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IVF for patients beyond their 40s

Raul Olivares, MD
Medical Director & Owner of Barcelona IVF , Barcelona IVF

Category:
Advanced Maternal Age

IVF for patients beyond their 40s #IVFWEBINARS
From this video you will find out:
  • What the difference between ovarian reserve and egg quality is?
  • How doctors identify and diagnose good prognosis patients over 40?
  • What the biggest challenges for over 40-year old patients are?
  • Why age is the most decisive factor infertility treatment?
  • What stimulation protocols are the most recommended?
  • How a suitable embryo is identified?
   

IVF treatment for women after 40

It is common knowledge that at the age of 40 and above, women have reduced fertility potential – which means that the chance of having a baby with their own eggs declines rapidly. But does it mean it’s completely impossible? Dr Raul Olivares, Medical Director at Barcelona IVF, discusses IVF options for women over 40 years of age.

It is the fact that motherhood is being delayed across the world. To support this observation, Dr Raul Olivares admits that the majority of his patients are in their late 30s and as much as half of them are over 40 years old. Although all of them look great and live a healthy and active life, the problem is their biological clock. The fertility window which is between 20 and 35 years of age is still undisputable – and it is not going to change in one generation, despite social changes. That is why the route to fertility for many women becomes more and more difficult. Achieving a healthy pregnancy completed with a live birth becomes a real challenge.

The aim of this webinar is to present the ways of treating patients who are over 40. According to Dr Olivares it includes identifying good prognosis patients and deciding what the laboratory can offer them to take care of their valuable embryos.

Ovarian reserve vs. egg quality

Dr Olivares starts with differentiation between ovarian reserve and egg quality. Ovarian reserve means the capacity of the ovaries to produce follicles and eggs. According to the studies, women between 18 and 34 years of age only need two eggs to achieve 15% of live birth rate while those over 40 may need up to 15 eggs to have the same chances. While ovarian reserve means the amount of eggs that ovaries can produce, the quality of the eggs is directly related to the age. Sometimes patients who are 40-43 years old may produce up to ten, twelve or fourteen eggs – but of poor quality. And then, the quality of the embryos is also going to be poor and, as a result, the chances of a pregnancy are not going to be good either. Dr Olivares admits that the most difficult are patients who are not only over 40 but who also have low ovarian reserve – and the latter cannot be changed. So if doctors cannot increase the number of eggs, it is going to be very difficult to help these kind of patients.

Problems 40-year old patients face

Age is highly important in terms of problems with getting pregnant – studies show that 50% of over 40-year old patients are going to be infertile, with no other problem causing infertility. However, getting pregnant over 40 is hard for many different reasons. It refers not only to natural ways of conception but also to assisted reproduction techniques. First of all, there is a reduced number of follicles or no ovarian reserve which is going to make it very difficult to get a good number of eggs. There is also reduced sensibility of follicles to follicle stimulating hormone (FSH) – meaning low response to the hormonal stimulation. It means that even if there is a high number of small follicles, these follicles do not grow after the stimulation – but they remain small.

Apart form that, there is a higher risk of anatomic abnormalities. Of course, it is not directly related to ovaries but, as women age, the possibility of having fibroids, polyps or other issues such as endometriosis (which is the disease that can reduce the ovarian reserve) increases. Another problem is an increased risk of genetic issues in the oocytes – it well known that older women have a higher risk of miscarriage or Down syndrome. It all comes down to the quality of eggs: the older the eggs are, the more genetic abnormalities there are. Besides, older patients are also endangered with cytoplasmic issues in the oocytes. The cytoplasm is the liquid that surrounds the nucleus of the egg. Among others, it is important to produce the energy through the mitochondria that the embryo needs to develop in the early stages where it lives on what it gets from the egg. So if mitochondria are not ok, the cell division becomes difficult and it leads to the self-blockage of the embryo.

Last but not least, there is a higher risk of epigenetic problems in the oocytes due to DNA methylation errors. This is age-related and it may affect other aspects of the oocyte that can also entail problems in the evolution of the embryos.

Identifying patients for the treatment

According to Dr Olivares, the first step in treating patients over 40 is identifying those who are able to produce a good number of eggs. The reasoning is simple: if there are a lot eggs, there are a lot of embryos and when there are a lot of embryos, there is a higher chance of finding the one that can become a baby. There are two different tests for achieving this goal. One of them is checking anti-müllerian hormone (AMH). AMH is inversely related to the age: the older the patient is, the lower her AMH is. Another way is doing the scan to count the number of small follicles called antral follicles – these are the follicles that can be recruited during the patient’s stimulation. Dr Olivares says that AMH and AFC (antral follicle count) – together with a woman’s age – are the most useful tools for identifying good prognosis patients. This is the fact that has confirmed by a lot of studies.

Age counts the most

The main problem encountered in the group of patients over 40 is that almost half of them (40%-45%) do not even reach the egg collection. That’s why when talking about the chances doctors can offer to these patients, the only statistic that is really useful is life birth per started IVF cycle. It is, among others, due to the fact that even after transferring the embryo successfully, up to 70-75% of over 40-year old patients who get pregnant have miscarriages.

The situation in which there is no success in the first attempt is quite common. Dr Olivares says that it is generally worth trying again. To support his argument, he recalls the study showing that with each treatment, a 40-year old patient slightly increases the so-called cumulative live birth rate. It translates into the probability of having a child either in the second, third or even fourth attempt. However, this is also limited by age – according to the study, these chances diminish completely once a women reaches the age of 45. That’s why, according to Dr Olivares, you can consider more than one treatment if you are 40-42 years old – but once you are 44-45, you can try once (if you think it’s worth trying ) but if it does not work, further attempts are not really recommended. The reason is that the chances of success are simply going to be very low. In other words, using own eggs over the age 44 makes very little sense. Dr Olivares stresses that it relates to the patients with a long infertility background – meaning those who have been trying to conceive for a long time and have problems resulting from the quality of their eggs. Nonetheless, there are still some exceptions (lesbian couples, singles, male factors like azoospermia, etc.). In these cases, since the starting point is different, the limit of 44 years of age can sometimes be flexible and doctors can conduct at least one attempt to see if it is possible to succeed.

