Watch the webinar recording with Vladimiro Silva, PharmD, Embryologist, CEO, Founder & IVF Lab Director at Ferticentro, who is discussing IVF and pregnancy after the age of 40.
First of all, I’m assuming that this patient has tried IVF twice so I’d say that we would certainly test the embryo, even embryos that are already frozen can be tested genetically. We can take the uncertainty factor out of the equation. If the embryos are genetically viable, we would focus our investigations on the endometrium. If the endometrium is okay and there is a lot to look for in the endometrium; there are any military factors, there are endometrial receptivity factors and also there are other more rare causes like thrombophilia, general hereditary disorders, gynecological issues like problems with implantation, fibroids, problems with the uterus and so on.
But, first of all, I’d start by testing the embryos to know whether they are viable or not. If the embryos are viable, I would then focus on the endometrium. If the embryos are not viable, we would need to see if there is any room for optimization in the embryo and the ovarian stimulation. If so, we would need to try again. There is no alternative.
I don’t know if they did preimplantation genetic testing so we don’t know whether the embryos were viable or not. But I’m assuming that if these treatments were done, the problem was most likely a genetic issue of the embryo. Then the patient did a treatment in Spain with egg donation and she miscarried at 7 weeks. That can happen. Again we don’t know the quality of the embryo. Miscarriages happen normally. Here there is an indication to search for miscarriage causes when we have at least 3 miscarriages. I wouldn’t say that this is an indication to start doing some tests but, in this particular case, the obvious solution is to do another egg donation treatment. Then, I would start with the endometrial receptivity evaluation. It’s a very important factor. It impacts a lot of patients. That’s also the most likely issue to be found. If everything is okay, if we have good quality embryos, if we have receptive endometrium, I would try them without any further tests. If it doesn’t work, we would probably look further and we could look for immune factors like natural killer cells, antigens, HLA C, antigens, etc. There are a lot of things that we can investigate. I would go one step at a time. I don’t believe in looking for everything at the same time. If in a new egg donation treatment we get good quality embryos and we get a receptive endometrium, I would try again directly. I think the prognosis would be very good assuming that everything is fine.
I will give you the most honest answer I can: I actually don’t know because a few years ago we all believed in this. There were a lot of people doing mild IVF including ourselves. There are several mild IVF protocols with less medication, lighter stimulation. Very often we just had one egg or two eggs and in principle, those would be better quality embryos. However, recent studies, especially published in the last two years, have shown that there is actually no upper number limiting the number of eggs regarding their quality. There have been studies showing that in cases where we get 30-40 eggs, the likelihood of having a genetically abnormal embryo doesn’t increase with the number of eggs. Nowadays the tendency to answer this question is no. But, again, five years ago the answer would probably be different. There is also an inter-patient variability – something could be true for some patients, for others it couldn’t. I believe that mild IVF in older patients is not the first choice. I would say that we would only do that if doing IVF with high dosages and a lot of embryos and eggs doesn’t work, maybe then we could try this approach. But in principle, we would not do this as a first line approach.
I believe in natural killer cells. I understand the question because this is not something that all clinics follow. We only start looking for these types of unusual or less frequent factors when we don’t have an explanation for previous failures. When we find out that there is an increased level of natural killer cells and all associated changes, we should treat them. We have protocols that are specific for patients with high natural killer cells. If you’ve been diagnosed with that, we will definitely treat you accordingly. We believe in the effect. We don’t search for problems with natural killer cells as a first-line approach while dealing with failure. There are other factors that we think are more likely to be the explanation for an IVF failure. However, if we find out that there is something wrong with the natural killer cells, we would treat them with specific protocols.
Egg donation is certainly a good solution and with a preventive protocol for the natural killer issue, the prognosis would certainly be good.
Not exactly because there might be other issues but, yes, they could prevent egg donation from working. We have to take care of that issue. We have to give the proper medication to avoid that.
