In this webinar session, our next expert Dr Héctor Izquierdo, Gynaecologist at IVF-Life Group, Alicante, explained the main common causes of implantation failures and possible solutions.
First, I would like to see how is your lining reacting. In patients above 45, sometimes the issue is that the lighting does not grow properly, with all nutrients they need. So it would be good to test the lining and see if it has a good thickness. If that is not working, there is a possibility to do PRP (Platelet-rich plasma) to help the lining grow. If the lining is growing enough, then I would need to categorize this patient as a repeated implantation failure case. We would need to run all those tests we talked about, before creating new embryos because if there is a KIR-HLA problem, for example, then it would be better if we found the perfect HLA donor for you. If there’s a husband, we would need to see what type of HLA he has and if there’s compatibility to give you a proper treatment. Therefore, first take care of the lining, if it’s bigger than 7.5 – 8 millimetres, test the implantation window and all those factors.
It’s important to understand that the donor is anonymous, which means that the woman who’s receiving a donation or the woman who’s donating or the child that is going to be born can’t get the information, but the doctors can. In the case of Spain, the Spanish Ministry of Health is controlling this and knows who’s donated, there is a national registry that lets us follow whose eggs are going where, and how many times, the eggs were donated. As I’ve mentioned, you should perform KIR-HLA type, but also your husband.
There are a lot of new things that come out all the time, and in this situation, there are still some things that we don’t know, and we cannot go forward in research. I haven’t seen that you did the KIR-HLA testing and that that would be something that could be checked. PGT-A increases the chances of the embryo succeeding, then perhaps egg donation might be an option and so on in this situation before you should think about surrogacy.
There’s one thing that comes into my mind, there are new studies that say if you want to do some extra test, to check the level of heavy metals. They might have a toxic effect on the implantation of embryos, so through eating or exposition at work, we can accumulate higher levels of heavy metals in our bodies, and those can’t make us sick because the concentration is low for us to get sick, but they can be very toxic and prevent implantation. I’ve had 3 similar patients like you, they all had very high levels of metals, and we changed the diet to reduce those levels, and they are pregnant at the moment. This would be something that you could do as well.
There are a lot more factors than just oestrogens, progesterone, and the quality of the embryos. In 30 to 40 of my consultations, I receive the such question. There are a lot of countries where all these factors are still not being tested. We’ve had patients from all over the world with very good quality embryos that were wasted because all the other factors were not tested, sometimes little changes need to be done. If your clinic does not offer this type of testing, there are a lot of clinics that do this type of thing, and you can always get information from each other, we are in a globalized world, so look for something else because you can get some information that you can use in the future transfers.
In cases of repeated implantation failure cases with egg donation, we always recommend PGT-A to be sure that those embryos are healthy. There are also non-genetically healthy embryos in egg donation, we need to remember that the chances of a healthy embryo of a young donor are higher than an older person but when you do a stimulation to retrieve eggs in a donor, some clinics are very aggressive, they want to obtain as many eggs as possible, that’s why we do it a bit differently and do fresh cycles with a very reduced number of eggs retrieved. The more you stimulate the woman, the more eggs she produces, and the worse the quality of those eggs is. If one donor produces 20 eggs in 1 cycle, in the end, some of those might be also genetically unhealthy because you’re pushing the body to the limits as well for this young woman. In egg donation, PGT-A is also recommended when we’re talking about repeated implantation failure.
Eggs are not everything, there are a lot of factors that involve the implantation. When you’ve done egg donation, and you’re not pregnant, the first thing to do is to go back to the basics and check everything before you move forward. This is also needed psychologically. When a woman has been trying to get pregnant with her own eggs and then takes the next step to go to egg donation, she hopes that with this huge step, we’re going to change the outcome, most of the time, it does. In egg donation, I normally do a very first embryo transfer with no further testing, and those patients in 75% are getting pregnant in the first transfer, r which is already amazing. I don’t do 2 transfers without further investigations because if you don’t get pregnant with egg donation, that can be very hard for the couple or the family. They start to feel that their bodies don’t work any more, and that might be some things that can be treated that we haven’t seen before. My advice will be to take a look around and see what hasn’t been tested already before you make a new transfer.
It depends on what we’re doing. If you have any friends that are very into immunology and for example the branch of medicine that takes care of rheumatology, you’ll know that prednisolone is just an all-purpose therapy/. When rheumatologists don’t know how to treat an immune disease, they just prescribe prednisolone because it just resets everything.
If we work on specific NK cells, TH1/TH2, I would rather know which is this balance to tell you about proper treatment for you because if the problem is just the TH1/TH2 imbalance, then IVIG or prednisolone is not useful. You’re a better candidate for Tacrolimus inhibits or sirolimus, but if the NK cells are low, then you need Ovitrelle, and if the NK cells are too high, then you don’t need IVIG, or Tacrolimus, prednisone, you just need infra lipids.
Nevertheless, some studies are running in the USA at this moment, they are giving IVIG or any immunoglobulin to patients with repeated implantation failure. The results are not back, bringing those antibodies anti-antibodies into the body of the womb may allow bringing a better balance and stop the embryo from being rejected and increase the chances of a pregnancy.
On the other hand, IVIG or antibodies could protect the embryo from being attacked by something else. Low antibodies in the lining have shown also to be detrimental. IVIG therapy alone for repeated implantation failure is not recommended in all cases because we don’t know why it’s also possible, but some testing might be helpful, we will have a look at which constellation is affecting you.