How stimulation protocols work

When considering possible IVF stimulation protocols, doctors have to take into account ways of increasing oocytes’ quality and quantity. Dr Olivares says that the former is simply impossible – regardless of protocols, medicines or vitamins used. According to him, the only solution is to try to get as many eggs as possible, hoping that among those eggs, there is a viable one that is going to produce the healthy embryo. When it comes to improving oocyte quantity, there are different methods available which can include increasing the dose of drugs, using new generation of drugs (like e.g. Elonva) or adding androgens.

Dr Olivares explains that in the past it was thought that getting too many eggs might have resulted in their quality worsening. However, four years ago there was a study carried out proving that the more eggs you produce, the higher the cumulative life birth rate is. Cumulative live birth rate means the chances of getting pregnant with any of the embryos a patient creates in a single cycle. It is true that doctors are not so focused on being successful in the first attempt but rather on being successful with one of the embryos – and cumulative birth live birth is directly related to the number of eggs that a patient produces. For example, if a patient produces more than 15 eggs, her chances of having a baby are going to be 5.6 times higher than someone’s who produces 0-3 eggs. Apart from that, if doctors gain a lot of embryos, they may be able to freeze them – and this is especially important if a patient (or a couple) wants to have a sibling in the future.

At this point of his presentation, Dr Olivares refers to the traditional method of increasing the doses of the stimulation drugs in order to produce a higher number of eggs. He claims that there is a lot of evidence that the higher the doses are, the poorer the quality of eggs. This was confirmed by a large study that included more than 650,000 cycles. It revealed that increasing gonadotropin doses is negatively correlated with live birth rate. That is why it is not recommended to go beyond 300 units – otherwise it’s going to be a waste of drugs and money and on top of that, the quality of eggs can be seriously impaired.

What Dr Raul Olivares strongly recommends for stimulation protocols is the drug called Elonva. One of the reasons for that is the concept of follicular output rate. It can predict clinical pregnancy in women with unexplained infertility undergoing IVF or ICSI and it means the capability of the drug to make small follicles grow. As it has been proven, over 40-year old patients have reduced sensibility to FSH which causes small follicles not to grow. Elonva is claimed to have the best follicular output rate. Its another benefit is that it has a very similar profile to the one that FSH has in the natural cycle – which is good for follicles. Finally, it stimulates a patient not only in a more physiological but also in a more comfortable way. The stimulation lasts for up to 7 days so there is no need to take injections on a daily basis.

The third way of trying to increase the number of follicles in the stimulation is adding androgens. The latter are claimed to be very important in the early stages, when going from the so-called preantral follicles to antral follicles – meaning the ones that can be recreated. It has been observed that younger patients have higher intra-ovarian levels of androgens. That is why stimulation protocols include adding testosterone during the first days and then following with FSH (in the form of e.g. Elonva). By doing this, doctors can basically improve ovarian response in low responders.

The role of time-lapse monitoring

When eggs are collected and fertilised, embryo cultivation plays a crucial role in assuring successful further treatment – especially when the number of embryos is low. Growing embryos to the blastocyst stage has been revolutionised with the introduction of new generation incubators called time-lapse. Dr Olivares says they have some indisputable advantages compared to the traditional ones. Most importantly, time-lapse incubators have a camera inside that takes a picture of the embryos every 15 minutes. With these images, doctors can assess embryo quality without having to take them out from the incubator and, by doing that, disturbing them during their culture. Besides, with the use of time-lapse incubators, doctors can record videos showing when and how embryos divide and this functional information should be always added to embryo morphology – proving that those looks are not everything. According to Dr Olivares, time-lapse incubators allow keeping embryos in an environment as close to the human uterus as possible – and that’s why they are a largely recommended tool in IVF treatments. As a proof, he recollects the data showing that ongoing pregnancy rates at his clinic are significantly better when time-lapse technology is in use.

Choosing the most suitable embryos

It is widely known that as women grow older, the risk of having genetic issues is growing as well. It means that the live birth rate decreases and the miscarriage rate increases. Dr Olivares says that in patient’s IVF over 40, the main reasons for having an implantation failure are genetic abnormalities in the embryo. Even if the embryos look good, it is highly probable that they have genetic issues inside of them. That is why it is crucial to have the embryos tested before the transfer. This is when PGS comes in.

PGS/PGD (preimplantation genetic screening/ preimplantation genetic diagnosis) is the procedure during which a hole is made in the embryo and up to 3-4 cells from the future placenta are taken out to have their chromosomes tested. By doing that, it is possible to transfer those embryos in which the risk of a miscarriage is going to be as low as in any embryo obtained from e.g. a 25-27-year old woman. Of course, the number of chromosomally normal embryos in an over 40-year old patient is going to be low – but if doctors manage to find a healthy one, the chances of success are going to be really good.

For years, morphology has been the most common way of assessing embryo quality. Dr Olivares does not share this view as he claims that embryo morphology is not really related to genetics – it means that even perfectly looking embryos may still have genetic issues. Nonetheless, it is true that the prettier the embryos are, the higher the chances of being normal they have. When morphology is good, the number of embryos that are genetically normal is higher (73%) than when morphology is poor (about 40%). On the other hand, once it is known that an embryo is genetically normal, its morphology is no longer relevant. The latter clearly supports the importance of PGS over morphological assessment.

Take-home message

Concluding his presentation, Dr Olivares gives some important pieces of advice. First of all, there’s no way to deal with time and the biological clock. Once you are over 40, the sooner you start your IVF treatment, the better as – literally – every month counts. Secondly, you should try to avoid treatment protocols with high doses of gonadotropins. Instead, it is much better to use drugs like Elonva, which are more physiological, comfortable and effective. Thirdly, look for clinics that use time-lapse technology in their labs. A time-lapse incubator is always a good tool to increase the embryos’ number and quality and to choose the right one for the transfer. Finally, add PGS to your treatment whenever it is possible. It does not only save your time, money and emotions – especially when the number of embryos is very high – but it also allows doctors to gather more information about the real quality of the embryos. Before external factors are started to be considered, it has to be identified which embryos are really good inside. Only when they are transferred and the pregnancy does not occur, it is time to take into account other problems, such as immunology and endometrium receptivity.

