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Fertility Treatment in Portugal: Ask Me Anything with Dr Vladimiro Silva

Vladimiro Silva, PharmD
Scientific and Executive Director, Ferticentro
fertility-treatment-in-portugal_IVFWEBINARS_Ferticentro-r
From this video you will find out:
  • What is your advice for anyone trying to conceive?
  • What are the most exciting developments in fertility treatment?
  • What makes Portugal different from other destinations for fertility treatment?
  • What is open-ID donation, and why is it important?

Fertility Treatment in Portugal: Ask Me Anything with Dr Vladimiro Silva

During this event, Vladimiro Silva, Scientific and Executive Director of Ferticentro, Portugal discussed various topics and available fertility treatment options in Portugal, including egg donation, egg freezing, its processes, procedural details, and donor selection criteria, etc.

- Questions and Answers

I would be interested to hear your view regarding PGT-A results. My last cycle had an abnormal result, and this cycle, I had a chaotic embryo. Are you able to give your thoughts? I haven’t received the report of the chaotic embryo yet, although I have asked, and I’m waiting to see the doctor. What would be your approach to that result in your clinic?

What happens when we have a chaotic embryo? A chaotic embryo depends a bit on the classification from the genetic lab, but typically, it is an embryo with several aneuploidies. What’s an aneuploidy? It’s an embryo with the wrong number of chromosomes. When we have multiple abnormalities, for example, an extra chromosome on the 14th or less of a chromosome on the 6th, some labs classify it above 6 abnormalities, while others classify an embryo as chaotic at 4 abnormalities. It depends on the abnormality threshold used by a given lab. Having a chaotic embryo typically is age-related. Unfortunately, there’s not much that we can do here unless we try again. Having a chaotic embryo, if it was just one abnormality, it would be enough to reject the embryo. Having multiple abnormalities means the same. It’s a random event and is very related to the age of the oocytes. Some younger women can also have the same problem. Here, what we would do is assess the case: how old is this patient? How many times has she tried before? Does she have a normal karyotype? The male partner should also be assessed in genetic terms. We need to make sure that he also has a normal karyotype. The karyotype is the genetic constitution of a person. All people have a karyotype. The chance of it being normal is more or less 98%. So, it should be normal. This is a kind of screening evaluation that we sometimes do in certain cases. If this is a patient with a very low ovarian reserve, and she’s above a certain age, typically above 43, we would consider this as being related to ovarian ageing. We can try again if the ovaries respond, but then we have to balance the cost and benefits. The next step would be to think about egg donation. If everything is okay, and she is below a certain age, what is her AMH level and other hormones? If her ovaries are still working and responding to medication, I would say that we can try again. We would try to optimize the ovarian stimulation protocol. We could try to accumulate eggs or embryos to have more embryos because she only had one. The more eggs we get and the more embryos we get, the higher the chances of having a normal embryo. But at the end of the day, we would need to try again either in a single stimulation or in multiple stimulation cycles, accumulating eggs or embryos, doing consecutive stimulations, or doing one stimulation per cycle. There are many options, but it’s always the same: try again. If this is a case of a patient whose ovaries are no longer responding to medication, and she’s above a certain age, it’s important.

At your clinic (Ferticnetro), do you transfer a high-level mosaic embryo? I mean, there are recent studies published last year that have shown that until a certain level of mosaicism, the chances of implantation are pretty much the same.

What is happening is that genetic labs, in principle, only report whether an embryo is good to transfer or not. They don’t specifically report whether an embryo is mosaic. They base this evaluation on their pool of embryos, often using artificial intelligence and learning from previous cases. In practical terms, what does this mean? The tendency and consensus worldwide now is that mosaic embryos, at least until a certain level, have the same prognosis as non-mosaic embryos. Mosaicism can’t be viewed as a negative thing because it doesn’t affect the chances of pregnancy. So yes, I would trust mosaic embryos if the genetics lab where I’m doing the test advises me to transfer the embryo. This analysis is made by people with detailed access to the genetic content of the embryo, and it’s based on thousands of cases that they have reviewed according to their algorithm. We need to trust the system, and that’s what we do.

Is it possible to do embryo banking in Portugal for PGT-A?

