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Implantation failures – causes and possible solutions

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

Category:
Embryo Implantation, Failed IVF Cycles

Implantation failures: causes and possible solutions
From this video you will find out:
  • How can I be sure that the implantation failure is due to a female problem and not an embryo problem?
  • Which immunological tests are useful in cases of implantation failure?
  • How must the transfer be done to maximize the chances of implantation?
  • My endometrium does not get a good thickness. How can I make it thicker to improve the implantation rate?
  • Is it worth adding an anticoagulant therapy (aspirin and/or heparin) in cases of implantation failure?
  • Could a natural cycle improve my chances if I don’t get pregnant using hormone replacement therapy?
 

What are the causes of embryo failing to implant and what can be the solution?

Raul Olivares, Dr., Medical Director & Owner of Barcelona IVF, is answering patients’ questions on embryo implantation in IVF treatment and its causes and possible medical solutions.

What are the causes of embryo failing to implant and what can be the solution? - Questions and Answers

How can I be sure that the implantation failure is due to a female problem and not an embryo problem?

The thing is that they are very, very strongly correlated. One of the probably oldest questions that I remember asking my professor was when we were dealing with the negative, which person that of this negative can be due to the egg, to the sperm, or the uterus. In fact, when we talk about the embryo, we are talking about the egg and the sperm, sometimes there could be other issues that are related, f. e. to the laboratory. I am not going to get into this field because I’m going to assume that most of the laboratories that are nowadays working have really good conditions. When w have an embryo problem, it is because of the egg, or it is because of the sperm. In some cases, this could be due to the conditions of the laboratory and uterus and things like that. It is much easier to study the male factor than the female one. When we have an embryo problem, our standard way of working is to do some tests on the male side because it is easier to study. Then, of course, when we have that embryo problem, if the male side is movement, we can assume that as long as the laboratory is good, these problems are going to come from the women’s side. If there is a male problem, we will have to be very careful because sometimes it could be mixed factors, and the fact that the man has a problem does not guarantee that the eggs are going to be healthy. But that at least allows us to carry out with changes to see if we can isolate the problems from the oocytes. Whenever we have an embryo problem, we should start doing some tests on the male side. If it’s necessary, once we are sure that the man is not playing any role in the embryo quality, then we will be able to see how the eggs are doing or if there is some kind of problem.

Which immunological tests are useful in cases of implantation failure?

Immunology is one of these things that were like the top issue in the 90s. Then we started with all the different genetic tests that started to be available in the 90s, PGS, and things like that, and then it just was kind of forgotten, and now it has come back, but in a completely different way. The evidence from the 90s was mostly based on even older histories that were issued. They were based on the idea that they were kind of things that make the body reject the embryo. They test for natural killers like TH1, TH2, CD19, things like that. There are even some tests, which detect the levels of natural killers and the endometrium. It was supposed that if you had abnormal natural killers, too high or TH1, TH2 was abnormal, you could be in the position of rejecting the embryo.

This is why there are a lot of therapies with immunoglobulins, steroids, intralipids that were also released, in order to kind of immunosuppress in these patients that were supposed to attack the embryos. I have to say that these theories are no longer valid. Natural killers are there, natural killers must be in the endometrium, and they play a significant and relevant role in regulating the implantation of the embryo. They are not as cytotoxic as they were supposed to be. There are other natural killers present in the bloodstream that are clearly cytotoxic, they attack the cells, they kill cells, viruses, cancer cells but the natural killers in the endometrium are just regulated how deep the embryo implants, so they have to be there, and it is important not to interfere with their levels. There is no single study that has been able to correlate the number of natural killers in the endometrium with recurrent implantation failures, so forget about all these old studies carried out. Forget about biopsies to detect natural killers in the endometrium.

The only tests that are now promising because the evidence that we have about them is still controversial are those that, in certain cases, correlate the KIR receptors, which are receptors on the surface of the natural killers that interact with the HLA-C antigens that the embryos suppress. Depending on which is the profile of the KIR receptors and depending on which genes suppress the embryo, we may have problems sometimes, which are mostly related to recurrent miscarriages and placental problems and not implantation failure. This is why I still think that we have to be very careful about doing these tests when we have pregnancies that end up in a miscarriage. In my opinion, these are the only test, that nowadays are kind of useful in some cases to try to maximize implantation rates – KIR receptors and HLA- C antigens on the embryos.

How must the transfer be done to maximize the chances of implantation?