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IVF treatment for women after 40 - Questions and Answers

Is anyone doing IVF in Europe now? For older women who cannot wait.

The only thing that I can tell you is that one of our IVF lab directors is working with the Spanish Fertility Society and they are now developing a document suggesting that in reproduction medicine, there are cases in which time is really crucial. We are aiming to start working again by the end of April and especially in those cases in which time is critical. We all hope that in May we will be able to start treating patients again – especially those who have lower ovarian reserve and may not be able to wait for months because this may reduce their chances. Another problem is how easy or how difficult flying is going to be for patients. This is completely out of our control. We are pretty sure that we are going to be able to start working with the local patients but I don’t know when patients from other countries will be able to fly to our clinic – hopefully sooner rather than later. I don’t know if in other countries, e.g. in Eastern countries like Russia, they will have different restrictions. In the European Union, at this stage and because of the recommendations of the European Society for Human Reproduction, all the IVF labs have stopped working.

I am 39, my husband is 59 and he has got varicocele and severe sperm infertility (low motility, no formal forms). We want to go for IVF with our own cells again. My ovarian reserve was 1.5 last April. I had a BB embryo implantation which was successful, resulted in a clinical pregnancy but still there was a miscarriage at week 5. What do you advise us? Both me and my husband have been tested genetically and we are ok (we tested over 700 genes).

We have a different problem here because we have a male factor issue. And this is something that should be studied. I understand that you have been through a carrier map test to check if you are not a healthy carrier of mutations. The main test to check if someone is genetically normal is a karyotype which is a blood test that checks if chromosomes are normal. But one thing are chromosomes and other thing is DNA that you have inside the oocytes and inside the sperm. As I have explained in my speech, one of the main problems is that the eggs, as they get older, have more and more genetic abnormalities. The karyotype of these patients is going to be normal but the problem is going to be inside the egg. So you can have a perfectly normal karyotype, meaning that all cells have 23 pairs of chromosomes and this is why you have 46. But there are two cells that only have 23 chromosomes: the egg and the sperm – because when the sperm fertilises the egg, you again have embryos that have 46 chromosomes. There is a process called meiosis and that is the main reason why, starting from a normal cell, you end up with normal eggs. This may also happen in men. In men, this problem is not so age-related as in women. However, in Spain you can be a sperm donor until you’re 50. Given that your husband is 59, sometimes the percentage of sperm that carries genetic abnormalities could be higher. This may mean that, despite having good eggs, the sperm is the one that is causing genetic problems. This could be the cause behind the miscarriage and the fact that you had just one embryo. So in this case my recommendation would be to do the karyotype first and then there is a test called FISH. It basically checks the percentage of sperm that carries genetic issues because this may also affect the quality of the embryo. Then, if the FISH test is normal, probably you may have to change the protocol. That’s something that we have to discuss in depth but the first thing that I would recommend is checking the genetics of the sperm. It’s true that the eggs are probably the most important part of this equation but the sperm also plays an important role. Sometimes patients, especially when they have good spermiogram, think they are fertile – and sometimes it is not like that. The problem with the FISH test is that sometimes it is quite difficult to have it done in a place with a reliable test. We are quite used to doing it because we’re quite fond of studying men when things don’t go right. We tend not to blame women every time we have a negative result or we have embryos that do not make us happy. So that’s something that you would have to consider. The FISH test basically checks if there is anything abnormal in the generation process of the sperm – and if there is something wrong, it will be always like that. Sometimes you can have a higher percentage or a lower percentage but it’s always going to increase the risk of having genetic issues.

So is there still a chance for us? Can we go for IVF with own cells despite the FISH test result?

If the FISH test is abnormal, it’s going to be very tough. That means there is no way of choosing any sperm with the right genetics. If you want to know if that sperm is genetically normal, you have to destroy it – but then you can no longer use it to inseminate an egg. So you may have a sperm cell that is abnormal but the other one beside it can be normal. So it’s a bit of luck when we choose it. But we know that when the FISH test is abnormal, there’s going to be a higher percentage of embryos that are going to be genetically normal. So you would only be able to identify these embryos with PGS – but taking into account the number of embryos that you have, I don’t know if the route of PGS would be a good one for you.

Is it true that sperm quality and motility can be improved by taking antioxidants for 3 months while sperm is regenerating?

That’s something that is related to DNA fragmentation. DNA fragmentation means that in terms of chromosomes, DNA of the sperm is normal but it is fragmented. So this is something that an oocyte has to deal with – it has to repair it. However, if you are over 40 and the quality of your eggs is not good, the impact of DNA fragmentation on the embryo quality is going to be greater than if you have egg donation or you’re at the age of e.g. 25. Then, one of the things suggested to do is taking antioxidants for 3 months to renew all the sperm. But again, in this particular group of patients, 3 months can make a huge difference – because of the age. So there are other ways of dealing with DNA fragmentation that, in my opinion, are much much more useful in patients over 40. For example, ICSI, which is a technique that allows us to identify which sperm has a higher or a lower degree of DNA fragmentation. By doing it, you don’t need to invest 3 months to get a result that sometimes can be better – but other times it can be just a waste of time. It may happen that you are not going to get any improvement and you are going to loose 3 months or more, trying to improve the sperm when there are other ways of doing it much faster.

I am 44, AMH 2.3. I had 1 failed IUI and had 1 canceled IVF cycle due to early ovulation. During the second cycle, 2 eggs were collected and fertilised by donor sperm but they didn’t survive 24 hours. Would you recommend trying another cycle using own eggs?

