Clara Colomé, Medical Deputy Director at Eugin Clinic, is explaining social egg freezing and fertility preservation options for patients.
Several changes have occurred during the second half of the 20th century. At the beginning of the 21st century, first, women started working outside the home and many effective contraceptive methods appeared that allowed women to decide whether they wanted to become mothers or not. This is a very important social demographic change, but it confronts the fact that the best biological age to become a mother should be around 18 to 30 years old. However, during this period time is well women are developing their professional careers, they are finding their place in the world, and sometimes this leads to a conflict of interest between society and biology.
The graph shows that the mean age of first birth for women from the 1970s has been steadily increasing all over the world. In Spain, the mean age for the first child is almost 32 years old, but the mean age in the European countries is 28.7 years old. The problem is that women have an ovarian reserve, which is the number of eggs in their ovaries since birth, and they are used until they are finished. That means that with age, there is a decline in fertility chances, and over the age of 35, it declines faster, and after 40, it just goes down very fast. On the other hand, there is also a risk of miscarriage, which also increases with age. The eggs that remain in the ovaries might have some alterations because they’ve been there for 35-40 years. At 40 years old, the chances of having a miscarriage are higher than the chances of having a child if you get pregnant.
Therefore, more and more women decide to use social freezing and postpone motherhood. How does this work?
Every month there’s an egg that is selected from many of them in the ovaries, and it’s ovulated mid-cycle. The idea of fertility preservation would be to stimulate your ovaries with some medication to develop more follicles that would be lost otherwise. This medical treatment lasts for about 8-10 days, and there are 2-3 checkups during the procedure with an ultrasound or a blood test to make sure that your ovaries are responding correctly to the treatment. At a certain point, when a response is correct, the eggs are retrieved through the vagina with a very simple procedure.
Patients often ask about the number of eggs that are usually retrieved. There is a very interesting article published by Goldman in 2017, it shows the probability of having at least 1 live birth at home depending on the number of the mature good quality oocyte. In patients who are younger than 35 with 10 eggs, the chances of having a child at home afterwards are 80%, which is high. On the other hand, a patient who’s 44 years old to have a 50% chance of having a child needs to have over 80 vitrified oocytes, which is a lot. Therefore, the younger the woman who vitrifies her oocytes is, the fewer oocytes she needs to have at least 1 child. That’s one of the reasons why after 40 years old, this technique is not usually indicated.
The live birth rate per vitrified oocytes varies between 4.5% to 12% depending on the series. If there are at least 8 good quality or metaphase II oocytes at 36 years old, the chances of having a child are 62.1%, which is very good. Usually, the range of oocytes that it’s best to vitrify is between 9 and 15. Many patients do 1 stimulation cycle and have a very good number of oocytes. In some cases, it might be advised to do more than 1 cycle to accumulate more oocytes.
It is possible to do a double stimulation, which means that two stimulation cycles are done one after the other. Or it is possible to do one stimulation and repeat it 2 months later. In the lab, the embryologists will take a look at the follicular fluid aspirated during the oocyte retrieval, and they will check if the oocyte is of good quality and if they are in the metaphase II stage, which are the ones that will eventually be capable of being fertilized. They are introduced in different straws and cryopreserved with nitrogen banks. The quality of these eggs from that moment on doesn’t change.
Other questions often ask are: Does the cryopreservation impact the outcome of these oocytes? Is it safe for the oocyte? Will my children afterwards have no problem? The answer is no. There’s been a lot of controversy on this subject for a few years, but for many years already studies have shown that this is a very safe procedure.
The fact of having had your eggs cryopreserved for many years does not have an impact on the risk of embryo malformations.
At Eugin clinic, the program called time-freezing started in 2011, where over 1400 treatments have been done already, over 90% of women who vitrified their eggs are single, which means that most of them haven’t had a chance of naturally conceiving, and they want to preserve this option for the future.
In 2011, the mean age of patients who applied for this program was 40 years old, which is a bit old. Later on, the mean age for this procedure has been steadily declining, so nowadays, the mean age of our patients is less than 37 years old.
When we look the mean number of oocytes obtained per cycle has been steadily increasing, there are around 9 and 10 eggs obtained. The mean number of cycles per patient is 1.2, so that means that most of the patients have enough satisfactory results after just 1 cycle.
Around 53% of the women who came back to use their vitrified oocytes had a partner, so from the 90% that were single at the beginning, half of them already had a partner. The other 46% decided not to wait anymore. The mean age of transfer is 41 years old, and the mean age at vitrification was 38.6 years old, which means that most patients who are already using these oocytes are the ones who vitrified them later in life. The older the patient is, the faster they want to use the oocytes. Using the eggs of when you were 38 years old at 41 gives you already a huge advantage compared to all other women at 41 who try to conceive.