There are two classical ways of doing the embryo transfer. I’m assuming that because this is something that almost all the clinics are doing right now. These transfers are done, and they are ultrasound-guided, so that means that someone is doing a scan to make sure that the tip of the catheter is placed at the right point. That’s the only way we can be sure that you are just doing the transfer at the right place and once you are doing this, well some clinics prefer to carry out something called a mock transfer before starting the treatment to see if the transfer is going upwards or there is a reverted uterus, or you need to use a soft or rigid catheter or if there are any issues that can make it difficult.

This is how I used to work many years ago, but we changed the way we’re working and now what we do is that on the day of the embryo transfer, we just place an empty catheter ultrasound-guided in the right place, the catheter is empty and that allows us to take our time to be sure that we are in the right point. In the transfer, time is critical, the catheters are designed in a way that they hold the temperature for 30 seconds, and the embryos are very sensitive to temperature changes. We need to be sure that once the embryo leaves that incubator, it is inside of the uterus in less than 30 seconds.

Why did we change the way? Because we have patients that on the day that we were doing the mock transfer, everything was perfect. On the day of the real embryo transfer, once the embryologist brought the catheter with the embryo, it took more than 30 seconds to get in, so basically, we decided to work as we do now. We do kind of a mock transfer with an empty catheter before and only once we are sure and we can invest 30 seconds, 2 minutes, or 10 minutes until we are in the right place only once we are in, the embryologist picks the embryo and brings it and we transfer and by doing that, we are a 100% sure that 99.99% of the transfers are done in less than 30 seconds and that the embryos are gently released into the uterus in the right place.

My endometrium does not get a good thickness. How can I make it thicker to improve the implantation rate?

Sometimes, it’s even difficult to know what is the right thickness. This is also something that makes it very difficult to compare different studies because everyone can have a certain thickness as the minimum or as the best one, so f.e. in our case, we work with the 6 millimeters as the minimum thickness in an egg donation or a cryo transfer, but this is a scan that is done on day 9-10, and once we reach that 6 millimeters thickness, we are sure that once we do the embryo transfer that is usually done 1 week or 10 days later, the thickness is going to be good. Other clinics may work with 7 millimeters, other ones prefer to work with 8.5, some clinics prefer to work with a pattern triple-line or not. What we do when we don’t get that minimum of 6 millimeters that we are looking for?

We prepare someone for an embryo transfer, sometimes we just need to increase the dose of estrogens, we prefer to work with a fixed pattern of high doses from the very beginning. I know that there are clinics and their protocols start with 4 milligrams, then go up to 6 milligrams, and some of them go up to 8 milligrams of estradiol. We usually start from the very beginning with 8 milligrams, so it’s 2 milligrams in the morning, 2 milligrams at midday, 4 milligrams at night, and we do the first scan 8-10 days later. By doing that, I would say that probably 90-95% of the patients have the right thickness.

When this doesn’t happen, we can go up to 10 or even 12 milligrams and take 4 milligrams every eight hours. If we manage to get the right thickness, that’s fine, we advise patients to keep doing the same doses. When this doesn’t happen, and we have to cancel the cycle because we don’t get the right thickness, we may sometimes use drugs like Cialis, which is the tadalafil between 5 and 10 milligrams a day. These drugs are supposed to increase vascularization, make the vessels wider. Then it should be easier for the estrogens to reach the endometrium and to improve the thickness. In some patients, it works, in some other patients, it doesn’t work. Sometimes we may change the way they are taking the estrogens, and we can shift from oral to transdermal and in this case, we may use patches, or we may use a cream to give the estrogens and changing the way.

When you make it through the skin the estrogens go straight away into the bloodstream and go straight away into the uterine. When you take them orally, there has a first passage through the liver that may remove part of the estrogen, so sometimes is a good idea to use patches of creams and even a combination of oral and patches, and this may be enough to increase. In those cases in which the thickness keeps being really low despite using these drugs, despite combining patches, creams, or increasing the doses, these are difficult cases. Certain studies have confirmed that the endometrium can still be receptive when they are 4 or 5 millimeters thick. In this kind of endometrium, one option can be carrying out the transfer, or carrying out a test to confirm the endometrium is receptive and if it is, try to see it. I have patients with endometriums of 4.5-5 that have been successful, and they’ve gotten pregnant.

There are other cases in which we have tried a protocol where we have combined high doses of vitamin E plus pentoxifylline for 2 or 3 months, and then we have tried to prepare the endometrium, and I’ve got probably 2 or 3 patients where it worked. We don’t have so many patients with this problem, but in the 2 or 3 cases in which I’ve tried this combination of vitamin E and pentoxifylline, I’ve managed to get a better endometrium. Sometimes, I’ve got a completely normal endometrium, but if the patient had an endometrium of 3.5, I’ve managed to increase it up to 5-5.5, and I’ve got pregnancies, so this could be the only different thing apart from increasing doses, combining patches, or adding tadalafil or viagra in some cases., I’m not really fond of viagra, I prefer tadalafil, in some cases, those can help to improve the thickness of the endometrium.

