Elective Egg Freezing

Dr. Andres Reig:

The information shared in this podcast does not necessarily represent IVI RMA’s stance. These podcasts are not a substitute for a consultation with a physician.

Hello. I’m Dr. Andres Reig. Welcome back to FertiliPod, the podcast where we discuss current topics and the latest research in the field of reproduction with some of the world’s leading experts. Let’s get started.

In today’s episode, we’re talking about fertility preservation. In particular, elective egg freezing, with two top experts. Dr. Ana Cobo is the director of the cryobiology unit in the IVF lab at IVI Valencia. And she’s joined by Dr. Juan Antonio Garcia Velasco, the director of IVI Madrid. Let’s start with you, Dr. Garcia Velasco, thank you so much for being with us.

Dr. Garcia Velasco:

It’s a pleasure.

Dr. Andres Reig:

Can you tell us a little bit about… Let’s talk first about the technical details. From the patient perspective, what does this entail for the patient? If they are choosing to elect to go for egg freezing, what do they have to do?

Dr. Garcia Velasco:

Well from the patient perspective, it’s quite simple and pretty straightforward. Obviously, they need to have a previous analysis of their ovarian reserve, so we can establish what is going to be the expectation of this fertility preservation. So they usually do a transvaginal scan to measure the antral follicle count, or/and AMH values. We do estimate their Anti-Mullerian Hormone any day of the cycle, combined with the antral follicle count, which can give you a very good estimate of what is going to be the outcome of the stimulation. And apart from a general workout, and then we will start the stimulation, usually, with the PPO day one to three, even though you can start almost any day of the cycle, and it’s going to take about two weeks. So altogether it’s about eight or 10 days of simulation with self-injections, two to four ultrasounds to control the ovarian development and follicular growth. And then the ovual pickups altogether is going to be around 12 to 15 days.

Dr. Andres Reig:

And then once we obtain those oocytes, Dr. Cobo, how does this work from the lab laboratory perspective? What, happens to them next?

Dr. Ana Cobo:

Yes, when we harvest the oocytes through the follicular function, as regularly performed, what we do in the lab is wait a period of two hours. And then we remove the cumulative cells of these eggs and proceed immediately with the vitrification procedure, which is, I could say, is a relatively easy procedure, but it definitely needs to be performed by expert hands. So if you wish to, we can talk a little bit more about the technical details, the procedure, and the implications for the IVF lab.

Dr. Andres Reig:

Sure, absolutely. You mentioned the vitrification procedure and I know this is obviously something that has changed in the last few years, a lot, from the kind of regular freezing to vitrification. Can you tell us a little bit about how that process has been, what has taken us from regular freezing to what we do today, and how it’s different?

Dr. Ana Cobo:

Yes, absolutely. Vitrification is really a great tool in assisted reproduction because of all of the chances and the new alternatives that bring to our hands. The main difference from slow freezing, which was the regular procedure, is that with vitrification, we avoid ice formation. Ice is not compatible with life. If we have ice crystals inside the cells or even outside the cells, it could be really dangerous to cells and could bring a cell to not survive the procedure. So, how can we achieve vitrification in the lab? The main difference with slow freezing is that with this former procedure, we need specialized machines, programmable freezers, which was much more expensive than the vitrification procedure, it takes around two hours, the whole procedure. It’s different from this point of view. But as I mentioned before, with vitrification, we need really practiced hands.

Dr. Ana Cobo:

What we do is subject the oocytes or the embryos to a very high cryoprotectant concentration. So with this solution inside the cytoplasm, once we get to the point which is a temperature below zero. And then this solution, these compounds will not solidify into ice forming ice crystals, but in a glassy state. It’s solid with a consistency of glass and this is why this is called vitrification. The full procedure takes around 12 minutes. It’s a huge difference with vitrification but the main difference, is absolutely, the success rates that we can achieve with vitrification.

Dr. Andres Reig:

Right? So Dr. Garcia Velasco, to that and from the clinical perspective what has, would you say, the impact of vitrification been both from the clinician perspective, in terms of the process itself and perhaps a little more from the perspective of counseling and what has the impact been to the patient? That we can now do vitrification instead of slow freezing?