We usually recommend it as you could imagine the sooner, the better, some women or doctors indeed say if I do it too early in life maybe I wouldn’t want to have children also when I am young, but I would say that if you’re around 30 between 30 to 35 years old, and you haven’t made up your mind of motherhood that would be the perfect time for you.
Yes, the eggs can be vitrified one by one, but whether it is recommended at 45 years old and already in infertility situation to vitrify your eggs, the answer is no. This treatment aims to preserve fertility when you do not want to consider that point, one of the first questions that I ask my patients when they come for a consult is if you want to have a child right now or not if the answer to this question is yes I want to consider then clearly other alternatives would suit you better than to vitrify your eggs, and at 45 years old, it’s a very delicate situation and depending on very different situations, but usually what would give you more chances of having a child at this point would be an IVF with your own eggs or most likely to have more chances using donor eggs rather than to vitrifying your eggs at that point.
Ideally, I would advise you to again whether using donor eggs or doing an IVF right, every month counts in your case. If you cannot create the embryos right now, desperate times require desperate measures, so this could be an option. We do not usually do it, as we never do it actually at 45, but I’m guessing that this is an exception, and it’s not for fertility preservation, it’s for an IVF that you will do once you and your partner can get together hopefully soon. The situation with the corona epidemic is improving little by little in Europe, and hopefully, you will have a chance to proceed with your treatment soon, but it’s something that we could take a look at.
There are several reasons to vitrify your eggs, of course, the first reason would be a professional career, we’ve done a few studies on this topic in our centre and in fact when you take a look in the literature and also at our results you would see that around 30% of patients vitrify the eggs because of professional reasons. The main reason is actually, that they haven’t found the right partner yet to create a family, but today it is 60% more related to that rather than to the professional career, but of course this would be the two main reason why women start to vitrify. I think it’s an incredibly good option and actually, I advise vitrifying eggs to all my friends who are getting again close to 30-35 years old and do not have children or do not want to have children yet.
Surrogacy is not legal in Spain. Laws in Spain are quite liberal and advanced considering other European countries but still, surrogacy is a no for us, so we won’t be able to help you with that.
It depends a bit on the medication and the centre while you do it, but it would be less than 2000 EUR for the treatment. In our facility we keep them frozen for 4 years with no extra cost and then you have to pay maintenance per year which is less than a coffee a day.
I didn’t discuss that during the presentation, the treatment is not painful, we advise to do a hormonal treatment. You usually go through injections, but they are very, very small injections and you inject yourself, and it’s really simple to do. Most of our patients do them on their own, and well of course as any medication it might have side effects but there you usually you might feel like if you had a premenstrual syndrome, so you might feel a bit bloated, and you might have more vitamin discharged, you might have a bit o migraine or breast tenderness, this kind of things, but usually, it’s very modern, it disappears after the treatment, clearly, it doesn’t have an impact on natural fertility because what we do is that every cycle the ovary recruits several follicles, several oocytes, but again in the end, only one is selected and the other ones are lost, so what we do is we take advantage of the ones that would be lost otherwise so it doesn’t absolutely have no impact on your natural chances of conceiving and it shouldn’t cause any bleeding’s or of course again if it doesn’t affect your natural fertility it doesn’t cause early menopause.
Fresh and frozen eggs basically have equivalent pregnancy rates with the techniques that we use vitrification nowadays, our chances are equivalent, the only thing is that the older the patient is, it is more likely that the oocytes won’t survive correctly to the thawing process. When we talk about a woman who’s under 37 years old, the chances of the oocytes to survive the thawing process is over 90%, after 40 these chances might get lower, so the pregnancy rate and at the end of these oocytes survive the thawing process are equivalent to fresh oocytes. We add this risk to the procedure, that is one of the reasons why, after 40 years old, we do not advise you to vitrify your eggs.
With the older age the ovarian reserve declines, the ovaries might not work as we expect them to. Usually, the ovary is working like in a Swiss clock, it means it is very regular, but as the age advances the ovarian quality declines, and the ovaries might react unexpectedly. It looks like there are follicles that are starting to grow but eventually, they don’t react, even with medication because the quality of these eggs is not good enough. If your ovarian reserve, the amount and the quality of those eggs are good, they will respond correctly to the medication. If they don’t, this means that usually, this is because your oocytes were not good enough, to begin with. There might indeed be a variation on the medical protocol that could be applied, we would have to take a look into more details, but usually, it’s linked to the quality of the oocytes.