Your chances are more or less the same as every other woman doing egg donation. I mean you have a good prognosis factor which is the fact that you’ve already had a baby and a successful pregnancy. We’ve proved that your womb can take a pregnancy to term. Assuming that everything is normal I would say that the chances would be the same as we have seen in my presentation – 60-70%. I would say that the chances are very good.
Yes, I would say that if we’re talking about 2.24 ng/ml, it would be a wonderful value. Obviously we cannot talk about quality and without checking but I would say that you are certainly a good prognosis patient because a good AMH is also associated with better quality eggs. The more eggs we get the more likely we are to find a suitable and viable egg. I would definitely recommend PGT in your case but I would say that it does have an impact on egg quality as well.
With the current technologies, it is not possible with an AMH of zero and being in their 50s. It wouldn’t be legal. In medicine, we don’t like to use the word impossible but from a strictly scientific point of view, the chances would be extremely low. I cannot say zero because I mean nature gives us a lot of surprises. Two years ago we had a patient getting pregnant spontaneously at the age of 51 so that can happen. I would say that chances are almost zero if not zero. Nuclear and spindle transfer – nowadays there is a lot of discussion going on this subject. There are studies and in fact, there are very reliable studies that have been done where we are doing cytoplasm transfer which means that we take the cytoplasm of the neck from an egg donor and we put it inside into the egg and leaving the nucleus of the patient. We know that by doing that we would have the nucleus of the patient who is getting pregnant which has all of her DNA and most important characteristics and that will work with the mitochondria from the egg donor. The mitochondria is a center of energy for the cell and that will give the egg enough energy to develop and correct potential genetic problems.
However, that only been properly tested in younger women. In older women where there are abnormalities already in the nucleus, it’s yet to be proven whether there’s any room for correction of potential genetic errors. Personally, I find it very unlikely. I think science will progress. There have been studies where a part of the ovarian function has been recovered even in menopausal women and so maybe within years from now, this will become possible. Nowadays, I would say it is no possible. I wouldn’t believe in it but science is evolving and so maybe in a couple of years it becomes possible but nowadays I personally don’t believe in it.
I’m assuming that you want to try with your own eggs. I would not recommend doing more than three ovarian stimulations. I would say that, first of all, we would need to assess the AMH, AFC (the antral follicle count), and also the FSH which is the other hormone that’s associated with how the ovary works in hormonal terms. We would check the data and if it’s still possible, we would do ovarian stimulation. Our goal is always to try to have 10 eggs because we know that by starting with 10 eggs, we will theoretically have at least one viable embryo. We would start with 10 eggs and try to have as many embryos as possible. We would do PGT-A and see if any of them is genetically viable. We can bank eggs, we can do ovarian stimulation, get 4-5 eggs, do second ovarian stimulation, accumulate 5-6 more, do it for the third time and then fertilize all the fresh and the previously frozen eggs. It’s about statistics. I think that up to three ovarian stimulations there is no doubt that they are safe. They don’t pose any risk to your health. We can have a try and check for further genetic content. All studies indicate that it is safe. There is no upper limit, there are studies saying that on the 10th ovarian stimulation your risk of cancer increases. There is no such information but there’s certainly a threshold above which we should not continue to do ovarian stimulation. Normally at our clinic, we say that three ovarian stimulations are a wise decision. It’s within what’s acceptable. After that, if we don’t get good quality embryos, it’s better to think about egg donation. But again every case is different. In some cases we try more than that, some others we try less than we move on to egg donation so it’s also a personal decision from the patient’s side.
Just to clarify I don’t mean three IVF cycles but three ovarian stimulations with pick-up cycles. We can do three IVF cycles but in my opinion, it’s better to accumulate eggs and then do one IVF cycle after three ovarian stimulations, three egg pick-ups and then one IVF procedure and one PGT-A procedure. It would be less expensive and more informative but the result, at the end of the day, would be the same as with three IVF cycles.