Dr. Garcia Velasco:

Well, I think there’s a huge impact of these new technologies, as Dr. Cobo has described, based on the success rates of thawing that we didn’t get with slow freezing. And this really has changed, dramatically, many areas where we work. First of all, is the issue of fertility preservation as itself. So we can freeze oocytes, we started with cancer patients, those patients who are going to receive chemotherapy that is going to be toxic and may have an impact on the ovarian reserve and compromise the chances of having a baby in the future. They can now safely retrieve oocytes before the chemotherapy and then safely have babies later. In fact, we have frozen oocytes for more than 1400 patients in the IVI group, in the IVI RMA group and we have already 48 babies, born. So that’s a routine technology that we use in this particular group of oncological patients.

Dr. Garcia Velasco:

But then not only that, I mean, there’s a huge impact also on social fertility preservation. Huge demand from women who postpone maternity until when they want to be ready or that they are ready to have a baby when they can have a baby. And they have this pressure from, not only from society but also from biology and they know that after a certain age it’s going to be very complicated to be pregnant. So there are more and more women coming to freeze oocytes because they want to reduce this pressure. And just freeze their oocytes, continue with their lives and, when they’re ready, come back and use the oocytes and have a baby.

Dr. Garcia Velasco:

Also, with what we do in our daily life, we have been able to avoid OHSS and one of the reasons to avoid OHSS is because we can use an agonist trigger, as we all know. For those of you who are working in ART, that if you do an agonist trigger, you have to freeze. And now we can freeze oocytes, we can freeze blastocysts and their survival rates are going to be beyond 90 or 95%. Also, it has allowed us to accumulate oocytes in those poor responded patients, and we can accumulate oocytes for embryos, pull embryos, and then do a PTA cycle in the future if needed. So there’s a huge variety of indications where patients do benefit from this big jump in technology that was vitrification.

Dr. Andres Reig:

That’s right. And it seems that from what you’re both saying, vitrification has really been clearly one of the biggest breakthroughs in the field of fertility preservation in general. Both from the egg and from the embryo perspective.

Dr. Andres Reig:

This is a question perhaps for both of you, but Dr. Ana Cobo, if you don’t care about starting, what role would you say IVI RMA’s played in the development of this technique? What are some of the key studies that have taken us where we are today?

Dr. Ana Cobo:

Sure. Actually, we were the pioneers in Europe to bring this technology to our labs. We started in 2007. I have to say that this technology developed basically from the animal field because as I mentioned before, the material necessary to do slow freezing is too expensive. So they started to research their research in this field. And there was a Japanese group, the leader was Dr. Uyama, and they were working on a device, a special device called the Cryotop, which add one of the latest developments in the vitrification procedure, which was the minimum volume. It means that we load the samples in the device within the minimum volume. So by, I have to say it was probably 2005 if I remember well, they published a study with the application of this special device with cancer patients. And then that was when we got interested in this special device. And we studied this procedure in our labs here in Valencia.

Dr. Ana Cobo:

Actually, if I remember well, in 2008 we published our first study, which was conducted with donors’ oocytes and we compared the quality developed with fresh and vitrified oocytes from the same cohort, and these oocytes were inseminated with the same semen sample. So it was the perfect scenario to compare the potential of these vitrification oocytes. So this was really the first, I would like to say the first time, which brings us to the actual scenario that we are at.

Dr. Ana Cobo:

Our next studies were also conducted with the donors’ oocyte program. And so the next most representative study was the clinical trial, the randomized clinical trial, in which we demonstrate the effectiveness of this procedure. And then, if Dr. Garcia Velasco may come in, we started the publication with the fertility preservation, either for social freezing or with cancer patients and lately in endometriosis.

Dr. Garcia Velasco:

I think as you said, it’s one stone after the other. So you started to develop the technology in Europe and brought it from Asia, from Japan, as you just mentioned. And we, I have to say as a clinician, at the beginning I was very skeptical. And then when you see the results, it was extremely convincing.

Dr. Ana Cobo:

It was. I have to say.

Dr. Garcia Velasco:

It’s interesting because I think these Japanese doctors were trying to communicate their findings for a few years, but probably the communication skills were not that great. And that sounds like a joke, but it’s not. The truth is that as soon as you visited Japan, you visited the lab, you brought the technology here, you brought the Japanese doctors to Spain. We realized that there was a really big change. And I think one of the biggest steps, after IXI, things that really change the lives in ART.

