transfer, which is only a third of the patients, we would like it to be higher. But again, these are not the most ideal patients and many of them are much older than the age you would like to freeze eggs at; under 35 would be ideal, although up to 37 we have very high success rates - in the 45 to 50 percent range.
If you look at our experience with donor eggs these are our donors and we had frozen their eggs. These are kind of the ideal patients. We have done 20 thaws where 16 of the 20 recipients were pregnant. There were three miscarriages, all of those from the slow freeze method which we no longer use. Do not quote me as saying with vitrification you will not have miscarriages, you will but I think the slow freezing method has a higher miscarriage rate. Now we do exclusively vitrification by a method that we developed exclusively at NYU in our mouse lab. We have a 65 percent ongoing pregnancy rate with those frozen thawed eggs, which is a little bit, statistically, better than our fresh cycles. Again, pointing towards freezing we may have some advantages that we have not thought about but we have 33 babies born and four ongoing pregnancies from egg freezing. We have pretty vast experience in having done about 1500 cycles where we have frozen eggs. We have become quite good at it.
Jaime Knopman is our next speaker who is a wonderful fellow. When I say fellow we train fellows who then go out to be the next generation of us. Avner and I were fellows together at Yale in the late 1980s. Jaime was my fellow, our fellow, at NYU and just finished now and works at RMA. She is a wonderful doctor. I think she is very well trained and I think her partners think so too, they are our competitors. Jaime actually put together our data and this is one of her data slides looking at what percent of eggs make babies. If you look at baby rates per egg IVF, and to be quite honest, even human nature is pretty pathetic. At home in bed about 10 percent of eggs or less make babies. Those are the facts, you just do not know that. It is really inefficient. Nature has designed a very inefficient system and as you get older it gets worse.
Those factors are at play in an IVF lab as well. With egg donors, which are our best candidates, only about eight percent of eggs make babies from a single cycle. The idea is that you want to try and get as many eggs as you can, although in that study I just showed you where we showed pregnancy rates comparable with fresh IVF, two patients had only six eggs on their egg retrieval and had babies. Several patients had more than 30 eggs and did not get pregnant, so egg number is not the answer, it is quality. Finding that one good egg is the task that we now have, we are not so good at it yet but we are getting better at it.
If you look at regular IVF patients four percent of eggs make babies in women under 35. That is how inefficient IVF is in a relatively poor prognosis group of patients. But, we still get a lot of people pregnant because we do more than one cycle and if you get enough embryos you are going to get most people pregnant. Once you get over 35 look at the change in percentage of those eggs being efficient. It is a pretty good reason why one might consider freezing eggs early if you know you are going to delay child bearing till later unless you want to use egg donors as a back up, which is a highly efficient very good option. Most patients I have ever met have said they will never do egg donor, at least once, usually about 40 or 50 times before they do it because it is not ever the way you ever thought you would have a baby as a patient. Yet when push comes to shove and you have no options you make choices that you never knew you ever would make unless you are sitting in that position. While these numbers are a little scary they are what they are.
The other thing is that a lot of patients who are going to preserve their fertility have partners. It is more efficient to freeze embryos if you couple freezing embryos with genetic testing. I am going to touch briefly on that right now. You take an embryo blastocyst and test it, test the cells that would be placenta and you can test all 24 pairs or 23 pairs of chromosomes and determine which embryos are normal. You can really have an impact on the pregnancy rate and I will show you this data.
We used to do embryo biopsy when I did my fellowship. That was what I was working on, day three biopsy, we had the first in the United States in 1992. Day three biopsy turns out not to be the most effective way, a blastocyst biopsy is much better. A later stage embryo takes cells that do not make the baby because in an eight cell embryo we do not know which cells make the baby. It does not harm the embryo in any kind of way. It harms the baby but it harms the embryo in that fewer of them make a baby when you are doing day three biopsy. We now have a paper in various throes of peer suppression/peer review showing to date that...day five biopsy is superior. We will see how long it takes to get that one published. You can get more cells too and there is less mosaicism, I cannot really spend much time explaining that, and very active because you have more cells. It does not affect the embryos, they survive and you process less embryos because fewer embryos make it to blastocyst because the embryos that do not make patients pregnant do not make it to blastocyst. Why should we test them and spend the time, energy and money on them? And now with this coupling with freezing you can put back single embryos because they are in the freezer and there is evidence now that a frozen thaw cycle is a better environment than fresh IVF cycle where the stimulation has an impact on the lining of the uterus.
So the idea of testing an embryo like this, and this is an actual embryo, one that actually made it to an ongoing pregnancy that has not delivered yet but is about 25 weeks pregnant, those are cells that will make placenta. We will take those cells from this embryo, we will then put that embryo in the freezer and about a week later we will know which embryos are chromosomally normal and which ones are not. We will then be able to take them out of the freezer one at a time, usually the next cycle. The patient will then be put on programmed estrogen then progesterone identical to Mother Nature using bio-identical hormones, put back a single embryo and get donor egg implantation rates. It does not matter what the age of the patient is as long as you get a chromosomally normal embryo. And that is the key, can you? Because in older patients it is a lot harder and in younger patients it is a lot easier.