The first part of the question related to mosaicism. When we’re doing PGT-A, we cannot genetically analyze all cells in an embryo. We have embryos with more than 100 cells at the blastocyst stage and we take 4-6 cells from the embryo. Our decisions and our classification of that embryo are based on what we found. We have criteria for mosaicism levels that are acceptable and mosaicism levels that are not acceptable. There is also a possibility that some of these mosaic embryos, those bad cell lines and those good cell lines take over the development of the embryo. So the part of the embryo that carries the abnormality doesn’t develop and the rest of the embryo develops. There have been case reports about this and we can obviously test for that. However, nowadays we work with labs that are very careful in assessing mosaicism in the embryos. If mosaicism of the embryo is zero and, theoretically speaking, that can happen to all embryos. But, again, we need to have criteria and the number or the percentage of embryos that actually are classified as abnormal embryos that end up leaving a viable child is very low. But, again, that can happen. It’s controlled, in the sense that we are genetic labs worldwide are lowering their cut-off levels for mosaicism and the process is getting better by the day. Nowadays, for example, at our clinic, we’re only working with next-generation sequencing (NGS) which is a technique where the accuracy is very good. It’s 98%. Obviously, it’s not 100%. The other way around can also happen. We can classify an embryo as viable and, theoretically speaking, it could have another line of cells that are genetically abnormal, that can take over the embryo and originate a baby with a genetic abnormality. I’ve never seen that in my professional life but it is a theoretical risk. So, yes, there are mosaic embryos and, no, I don’t believe that they are the reason to stop doing PGT-A. It’s not about changing the embryo, it’s about getting information. If we have an embryo which is a carrier for a genetic abnormality, we have to see what type of abnormality we are talking about. There are different types of abnormalities, with different impacts and different chances of originating in a normal child. It is a complex question. I’m not a geneticist but we have people specialized in that. This is something that we always have to explain to patients. There is a risk of mosaicism.
Now about the other part regarding the conflict of interests. I cannot talk on behalf of other people. At Ferticentro, we do the test ourselves. This is not the case of doing nothing because we actually do the treatment and we only charge the patient. I can tell you testing an embryo costs EUR360 so it’s a lot of money but it’s nothing compared to the total. It’s less than 10% of the costs of an IVF cycle. Perhaps this person is talking about some other clinics. In the clinics I know worldwide I don’t think that this is happening. I don’t know everything that happens everywhere but as I said we’re talking about EUR360 – that’s how much patients pay for testing an embryo.
As for the Canadian clinics’ practice, I don’t know anything like this in Europe. At least, it’s not like this in Portugal, Spain, the UK or Poland. I don’t think in Europe you will find this.
This is actually an interesting question because a classical egg donation cycle at our clinic (Ferticentro) with the 2 blastocysts guarantee is EUR6,440 and that includes everything. We also have programs with 5 blastocysts guaranteed that cost EUR10,800, if I’m not mistaken. What’s the difference? In the lab, we always do the same. We stimulate an egg donor, we collect all of our eggs, we fertilize the eggs and we try to get as many embryos as possible. If we have a compromise of obtaining 2 blastocysts with the patient, this means that if we only get one, the patient gets another egg donor free of charge. If we only have a compromise of having 5 blastocysts and we only have zero or one, the patient gets as many egg donors as necessary to achieve the agreed number of blastocysts. We’re talking about financial guarantees. From the clinical and the lab point of view, what happens is always the same – we try to do our best, we try to have as many viable embryos as possible. We don’t know how many we’re going to get. It is cheaper to have a 5 blastocyst guarantee than to try twice. Essentially we work with these two modalities. You can buy two blastocysts guarantee and end up with many more. For example, today we had a lady who went for 2 blastocysts guarantee and she ended up with 11 blastocysts. That happens. It’s a question of luck but we always try to get as many as we can. This is about finances because we don’t make any distinction between donors and cases. We always try to get as many embryos as possible.