No, we do the oocytes retrieval and then inside the lab before vitrifying the biologist takes a look at the oocytes and see if they are in metaphase stages of development. Which are the ones that are good enough quality to be used, once they have been vitrified, we cannot verify their quality or their genetic material. Eventually, if you use them in the future, we could do a PGT diagnosis on the embryos once they are created, if there’s an indication for that. Now there are no specific tests to verify the quality of the egg once it’s vitrified.
Different medical protocols are used for ovarian stimulation, we can use agonist for blocking, we can use antagonist for the blocking. I don’t want to be too technical about that, but there might be slight differences using one protocol or the other, depending on the patient but, indeed, scientific evidence doesn’t show one protocol is statistically better than the other. For one patient in particular years, the short protocol might work better than a long one, or the other way around, but in general, there’s not a better or worse protocol. Usually, when we do the vitrification protocol we use a short antagonist protocol because it allows us to trigger the ovulation with GnRH agonist which allows us to control better the risk of hyperstimulation, and it allows us to go back to normal faster and minimize the discomfort that might be linked to the procedure.
Yes, lifestyle has an impact on almost everything, it has a clear impact on egg quality, not just during the protocol, but before that, so the first thing I advise my patients to quit smoking, this is the most important factor. If you’re overweight, I would advise losing some weight because obesity might have an impact on the egg quality as well, and of course, alcohol intake might have an impact on the quality of the oocytes as well. Basically, I would always advise you to carry a healthy lifestyle, but especially during the stimulation procedure, I would advise you not to drink alcohol during this procedure. Intercourse during this process, yes it is possible however, we know that we are doing this procedure to not get pregnant at that time and when we’re stimulating your ovaries your chances of getting pregnant increase and we would risk multiple pregnancies, so my advice is you can continue to have sexual intercourse during the first days of the simulation but of course, usually using contraception, so condoms and we only advise you to avoid sexual intercourse for a few days around the date of the oocytes retrieval because then it would increase your chances of bleeding f.e., which is very unlikely, but if you have sexual intercourse, you can increase that risk. Working on your laptop and keeping it on the lap, well this is a very specific question. I guess you mean the radiation and heat and everything, clearly, in all situations, it is better to keep your laptop on the desk, but I honestly do not think this has a direct impact if you do it just once now and then on the quality of the eggs. If you spend 10 hours a day with your laptop on your lap, then I could advise you to avoid it.
I do not have the details of everything but regarding the quality of embryos in particular that you were telling me, we have a different system of classifying the embryos regarding their morphology. There are minimal requirements that an embryo has to have to result in a pregnancy, and it depends on whether it’s a day-2 or day-3 embryo, or if it is a blastocyst so day-5 embryo. The morphologic quality of the embryo doesn’t have a direct impact on your pregnancy rates, it has some correlation, yes, but it’s not the most important thing. I always explain this to my patients when we take a look at two different embryos, morphologically they might have the same aspect meaning they might be 2 blastocysts 4AA, which is just a good quality of the embryo, but when we take a look at them under the microscope, the biologist is incapable of telling me the age of the embryo, the age of the oocytes, this is the most important factor, so it’s not the same thing 4AA blastocyst in a 43-year-old woman than 4AA blastocyst in a 32-year-old donor, and clearly your chances are completely different. In the first case, you would have very small chances of having a child, and with the other one there will be 50% or 60% chances, so clearly the embryo quality is something that has to be taken into account, but it’s not definite for us to decide whether we are going to have a child or not, so basically this is something that would have to be discussed. It’s very difficult for me to doubt the indications for a particular embryo to be transferred or not in another facility without having all the details, but usually, with donor eggs, we are more strict with the quality but the chances of an embryo of the donor working even though the aspect is not as perfect and we would expect, are still surprisingly high.
The number of eggs that we obtain in one cycle in our facility, I showed you on the slides, it was around 9 good quality oocytes, and whether it is enough or not, depends on your age and your expectations. Also, I didn’t tell you that, but of course, it’s not the same thing if you’re planning on having a large family with four children, then if you’re just planning on having one, clearly you will need more eggs for the first lifestyle choice, than for the second one. But in general, it is between 7-9 mature oocytes. If you go through the medication and only deliver a few eggs, well there are different options, we could do what we call a double stimulation which means we do the egg retrieval, and two days later we start again the stimulation and around 10 to 12 days after that, we repeat the egg retrieval to accumulate more oocytes. Usually, when we have a low number of oocytes, we will advise you. If we know beforehand that your age is advanced for the procedure or your ovarian reserve is lower than expected, we will talk to you about that and we will offer you this option from the beginning. We can also decide it afterwards, depending on how the cycle evolved and decide last minute whether we want to repeat it or not, and we can do two in a row, or we can just leave it. Some patients for logistic organization reasons prefer to just skip a couple of months and then come back, and we can also do that this.