Is it worth adding an anticoagulant therapy (aspirin and, or heparin) in cases of implantation failure?

This is probably one of these kinds of treatments that can be included into that rule of first do no harm, and sometimes we are just giving treatments to patients, and when I read the protocols, it is kind of a surprise, and now they start from the first treatment with anticoagulant, with the steroids, with probiotics and it’s like they are just trying as we say here in Spain try to kill flies with canons. I think that as doctors, we have to decide what is worth and what is not, and we don’t have to use all the drugs from the very beginning, we don’t recommend all the tests from the beginning, we just try to decide which is going to be useful for each patient. These kinds of drugs, aspirin, and heparin, I recommend them.

There is some evidence that coagulation problems like antiphospholipid syndrome or thrombophilia, those may reduce the implantation rates. The data is really controversial because these conditions are mostly related to recurrent miscarriages, not with implantation failures. Of course, every year, we learn more, and in this case, especially with regards to aspirin, we cannot discard that in the future, we are going to identify other coagulation problems that may explain implantation failures. I’m not really fond of starting any treatment adding aspirin and heparin, but in cases of recurrent implantation failures, especially those cases in which we are sure that the embryos are of good quality and all the tests are complete in all manner, and we cannot identify any factor that is causing this implantation failure, using aspirin and heparin may be helpful.

Another thing is how they must be used because I see a lot of patients start the aspirin too late or the heparin once they’re pregnant, these are drugs that if they are useful should be stated clearly before the embryo transfer is done, and the aspirin to get a full effect should be started at least 4 weeks before the embryo transfer. If you start on the day of the embryo transfer or you start it once you’re pregnant, the implantation has already taken place and you are not going to get any benefit from these drugs, so aspirin 4 weeks before the embryo transfer, heparin at the beginning of the cycle in which you are going to have the embryo transfer but at least they don’t cause any relevant side effects like for example steroids, so in some cases in which everything seems to be okay and can be used and maybe they are helping.

Could a natural cycle improve my chances if I don’t get pregnant using hormone replacement therapy?

This is quite interesting because I really think that the answer is yes. I would say that when a patient has her cycle, everything goes in a more fluent way. I would say that the body is preparing itself to get ready to get a pregnancy. The HRT is quite a standard therapy, and we prepare all the patients, in the same way, starting with the progesterone at the same time, using the same doses. We assume that this is going to work in most of the cases, and this is basically what the majority of the studies confirm that in terms of live birth, the HRT and the natural cycle offer very similar statistics. I would say that is the first approach in those patients that have the natural cycle because if the patient is menopausal, there is no other option, we have to work with hormone replacement therapy.

If you have patients with the natural cycle and especially, in those patients that have been naturally pregnant before, regardless of the outcome, even those patients that got pregnant and had a miscarriage, but they have been able to have an embryo implanted. In those cases, changing the hormones and doing a natural cycle and then we probably say what we call the natural modified cycle, it means that we just monitor how the follicle grows and once the follicle has reached like 17 millimeters or something like that, we trigger the ovulation with HCG in order to be sure that we transfer the embryos at the right moment. This is a kind of a modified natural cycle, it could be a good solution, a good answer, and in cases that we had negatives in using hormones, we have managed to get positive using the natural cycle whenever it has been possible.

We have had 3 fresh cycles with ICSI. Our 3rd cycle was the furthest we got & had a transfer at day-5, but it wasn’t quite a blastocyst at the time of transfer. But unfortunately still did not implant. We have been diagnosed as male factor infertility, low ovarian reserve & low AMH & I’m 40yrs old. I am thinking for our 4th cycle, we will go frozen & do 3x batch cycles & do frozen transfer instead. I am thinking if we have enough embryos, then to do PGD testing too as well as ERA test.

As I said at the very beginning of the webinar embryos are critical, probably close to 90% of the implantation failures are due to embryo issues. Embryos that can come from the egg, from the sperm, or even from the embryo itself, so before considering any study on let’s say the woman side and these includes endometrium, uterus, or blood work, we need to be sure that the embryos we are transferring are of good quality.

This is sometimes quite difficult because there are factors involved in the implantation that we barely know. F. e. there is a very recent study that has tested the implantation rates of the embryos when they were genetically normal, and because of the large data that this study has included, they have been able to notice that there are different implantation rates even when we transfer genetically normal embryos based on the age of the woman. Why does this happen? This happens because other structures come from the egg that is relevant for the embryo evolution f. e. mitochondria’s, the mitochondria are structures that come from the egg, they are the ones, which create the energy that the embryo needs to go ahead with the cell divisions, so genetics is very important, but it’s not 100% In your case, we are dealing with a mix factor because there is a male problem and we have someone who is 40 with low ovarian reserve, so that means that is really difficult to get it.