In Portugal, what the law says is this: you cannot create new embryos when you still have frozen embryos unless there is a strong medical indication for that, and doctors need to justify it. One of the accepted justifications for that is doing a PGT-A cycle or a PGT-M or PGT-SR. So, if you are doing genetic testing or genetic screening, you can accumulate embryos. However, if you are doing embryo banking to preserve your fertility, you are not allowed to do that. In those cases, even if we were allowed, we would always suggest egg freezing because it is much more flexible. Nowadays, we have consistent survival rates above 90%. We are certified for best practices in vitrification, and many clinics worldwide are achieving this level of proficiency in the egg-freezing technique. So, the egg-freezing technique is very reliable, and there is almost no reason to freeze embryos instead of eggs. We do it in PGT-A cases, in some of them, but in others, we don’t. It depends on the specific evaluation.

Can you tell me more about the process of the PGS/PGT-A test?

PGT-A and PGS tests, first, mean more or less the same thing. PGS is the acronym for preimplantation genetic screening, which was used in the past. It has been replaced by preimplantation genetic testing for aneuploidies or PGT-A.

How does it work typically? We create the embryos and culture them until day 5 or day 6, usually until the blastocyst stage, when the embryo has more than 100 cells. On that day, we used a laser system to make a hole in the embryo and take five to ten cells out of it. Then, we freeze the embryo and prepare those cells to be sent to a genetic lab for analysis. This analysis allows us to determine if the embryo has a normal constitution.

Why can we say that? We take those cells from a part of the embryo called the trophectoderm, which is considered representative of the whole embryo. These cells will later form the placenta, so it’s not the embryo itself, but according to multiple studies conducted over the years in many countries, these cells reflect the true genetic content of the embryo. However, it’s important to note that this is a sample of five to ten cells, not all the cells of the embryo.

What are the cases in which we recommend PGT-A? We advise patients to undergo PGT-A if they are 39 years or older if they have had three or more failed IVF cycles with embryo transfers without achieving pregnancy, if they have had two miscarriages, or if they have had an affected pregnancy with a genetic abnormality like trisomy 21. In such cases, there is a clear indication for PGT-A. These are also the legal conditions for proceeding directly with PGT-A in Portugal. If PGT-A is needed for other reasons, we must submit a request to the authorities, who usually respond quickly. This covers most cases where there is a clear scientific indication for PGT-A.

I have a rare genetic disease. What are the regulations for that in Portugal?

There is a list of genetic diseases that are immediately authorized for PGT-M. When we test embryos for genetic diseases, we can test for chromosomal abnormalities that are usually age-related or for monogenic diseases, which affect just one gene. This is likely what affects you. Some of these diseases have a high chance of being transmitted to children. The first step is to identify the disease and its risk through a genetic consultation with a medical geneticist. They will inform the patient about the disease, the chances of it being transmitted, and the potential consequences. Then, we can test the embryos. We culture the embryos until day five or day six, perform a biopsy to take five to ten cells from the embryo, and analyze those cells. If the affected gene is present, the embryo is a carrier of the disease and cannot be transferred. If the embryo is not a carrier, it is considered healthy. We also test for PGT-A to ensure the embryo doesn’t have other chromosomal abnormalities like Down syndrome. In Portugal, there is a list of hundreds of diseases that are pre-authorized for PGT-M. If a disease is on this list, there is no need for a special request. If the disease is rare and not listed, we need to submit a request to the authorities. They are usually quick to respond and only authorize diseases associated with significant risks and suffering. To date, I have never had a PGT-M request rejected in Portugal.

Is there a specific protocol you use for those with KIR/HLA mismatch (I am KIR AA myself/HLA C1C2 for partner)?

Let’s also discuss the HLA mismatch. What is it, and what is the protocol for handling it? HLA mismatch refers to a potential incompatibility between the embryo and the uterus. The uterus has receptors called KIR receptors, which can be AA or BB. If the uterus has KIR AA receptors and the embryo has HLA C2 genes, it can cause an immune rejection reaction, leading to complications like implantation failure, early miscarriage, or later pregnancy issues like preeclampsia. In such cases, if we use donors, we try to select donors who do not carry the C2 gene. If that’s not possible, we use special protocols, which are relatively experimental. These protocols typically involve aspirin, growth factors, and other medications. The most important are growth factors, as they have shown better results. We have successfully used these protocols, and many babies have been born despite a KIR AA and HLA C2 mismatch. However, these treatments need careful assessment due to their implications for overall health.