I don’t know if anyone can really answer this question. In theory, yes, but again there’s no alternative because it will depend. If a woman has a low ovarian reserve, if her hormonal levels are lower, the quantity of hormones that are stimulating the ovaries during the development of the egg would be very low. Then maybe in a natural cycle, the egg will not be normal. By doing an artificial cycle, we can assure that the quantity of hormones is appropriated for normal development of the egg. In this particular example, an artificial cycle would be better than a natural cycle, however, if we’re talking about a 25-year-old woman with normal hormone levels and we are giving her stimulation, obviously since we’re going get so many eggs, it’s probable that some of them are abnormal. They could have some abnormality. The right answer to this question is it will depend on the age of the woman, it will depend on the hormonal levels of every woman. In principle, if we have a low ovarian reserve and if we have a very high FSH that will mean that in a natural cycle life will not be viable.
With blocked tubes that are not working, there’s actually no way to get pregnant naturally so IVF is the only solution. I don’t know the circumstances of the treatment. I would certainly prefer to test the embryos once again to see if they are viable or not. If they are not viable, I would focus on endometrium to see if there is any gynecological factor, then check the endometrial receptivity. We always go like this: the first line, we take a look at the uterine cavity to see if we have perfect uterine conditions for implantation; on the second level, we look into endometrial receptivity, things like the ERA test, etc. We test for endometrial receptivity and we also test for problems in the endometrium like natural killer cells, etc. But, again, we don’t test everything at the same time. We start with the most likely causes and then we go for the less likely ones. We also screen for thrombophilia and other internal factors so we would see if we find anything. We probably know how to deal with it and how to maximize the odds. It’s a good thing that you have your eggs frozen because that will allow your clinic to work with eggs collected at a younger age. However, if you’re 37, I would probably try to do another ovarian stimulation and leave those eggs as a last resource. At the age of 37, a lot of women don’t produce normal eggs and so those eggs could be kept for a second child. Obviously, there is money involved. We have to think of the economic factor but I would recommend saving those eggs for later and do another ovarian stimulation while the ovaries are still working.
The success rates for fresh vs. frozen embryo implantation – there is no difference. Nowadays, with the current vitrification methods, the odds of an embryo surviving the process of freezing and warming are more or less 98%. With modern vitrification techniques, it’s almost the same. Sometimes we’re freezing embryos from the die to the other. The example that I just gave of the lady that had 11 blastocysts, we’re freezing all of them because she is now going to start her treatment. We prefer to wait for the egg pickup of the egg donor. We fertilize her eggs, we develop the embryos, and then once we have confirmation that the embryos were viable and good quality, she will stop. We’re doing this in an elective way. Also, we prefer to use frozen embryos because that leaves us room to optimize the endometrium and also to organise the treatment. Not only especially for international patients but also nowadays with the Covid-19 situation. Planning travelling is sometimes not very easy and so for all of those reasons but even before Covid-19, we were always recommending to use frozen embryos because that will allow us to optimize the uterine conditions for the implantation.
The scenario for assisting international European Union patients – 80% of our activity is with international European Union patients because we’re one of the few countries where we have non-anonymous donations and we do have donors. Countries such as the UK have non-anonymous donations but their donations and treatments are very expensive. Countries such as Spain, Greece, and the Czech Republic have eggs from the anonymous donors only. This is what we do on a daily basis. We work in six different languages and so we’re very happy to receive you. If you want, I can help. You can talk to me. I’m leaving my e-mail address and phone number so you can write to me directly.
Information on the donor, physical characteristics – all of that, hair colour, eye colour, age, height, the level of education. At our clinic, some of our donors have extended profiles. We’re not allowed to disclose identifiable information but we are working on providing other information about the donors things like kind of music they listen to, kind of studies that they have done if they like riding a bike, favourite color because it is important for us that patients feel connected to the donor. This is just to build a relationship, to build trust in the process with patients. Some of the donors have already an extended profile, some others still don’t. That’s something we are developing and we’re getting more and more information. The are more and more donors with this extended information model. But, obviously, the physical characteristics and the age of the donor are available to know in 100% of the cases.