My recommendation would be to study your husband first. Carry out some studies on the male side, specifically genetic tests to detect if he is carrying a chromosomal issue or if there is any genetic problem in the sperm, f.e. what is the percentage of the sperm that is having genetic abnormalities. We know that when there is a male factor, it is not so uncommon to find that even sometimes the spermiogram can be normal or despite being normal, there is a high percentage of the sperm that carries a genetic abnormality. This is something that can be tested with a test called FISH or a mitotic study on the sperm. Once we are sure that the sperm is okay, the only thing that we can do is to check the quality of the eggs. As you said PGS, but if you test the sperm and you see that the sperm has a problem and one thing this also can be tested for example doing a DNA fragmentation if there is a problem on the male side, and you have few eggs of not very good quality it’s going to be very, very hard to obtain healthy embryos. So probably you will have to consider to change something and see f. e. in the event of an abnormal result of a FISH or of a meiotic study or DNA fragmentation, you will have to consider what both sides are able to do, with normal sperm and then probably consider the sperm donation. Let’s say that you want to go ahead despite or regardless of the results of the male side – what you have suggested makes sense.

You can’t just go through different cycles to do kind of an embryo banking to carry out a PGS and to make sure that the embryos are genetically normal and then depending on the results of the PGS, you could decide if it’s worth doing some research on the endometrium side but first wait until you get the results of the PGS if you have and you can test 6 embryos, and only 1 is normal, it will be very clear that the problem is inside of the embryos and I would not consider ERA test in that scenario. If you check 6 embryos and 5 are normal, something very unlikely, but if that happens, it would probably mean that the embryos are not so relevant, and then it could make sense to do some research on the endometrium side before you transfer those embryos. As I’ve said, focus on studying the embryos, first the male because it’s easier, cheaper, and it would let you decide if you want to keep working with that sperm or not before you start doing IVF after IVF, and you will be a word of what you can really expect from those IVF taking into account that you may be dealing with problems on the sperm and on the eggs.

If PGD tests have been done on the embryo and the embryo has presented as a 100% normal euploid, and there are no endometrial layers or womb issues, but implantation still fails, what could the cause of that be? I’m 36 years old.

Unfortunately, even if the embryo is genetically normal, we are still far from a 100% success rate. According to a recent study that has not been published, as I’ve mentioned at the beginning of the webinar, the estimated live birth rate when you have transferred 3 genetically normal embryos is close to 90%, it could be in the first, in the second, or in the third attempt. The estimated live birth for the first time when you are transferring a genetically normal embryo, and you are young is about 60%, which is slightly higher than tossing a coin, so it’s not that really great. These are the limitations that we have because we are human beings, so what happens when we are transferring an embryo, and it does not implant, genetically normal embryo. The first thing that I will suggest is that we need to consider more transfers until we get it, and we shouldn’t be worried until we have transferred 2 or 3 genetically normal embryos because even in those cases, we are not going to have a 100%.

Things that can happen with transferring good embryos and they don’t implant, nowadays, one of the things that are coming back is adenomyosis, which is a condition that affects the structure of the uterus that can be diagnosed and sometimes is underestimated. In the negatives, adenomyosis is a condition similar to endometriosis, it affects the muscles of the uterus, different things can be seen on the scans to suggest that would be adenomyosis and it has been confirmed, and there has been a study that describes up to seven things that can be related to the adenomyosis and this study confirms that the more of these things that you have, the lower the implantation rate is going to be. How can adenomyosis be improved? We are now working with long downregulating protocols using GnRH agonist, so kind of creating menopause for 2-3 months because the adenomyosis is like the endometriosis, it’s hormone-dependent, so if you just reduce this before transferring the embryos, you may improve the implantation rates, but adenomyosis should not be treated before the stimulation because these long down regulations may also affect the number of eggs that the ovaries can produce.

The idea is – if you think that the adenomyosis can be the problem, you still go through an IVF. We obtain the eggs, we create the embryos, we freeze all the embryos, and then you can start working on the uterine side to reduce the adenomyosis. In some of the cases, it is becoming very much notorious, all these tests that are now checking the microbiome, so the flora that is inside of the endometrium, and there are some tests that are trying to find out if you have the right proportion of the lactobacillus, the different bacterias, and they are suggesting antibiotics and probiotics restore the normal environment in which the embryos are transferred. This is very promising for me, and I am now doing the test from the research and I have cases in which only after I’ve been able to restore the normal conditions, the patients have gotten pregnant, so this is another thing that can be done and checked.