I’m considering going to Portugal to freeze my eggs. How would the process normally go? Can I do some tests in Germany where I now live beforehand, and if so, which ones? How do I schedule the collection? Would it be better to go to Portugal to do all the tests and then collect them?

Yes, you can undergo the process in Portugal. Typically, we ask patients to book an online consultation with one of our specialists. If the patients have already done some blood tests or exams in their country of origin, they should send them to us beforehand so we can review them before the consultation. If not, we will address it during the consultation and provide a list of tests that can be done in their country of origin. The problem here is specific to Germany because IVF doctors there are very limited by law and are usually not keen to collaborate with foreign clinics for these types of processes. However, if you find a doctor who can collaborate with you, we can certainly start the process, and we have done so with many patients. Our experience with German patients shows that it is never easy; it depends on the personal relationship that patients have with their doctors. If they have a good relationship, they can do the initial tests in Germany, start the process there, and do the first control scans in Germany, traveling to Portugal directly for the egg aspiration. Typically, they arrive here a day before so we can assess them, perform the oocyte aspiration the next day, and then the patient can return home. Regarding your second question, if you have difficulties in your relationship with your German doctor, yes, it will be easier to do everything in Portugal. This way, we can evaluate you, perform the scans ourselves, and provide medication, which will likely be cheaper. It will also be easier to do the blood tests and other necessary procedures. This option will save you time and money, even considering the cost of traveling. In Germany, there is the “Krankenkasse,” a type of health insurance where patients have different rights according to their insurance type. Sometimes foreigners living in Germany don’t have access to these rights, making medication very expensive, like €2,000 instead of €300- €500. This cost difference alone can justify the trip to Portugal. The fertility preservation process itself is straightforward. We use methods that are safe and reduce the risk of hyperstimulation, which is the main side effect, to less than 1%, making it almost zero. It is a very effective and easy-to-organize type of treatment.

I am 39 years old and, had 4 transfers but not even an implantation, medium-quality embryo. Two of the blastocysts were checked with PGT-A and found healthy. Values are okay, hysteroscopy is okay, immunology checked, and genetics too. What else can I check? Is donor egg a possibility, or will that not work either?

It’s a difficult case because there was the transfer of 2 healthy blastocysts confirmed by PGT-A. If we are transferring euploid embryos and not achieving a pregnancy, the problem is most likely on the uterine side. There are things, for example, on this list that we would check if it were at our clinic. For instance, the microbiota: sometimes patients have chronic endometritis, local infections, or an imbalance of the bacteria inside the uterus that can cause local inflammation and prevent the embryos from implanting.

In some cases, we need to look at the ovarian preparation protocol. Some patients respond better to natural cycle or modified natural cycle protocols. In other cases, to get good endometrial thickness, we need to use special protocols. There is a lot we can examine, such as the window of implantation.

If this conversation had taken place 5 years ago, or even 3 years ago, everyone would be talking about the window of implantation and how important it is. More recently, studies done on unspecified populations concluded that it was not associated with an increase in pregnancy rates. However, we know that for very specific groups of patients, it can still play a role. Given this history, I would take a look at that as well.

Maybe there’s something else that we are not seeing here. So, treatment protocol, microbiota, potentially the window of implantation, and an ultrasound scan to check the characteristics of the endometrium after stimulation are areas to consider. We might also try a natural cycle. There are a few things we can look at.

Regarding the last part of the question about donor eggs: we were not achieving a pregnancy with euploid embryos, so I would say it’s unlikely that the result would be different with donor eggs. I would try again with the patient’s own eggs. If the embryos are healthy, then we would think about what to do to optimize the uterine conditions. I wouldn’t transfer those embryos until we have ruled out all factors. Sometimes, there are factors we don’t control, and medicine is not always aware of them. There are specific cases where patients had similar results and suddenly got pregnant without any clear reason.

Which type of genetic test is required for men with egg donor treatment, and what is the reason for this?

