In this webinar, Vladimiro Silva, PharmD, Embryologist, CEO, Founder & IVF Lab Director at Ferticentro, Coimbra, Portugal. Dr. Silva has been talking about gynaecological factors, endometrial receptiveness, genetics, or immunity factors that can impact your IVF success.
Despite all the pink scenarios that science paints. We have to acknowledge that IVF does fail a lot more often than we would expect.
One of the main reasons for IVF failures is naturally low fertility in human beings. What happens when a treatment fails, and what can we do? It is suggested to address failure as a learning experience not only for patients but for specialists as well for future optimization of the treatments that will be useful in the long run.
First, you need to take care of yourself and ask yourself?
Take your time, and don’t be afraid to wait if necessary – however, know your odds. In IVF, the awareness of time is crucial for the treatment, especially with patients over 35 years old. While it is important to focus on the emotional part, it is also important to move on with the treatment as soon as possible. After being ready to move on, it is time for medicine to take over the process, we need to know everything that happened before, all the details below are important
What are the causes of IVF failure? It is known that there are many possible causes.
It is important to acknowledge that humans are not a very fertile species. As shown in the graphics, after age 35 years old, fertility starts to decline whilst the miscarriage rates start increasing, especially after age 42 years old due to naturalistic reasons. Why does this happen? It is said that one of the reasons is the poor quality of embryos. For instance, when comparing the two graphics of a genetic study
On one of the graphs, it is shown that more than 20,000 normal embryos are available. By age 34, 60% of embryos were viable but with the progressing age, the quality of embryos decreases significantly. Another graph shows the probability of retrieving at least one viable embryo from an egg pickup. With the progression of age, there are 80% percent of low numbers.
As shown in another graph, regarding egg viability, we need to remember that age does play a role.
Additionally, as the decision to conceive started to be postponed later in life as time passed, the risk of trisomy became higher (embryos that are less likely to implant, resulting in negative results and miscarriages).
Trisomy 21 risk at 10 weeks of pregnancy:
After having an implantation failure, it is important to analyse the uterus.
Uterine evaluation includes:
It is known that the transferring of an embryo into the endometrium after 5 days of progesterone, the endometrium should be prepared to receive a day five embryo (blastocyst). Therefore, an endometrium preparation is performed. Then, when an appropriate thickness of the endometrium is perceived, the patient is given progesterone, which will turn the endometrium more receptive to receiving the embryo, forming a network of blood vessels that will nourish it for implantation. However, even after preparation, some women are not yet ready to receive an embryo due to possible post-receptive endometrium (regeneration process)
How do we assess that?
Results can show whether the endometrium is:
An estimated time for endometrial receptivity will be provided through these results. According to studies published by Igenomix, on the one hand, 3 in every 10 patients with recurrent implantation failure are found to be nonreceptive when tested for endometrial receptiveness. On the other hand, after comparison between non-tested patients and patients who have been tested, it is said that there are significant results, not only in incremental pregnancy rates but also in the decrease of miscarriages.
In the case of genetics, PGT-A (pre-implantation genetic testing for aneuploidy) is the first test for consideration. Embryos are created in the laboratory and during the blastocyst stage, their cells are analyzed by a technique called NGS (next-generation sequencing) to confirm whether the embryo is viable. It is important to highlight that it does not improve the quality of embryos, it does provide information about embryo quality.
As shown in the graph, the implantation rates for patients who had done PGT-A are relatively steady for all age groups with a percentage of 50-60% because of the selection of embryos while rates for patients without PGT-A lower up to the point of 7% after the age of 42. One of optimizing the process is egg banking which encompasses the stimulation and collection of eggs to be frozen to repeat the implantation process after a previous IVF failure.
When talking about immune causes of failures, the first thing to check is KIR/HLA-C compatibility. Uterine NK cells (Natural Killer cells) have receptors (KIR) that bind to the embryo paternal origin HLA- C molecules. It’s important to note that each person has her/his own profile, the combination of KIR AA/HLA-C2 is associated with a poor reproduction prognosis and higher obstetric risk. In addition, there are other immune factors at the endometrium level that can be the cause. It’s also possible to perform a test called The MatriceLab Test, which is said this test based on the dialogue that occurs between the endometrium and the embryo as these factors must be interrelated. Three kinds of evaluations are performed.