These are usually called ALICE and EMMA tests, but the idea is to check the microbiome to detect if there is any kind of dysbiosis. Things that are useless f. e. I would not recommend going through a hysteroscopy, there’s a lot of evidence that if everything is okay in the scan, the hysteroscopy is not going to add or is not going to improve the success rate of the next IVF, so probably and with the information that we have nowadays, I would stick to check if there is any adenomyosis, check if there is any abnormality of the microbiome and in some very specific cases, the ERA may make sense, but the ERA, which is the test that checks the window of implantation is only useful in those transfers that are done using hormones, it is absolutely unnecessary if you can have a natural cycle. As I’ve said before, in some cases, doing some research and trying to see if there is a coagulation problem, antiphospholipid syndrome either thrombophilia to later use heparin or aspirin, which can also be a good option because it’s quite easy, the treatments are not really expensive and free of side effects so it could make sense.

How accurate is an ERA test to increase the chances of implantation on a second-round IVF? I’m a 36-year-old woman.

If you mean the second round of fresh IVF, the ERA is completely useless. The ERA is designed to work in a very controlled environment, so ERA only makes sense if your endometrium is prepared in the same way using the same hormones, starting them at the right moment. In an IVF, the number of follicles, the level of hormones – everything is going to change from cycle to cycle, as it happens in the natural cycle. So forget about the ERA or any other test designed to identify the window of implantation if you are not working with hormones in either an egg donation cycle or in cryotransfers. Because if you want to have the ERA you have to replicate the same environment in the same treatment once, twice, or three times and every IVF, every stimulation is completely different, you can even work with different drugs, so it is absolutely useless in these cases. Only in cases in which you are under a fixed protocol of hormones can be replicated, and that can be done in the same way in the future.

Will CoQ10 and DEHA improve the quality of fertility? How long should we take and how much to take?

I know there are some groups, especially in the United States, they are really fond of DHEA. With regards to the CoQ10, I have to say that so far, there is no evidence that it could improve the quality of the eggs. In fact, all the antioxidants that have been used in all the studies have not been able to prove any improvement with regards to the live birth rate when they are used in women. Men are another history, and some of them may be helpful if you are trying to improve the quality of the spermiogram, but in terms of the egg quality, so far no antioxidant has proved to be useful. Androgens are another world again, they are promising. I think that the main problem that we have with androgens is that we cannot yet identify the group of patients in which these drugs can be used. We lack the tools. Androgens have proved to increase the number of antral follicles, so if you have more antral follicles.

If you stimulate the initial number of follicles, that can potentially grow is going to be higher. Androgens have proved to increase the number and sensitivity of the FSH receptors in the antral follicles. So that means that if you have more receptors, you may need lower doses, or the doses that you are using may help to recruit more antral follicles, and then you may get more eggs. It has been suggested that androgens increase or improve the genetics of the eggs. This is a big base, and some studies have confirmed that younger girls have higher intraovarian androgen levels than older girls. This is why it has been suggested that if we can somehow reproduce these conditions of the younger ovaries with higher levels of androgens, we may get more eggs, and in some cases, it has been suggested that even better eggs. The problem is, we don’t know for how long and which doses and what substances can be used to create or to obtain this improvement. DHEA has been suggested to be taken for 3 or 4 months. If we are going to make a patient who is 41 years old wait or invest 3 or 4 months taking this drug, the benefit that we are going to get from this drug can be compensated by the fact that she is going to be 4 months older.

The questions are are they willing to wait 3-4 months knowing that these can reduce their chances, especially in those cases of patients who are over 40, this is very delicate, so probably if you want to keep on taking DHEA, and you are 34 or 35, and you can wait these 3-4 months, you can do it, but the results are not that promising in an older woman. You have to be very careful with recommending or delaying treatment for 3 or 4 months for something that is not completely demonstrated and knowing that your prognosis can be worse if you just delay the treatment 3 or 4 months.

The only treatment that I sometimes have used is to add testosterone at the beginning of the cycle for a very short period of time 5 to 7 days, so the idea is that the patient has superior, we add treatment with higher doses of testosterone just to create this environment at least to increase the number of receptors and to try to have more not focus on improving the quality of the eggs. It’s mostly focused on obtaining more oocytes and then for 5-7 days, we give testosterone, and then immediately afterward we start the stimulation. I’ve got some cases in which I’ve really been able to increase the number of eggs, and if we have more eggs, we have higher chances of having a good embryo.