Men, let’s say are luckier than us on this evolution subject, we can carry children, but they are fertile longer. Age doesn’t impact the quality of the sperm that much, it impacts the quantity and the mobility of the spermatozoa found on a sperm sample. Some studies state that the risk of some genetic diseases such as autism, some psychiatric disorders or some other malformations might be increased in older patient sperm but this is something that would be expected in even older men who over 50 or 60 years old. In fact, a group published a study a couple of years ago comparing our pregnancy rates in oocyte donation cycle depending on the partner’s sperm and the partner’s age. The pregnancy rates were exactly the same, no matter the age of the partner, so again well age is an important factor for everyone but not depending on the difference of age between the donor and the men, but Rather depending on how old the man is, and at 42, he would still be considered young, we are talking about this type of problems that are starting to increase very slowly after 50-60 years old.
These are very interesting reasons that we could discuss for hours. There are different elements when we talk about the implantation equation, there are the oocytes, then the embryos which are created from the oocytes but also from the sperm, which is something that we cannot forget. So there could be a problem on the oocytes, but this is unlikely when you’re discussing donor eggs, there could be a problem with the sperm f. e. sperm fragmentation that is altered even though the quality of sperm looks normal. Then there can be problems with the development of the embryos, or problems with the endometrium, adhesions, fibroids and other alterations in the uterine cavity and in the endometrium itself. And then, of course, other general diseases or other more general syndromes such as hypothyroidism, clotting problems such as thrombosis or thrombophilia and other disorders that could affect the implantation rate. Implantation is one of the most interesting but more complex aspects of fertility, once we leave the embryo inside the endometrium, we are not really sure what happens there, it’s like they have to discuss one with the other the endometrium and the embryo, and reach an agreement in order to understand each other and implant and why this doesn’t always happen, even though the embryo has the best quality and the aspect of the endometrium is excellent, this is one of the aspects that are being more thoroughly studied right now, more scientific studies, more efforts are put to be able to clearly answer that question. Unfortunately, we cannot do that yet.
Not really, usually the period between the medical triggering and the retrieving of the oocytes is 36 hours. I mean in 36 hours it can be done in certain cases, maybe 34-35 even we could get to 38, but 12 no, unless you’re already ovulating which changes the question, but the medical triggering for the ovulation if we do it 12 hours in advance, your ovaries won’t have released the oocytes yet when we go for the egg retrieval so I wouldn’t recommend doing that. The only reason I can think of doing an oocytes retrieval with 12 hours would be that you’re already ovulating maybe and we’re trying to recover some of the eggs before they are being lost.
I would say the easy question and probably the one that you hear most would be day -5. I would say it depends on the case, clearly, if all conditions are there if we have a very good number of oocytes and a very good number of embryos allowing the embryo to develop up until day five or blastocyst stage gives us more information about the embryo. That’s why this is what we usually do everywhere as a standard procedure f. e. for donor eggs, it allows us basically to select better the best embryo, and it also allows us to minimize something that we gynaecologists don’t like that much, which is multiple pregnancies. If we go for day-5, we can select better and easier the best embryo, and therefore we have more strict on the number of embryos that we allow our patients to transfer. In our facility, when we use donor eggs with a day-5 transfer, we always transfer just 1 embryo. Day -3, however, is still a very good alternative in certain cases. We have very good chances on day-3 f.e. 2 embryos on day-3 give us the same pregnancy rates as 1 day-5 embryo, but that’s again the reason why we prefer 1 day-5 to minimize twins. When do I advise to transfer the day-3 embryo, well basically in patients who are using their own eggs, and do not have many embryos and they are not intended for a PGT study. When we have 1 or 2 embryos on day-3, it’s been so hard for us to get there, your stimulation procedure, the egg retrieval, waiting for the embryos to develop, then risking not having any just for two more days in the lab. If we do not doubt the characteristics of the embryos and of course they look quite okay, I would advise transferring on day -3 because we know they’ve got there and we know we have 2 f. e. at that point but we do not know if they will get to day-5. This might be because the embryo was not destined to develop, but it might just be because the lab is not the best environment for an embryo, the best environment for an embryo is in the uterus. It’s a tricky question I hope I was able to help you and we could discuss it individually with more detail.
In the same menstrual cycle, we can do 2 egg collections, when we do a double simulation, you have your period, then we stimulate, we retrieve the oocytes, and then we stimulate again so within a month time we can do 2 egg collections.