Patients are divided into 3 groups:
Some other immunity factors include Anticardiolipin antibodies (lgM), Anticardiolipin antibodies (LgG), Lupus anticoagulant (detection), and so on.
Another group of factors that should be considered is haematological factors. Thromphobilia is a group of diseases that are related to the ability of blood vessels to connect with the embryo and create the necessary network of vessels thus triggering the implantation process. A thrombophilia screening will be requested.
Aneuploidy and maternal age studies show that overall the egg’s contribution is greater and could be hypothesized to be 70- 80%. However, when the paternal component is abnormal, it can drastically affect the ability of an embryo to reach the blastocyst stage and/or a fetus to develop and result in a live birth.
Is male fertility declining? According to a study published in 1992 in the British Medical Journal by a group of researchers from Denmark. They concluded after reviewing the results of sperm counts since the 1930s that there was a clear decline in the total number of spermatozoa in different groups. However, other studies reached different conclusions. In the United States, it was concluded there had been no major change over the years in sperm quality as it was more associated with geographical, environmental, and lifestyle factors.
So, we’re mostly not treating male infertility. We are helping infertile men become parents (the second-best option).
Although it is preferable to treat the patients to conceive naturally, there are very few cases where that is possible. However, there is always the last, yet most effective resource which is egg donation.
The first reason to consider egg donation is because of its efficiency. According to some results from the United States, for all age groups, pregnancy rates with egg donation are between 60 and 70% compared to treatments with own eggs. In Portugal, egg donation is non-anonymous, and is important to respect every child’s right to know their origins in a transparent, limited, well-controlled, and properly counselled way.
I will start with the last question, it doesn’t make any sense to try IUI in this case. If the tubes are patent, so if we don’t have a problem, any blockage at the tube level, intrauterine insemination is a good option, and it’s cheaper and less invasive.
However, the odds of IUI to work at the age of 38 are between 7 -8%, so as you had a problem with insulin resistance, hypothyroidism and you have a nice level of AMH, I would say that the odds seem okay. We have lots, and lots of patients doing IVF and getting babies at 38 and older. I would say 6 eggs doesn’t seem like a lot, but my advice here would be to try again, obviously trying to optimize the ovarian stimulation process. There are different protocols that we can use. Sometimes, one protocol works better than the other, we can try different strategies for different patients, and even the same patient responds differently to different strategies.
I don’t know if it was bad luck, I don’t know if there’s also a male factor problem, but I think with an AMH level at 1.6 at the age of 38, we can hope to get more than 6 eggs, and if we want to increase chances, we can do the egg banking. If we can’t get more than 6 eggs, we can try to do 1-2, maybe 3 stimulations to get a good number of eggs and then fertilize all of them, do the PGT-A if that’s legally possible, and see whether the embryos are viable or not.
irst of all, just to clarify, the level units of AMH in a previous patient are different than in your case. AMH at 4.2 indicates picomoles per liter, it is equivalent to 0.53 on the same scale as the previous patient. This is not a very high AMH if it is 0.53. If it’s 4.2 nanograms per millimeter, it would be great.
Bottom line, you have done 3 cycles, and you’ve produced 4-6 follicles, which is not a lot. I don’t think PGT-A will damage the blastocyst, that’s a risk that always exists, but it probably affects like 2% of all blastocysts if it’s done by an experienced technician, biologist, someone who does it daily, and that’s what it’s a very delicate technique that requires a lot of experience so if you’re doing this you should be doing it in a clinic that does a lot of these procedures, whose embryologists are certified to do this technique. For example, here at Ferticentro, we had to certify all the embryologists before starting to do PGT- A on our own, so we did hundreds of procedures on mouse embryos and embryos that were offered to scientific investigation before starting doing it in real cases years ago.