As I’ve said, the problem is mostly that we cannot identify for which patients it’s going to be useful, we don’t know the time that you need to be taking those, and in some cases, this 3, 4, or 5 months can have a really negative impact on the ovarian reserve of the patients and probably if you want to try them, my recommendation would be to use testosterone at the beginning of the cycle to make sure that you kind of has these conditions of the younger ovaries.

What are the most important things that a surrogate should do to make sure the embryos implant and grow into healthy babies?

I would say that the surrogates should do what any pregnant woman should do. Try to be as healthy as possible. But in terms of implantation well as long as the surrogate has a healthy uterus, there is nothing that they should do. We are not very straight with regards to the things that the patients can do after the embryo transfer. Once we do the embryo transfer, we keep them here for a couple of minutes, we recommend them to go back to their hotel or their homes and stay there for a couple of hours in order to try to relax because sometimes if you manipulate the uterus, you can create kind of contractions, and it may interfere with implantation, so we recommend resting, and that’s it. From that moment onwards, what we tell our patients is to consider themselves pregnant and do what a pregnant woman is supposed to do.

When someone is trying to conceive naturally is living a completely normal life until she has a positive. So we recommend to take it easy, avoid strong physical exercises and things like that it’s a must because of the psychological aspects of the treatment and in the event of a negative, the patient does not blame herself thinking that she could have done something different. I really think that as it happens in the natural cycles when the patients go to the gym, drinks some wine, and having sex until they know they’re pregnant, that this woman would not change that much the outcomes. I would say just try to keep it as simple as possible, try to live a healthy, normal life, eat healthily, avoid toxins, well try to avoid strong physical effort unless they are just really necessary and you can go to the gym, but adjust the intensity of the exercises to your condition of being pregnant, you can do yoga, you can do whatever but as if you were pregnant.

What has higher success rates – fresh transfer v frozen transfer?

I know that there has been a trend in people who have thought that it was worth to freeze all the embryos and to carry on a kind of a freeze-all treatment. They were suggesting that the conditions of endometrium could be different after stimulation than in a normal cycle. Now, there was a study published the last year 2019 that’s confirmed, that the endometrium has exactly the same conditions after stimulation or in the natural cycle, so there is no reason to carry out a freeze all systematic treatment. We don’t recommend that we only recommend freezing the embryos when there is any kind of a medical indication to do that either because the patient has a breakthrough bleeding or because the thickness of the endometrium is not okay. Or in cases in which there is a higher risk of hyperstimulation syndrome or any other issue that recommends canceling the cycle. If not, there is no advantage, and in fact, when we do this kind of freeze- all treatment because of any of the reasons that I’ve explained, we have confirmed that the pregnancy rate that we have in the first frozen embryo transfer is exactly the same as the pregnancy rate we have in the fresh transfer. It is not better, it’s not worse, it’s exactly the same, so based on that, there is no reason to delay the treatment if there is no medical condition that recommends doing it.

What is your opinion about the biopsy and testing the endometrium? For example, doing a mock cycle and doing some testa, quality of the endometrium. I’ve heard doctors say that the data is valuable and others that say that there is no relationship between one month and another, so there is no point in doing a mock cycle. I’m talking about a donor egg frozen cycle for a 51 y.o. a woman who has a child with her own eggs. She has had 3 DE unsuccessful transfers of the 5-day blastocyst.

This is what I was saying at the very beginning. If we are talking about doing an endometrium biopsy in natural cycles, that’s a complete waste of time and money. The conditions of this endometrium are going to change from cycle to cycle, and it happens in IVF, but it also happens in the natural cycle, so there is no point. The thing is when we are working in a controlled environment using a standard protocol like in normal replacement therapy, and we have no option because the patient is menopausal, and she does not have a natural cycle, that would be my first option if the hormones aren’t working. In these conditions, a mock cycle I would say that rather than talking about the mock cycle, I will say what are you testing?

Because there are things that can be tested and they are going to be the same in one cycle and another cycle and things that can be completely different, but if you reproduce the exactly the same conditions in some cases in most of the tests that we currently have available the conditions are not going to change, so that means that if you go and test the window of implantation, and you reproduce exactly the same cycle next month starting with the same doses of estrogens, starting the progesterone on the day that you’ve been told to do it and the same doses, the conditions are not going to change. Some studies have confirmed that once you have an ERA test and if you do the same conditions 1,2 or 6 months afterward, the window of implantation does not change. If you test the microbiome and it will be confirmed that the bacterias are okay, they are going to be okay in the next cycle. If they are not, of course, you need to decide if you want to go through the treatment of antibiotics and probiotics to restore the normality and carry out biopsies to confirm that the conditions are again normal.