Here is how we analyzed the cells. We had this test called the Array CGH or Array Comparative Genome Hybridization. You take about 400 spots from each chromosome of normal DNA and stick it on a glass slide. Take your test DNA, which is normal, labeled in red and your embryo DNA, which is labeled in green. Then comparing the colors you can make an assessment of the number of chromosomes. Here is kind of what it looks like. If you have an over representation of green that tells you you have extra copies in your embryo and that embryo is not going to make a healthy baby like a trisomy 21 or other trisomies. Most of those embryos do not make babies period.
If you have an over representation of red, normal, it means you are missing a copy of the chromosome, so now you have a monosomic embryo. Those do not make pregnancies generally. If you have an equal amount of DNA from each then you can say it is normal and you can do a lot of plot analysis from each 400 points from each chromosome and when you get a straight line like that you can say that that embryo is normal. In this case 46 XY, or if you have an under representation of chromosome ten, as you see in this slide, that is monosomy ten and an extra copy of chromosome 16.... What we find in IVF is that many of the embryos that look really nice under the microscope that we transfer blindly in IVF do not make pregnancies. They do not make pregnancies because of this, not because of what the patient ate or drank or smoked or did - that two weeks waiting to find out what their pregnancy test was and that embryo was not going to make them pregnant anyway. They just did not know it. Unfortunately they had to wait two weeks and ten progesterone shots later to find out.
I showed you this slide before to think about it. What is responsible for this change in pregnancy rate? It is this, if you actually look at the embryos that we have looked at now several thousand embryos, we have done this biopsy procedure and you say what percent are normal even in the young donors. Only 60 percent of those embryos are normal. This is the reason why donor eggs do not have a 100 percent pregnancy rate. Because even of those beautiful embryos 40 percent of them are abnormal and do not make a pregnancy. But look what happens with age. When you get up to 38 to 41 about 70 percent of embryos that make it to blastocyst, which, by the way, is a tiny percentage of the eggs you start with, because the eggs got fertilized 70 percent do, then those embryos have to go to blastocyst and most of them do not, about half do. This is looking at the best of the best of the embryos that give you the best chance and look at how many are abnormal. But when you take chromosomally normal embryos you wipe out the age effect because you get the same pregnancy rate as an egg donor. If you take one of these single, thawed chromosomally normal embryos and put them back in the patient, if she is 43 if she is 33, it does not matter. These embryos, 55 percent of them, make a pregnancy. They make a baby because they are chromosomally normal. Finding that one chromosomally normal embryo is what we do in IVF for the older patient we are successful with. But it is a lot easier to do it with a young egg and that is one of the advantages to having them in the freezer.
Here is our experience with this - these 177 retrievals are a bunch of patients who failed multiple IVFs elsewhere, who had recurrent miscarriages, they were miscarrying chromosomally abnormal pregnancies. This is one of the main causes of miscarriage. From those 177 retrievals some of the patients had more than one embryo transferred and we did not transfer all the embryos, but right now, looking at our recent data 53 percent of the embryos transferred have made a pregnancy. The clinical pregnancy rate per transfer of 58.6 in a mean age group of 36 (if you go back to STARD registry nationally that number is about 30 percent and in our program it is about 40 to 45 percent) we are still better. But the registry looks at retrieval and you have multiple embryos that are transferred usually putting in one with the patients we can talk into one. Some want two, so 1.24 - there is a 1.24 per embryo transfer per cycle. But we have a clinical practice rate of 72 percent from retrieval and when you are putting back normal embryos you are screening out a lot of patients who would have had a failed IVF cycle. Some of them are told, "Look, you had ten embryos. We tested them and they are all abnormal" - they are not getting pregnant. But that is a good thing to know and it is a good thing to know why as opposed to wondering why it did not work, or what the patient did wrong or the doctor did wrong.
I think for someone who wants to preserve their fertility and who has a partner, this is perhaps a better way. You are going to have to freeze the embryo anyway. You might as well know what you are freezing and then you have a better chance of knowing what your chances are of it working, because if you have three chromosomally normal embryos it does not matter what your age is. Ninety-five percent of those patients will have a baby from our data and our multicentre study, which is impressive.
Egg freezing is an option to preserve fertility. It is a hope, it is not a promise. It is an option, not an obligation. Not something people should do but something that people should know about. It is very costly, it is not 100 percent. Does it change how you view your fertility knowing you have eggs in the bank? Does it change how you behave? We do not know that is part of the social aspects that people are concerned about. But who should make that decision? A politician, a legislator or a group of doctors like me who make policy, or should patients be allowed to make these decisions? Give patients informed consent. Let patients make the decisions, let them know their options and let them make decisions. Do not let someone to make decisions for you. Again, it is a hope, not a promise. But it is an option and again, not something everyone should do.