This is a very interesting question because the answer can be quite complex. What we are advising all patients right now is to do the carrier genetic screening test. All human beings are carriers of recessive genetic diseases. Even if you are a healthy person, you are certainly a carrier of four, five, or six diseases that don’t affect you but can be transmitted to your children.

When we assess egg donors, we test them for their karyotype and screen them for the most common genetic diseases. Typically, at our clinic, egg donors are tested for around 70 genetic diseases, but there are more than 4,000 well-known genetic diseases. We can upgrade this testing to packages of 570 diseases or even packages of more than 2,200 diseases.

We already have the DNA from the donor. The results from the amplification of that DNA are in a black box. We don’t know those results. We test the male partner similarly. If Mark wanted to exclude 2,200 diseases, we would amplify his DNA, and send it to the genetics lab, and they would say Mark is a carrier of four or five diseases, and the donor is a carrier of four or five diseases. The results would indicate whether the genetic matching is favourable or not. If favourable, it means that whatever diseases Mark and the donor are carrying are not the same. We can exclude all of those 2,200 diseases.

The reason why these 50,000 variants have been selected is that they are the most common among the very rare diseases we test. This is why we recommend the male partner to do it. If you are doing egg donation, you are already introducing DNA from someone else into your family. Increasing the safety of the process reassures the patients.

Sometimes we already know that a donor is a carrier of diseases A, B, and C. This information means that we can ensure that your child will not have these diseases. If there was a mismatch, we wouldn’t use that donor. The matching report would be negative.

Another situation where we can test the male partner is if a patient has a long history of miscarriages or bad embryo quality. If there are reasons to exclude the risk of having a genetic abnormality based on the medical history, we might ask for the karyotype of the male partner. In some clinics, they test it from the beginning, and we sometimes do, depending on the medical history of the couple or the patient.

What could explain the early fragmentation of many embryos? I am 40, I had 2 IVF cycles done at 2 different clinics in 2 different countries with 2 different donors and 2 different protocols. Each time, almost all embryos fragmented on day 2, and none reached the blastocyst stage. It was suggested that it might not just be an age or chromosomal issue, but that the egg quality was affected by a high level of hormones. What is your opinion on the reason for this early fragmentation? What would you suggest doing differently?

If we are talking about a treatment with the patient’s own eggs plus donor sperm, early fragmentation is very often associated with egg quality. If there is a problem with the sperm, we will usually see fertilization failure. However, the effect of the male factor typically becomes apparent from day three onwards. The embryo development in the first three days relies heavily on the quality of the egg.

From the initial protocol, the ovarian stimulation was not very aggressive. A dosage of 225 is not high, and six embryos is not a high number, so I wouldn’t call this an aggressive stimulation. Initially, this was a short protocol with Follistim and Menopur. Then they moved to a long protocol with Decapeptyl and Pergoveris at 375, which is already a high dosage. No surprise it ended in hyperstimulation, but nine embryos is a good number.

We can optimize ovarian stimulation by using a high dosage but not a long protocol to avoid the risk of ovarian hyperstimulation syndrome (OHSS). We can also ensure that embryo culture occurs in the best possible conditions, using an Embryoscope with the best culture media. If we still don’t get a blastocyst on a third cycle with truly optimized conditions, then it may be time to consider embryo or egg donation.

There are theories suggesting that a mild stimulation protocol might yield one or two eggs of better quality. This approach was more popular ten years ago. Nowadays, the consensus is that having a good number of eggs and the highest possible number of embryos is associated with better results. These mild stimulation theories are less favoured today. The current tendency is to do short protocols with agonist triggering to prevent OHSS and try to get a good number of eggs.

I wouldn’t give up on this case yet. There is room for improvement. The first stimulation was likely too mild, and the second one resulted in hyperstimulation. A well-balanced stimulation could provide better results.

Over 35, age is always an issue, but it affects some patients more than others. We don’t know if she would have had the same problem when she was younger. We should focus on the current situation, and I believe there is a fair chance to optimize ovarian stimulation now.

This is not about criticizing other clinics’ work but learning from the response to the previous cycles. Sometimes we learn from cycles where the ovaries did not respond well. This patient’s experience offers a good learning opportunity for her doctors. If an improved stimulation still yields the same results, then it might be time to consider egg donation. However, I wouldn’t jump to egg donation immediately unless the patient prefers not to go through another ovarian stimulation. It’s a personal decision, but from a medical standpoint, it’s worth trying again with a different protocol.