How many days after implementing should we test for pregnancy result?

This is relevant for patients who undergo IVF or intrauterine inseminations because sometimes they tend to do results too fast, and they get false positives, and the main reason is that when we trigger the ovulation, we are using HCG, which is the drug that is detected by the pregnancy test. Sometimes patients come and explain that they’ve had the chemical pregnancies, and you ask questions about the treatment. HCG may need 7 up to 9 days to get clear from the bloodstream, so if you do a pregnancy test on the day of the embryo transfer, I would say that probably 70% of the patients are going to be positive. If you are doing a cryo transfer, if you are doing an egg donation where no HCG is used because there is no ovulation triggering, then if you do the test too fast or too soon, you are going to get a negative probably. I will say that we’re usually doing the pregnancy test 12 days after the transfer, and that’s because we usually recommend having the first test done in the urine. If you do the tests too close to the embryo transfer, it’s easier to have false negatives, but if you want to do the test in the blood, probably if you do the test 10 days after the embryo transfer you if you’re pregnant, you’re going to get a positive.

You mentioned NK cells earlier and how they should be present to some extent. What about the Th1, Th2 cytokine ratio? My TNF-a/IL-10 and IFN-g/IL-10 ratios are abnormally high, will this compromise implantation?

The fact is that the ratio with the TH1, TH2, we don’t know exactly what is the normal ratio, so it’s very difficult to know. The variety of theTH1 or TH2 changes a lot between different patients and different conditions. As I’ve said all these kinds of things cytokines, interleukins, tumor necrosis factors are kind of things that were supposed to somehow detect implantation failures, but so far, most of them are abandoned. My feeling is that in some patients, they could be useful, but we are far from knowing who is going to have any benefit from these and how are we going to restore the normality when these kinds of things are abnormal. We don’t use them, we don’t recommend this kind of tests because we lack evidence in terms of correlating these results with ongoing pregnancy rates because the lack of evidence with regards to the treatments and has been recommended to deal with these conditions, they are not true, they have not been as useful, and there are no studies that have confirmed that you can get any benefit from them, so until we don’t have more evidence about what is really going on during the implantation, I don’t think that it should be recommended based on this test because there is no evidence that you are going to improve the outcome.

I have done the ERA twice (once I was pre-receptive, the next time post-receptive), so their recommended number of hours was in the middle of these two. Based on what you said earlier, is it worth at all doing a fresh transfer? Or should I always only do frozen?  If I do fresh, should I try to arrange the transfer at Day- 5 as close to the number of recommended ERA hours as possible? (My ERA recommendation was about 133 hours)

I have to say the same thing that I’ve said before, do not extrapolate the results of the ERA to a natural cycle, to stimulate a cycle because they are completely different. An ERA is only useful in cases in which you can reproduce the treatment or the protocol that you have used to do the ERA. When we’re talking about the window of implantation, there are cases in which is pre-receptive, which means that this displays, and it takes place later than usual and post-receptive, which means that the endometrium is ready. Then you need fewer days of progesterone or in some cases, the companies that promote the ERA, they say that there could be a narrowing of the implantation of the window, and this is why sometimes you get one pre-receptive they basically tell you to adjust when you have to start the progesterone and when you get a post-receptive that usually means that the window of implantation will start in 3 days and in cases like yours it could be just 1 day 1.5 and then you have to stick to the results of the ERA because if you do the ERA, the logical thing is to follow the instructions. My recommendation in your case, it would be if you want to go for a natural cycle because you can go for a natural cycle, forget about ERA, it’s not going to help you. If you need to work with hormones either because you are doing an egg donation and you need to be synchronized with the donor, or because you don’t have natural cycles, then follow the instructions of the ERA. Try to have your embryo transfer between the hours that you’ve got in the 2 different cycles.

For testosterone treatment, when to start? On the day the period starts? Can it be taken alongside stimulation medications? Or should it be started 5-7 days before the period comes (and before stimulation has started)?

The testosterone should be started, and the treatment should be done before you start stimulation. You have to somehow keep the patient down-regulated for those 5 to 7 days, and then you can start stimulation. There are 2 standard protocols. The first one is, we use low doses of GnRH agonists. The second one is that we start 1 week before the patient has her period and then once the patient has her period, we will reduce the dose of these down-regulation drugs, and we give the testosterone for 5 days, and then we start the stimulation. Sometimes if we don’t want to use these drugs because the ovarian reserve is really low, we may get the same effect adding estrogens at the end of the previous cycle. That means that the patient starts with the estrogens like Progynova or any other estrogen, 1 week before she has the period. Once she has the period, she continues with estrogens, and we add the testosterone and 5 days later, we stop everything, and we start straightaway the stimulation. The idea is to give the testosterone for 5 days usually. I’ve said 5 to 7 days, but usually, it is 5 before we start the stimulation. Either in a long down-regulation protocol using low doses because we cannot forget that these protocols are used in patients with a low ovarian reserve. So we can’t go ahead with really strong down-regulation because this may affect the response that we’re going to get later. So, low doses of down-regulation or estrogens just to make sure that the ovaries are going to start working during those 5 days in which we are going to try to prepare them with testosterone.