Dr. Garcia Velasco:

And I just mentioned, you started with the papers on donor egg vitrification, on randomized control trial, to convince that there’s similar fertilization rate, implantation rate, and life expectancy rate. And then we went on to a series of papers that we have published, around 10 papers on this topic in the last 10 or 15 years. So in cumulative experience on social freezing. The first patients that had babies after cancer treatment and freezing the eggs prior to this chemotherapy. Doing fertility preservation, prior to surgery and demonstrated that if you freeze your oocytes before the surgery, you’re going to have a much better outcome in terms of fertility than if you freeze your ex after the surgery. And I know there are different indications that are being discussed today. And I think it’s a great tool that if it’s done in a great lab with experienced hands is going to provide you as good an outcome as fresh oocytes. But with the benefit of stopping the clock.

Dr. Andres Reig:

We’re going to get back to the whole development and research part of it. But from the patient perspective or from the counseling perspective, if your clinician, who is this for? Why is it so important and who should consider elective egg freezing?

Dr. Garcia Velasco:

Well, that’s a good question. And in fact, Dr. Cobo and I published, a few years ago, a paper with a very, I’ll say provocative, title saying, «Should all women freeze their eggs?». And, and of course, this is not for all the women in the world. It doesn’t make any sense, mainly because most women will have babies without the use of ART. And we hope that that stays like that for many years. But the truth is that it’s a huge pool of patients, women out there that may benefit from this technology. And I think that the biggest indication today is the selective source for freezing, as you just mentioned. Elective freezing, due to social reasons, I think it’s increasing in demand. And I think it’s a beautiful way to reduce the pressure on women to be forced to have a baby when they don’t want to have a baby yet, or when they don’t have a partner that they’re convinced that they want him to be the father. And this is a daily conversation at the clinic.

Dr. Garcia Velasco:

You talk to patients and when you ask them, «What is the reason to freeze your eggs?» The main reason is not, «My professional career.» It’s not «I want to travel for one or two years.» It’s not like that, the main reason is, «I have a partner with whom I can’t have kids, and I don’t want to go too fast in the decision-making process when I meet someone that I want to have a family with.» So by freezing the eggs, they reduce this pressure. But then I think there’s a crucial point here that we, as clinicians have to be very, very clear. Very careful. And it’s mainly to avoid over expectations.

Dr. Garcia Velasco:

I think we have generated enough data today that is a great tool to counsel these women. And I think they have to be fully aware of what is the failure rate and what is the success rate according to your eggs. So, it’s not the same freezing oocytes when you’re 32, then when you’re 37, then you’re 41. I think this is very important, not to say, «Yes.» Or, «No.» To freeze the eggs, but to be aware of what is the possibility that if I came back to your clinic and I want to use my eggs that I froze when I was 38, what are the chances of them to survive? And what are the chances of having a baby, according to the number of oocytes that I froze at the same time? If you freeze five oocytes, then you freeze 15.

Dr. Garcia Velasco:

So all of these numbers and statistics, I think they need to be clearly discussed with the clinicians and, probably, this is the best way to provide good care to our patients. And then, of course, there’s a huge amount of other indications that we discussed, but I think elective social freezing is becoming something that is more social than medical, to be honest. And still, these women come to us because they know someone who did it. They don’t come to us referred by a doctor, unfortunately, and this is what probably we should think ahead. Thinking in the future, I think the future of OB/GYN doctors will be to counsel women, not only on, on HPV vaccination and cancer prevention but also on fertility counseling. And I think part of the route, basically, to your OB/GYN would be a sort of questions, «Have you considered having babies? Yes or no?», If they don’t, that’s the end of the conversation, but if they say, «Yes, not right now.» Maybe that’s a moment to explain briefly what ovarian reserve is or the chance of having a baby beyond 35. And maybe to consider this.

Dr. Garcia Velasco:

Still today women come to us, because they met at a dinner, a party, or a job, someone who did this procedure. And sometimes, the ideas that they have come from the web, and sometimes these over expectations are there. And we have to sometimes, tune them down a little bit. So I think it’s our responsibility to educate the society, educate our colleagues as general doctors and general OB/GYN and provide them this information and this training, so they can properly educate the patients. There are two papers published, not long ago. One was a huge questionnaire down in Australia on university students. And the other one was among U.S. doctors. And was asking simple questions about, «Do you do this? Do you counsel your patients about fertility?» And what these two studies demonstrated was a huge lack of knowledge, to be honest. And there is a big need for education, it’s being demanded, especially, by our colleagues. And I need more time, but I need also more information on how to explain this to my patients.