I am 47, do you treat women who would like to undergo IVF with their own even if there’s only a tiny chance of success?

It’s all about informed consent. What we normally do, because we get a lot of requests from older patients, is this: First, we test the ovarian reserve. We need to assess this, and then we decide accordingly. For example, if we have an AMH of 0.5 and an FSH of 3 or 4 we can try. If the patients understand that at the age of 47, the chances are really low—around 1 or 2% maximum—and they still want to go ahead, fine. We won’t deny them that possibility, and we will do our very best to take it to the limit.

However, if a patient comes to the clinic with an AMH of 0.05 and an FSH of 43 (and this has happened), we will not proceed because it’s impossible. Maybe in the next cycle, the situation changes, but at that moment, the ovaries will simply not respond, and it wouldn’t be ethical to do an ovarian stimulation in those circumstances.

What we do in these cases is evaluate if there is a theoretical possibility, as low as it is, and discuss it with the patient. If the patient accepts the risk and understands the odds, we can go for it. We won’t cut her off from this option, but we know that it is unfortunately relatively unlikely to obtain good results after that age.

My problem is to keep the water in my bladder doing the transfer. What can I do to help myself wait enough time after transfer? I was using egg donors, but I think, that’s my big problem. Or maybe it’s not a problem. Does that affect pregnancy?

Well, it depends on the doctor, okay, that does the embryo transfer. We, for example, at our clinic, some doctors prefer to do it with an empty bladder or a half-full bladder. Some others prefer to do it with a full bladder. It’s possible to do it. It’s very related also to the personal experience of the doctor.

For example, our clinical director has someone who has a lot of experience, and she has that touch, and so she prefers that the patient have the bladder empty because she can do it in a better way if she is the patient has a’s easier for her. Some other patients prefer the patients to have a full bladder because we can do an ultrasound, and easy to spot.

I would say that in the first line, I would say this is a question that depends on the doctor who is doing the procedure. Sometimes, if the patient is not comfortable, we find a way to do it. It’s a question of dialogue, talk to your doctor, discuss this with him or her, and I’m sure they will find a way because patients need to be comfortable. That’s what we do.

How does the embryo testing affect the quality of the embryo? Does it hurt the embryo when you puncture it to take the cells for testing?

Okay, that risk exists. I would say it’s a very low risk, certainly below 2%, but it can exist. It’s an invasive procedure; we are making a hole in an embryo to take 5 to 10 cells. But if it is done by an experienced embryologist – for example, at our clinic, all of the embryologists who perform PGT-A are certified to do that – to be certified, they need to go through a training program. They need to practice on disposable embryos many times with other, more senior embryologists by their side. It requires a lot of expertise from the person who is doing it. It requires the availability of good equipment, a good laser system, a good microscope, and so on.  I would say that in good embryos, chances are very low, but they are not 0.  I would say 1% or less than 2%, maybe 1% chance of losing the embryo.

What about diverse ethnic availability donors in Portugal, are there any restricions? Is egg donation treatment cheaper than in the UK??

The availability of diverse ethnicities of donors is a reflection of the country because we are multicultural; naturally, there are phenotypes and groups where it is more difficult for us to find donors. For example, we do have a lot of donors of African origin; there’s no problem for us. We have a very good number of black donors, mixed-race donors; a lot, really, no problem with that. I’m a typical Portuguese person – so the majority of our donors are like me. Yes, someone else asked if we have Black Caribbeans; of course, we do, so really no problem at that level. Our difficulty is with Asian donors. Okay, we struggle to find – I think it’s kind of cultural – because Asian-origin communities are less prompt to donate. We don’t know why, but we also have our Asian-origin donors. From time to time, Indian donors, for example, at the moment, we do have Indian-origin donors, but we don’t have Asian-origin donors in the sense of China, South Korea, Japan, all of that. So, that’s our main difficulty for now. But yes, aside from the Asian donors, South Asian donors, let’s call it that, are difficult to find; the rest, we are okay. We don’t have waiting lists, and we have good availability of donors.