I’m 46 years old, and I did my first embryo transfer in October 2019, which was negative, with the egg donor. I did just two endometria checking on my 8 days and 12 days of cycle menstruations. It was 8 to 12, the second frozen embryo transfer was in January 2020, and my endometrium liner was the same. It was a negative result, as well. I want to specify that in both cases, my transfer was done on day 19 of my menstruation cycle. In February, I did a hysteroscopy, and they found some inflammation. I’m preparing for the next transfer, and I need to know what I can do? 

I’m going to assume that you had blastocyst transfer, not day-3 and I’m going to assume that you had only 1 blastocyst each time and I’m also going to assume that there is nothing wrong on the male side, that there is no male factor or that you were using a sperm donor or that there are no other problems. As I’ve said after 2 transfers of 2 blastocysts and assuming that they were genetically normal, we should not forget that even in an egg donor has a 20-25% of the embryos created after an egg donation are going to be genetically abnormal. Having a good embryo, so good morphology and good evolution and everything does not guarantee that the embryo is genetically normal. I previously mentioned that 90% live birth rate, I was talking about embryos that were certified to be genetically normal, something that in some cases, can happen in egg donation. It is not the same if you had 2 blastocyst transfer in each transfer or you only had 1 in each obviously I mean if we assume no male factor and blastocyst transfers, as I’ve said, the hysteroscopy does not usually improve it because it’s very subjective, this kind of inflammation, and we now have tools like this test to assess the microbiome and the chronic endometritis that are much more specific, or you can do an embryo culture and see if this information is related to any bacteria and then go with the right antibiotic treatment and also consider probiotics to restore the normal flora of the endometrium.

If you cannot have this specific test done, they could suggest an empiric treatment with a course of antibiotics for 7 days using amoxicillin and then using vaginal probiotics to restore it. I would consider a 3rd transfer because as I’ve said, even with these 2 good embryo transfers, we do not have a 100% success rate, so sometimes, it’s just a matter of keep transferring. If there is any malefactor because these are kind of things that should be taken into account but in your case, assuming that everything else is normal probably if you can have a more specific test to identify this inflammation and to try to identify if there is any endometritis, which bacterias or if there is any dysbiosis of the endometrium that can be treated and if you cannot have the test, then go for a course on antibiotics, continue with the course of vaginal probiotics to restore the normal environment and if it’s possible and you’ll be using hormones, and you still have your natural cycle change and do not use hormones and try with a natural cycle, and probably you may get a positive if you fix all these kind of things.

Do you recommend a PGD test before embryo transfer? My embryos were frozen when I got diagnosed with colon cancer. Should I be worried about using them (quality)?

In some cases of cancer f. e. in cases of breast cancer, there are some mutations and genes that are related to a higher risk of having cancer in the babies, and this can be identified in the embryos, and these genes occur BRCA in the breast cancers. I don’t know if your colon cancer has some kind of genetic background, and if you have some genetic background, that increases the risk of your baby inheriting it. But it could be possible to test if the embryos have the same problem as you do. Then those embryos develop a higher risk of having cancer. If your embryos were frozen before you had the chemotherapy, all your treatments are going to be as good as they were when they were frozen. In terms of PGD/PGS, that depends on whether there are risk factors or not, and despite, all the things that I’ve been saying and that even in egg donation, 20% of the embryos may have genetic issues, I’m not really fond of doing genetic testing in all the embryos.

Nowadays, it is still an invasive technique, we need to make a hole, we need to disrupt the trophectoderm to take some cells out. There is not so much evidence there because it’s quite a new technique that is now the PGS on blastocyst is a valuable thing from ten years ago, so that’s the only evidence that we have. It does not have any midterm or long-term effect, but it is an invasive procedure, so we don’t want to stress the embryos more than what it is strictly necessary. We only recommend PGS when we think that there is a high risk of having genetic problems either because the woman is too older or because there are recurrent miscarriages. Or if there is a kind of a male genetic factor, karyotype abnormalities, or kind of mutations that can be inherited by the baby. If your embryos were frozen when you were 33, you should not consider PGS in these cases.

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.

Disclaimer:

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