There is one thing that is really important regarding AMH: there are two different units for assessing it. It can be assessed in picomoles per litre (pmol/l) or in nanograms per millilitre (ng/ml) – and the values are completely different. In your case, given your response, I assume we’re talking about pmol/l – which is quite low AMH. If there were ng/ml, that would be lovely AMH. So sometimes it’s difficult to explain it. Another important thing to take into account in your case is DNA of the sperm. Most of the time, it is true DNA of the sperm is activated on day 3 – so it means that for first 3 days, the embryo lives on what it gets from the egg and when there are problems in the sperm, they sometimes appear when the fertilisation takes place and when the embryo is of day 3, 4 or 5. So most of the time, when the embryos have any problems in the
first days, it means that they don’t have the right quality from the very beginning. This basically means that there is a problem with the egg. When we have an embryo that is really good and suddenly, on day 3/4/5 it gets worse, sometimes it could be due to the sperm because it is on day 3 when the sperm DNA is activated. As I see in your case, both embryos got fertilised but they didn’t survive 24 hours. So it looks very much that you have a problem with the quality of your eggs. That’s why in your case, given your age, your ovarian reserve, the results that we have seen in the largest studies and the fact that you have already had IVF treatment, my recommendation would be egg donation.

Is AMH of 1.5 ng/ml a low ovarian reserve for a 39-year old? And how many follicles are expected to be retrieved with this AMH? Would you recommend IVF with own eggs in this case?

AMH of 1.5 ng/ml is good ovarian reserve. With such AMH and 39 years of age, I would say that you can expect to produce probably 8 to 10 eggs. Another thing is quality – but if there’s nothing wrong with these eggs, then yes, I would consider IVF with your own cells.

Where is Elonva manufactured? I’ve never heard of it before. Is this a new drug? Is this the equivalent of Menopur?

It is not new, it’s a drug that we have been using for 6 or 7 years now. I think the problem with Elonva was that the laboratory didn’t advertise it very well. Elonva is a very strong drug and the laboratory was focused too much on the risk of having ovarian hyperstimulation syndrome (OHSS) because of the number of follicles that you can produce. So doctors were really very afraid of using it. Of course, in case of patients who are over 40, the risk of hyperstimulation is negligible because usually we deal with very low ovarian reserve. The risk of getting 40 or 30 eggs would be minimal – in fact, if you are 42 and you produce 30 eggs, you may not need IVF at all. So Elonva is a drug that I use in probably 90% of my first IVFs. What is different from Menopur is FSH (like in Puregon or Gonal F). It has been modified in a way that it keeps stimulating the follicles for 7 days. It’s called corifollitropin alfa. So it’s not HMG like in Menopur – it’s just FSH.

About Elonva – what would you supplement it with after 7 days, up until the trigger? Should I add Menopur? At what dose?

The standard protocol with Elonva – in a normal patient not using androgens – is that the patient contacts us on day 1 of her cycle, she takes Elonva on day 3, then on day 7,8 and 9 of the cycle she starts the antagonist to block the ovulation and she has the first scan on day 10 of the cycle.There is no need to do a scan before because we are on a fixed protocol so we are not able to change anything. It also makes the treatment quite comfortable for the patient because you don’t have to go to the gynecologist to have a scan every two days. And then on day 10, about 25% of the patients are ready for egg collection. It means that they have enough follicles of the right size and we can trigger the ovulation. So they’re going to have one scan, four injections and then they are ready. The remaining 80% may need between one and three more days of the stimulation until we get that amount of follicles of the right size. And in this case, I usually prefer to work with AMH because in this phase of the natural cycle, the LH levels are higher. So for me, it is much more physiological to add Menopur. For example, I work a lot with Meriofert, which is HMG obtained from the placenta – so it’s slightly more powerful. I work with doses of 150 because the only thing that I cannot modify at that stage is the number of follicles. I just want them to grow until they reach the right size. So I’m not focused on using a lot of doses because if the patient has not respond with Elonva, it’s very unlikely that she’s going to respond if I continue with the stimulation. If I work with Menopur, I use doses of 225 – because it is not as strong as Meriofert.

What does normal antral follicle count (AFC) look like? How many antral follicles should be there?

The more, the better. I mean, it depends on the age. One of the things that I have to say is that when I compare AMH and antral follicle count (AFC), sometimes there are differences. So for example, I have very low AMH and I do a scan and the patient has 7 follicles. And you have to decide because there is a really big difference between what you get from the scan and what you get from AMH. In general, my opinion is that AMH is much more relevant than AFC. If you have low AMH and a good number of follicles, it is very likely that, if you go through IVF, these small follicles are not going to grow. There was a study carried out many years ago where they were measuring the levels of AMH inside the follicles. They noticed that there were follicles in which AMH was absolutely high and follicles where AMH was very low. So they correlated the idea of these high or low internal follicular levels of AMH with the possibility that the follicle was of good quality or not – and if that follicle could grow or not. So when I have really very different results from AFC and AMH, I rely more on AMH. In terms of AFC, I’d consider between eight and ten follicles to be normal antral follicle count.

Can antral follicle count (AFC) be determined during a normal gynecological check-up?

Yes, but the only limitation is that AFC should be checked in the first 3-4 days of the cycle. At any other moment of the cycle, it could be different. AMH can be checked at any moment of the cycle – unless, of course, you are undergoing some kind of a treatment. But in general, even if you are on a contraceptive pill, AMH can be checked. It tends to be slightly lower if you’re being on a contraceptive pill for a long period of time – but, on the other hand, it is very unlikely for a person who is trying to conceive to be on a contraceptive pill for a long time.

I am 40 and I have AMH of 0.739 ng/ml and AFC of 6. What would be the chance to get pregnant with IVF for the first time?

If everything else is normal, the chances of having a baby could be between 15 and 20%. But it depends on other clinical factors, too. For example, the duration of infertility – it is not the same if you’ve been trying to conceive for five years or for two years. It also depends on the fact if there is any male factor or if there were any miscarriages or pregnancies. It could also depend on the uterus – if there are any fibroids or not. These are the kind of things that can modify the pregnancy rate. But assuming that everything else is normal and you do not have long-standing
unexplained infertility, with this AFC and AMH, the chances of having one or two good embryos are good. The chances of a life birth should be around 15-20%.