Regarding restrictions, no, there are no restrictions. No restrictions, aside from the normal restrictions of access to treatments. If it is more expensive than in the UK – well, I don’t know the price of all UK clinics, but it is typically way less expensive. In Portugal, an egg donation treatment at least at Ferticentro costs 7,500 euros, whereas in the UK, it can cost up to 10,000 or something like that. So, it’s less expensive than in the UK and there are no restrictions on access.

Can you bring a donor from a bank, such as Cryos?

 Yes, and as long as it is an open ID donor, it’s a legal requirement. Sperm donor from Cryos, yes, we can – we work a lot with Cryos or the European Sperm Bank as well. In Portugal, we can’t do anonymous donations, and as long as the donor doesn’t have adult photos, those are not allowed in Portugal. We can work with baby photos, with photos from other ages of the donor, not adult photos.

How long does the egg-freezing process take?

It will depend. Okay, so if you do everything here in Portugal, it takes 2 weeks. You have your period, and then you do the ovarian stimulation. Collection typically is done on day 12 to day 14, so 2 weeks, roughly speaking. If you live elsewhere, and you have a doctor who can support you, you can do everything in your country of origin, and you just need to travel to Portugal at the final stage. For this to be possible, we need to validate it, we need to make sure that we receive all the relevant information and that’s it.

How much does a complete fertility test cost?

I mean, it will depend on exactly what we need to test. Okay, so let’s say, for example, that a doctor’s appointment costs €110. Then, the blood tests in the lab can be around €200 to €300, depending exactly on what we are testing. That’s it. If you need to do an MRI or hysteroscopy or whatever complex additional testing might be necessary, these are unlikely. But I would say €300 in blood tests, probably less than that, plus the cost of the consultation.

Are you allowed to know the weight, height, hair, and eye colour of a donor for embryo donation?

Yes, this is some information that we provide. Just a little context: embryo donation in Portugal is a little different from in other countries because clinics are not allowed to create embryos to sell them. For example, in Spain, clinics can create embryos to sell. In Portugal, we can’t do that. So, donated embryos are surplus embryos that were donated by other patients. Typically, we tell the story of the embryo. It’s like, for example, this embryo is from a recent donation cycle that used donors one, two, three, four, and five. Here, you have the full profile of the donor. We can even give you a 6-page document where you will know everything about the donor. But regarding the male partner, it was the husband of the couple, and we can only tell you that he is 1.82 meters tall, blond with brown eyes, B positive (B+), and weighs 83 kilograms.

It’s something that we would give that information. That’s what we have, and it goes like that. Obviously, in some cases, we have more information available. If the embryo comes from a double donation, we can even give you the full background on both the egg donor and the sperm donor. But in some cases, if it’s a couple, for example, a 32-year-old couple donating their extra embryo, we will probably just have very basic information on each of them. But we are transparent about that, and, if you’re not happy with the embryo, you don’t move on. You will only commit to the treatment if you are happy with the embryo that is being offered to you.

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Authors
Picture of Vladimiro Silva, PharmD

Vladimiro Silva, PharmD

Vladimiro Silva, PharmD, embryologist, Scientific and Executive Director at Ferticentro and Procriar, two of the leading IVF centres in Portugal. Doctor of Pharmacy, Faculty of Pharmacy, University of Coimbra. MSc in Health Economics, Faculty of Economy, University of Coimbra. Post-graduated in Health Services Management, Faculty of Economy, University of Porto. Post-graduated in Clinical Analysis, Faculty of Pharmacy, University of Porto. Author of hundreds of lectures, oral communications, posters and scientific articles in Portugal and abroad. Vladimiro Silva speaks: English, French, Spanish, Italian and Portuguese.
Event Moderator
Picture of Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is managing MyIVFAnswers.com and has been hosting IVFWEBINARS dedicated to patients struggling with infertility since 2020. She's highly motivated and believes that educating patients so that they can make informed decisions is essential in their IVF journey. In the past, she has been working as an International Patient Coordinator, where she was helping and directing patients on their right path. She also worked in the tourism industry, and dealt with international customers on a daily basis, including working abroad. In her free time, you’ll find her travelling, biking, learning new things, or spending time outdoors.
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