One thing is ruling out that the embryos are genetically healthy. At 35, we expect that around 30 to 40% of the embryos that we produce might be genetically unhealthy, and PGT-M testing is ruling out mutation that is the main cause of disease of the embryos and this changes dramatically the number of available embryos that we can use. In my experience, when you produce a lot of embryos, from 8 embryos that you had, it may reduce the number to 3 or 2, which is very challenging. In this type of situation, I wouldn’t do any transfers before I’ve tested everything because going that way and producing transferable embryos is very hard, and the possibility of getting them again is not that high. In this type of situation, I would test everything before making transfers to be sure that we’re not missing anything.
Were those embryos genetically tested? This is one thing I’ll be interested in because you have done previous transfers and you miscarried. This is one of the most common causes of miscarriage, the genetic quality of those embryos. I would consider that.
Speaking about the Chicago test, we need to remember that doing blood tests to see how immunology works is not as accurate. We need to understand that the blood is the transporter from all the immune cells to different tissues, but the concentration of those cells in any tissue is very different, we have organs in our body that have no immune cells like the eyes and the brain. Still, we have organs in our body that have tons of them. Making conclusions out of blood tests is not accurate, we cannot extrapolate it one to one, it might be an association there but it’s not always like that, so it can be dangerous. I’d sooner test immunology directly on the womb to be sure how it works at the moment.
The second thing we need to understand is that a woman’s immune system is not the same throughout the whole time. Women who get pregnant are immune differently, the immune system of a woman goes down to be able to implant, therefore, testing your immune system in your womb or your blood before that moment is not going to be accurate because one way or the other during the pregnancy or when you get pregnant, your immune system goes down. That’s why women who get pregnant experience mood changes or acne, etc. because the immune system needs to go down to allow the implantation. Therefore, testing it outside the implantation movement is not as clear and specific as it should be.
A woman at 35, and a lower reserve and low response, in terms of genetic egg quality, is more similar to a 40-year-old woman than to a 30-year-old woman. That means that PGT-A in this specific case might not be a bad idea, it would allow us to know that those embryos were not all healthy and therefore not capable of producing a pregnancy.
The second thing is that if you have endometriosis, it’s better to avoid fresh transfers. Every time we do a stimulation, we trigger endometriosis back with a high dosage of FSH and oestrogens, which makes endometriosis more active. Thus, endometrial tissue lying somewhere else but in the womb produces inflammation. This inflammation makes the whole environment less welcoming for an embryo.
Then frozen transfer with down-regulation and Decapeptyl, some studies are saying that using Decapeptyl for 3 months before transferring an embryo reduces the inflammation and therefore increases the chances of implantation. Saying that 2 embryo transfers failed is not a problem in a woman that struggled that much to produce embryos, for me, I would test her before I make an embryo transfer.
First thing is that testing embryo that is already frozen are not a good idea. However, this is a very common technique, because the frozen embryos must be thawed, then biopsied and then frozen again. From my perspective, this has little sense, the chance of implantation decreases a lot.
The second thing is that if the embryo is not genetically tested, we don’t know if it’s healthy, and if it’s not healthy, it might not have enough information to implant at all, that’s why PGT-A tests might not be helpful for you. Another thing is to always look for a clinic that performs the biopsy of your embryo directly where they do the culture. Some clinics do the stimulation, they do the egg retrieval, they put the embryos to culture, freeze them and then send them somewhere else where they decrease them and refreeze them and send them back to the clinic, so they can transfer them back. This is a total no-go, this is something we should always avoid. A clinic with good work standards should always biopsy embryos fresh at the perfect moment day 5 or 6 and then freeze them.
ERA test for sure, immunological mapping of the lining as well, and I always say BMI is important, we need to understand that blood sugar acts like a toxic thing in the blood for the embryo, for ourselves and more than reducing the BMI what I always say to my patients is change your style. I don’t want to say to my patients that they just should lose weight because it’s very easy to say that, but once you say it that way, you add additional stress to the whole process, which in the end, makes the whole process even harder. Forget about the weight, forget about the BMI, and start eating healthy, change carbohydrates to vegetables and fruits, change processed food to fresh food, and change fried things to grilled things.
All those simple changes, simple carbohydrates like bread and sugar, pasta, potatoes, and things that are complex carbohydrates can help you. Focus on changing your habits and doing sports, but when I say a sport, I don’t want you to run New York Marathon a day, I just want you to wear some comfortable shoes and do half an hour 3 times a week walk along those small changes in your habits are helping you to get pregnant. Sometimes some patients focus on trying to lose weight, and in the end, it’s all stress in these old currents that their body makes it even harder for them to get pregnant.
Indeed, there are many environments very exposed to a lot of things, for example, dentists are exposed to radiation and X-rays, and there are some chemical things they use as well. We need to understand that the toxins are not just in your work, stress, long shifts and things like that, those are all very important as well.
We must say that the transfer is not a very complicated procedure itself, but doing it right demands certain expertise on that, that’s been proven. If you see the studies, a doctor who has 5 years of experience performing the transfer is more likely to produce a pregnancy than one who is just starting. That’s the fact and it’s not just the experience of the doctor, but also the clinic’s experience. The clinic that performs 600 transfers a year is going to be much better than a clinic that performs 100 transfers, how you do it, how you proceed and how you know the anatomy, how you get in the lining and put the embryo back is also very important.
There are a lot of things to talk about, you are considered as a repeated implantation failure case for sure. Provera is not my kind of medication and I’d use subcutaneous intramuscular injection, for example, Lupron or something like that. I would do some testing regarding immunology, and antibodies to rule out the causes of repeated abortion as well before going ahead with the next transfer. You should do it, especially that you don’t have more embryos left.
You just need to be taken care of, before the egg retrieval, we just need to make sure what type of medication you’ll need. Whether you should get Clexane, Heparin or whatever and stop it before the egg retrieval at the right moment. People with Thrombosis can get hip replacements, and have difficult operations, how are we going to tell a woman who has Thrombosis that she’s not going to be a mother, she just needs to be well taken care of.