Dr. Ana Cobo:

I see. If I may add the mean age, which they are coming to have their oocytes vitrified, is a confirmation of this that you are saying. Because the mean age is too old. It’s 38. So this is typically the population that we should consult for fertility problems. So I think there is really a need for these information campaigns, for them to come earlier, to have their oocytes vitrified for fertility preservation.

Dr. Ana Cobo:

I would say in our last studies, we have analyzed the number of oocytes we need to vitrify to achieve a baby according to age. And as you said before, even if a patient with 41, 43 years old can achieve a baby, the possibilities are really, really low. And this is clearly shown in the course we have published. So this is a reality. Sadly, they are coming too late for fertility preservation because we know from the biological point of view, the possibilities are really, really high if they come earlier than in the early thirties. That’s a reality.

Dr. Andres Reig:

Absolutely. And in fact, I found it very interesting, there was a recent publication from the press release, I guess, from the Spanish fertility society that in the latest data they had from 2018, about 10% of births in Spain, came from IVF procedures, which is incredible. It’s very impressive. And I don’t think, clearly, that this is because so many people, so many more people, than before have fertility problems, but rather because a lot of people are definitely using fertility services to preserve fertility and to get pregnant later and are also more aware that all of this is available.

Dr. Ana Cobo:

Yeah.

Dr. Garcia Velasco:

Yeah. There’s also a big handicap in Southern European countries. Spain, as you mentioned, but also in Italy, in Greece and Portugal. And we have the oldest mothers when they have the first baby compared to Northern European countries or U.S., for instance. And this is a big issue and it is a social problem that is affecting medicine and ART. We are aging and we’re having babies at a later stage. And there’s a big disparity between social life and biology, as Dr. Cobo mentioned. When you talk to a patient of 40, she is socially very young, and she has been in front of her future, and she’s starting the family, and she’s running marathons and she’s still extremely strong and with a bright future ahead. But from the biology point of view at 40, the ovaries are near the end.

Dr. Garcia Velasco:

And this discussion is a daily discussion with our patients because no one told them in advance. They didn’t tell them at school, they didn’t tell them in their annual checkup. And I think this information has to be disseminated. I think we have to do this because otherwise, we will always think, «Okay, well maybe if I’m 40 and it’s not so easy to have a baby, then I do an IVF cycle and that’s it.» And we know it’s not like that. And you have to have good oocytes. So elective freezing is going to help them. And it’s actually helping, today, women who postpone maternity, maybe not for too long, but maybe for three to five years, that if you freeze at 35, you can have babies at 40 when the eggs of 35. Which is a huge difference from the clinical point of view.

Dr. Andres Reig:

Yeah. What would you say are some of the most cutting edge things that are being talked about now, within the field of selective fertility preservation?

Dr. Garcia Velasco:

Well, I think, and here we have Dr. Cobo which is an expert in the technology, that what I’m saying towards the future is that most of the labs are trying to go into this automation and trying to simplify the procedures by having machines doing what is being done by hand today. And I would like to hear Dr. Cobo’s comment, but I think oocyte freezing is an extremely sensitive procedure. It’s not as easy as embryo freezing or sperm freezing. And I think that technology has, still, a long way to develop a machine that is efficiently freezing oocytes.

Dr. Garcia Velasco:

I think we are always looking ahead and with our eyes open to see what is the technology today? The thing is going to be not so easy. And especially because in the future, if we are dreamers, we may state that egg freezing could be a commodity. And you can go just to the next corner and just get your oocytes out and frozen in a symbol device that can be in any office. And then you freeze the oocyte and you can wait for the future. And I think there are so many things that need to be developed, and improved, and trusted, that they’re going to work. But this would be a nice dream for the next five, 10 years.

Dr. Ana Cobo:

Yes, I totally agree. The real challenge right now is the devotion of the procedure, because, as I mentioned before, the procedure is really easy and simple, but you need really practiced hands. And I would say that the main drawback of the vitrification procedure is the lack of standardization. Not everyone doing vitrification, not every lab in the world is achieving the same results. And then the question is, «Why? This is an extremely sensitive procedure. So there are different modifications and different little things that everyone adds to the protocol, so in the end, it’s a completely distorted thing. And this is really a huge problem. So, for more than 10 years, people come to us just asking, «Why is it, we can not achieve the results you achieved?» So they came to our labs, they watch, they see all of our procedures. And then. «I don’t do this thing like this.» And, I mean, there is a really, really, need for standardization.