If we only have 1 blastocyst, I think the reason PGT-A is a good option as you don’t know why your 3 previous cycles failed. We don’t know if it was a problem with the endometrium or the embryo, so maybe your embryos were good, and the problem is with the uterus. PGT-A will help you to decide in the future whether it makes sense to try again with your own eggs, or if it’s better to think about egg donation. Some patients don’t want egg donation, they say it’s either with their own eggs or I don’t want to try, so if that’s the case, I would say you shouldn’t do PGT-A because it’s preferable to let nature decide, do the embryo transfer and see what happens. If another IVF failed, I would advise doing PGT-A because if the embryo is viable, then before transferring the embryo, you would have time to study the endometrium and all of those factors that I’ve talked about in my presentation.
Before transferring the embryos, we would have the possibility to optimize the conditions of implantation. If the embryo is not viable, then it will be pointless. Probably, the most likely reason for the previous failures was the genetic part of the embryos. We would never know, we can only speculate on that. I think PGT-A is about information and is about helping patients making decisions. I would probably advise doing PGT-A unless the patient says that egg donation is not a possibility.
The AMH of 1.62 at the age of 40 is a nice value. Normally, we expect to have 1 egg for every 300 micrograms per milliliter of estradiol, so in this case, we would probably expect to have 6 or 7 mature oocytes. Unfortunately, this doesn’t tell about the quality, if we have, let’s say 6 eggs with 2000 picograms per milliliter, it’s in line. When we have a correspondence between the hormonal levels and the number of eggs, that’s usually a good sign, and it’s a good prognosis. The exact response on the egg quality, we will only get either from the genetic testing or from the embryo quality that we obtain in the lab.
Sometimes, the eggs are fragile, and they can degenerate. It happens especially in women at an advanced age when we start manipulating them, for example, by doing ICSI. Without looking at the case, I cannot give you an opinion, but usually, when they start to degenerate, it means that those eggs were not viable. They would never originate their pregnancy through a natural conception. In some cases, we only have eggs like that, some other patients have a few eggs like that and a few normal ones, and it’s really hard to tell. This has to do also with the lab conditions, we would need to have more information to be able to give a fair opinion.
Starting from the beginning, so 450 units of Menopur per day is a lot. In theoretical terms above 300, we will not get a better response. Usually, at our clinic, we use 375, just to be a little bit over the theoretical limit of 300 hundred, some doctors try 450, that’s a respectable decision. It’s not only about the Menopur, but we also have to think of the rest of the protocol, whether it was a long protocol or a short protocol, and in the case of a short protocol, but there are also different types. At Ferticentro, we don’t like to convert to IUI, even if we just have 1 follicle. We prefer to do the egg pickup, it’s our policy because we do have pregnancies with just 1 egg being collected, just one embryo, and so we prefer to do it instead of an IUI because the ICSI method is a lot more effective. This is a common practice, it’s a respectable opinion from other doctors. A lot of clinics worldwide are doing this. We just feel that it’s preferable to collect the egg, it’s all about optimizing the process because clearly, you want to get pregnant with your own eggs instead of moving to egg donation. If you only have 1, we would try to use that one egg as best as possible. I do agree with what you’ve stated at the end. There is evidence that says that repeated attempts, consecutive attempts, tend to optimize the ovarian response. So yes, this previous attempt could have worked as priming for your ovaries and subsequent new stimulation. Especially, in the 3 months after this previous one will certainly have a better response from the ovaries.
Sometimes, it’s hard to predict whether this will make a difference or not, but I do think it’s worth trying. If we’re only getting 1 egg after an aggressive stimulation, we can also think of changing the protocol. Possibly they already tried that, but in principle, it would be an indication to try egg donation.
We don’t know how many eggs we need to get a blastocyst. In theory, 1 could be enough. On average, at our clinic for older women, we can have a blastocyst rate of 40-45%, it also depends on the male side. Maybe 30% of the eggs will turn into blastocysts, it’s hard to tell. At Ferticentro, we have more or less 90% of survival of egg vitrification. We don’t vitrify MI (metaphase 1) eggs. We only work with metaphase II eggs. On the other hand, I don’t see any reasons why the metaphase I eggs wouldn’t survive vitrification, so I would say it’s 90%.