How do you know that a woman has got a high level of androgens? How does this manifest?

The androgens that I mentioned are not androgens that you can assess. I’m talking about intra-ovarian androgens. If you want to know them, you have to go through a very selective puncture to obtain blood from inside of the ovaries or the follicles. So it’s not something that you can do in an easy clinical way. It’s basically done when you are trying to do some research. It has been confirmed that when you aspirate small follicles and you check the levels of androgens inside of these follicles, younger patients tend to have higher levels. So that’s something you
can do when you don’t have good ovarian reserve. One of the reasons that may be causing the poor ovarian reserve is the fact that the ovaries have low levels of androgens. So then you may supply these androgens – but you can supply them for only five days. If you use too much of androgens, it may cause a negative effect. So having high levels of androgens is not good either. So it’s possible for only five days at the very beginning – but this kind of test has only been done for research purposes so far.

Why is it important to know when the cells divide? Which day do you mean (from 1 to 5)?

Embryos keep dividing during those five days. One thing that is really important with regards to time-lapse is that the cell division pattern may change from laboratory to laboratory – so sometimes it is very difficult to compare. I cannot go to another laboratory and import their protocols. They probably are not going to be good for me as my lab is going to have different conditions. So you have to develop your own patterns and you have to identify when the embryo divides and whether it is going to mean a good or a bad prognosis. The timing when the embryo goes from one to two cells and from two to four cells is different, depending on a laboratory. And sometimes it is not only about timing but also about how the embryo is dividing. It happens that an embryo goes from one cell to three cells – and this is an abnormal condition that worsens the prognosis. So we gather a lot of information during the culture using time-lapse. This basically means that, firstly, we have to invest time to develop the normal patterns in our laboratory.

Do all the clinics use time-lapse technology? If not, what is the alternative used by these clinics? Does it make a difference in the sense that it allows embryos to develop up to the day 5?

Time-lapse is becoming more and more used these days. In my personal opinion, it’s really useful. But we didn’t start working with time-lapse incubators when they were released. We needed about 4 years to add them to our standard procedure because we first wanted to confirm that the results were going to be better. So we had invested four years into working with time-lapse incubators until we added them to our workflow in the lab. If the clinic that you are going to does not have them, this is going to be a problem. Of course, that depends on how many embryos you have. In my opinion, this is crucial because we are talking about the group of patients that does not produce a lot of embryos. If you are 27 and you have a problem with your tubes but you’ve got really lovely ovarian reserve, you produce 11 or 18 eggs during IVF and you have 10 embryos. And if you end up with 8 to 12 embryos, this is not going to make a really big difference in terms of results. But if you only have 4 or 5 eggs and you have just 1 or 2 embryos, then it is going to be a really big difference in terms of cumulative life birth. So if there is anything that we can do in order to take care of these embryos and slightly increase their number, it is going to boost your chances of success. Maybe not in the first attempt – but you are going to have more options without having to go through another round of IVF. So according to me, if it’s possible, choose the clinic which has the time lapse technology in its lab.

How much better is NGS than PGS?

In fact, PGS stands for pre-implantation genetic screening and there are different techniques to do it. It can be done through PCR, NGS, the microarray technique, etc. NGS stands for next-generation sequencing and is of the techniques that helps us identify which embryos are normal or not. In my opinion, NGS is currently the best technique to do PGS. So when we do PGS, we always use NGS.

How much time until the next simulation do I need to wait after a still miscarriage at 5 weeks?

It usually depends on how complicated the pregnancy was and when the miscarriage took place. If you had a natural complete miscarriage, we usually recommend waiting for the second period after the miscarriage. So after you miscarriage either naturally or through an aspiration (D&C), you are going to have your first period in about 30 to 40 days. And you can start the next stimulation with the second period – there is no need to wait longer.

I am 40 and my husband’s 38. We had four miscarriages within the last three years – two tested with genetic problems. What would you recommend? The last miscarriage was eight weeks ago – when would you recommend to start again?

In regards to the recurrent pregnancy loss, I have to say that the most important reason is the genetic problems. If these genetic problems are related to your age and the quality of the eggs or to something else, that’s something that you would have to test. My first recommendation would be doing karyotypes to both of you to see if you are not a healthy courier of any chromosomal abnormality. That may explain these miscarriages. If the karyotypes are normal – and it is very likely because the abnormal karyotypes are quite strange – then my recommendation would be IVF + PGS. In a patient who gets pregnant naturally, there is nothing that we can do to increase the quality of the eggs. And the more miscarriages you have, the more likely it is that the next pregnancy ends up in another miscarriage, too. The chances of a miscarriage in the third or the fourth attempt keep increasing so – as I’ve said – my recommendation in your case will probably be IVF and PGS. You don’t want just an embryo – you want a genetically normal embryo. So it doesn’t make sense to try IVF and transfer embryos without caring a genetic test on them. That’s something that you have already done – now what you should do is to discard abnormal embryos. Once you have had your second period, you can consider IVF. You can of course keep trying and trying naturally, but if you keep having miscarriages, every miscarriage means quite a few months before you can get pregnant again. And time starts being crucial in your case.

I am 40 and my partner is 42. My eggs and his sperm don’t fertilise. We have had better success with ICSI – I got 8 eggs and 5 blastocysts in the first cycle. As a result, there were 2 chemical pregnancies and 2 negative ones. In the next cycle, I got 6 eggs and 3 embryos. I miscarried at 6.5 weeks with twins. We will go with the treatment again but I’m wondering is the lack of fertilisation through IVF a bad sign in terms of cells’ normality? And should I be getting more eggs? My AMH is 14.2 pmol/l.