At what age would the child be able to get the information? At the age of 18. That’s what the law states. It is a guarantee from the Portuguese state so even if a clinic closes, it’s the national IVF authority that will give the information on the ID of the donor to the child. That information is kept for 75 years. Regarding the legislation in Portugal, there is another webinar where I’ve talked a little more about this. But very briefly we have non-anonymous donation where children can access the ID of their donors at the age of 18 and every egg donor can donate four times in her lifetime, separated by three months. It is controlled by the national IVF authorities. Before we can accept the donor, we have to register her in the national online database. We are audited and inspected several times for this process. The donors get a payment of EUR878. That amount is fixed by law. We cannot pay cash. It has to be paid by bank transfer – it is a very transparent process. The egg donor signs a receipt and we have to have that proof of payment. It’s the same value for every public and private clinic. All egg donors need to be non-anonymous so they sign the document where they acknowledge the fact once the child is 18, their identity (the donor’s) can be disclosed to the children. Donors are prepared for this; they will not be surprised. That’s one of the advantages of the Portuguese law.
The problem is that people who have donated anonymously in countries such as Portugal a few years ago or Spain, they think they are anonymous but nowadays with those DNA banks that are popping all over the world, it’s very easy to find the donor and the donor himself doesn’t even need to send his DNA to those banks. It can be a coincidence when one or two of the donor’s cousins decide to put their DNA in one of these banks, so the children born from her donation can find their donor. Nowadays, there is no such thing as an anonymous donor so we have to do this in a controlled way. We don’t want your child to knock on the door of someone who doesn’t want to be found, who doesn’t expect to be found, whose family would be probably very impacted by that information. Everything has to be done in a transparent, well-counseled, balanced way instead of the way it works nowadays with anonymous donation where things are completely out of control.
All IVF treatments need hormones. Without hormones, we don’t have pregnancies. If women are reaching menopause, we have to do hormonal replacement cycles where we give the hormones that are required to hold the pregnancy and to take a pregnancy to term. That’s always required. We tailor every protocol according to each patient’s needs but that’s always required.
There are no waiting lists for black women. We have lots of black donors so there’s no problem.
Nowadays, there is a tendency worldwide to do transfers on day 5. 90% or more of our transfers are on day 5 or sometimes even days 6. However, what changes is the amount of information that we have on this particular embryo? We have had a few cases of patients that have never had a pregnancy with day 5 but only with day 3 embryos. There is this dialogue between the embryo and the endometrium, there are some theories saying that if the embryo gets earlier to the womb, the womb is the best possible, ideal incubator. So the sooner we put the embryo to the womb the better so the embryo starts its dialogue with the endometrium and it has maybe more chances of being implanted. There are studies also stating that extended culture could be associated with some problems like epigenetic abnormalities and so on. I would say that day 3, in principle, should be more physiological. However, nowadays day 5 is also fine and it allows us for a better selection of embryos. Only the best embryos reach day 5 so we have a selection of embryos on day five. Some studies have been published that show that day 3 could be more physiological and so if we want to optimize the chances probably day 3 would be better. But again day 5 gives us more information and it’s perfectly safe. Worldwide there’s a tendency towards day 5 and I don’t think it is going to change.
I actually recommend one embryo at a time because of the risks associated with multiple pregnancy. Also, there have been recent reports on unitary factors that in some cases where women have two embryos transferred, two embryos can actually be less likely implant than a single embryo because of the unitary effect. Also, the risk of multiple pregnancy is higher and it could let lead to complications. I would recommend just one embryo, especially for older women.
I actually have this same doubt. We’re talking about the window of implantation here. In a physiological cycle it should be the same because the window of implantation can be open for up to 4 days. However, what we have seen in recent years especially with the investigations of groups like the ERA test is that the window of implantation, especially in older women, is a lot narrower than we initially thought. Nowadays we are programming transfers for 120+/- 3 hours so we’re being very precise while programming embryo transfers.