It’s the maximum dosage. Theoretically speaking, above 300 international units, all the FSH receptors on the ovaries are already occupied, and so it’s pointless to increase after that. Sometimes, we go a little beyond because some patients could be outliers, and they might respond a little better to 375. We’ve tried higher dosages we haven’t seen a difference, so this is why we usually don’t go over 375. 325 is a little higher. I would say that it could make sense, and based on what you have mentioned, I wouldn’t say it is too high for such a case, as yours but again, we don’t know about your specific situation.
Those are different treatment strategies, we also do mild stimulation IVF. In some cases, there’s a theory that it’s preferable to try to get 1 good quality egg instead of many bad quality ones. It’s never a first-line approach because most studies indicate that the more eggs we get, the better results we have until a certain level. Recent studies are saying that there is no upper limit on the number of eggs on the dissociation between the number of eggs and the odds of pregnancy, but for quite a long time, we thought the ideal number would be between 8 and 15, so obviously when we’re not getting good quality eggs, and we’re getting a good number of eggs, sometimes we resource to mild stimulation IVF. In those cases, we give the minimum medication necessary, and we try to go in a very controlled and balanced way with just one follicle, hoping that it will work better than the other ones. More or less, 10 years ago, we did many of these cycles at Ferticentro, results were nice, but as I said, this is not a first-line approach. This is something that we use for patients that have a history of poor embryo quality.
These days we are focusing more on testing the embryos, but again this is something that we can also do.
No, the Portuguese law states that donors are not anonymous in the sense that at the age of 18, the children born from the donations have the right to access the identity of the donor, that access is granted by the Portuguese IVF authority, but this means that the donor is anonymous for everybody but the children. This is a right of the children, not the right of the parents, and so if it were a known person, we would be disclosing the identity of the donor before the children reach the age of 18, so it’s not possible to do what we call a direct donation.
It’s the same with an egg donor. We can only disclose the donor’s identity when the children born from a donation reach age of 18. This is the same in many European countries like the UK, Ireland, the Netherlands, Sweden, Austria, Denmark has a mixed system. I think in 10 years from now, all countries will have non-anonymous donations. The anonymous donations don’t make sense in the actual times, not for the children, not for the family, not for the donors. I think it will end soon, hopefully.
Yes, sometimes, follicles can grow too big. Typically, we trigger ovulation when we have follicles at 17 millimeters. We often have a mixed population of big follicles and follicles that are smaller, and so we try to bet on the population that gives us a better probability of finding better quality and a better number of eggs. There are some other more recent strategies like dual stimulation, but we’re still living the early days of those strategies. Ideally, we’re talking about 17 millimeters above a diameter, I cannot tell you whether it’s 20 or 21, or so but above a certain limit, the risk of the eggs starting to degenerate increases. There’s this optimal moment to trigger the ovulation, and that’s certainly between 17-19 millimeters.
At our clinic (Ferticentro), we have many programs, but it will depend on the guarantees that are included. We have two blastocysts guarantee program that costs 6440 EUR, and we have 5 blastocysts guarantee program, that costs 10840 EUR. In the lab, we always do the same, we don’t have first category donors or second category donors, all of our donors are subject to a very complete selection process. The difference between these programs is on the obligations of the clinic. If we only get 3 blastocysts and the patient has paid for 5 blastocysts guarantee, the couple is entitled to have as many cycles as necessary to achieve the 5 blastocysts. On average, we have 4-5 blastocysts, but obviously, we’re dealing with human cells, so a lot can happen, and so this is why we focus our guarantees not on the number of eggs but the result of the number of good prognosis embryos. If those blastocysts are not good prognosis embryos, we will not use them. We also have programs where if you don’t have a baby, you get all your money back, but those are more expensive, they cost 15 000 EUR. We work with a British company called Access Fertility on that.