I would like to know the protocols that you’ve been on so far. It looks like there is something wrong inside the embryos. These abnormalities can come from the sperm or from the eggs – and most of the time they tend to come from the eggs. The main problem that we have is that we don’t have any way of checking the quality of the eggs other than going through IVF. One of the things that we do in cases like yours is that we first try to confirm that there is no genetic issue on the male side. For this reason, we are basically doing the FISH test which is going to confirm that the percentage of abnormal sperm is normal. Once we are sure that there is nothing wrong on the male side, we can try to work with IVF and perform genetic testing of the embryos. We know that if the man is healthy, anything that we can find in the embryos is very likely to be due to the quality of the eggs. With that AMH, you may be able to produce like ten eggs – so in your case Elonva would be a good option if you have not used it yet. It could increase the number of embryos. I have to say that in patients over 40, we often end up with 2-3 embryos. Sometimes patients are reluctant to invest money in PGS – so then, one of the things that can be done is embryo banking. It means that we can do IVF and if we have 2 or 3 blastocysts, we can do a biopsy and freeze them – but we don’t do PGS yet. We go through another round of IVF and we get 2 or 3 more embryos and then, once we have 5, 6 or as many embryos as the couple or the patient want to have, we can go through 1 or 2 rounds of IVF. Then we get a good number of blastocysts and we carry out a single PGS in all the embryos that we have got from the different cycles. By doing that, we can increase the chances of finding a normal embryo. Of course, you have to discuss money and balance everything very well if it’s worth doing or not. But this could be a good option for those patients who want to keep working with themselves and they don’t produce too many embryos. In regards to the lack of fertilisation, I have to say that we never try conventional IVF in our clinic. 100% of the cycles are done with ICSI because sometimes it could be just an isolated issue. It could be nothing relevant and you are loosing the cycle that can be perfectly treated if you did ICSI. So yes, sometimes the lack of fertilisation could be a problem. It could be a problem in the natural fertility but once you do ICSI, you’re solving the problem.

Is AMH of 16 pmol/l low or good for a 43-year old?

16 pmol/l is 1.8 ng/ml which is not bad for someone who is 43 years old.

What about inhibin B as an indicator of ovarian reserve?

It is an old tool is that we no longer use today. When inhibin B was very low, it was related to the acceleration of the cycles that take place when someone is starting to becoming menopausal. Now it is used in men because it’s related to lower spermatogenesis. But it is rarely used in women – once we have started using AMH, these tools do not add any really useful information.

Can you please name again the technique used in case of DNA fragmentation for identifying normal sperm without DNA fragmentation? You mentioned it in correlation with the FISH test.

The technique is called IMSI. It stands for high magnification sperm injection. The difference between IMSI and ICSI is that when we do ICSI, we choose sperm at 400x magnification – and when we do IMSI, we choose it at 8000x magnification. So we see a lot more of things inside. One of the things that we can see is that the sperm has a high degree of DNA fragmentation, meaning some small buckles or vesicles inside of the sperm head. Then we can discard such sperm cells and we can work only with the ones that have no vesicles inside or have only the smallest ones. By doing that we are very effective in reducing the impact of abnormal DNA fragmentation. Unfortunately, IMSI does not help to identify which sperm cells are genetically normal. It can be only used when there is a severe teratospermia, meaning that the abnormal forms in the sperm cells’ spermiogram are very high or when there is a high DNA fragmentation rate.

We have made 4 ICSIs in less than one year (between the age of 42 and early 43). 7/8 oocytes were retrieved each time and most of them deteriorated on the 3rd/4th day – even if some of them arrived at the blastocyst stage. Only one embryo arrived at PGS – the result was 3 chromosomal anomalies. Based on what you said, could it be due to my husband’s DNA abnormalities? Based on the FISH test, he’s got a little higher than the average risk on the 13th chromosome.

Those cases that are really complicated because we have many factors and sometimes it’s very difficult to decide what we have to change. According to the result of your PGS, you had 3 chromosome abnormalities. I understand you mean that there were three chromosomes with abnormalities and not that you had three copies of one chromosome. This is a kind of complex abnormality. What I can tell you is that in your case, we have the combination of many different things that really make the prognosis poor. First, it’s the number of attempts. You’ve tried four
times and in any of these attempts, you have not managed to get a good embryo. You had 4 ICSIs and 7-8 oocytes which means that you have produced like thirty eggs so far. Your age is really relevant but you also have the problem with an abnormal result of the FISH test – so determining which is the most important problem is very difficult. The only thing that I can tell you is that I wouldn’t recommend you to keep working with your eggs and your husband’s sperm. You must change something in this scenario. I feel that the eggs are still much more important than the sperm because of all the things that they offer to the embryo, like mitochondria’s energy, etc. My recommendation for you would be to consider egg donation using your husband’s sperm – but still together with doing PGS because, basing on the FISH test, the risk of having genetic issues in the embryos is high. And it’s high regardless of using an egg donor. Obviously, the best option for you would be a double donation or an embryo donation. But if you have to choose between IVF with your eggs and a sperm donor and egg donation with your husband’s sperm, I would recommend the latter and adding PGS to check which embryos are genetically normal.

What is your experience with using Clostilbegyt by a man to improve his spermiogram?

I hear about it for the first time so my experience is below zero, I’m really sorry. In general, one of the main problems that we have with vitamins and antioxidants is that they improve the quality of the spermiogram but they don’t improve the life birth – this is what the studies have shown so far. Having better sperm would make sense only if it allowed us to change the technique. For example, you have sperm that is bad – but not that bad – and you are considering IVF and you use something that can improve it enough to consider IUI. So then it makes sense. But once you are doing IVF, the fact whether you have e.g. 10% motility or 20% motility is not going to change the outcome. So for me, it is a waste of time. And when you are over 40, time is crucial. So we have to be very careful about what we recommend to our patients and how much time they need to see the benefits – because what we can get from that could be lost in terms of eggs’ quality

If you are in a perimenopause and plan to use donor sperm and donor oocytes, how is the preparation for the embryo transfer done when period stays away for a couple of months and you have no much time remaining? I am 49 years old.