Dr. Ana Cobo:

And once we have the possibility to have a machine able to vitrify and warm the eggs and the embryos in the same machine, same protocol, then there would be a second breakthrough in the field of vitrification. We really need standardization of the protocol. And there are of course things brought into the table right now, as they use flash liquid nitrogen, which is much cooler than the regular liquid nitrogen it’s around minus 200 degrees Celsius or below. And when you mentioned before that our dream would be to have our oocytes freezing service provided in, I mean, an easy everywhere. In Israel, they are working on a new freeze station. So probably this will be the future, in my opinion. It’s too far away, still. But probably, you could come to your home with your sperm or eggs just in an envelope and just store them for whenever you want to use them.

Dr. Andres Reig:

Last week on the podcast we had Dr. Emily Osman from RMA New Jersey who was talking to us about the use of slush nitrogen in embryos. And it was actually very, very interesting. Also a couple of weeks ago was the ASRM conference, the ASRM Congress. And there were a couple of interesting oral presentations about what Dr. Garcia Velasco was talking about earlier, in terms of success rates and kind of, actual return rates. How many people actually use these eggs that they have frozen before?

Dr. Andres Reig:

I’ll tell you very briefly about one of them that I found very interesting. It was from NYU, from New York University, and they basically looked at a relatively small sample of 231 patients who had essentially done elective egg freezing just for social cryopreservation. And they said this was the first study to actually report final outcomes for how many of these patients actually come back and use their eggs. And they reported a utilization rate of 38.1% and a no use rate of 58.9%. My first impression was that 59% no use rate was kind of high, but then I thought actually a 38% utilization rate is huge, considering this as something you do, more or less, preemptively. And it was pretty similar across age groups. Now, I know this is the first study to actually look at that, but do you have any data from within your groups that is similar to this? Different? What is your experience and how many of these patients actually come back to actually use these eggs and what are their success rates?

Dr. Ana Cobo:

Yes. In our experience right now in our publication from 2016, if I remember well, for elective fertility preservation, the return rate was around 12 to 15%. And probably it is because, I mean, they are coming to use their oocytes. But our mean age for vitrification was very high. So probably, in this specific population, they finally have found the right partner or there are many, many reasons why that could explain they are not coming, but it’s much lower in our hands. It’s around 50% elective fertility preservation. But when there is a specific condition like endometriosis, as we recently published in our study from this year, actually, the return rate was around 50%. So half of them have returned to you to use the oocytes because they have a condition that could be potentially harmful to the ovarian reserve. So in these specific populations, they are coming earlier to use their oocytes. So the reasons why, I don’t know, maybe Dr. Garcia Velasco has another explanation or another point of view, why our return rate is much lower than those resources and you just comment.

Dr. Garcia Velasco:

I think that the return rate is very much correlated to the reason why you freeze. And this is why elective freezing, most of these women will never come back. More than half will never come back to use their oocytes. Some of them will find a partner and will get pregnant internally. Some others will never have babies, but they want to reduce the pressure that they have on themselves. But you freeze for indication, as you mentioned with, within the endometriosis, this freezing is part of the treatment. So they know endometriosis is kind of eating their ovaries, it is destroying the healthy ovarian tissue. They want to have a baby. Maybe they need to do a surgery or maybe postpone it for a few months, or a few years, but they want to come back. So that’s why, I think, we found a very high return rate, as you mentioned, around 50% in women with endometriosis and very low in elective freezing and also low in oncological patients, which is around 10%.

Dr. Garcia Velasco:

And again, the reason is that oncological patients, when they freeze, they’re significantly younger. The mean age is around 32-33 years. So, young. A lot of these women will get pregnant. The difference between the work from NYU and ours, I think it also depends on how long do you do this for? So if you remember the first time we looked at these data, the return rate in elective freezing was only 6%. The longer we wait was after 12%. And if we keep looking at this data, it will become probably 20, 30%. I think it’s a matter of how much are you observing these patients and how long the follow-up is.

Dr. Andres Reig:

That’s a great point, actually. How long it’s been since the retrieval is key to analyze utilization rates. Of course, this has been such a great discussion with both of you. I really appreciate that you both were able to take the time to talk to us today.

Dr. Ana Cobo:

You’re welcome.

Dr. Garcia Velasco:

Thank you very much.

Dr. Andres Reig:

Thank you. This has been another episode of FertiliPod by IVI RMA. Thank you so much for listening. Tune in next week for more research and topic discussions on all things reproductive medicine. See you next week.