I would say that it is more important to be sure that the endometrium is ready. What counts is the number of hours of exposure to progesterone. We need to know if the endometrium is receptive after being exposed to 120 hours of progesterone – that’s when the embryo should be transferred regardless of whether it is a day 5 or 6 embryo. However, we do need to understand what we are talking about when we say day 6 embryo or day 5 embryo – because nowadays we are in the era of time-lapse technology. We know that some embryos on day 6 are already hatching and so they are in a very advanced stage of their development and some others look like day 5 blastocysts okay. They could still be viable so it will depend. I would focus more on the receptivity of the endometrium, then on the degree of development of the embryo. Obviously, it will depend on the clinic, on the conditions of treatment but usually, we only take the embryos until day 6 or even day 7 when by day 5, they are not developed enough. They are going a little slower than usual. Nowadays, we’re not even thinking in terms of days because what you mean by day 6, it could be 144 hours because that’s 6 times 24 but 144 hours it’s already a very advanced embryo. Some people say that they see the start at 121 hours because it’s the first hour after day 5. It’s preferable to think in terms of hours of embryo development and also hours of exposure to progesterone. We need to make sure that the embryo starts blastulation before 123 hours or ideally at around 96-100 hours. Those are the most important parameters that obviously could change from clinic to clinic. But again I would prefer to focus on the endometrium receptivity rather than the degree of expansion of a blastocyst.
We’re actually talking about two different things. First of all, my view on the epigenetics from the surrogate and egg donor – I don’t like the word surrogate because a surrogate mother is someone who doesn’t want to keep the baby, while the woman who gets pregnant with egg donation is someone who wants babies but can’t have them with her own eggs. This is why she’s using another person’s eggs so I wouldn’t call her a surrogate. I would call her just the mother. Also, when we transfer an embryo into the womb there is a dialogue that will start between the genes of the embryo and the genes of the mother which are activated and inactivated accordingly. It’s the mother’s genes throughout the embryo when it should develop, the pace of its development, the rhythm. This is impossible but if we were to transfer the same embryo to the womb of two different persons, the baby that would be born from these two theoretical pregnancies wouldn’t be the same. Because every woman’s genes or uterine environment make a difference, also when they are feeding the embryo through the placenta, if they are diabetic, even the music they listen to – it all can affect the embryo. But on an epigenetic level, so it’s the mother’s genes that will trigger the genes in the embryo on the embryo development. That has been proven that diet that genetic dialogue between the mother and the baby. There is definitely an effect on how the embryos genetic develops and that effect is controlled by the mother.
Another completely different thing is the genetic carrier tests that we can do on the baby. The genetic carrier tests that we can do between the male partner and the egg donor or the female partner. Nowadays, we have lots of packages commercially available. There are packages of 300 diseases, there are packages even above 1,600 diseases. We’re all carriers of 5-6 genetic diseases and I’ve never done one of those tests so I don’t know but I’m certainly a carrier for a lot of those diseases. When we do those tests we try to make sure that the egg donor is not the carrier for the same genetic recessive diseases as the male partner. If they were both carriers for the same recessive disease, the child will have a 25% chance of having one of those diseases. This example is 301 genes. We know that if the donor and the male partner are not carriers for any of these diseases at the same time, there is no way that the child will have any of these diseases. That is completely warranted so you can be completely reassured. Don’t worry about this because your baby will not have any of these diseases. That’s guaranteed. Obviously, there are hundreds of thousands of genetic diseases; we cannot test for everything. I think in the future we will end up testing for everything but nowadays we can’t. But 300 diseases are already very complete study. I would say – don’t think about it. I think 300 diseases are already very good genetic matching and there is no epigenetic influence that can trigger one of these genes to have to turn on the disease because it is required genes from the male partner and the egg donor so the child can have the disease. By doing these tests, if they are obviously well done, there is no way your child won’t have any of these diseases.