You don’t even need to have your period to undergo egg donation. Egg donations are always done using a hormonal replacement therapy. In our clinic, when we do egg donation, we synchronise the cycle of the donor and the cycle of the recipient. This is done by putting the recipient on a contraceptive pill. If you have periods, you start the contraceptive pill on day one of any of your cycles. If you have very irregular periods, what we recommend sometimes is that you have a scan and if the scan confirms that the ovaries are not working, then you can start straightaway the pill even if you don’t have a period. By doing that, we take control of your cycle and then we can use a donor that is also going to be on the pill. We make you and your donor stop the pill on the same day, having your periods (because if you have been taking a pill, you are going to bleed) and then start with hormones that are going to prepare the endometrium. We are going to synchronise your cycle with the cycle of the donor in a way that once we do the egg collection from the donor, five days later you are going to be ready for the embryo transfer. So it is not really difficult.

You spoke about scan, do you mean ultrasound? It has been done and there is almost nothing. My AMH is below 0.03. My last ovulation was in January. Do vitamins influence the cycle? My periods stopped when I started using Gravitamon (all B vitamins with folic acids, vitamins A, C, D, E, calcium, zinc and selenium).

Probably you are menopausal as most women when they are around 50. As a clinic concept, menopause means that you have been one year without a period. It’s not uncommon that some patients may not have a period for 3, 4 or 5 months and then suddenly have 2 periods – and this is another period called climacterium. It lasts like two years or something. When I said a scan, I meant an ultrasound. Basically, that’s something that you must do when you are about to start the treatment. As I’ve said, the fact that you had the last cycle only two months ago does not mean that in 4 or 5 months you won’t have another period. And if that happened when the donor was on the way for the egg collection, it would be a disaster. And we would have to freeze all the embryos. So the only thing that we can do in this case is to take control of your cycle by putting you on a contraceptive pill. If you want to start the egg donation route, you need to repeat the ultrasound before starting the synchronisation to confirm that everything is quiet and that the endometrium is really thin. And if there is no activity, then you can start the pill and forget about
your cycle.

My feeling is that the clinic reduced my chances of obtaining many embryos. After fertilisation, of 6 embryos I only got two with AMH of 1.5.

In egg donation, only 60% of the embryos that we have become blastocysts. One of the things that you have to be aware of is that when you take embryos to day 5, you’re going to lose a lot of them on the way – even if do egg donation. So if you have 6 embryos and you end up with 2, in someone who is around 40 it is not a bad result. Of course, I don’t know which clinic and which lab you were in, I don’t know the conditions of the lab, there was also a male factor that may have reduced your chances, etc. AMH is important only in terms of oocytes – but once you go beyond that point and you are talking about embryos, then the sperm also comes into play. Of course, the laboratory conditions and procedures may sometimes play a role and may change the outcome, too. So remember that AMH is not directly related to the amount of embryos – there are other factors in between as well.

Would you recommend acupuncture? Do you have positive experience with patients who underwent acupuncture in your clinic?

We offer acupuncture in our clinic. However, in regards to all these kinds of things, it is important to know how to use them. The main problem that we have with these techniques is that they sometimes offer things that are impossible, like having more eggs or better eggs. And patients invest a lot of time in using such techniques. Nowadays a lot of studies confirm that acupuncture does not have any impact on the quality or a number of eggs. In some cases, in which the endometrium is not good, it may help to improve the blood flow – but its effectiveness in terms of improving the life birth is very poor. However, another thing is how acupuncture is going to help you to cope with your IVF. We offer it right before the embryo transfer and right after the embryo transfer because it helps patients to stay relaxed and then it makes the transfer easier. In this sense, there is a correlation because the more difficult the transfer is, the poorer the results are. So if we can do anything to assure a safe, easy and fast embryo transfer, then we do it as the results are going to be better.

My problem is that I would need to fly abroad twice for NGS (as I believe it takes a month). Considering that I might have difficulties going abroad now, I was thinking that it might be easier to skip NGS and spend a week abroad. How much would that worsen the chances?

When we do IVF and patients want to do PGS, they basically have to fly to Barcelona twice. We try to do the whole process in their countries of origin. Basically, we can send you the prescriptions and the protocol, you contact us on day one, you have your scans with your doctors, you send us the reports and based on these reports, we decide how to proceed. And only when we want to trigger the ovulation, we ask patients to fly to Barcelona. They usually fly the day before the egg collection, we do the egg collection and the next day – if we are going to do PGS – they fly back home. Then we keep them posted about how the embryos are doing on the day of the fertilisation, on day 3 and on day 5 and 6 because days 5/6 is when we are going to do the biopsy. Then we need two weeks to get the results of the genetic test. Once we know there is some normal embryo, we get in touch with the patient, we prepare the patient for the transfer with hormonal replacement treatment (with estrogens) and ask them to do the scan in their country. Then they just fly for the embryo transfer – they fly the day before the embryo transfer, we do the transfer and they fly back the next day. This is a standard way of proceeding with PGS. So if you need it, you will have to find a way of doing that. Transferring embryos without having tested them – if you have had the problems previously – is not going to change anything compared to what you’ve done before.

I tend to get depressed from the hormones. What can I do to improve the impact of the treatment on my mental well-being? I had two IVFs and three KETs. I am 40. I got pregnant once during the cycle but it was a cervical ectopic pregnancy.

That’s really rare. I’ve seen a cervical ectopic pregnancy only once in my life so that is a very strange situation for me. When it comes to depression, we will have to see if your problem is just because of the hormones or because of the whole process you have been through. Sometimes it’s a mix and it’s quite difficult to determine. One of the things that we recommend is to be open about what you’re doing. One of the main problems of IVF or assisted reproduction techniques in general is that patients tend to keep it very private and not share their feelings. Sometimes this even happens inside the couple – just as if you were afraid that someone is going to blame you or that you’re going to blame your partner and so on. We have a psychologist working in our clinic because it’s very important for the patients to understand how to cope with the negative results and the uncertainty of what is going to happen. The treatment is always very stressful. A lot of times patients ask me about stress and I say that stress belongs in the treatment. Patients go through the stimulation without knowing how they are going to respond to it, then they’re worried about the quality of the eggs, then the quality of the embryos. If you want to have PGS, you’re worried if embryos are going to be genetically ok and once you transfer the embryo, you have no guarantee about the outcome. So I can only imagine how hard the whole process is in terms of emotions. That’s why it is good to look for psychological support and try to be open about it. Of course, you do not want to inform everyone because then you’re going to get a lot of pressure from other people giving their opinions and telling you what to do or what not to do. But at least, you should tell it to people who you think are going to support you. It’s also very important to have very good communication within a couple. And if it’s necessary, I believe acupuncture and Chinese medicine may help to reduce the stress that all these treatments are surely going to cause.

I am 39. I got slight depression due to the hormones after the stimulation, especially after the clinical pregnancy was confirmed. How can this be improved?

In my opinion, patients tend to blame hormones too often. Hormones very seldom cause depression. I think it is much more complicated and it usually involves more things than just the treatment that you’ve been through. If the drugs caused depression, we would have a lot of egg donors with depression. And believe me when I say that my egg donors don’t get depressed. So it is not just the treatment itself but it’s the environment and everything that made you go through this process that is causing the depression.

What do you think about Inositol for ovarian stimulation?

There is a lot of ongoing research on Inositol. Basically, it has been suggested for cases of polycystic ovaries in which the number of mature eggs is sometimes quite low. There are people who tend to have very good ovarian reserve but the main problem they have is that it is very easy for them to go into hyperstimulation syndrome – because of the number of follicles that they produce. But then, when you pick up the eggs, you get a lot of immature eggs, regardless of the time when you pick them up and their size. Inositol has been claimed to improve the percentage of mature eggs and it has been tested in patients trying to improve the quality of the eggs. However, so far the information that we have in this particular field is of very low quality. I’m not aware of any study confirming it could improve the quality of the eggs or even the number of follicles.

Can the biopsy of the embryo, following a miscarriage, detect whether the endometrium was the cause of the miscarriage or not? As parts of the endometrium also analysed during the biopsy.

It depends. If you check the endometrium, it sometimes can give you information about if there is any kind of infection or something that may have caused the miscarriage – but not the endometrium as a cause. The endometrium can reflect a current infection that – maybe due to all the factors – can have caused the miscarriage. If the endometrium causes the miscarriage, it is usually because there is a kind of an abnormal implantation. It means it can allow the embryo to implant but then, later in the pregnancy, there are restrictions in the blood flow between the endometrium and the embryo and these may cause a miscarriage. But this is something that is very difficult to identify – if it’s possible at all. In fact, I think it is not. However, you can study the stuff that you get from D&C – it is basically something that you can use to check if there is any kind of a genetic abnormality or not or if there has been any infection.

Is it true that sperm taken directly from testicles has less DNA fragmentation?

According to my experience – no. We did a lot of research on this issue. The main argument for a testicle aspiration or a testicle biopsy is that you may get lower fragmentation because DNA fragmentation takes place in the epididymis which is the channel that is right after the testicles. So the idea is that if you avoid the passing of the sperm through this channel, where it gets damaged, the sperm is going to be of better quality. But the problem is that when you use this sperm from the testicle, you may have a higher risk of genetic issues in that sperm. So the benefits of having better DNA fragmentation (because there are other kinds of DNA fragmentation that take place inside of the testicle) could be counterbalanced by the fact that the sperm is more likely to have genetic problems. So in cases of DNA fragmentation, I’d recommend IMSI as it is something that is not going to change your protocol at all. Doing a testicular biopsy is much more expensive, much more complicated and, in our opinion, unnecessary if you have IMSI.

If you do a biopsy of the endometrium, what are you looking for?

For a lot of things, in fact. The first thing is a pathology study to check if it’s normal or not. You can also check different new tests like the window of implantation, you can check if the microbiome – which is the normal flora that should be in the endometrium – is correct or not. You can try to see if there is any bacterial DNA suggesting that you may be having a chronic infection in the endometrium, like a chronic asymptomatic endometritis that may impair the implantation. So there are different reasons you can do a biopsy for. What you’re looking for depends on
the clinical context, on the history of the patient and also on what you get in the cycle. If you don’t have good thickness of the endometrium, you may be looking for problems that have to do with the development of the endometrium, etc. So there are quite a few tests can be done on the endometrium.

Authors
Raul Olivares, MD

Raul Olivares, MD

Dr Raul Olivares began working in assisted reproduction in 1996. In 2003, he created one of the first Spanish international Departments in the Institut Marques and was its Director until 2010. He became the medical director of Barcelona IVF in 2010. Dr Olivares says: "I would describe myself as a vocational doctor. As far as I can remember from my childhood, my dream was not to be a doctor; rather, it was to bring children into the world. Firstly I made it come true in the delivery room, where I thoroughly enjoyed myself, and now before conception. I am one of those who believes that while the end result is essential, it is not the only thing that matters. That is why I have always defined Barcelona IVF as a philosophical programme because, when we started it, we gave up many amenities in trying to fulfil our dream of successfully performing the medicine we like. I truly believe that assisted reproduction should be like this, a strange combination of idealism whilst keeping our feet on the ground. The speed at which we acquire knowledge is dizzying and this leads to our results improving; however, we must of course always try to ensure that the entire process is worth it, without losing sight of the fact that our end goal is to fulfil the dreams of those that trust us."
Event Moderator
Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is an International Patient Coordinator who has been supporting IVF patients for over 2 years. Always eager to help and provide comprehensive information based on her thorough knowledge and experience whether you are just starting or are in the middle of your IVF journey. She’s a customer care specialist with +10 years of experience, worked also in the tourism industry, and dealt with international customers on a daily basis, including working abroad. When she’s not taking care of her customers and patients, you’ll find her traveling, biking, learning new things, or spending time outdoors.

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