Why do implantation failures happen to me?

Dr Héctor Izquierdo
Gynaecologist at VIDA Fertility, IVF Life Group

Category:
Embryo Implantation, Failed IVF Cycles

From this video you will find out:

What does the implantation process look like?
What is Repeated Implantation Failure (RIF)?
What are the most common causes of implantation failures?
What tests and investigations can be performed to identify the cause of IVF implantation failure?

Why do implantation failures happen to me?

What are the main causes of embryo implantation failure?

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.

Dr Izquierdo started his presentation by explaining what implantation is, how it works, and how it should work. This is crucial to better understand the main causes of recurrent implantation failures. The causes may be divided into three groups, the causes related to the embryo, the womb or other causes.

Embryo implantation

The first part of this process begins with transferring an embryo and getting it in the womb in the endometrial lining. Once it’s there, and that happens on day 5 or day 6 of the embryo development, the embryo starts expanding and contracting until it has enough energy to break the capsule, that’s holding it and then starts to wander outside. First, is the trophectoderm, a structure outside the embryo, which is the future placenta, and this structure goes and starts rolling in the lining. At the very beginning, the embryo presents itself to the womb, to the lining and all factors, such as NK cells, lining, blood vessels, arterial, venous, and immune systems, have to communicate with each other. If this communication is taking place appropriately, then the embryo is letting the trophectoderm start digging in the lining. In the end, a whole new structure called the placenta is produced from the embryo, which is going to provide all the blood supply that they need, and from the side of the lining, it is going to nourish the lining that gives a lot of blood to this embryo.

Recurrent Implantation Failure (RIF)

There are two ways to approach Recurrent Implantation Failures (RIF). The first one is that all patients above 40 years old should be treated like patients with repeated implantation failure because the opportunity of producing good quality embryos is much lower than in patients much younger. If the problem is the number of embryos available, we need to try to evaluate these causes of not succeeding from the very beginning. If there are 3 or more good-quality embryos transferred and none succeeded, we call such a situation recurrent implantation failure.

Embryonic causes

One of the solutions to deal with that is performing IVF with PGT-A, PGT-M or PGT-SR testing. That way we can exclude the embryos that are not genetically healthy and therefore avoid the transfer of unhealthy embryos that won’t implant.

Some data shows that when IVF is performed with PGT-A, in 35 and younger women, the chances of implantation and pregnancy are around 62%. Above 35 and up to 40, those chances reduce dramatically from 62% to 18%. Therefore, if we do the genetic testing on the embryos, we overcome this and will have a much higher rate of implantation.

We shouldn’t forget about the male factor in this matter as well. One of the most important factors is DNA fragmentation. We need to remember that 40% of infertility cases are due to male factors. Sperm is just a genetic career, the rest of the sperm structures are meant to do the fertilization, and the rest stays out, but the DNA is inside the embryo.

Nowadays, there are ways to test and see how many of these sperm that are produced in the sample are DNA fragmented. In case the DNA fragmentation rate is high, we can use some techniques to isolate or take sperm that are DNA fragmented and use them for fertilization via ICSI or any type of treatment.

When we talk about those embryonic factors, there are some other solutions available if you cannot proceed with your eggs due to bad egg quality, and when you cannot produce a healthy blastocyst, there are two possibilities that we can be offered. It is embryo adoption or an egg donation or double donation if needed as well if the sperm quality is also an issue.

Endometrial factor

One of the things that affect the chances of implantation is the implantation window (WOI). What does it mean? We know that the thing that triggers the moderation of the lining itself is not the beginning of the cycle, but the beginning of the ovulation. The beginning of ovulation is marked by the production of progesterone. The progesterone is what triggers the moderation of the lining itself. If an embryo takes around 5 days to be ready to hatch and wander inside the womb and implant, the lining should be prepared to receive the embryo after 5 days of progesterone. However, some things can happen along the way, sometimes the eggs require a bit more time to get to this blastocyst stage and on day 6, for example, they need more time to get to this moment where they can hatch and implant. That’s why one way to help patients with implantation failures is to do a frozen transfer. It allows us to freeze the embryo and capture the moment when it’s ready to implant, and in the meantime, confirm that your lining is ideally prepared for an embryo transfer after 5 days of progesterone. When you do a frozen transfer, it’s possible to put back the embryo at the perfect moment and make it more likely to implant.

The window of implantation (WOI) is very important and usually happens between days 19 and 21 of the cycle, but it can be normal or displaced. Alterations in the window of implantation can cause implantation failure or early pregnancy loss. There is a test that helps to estimate the best moment for the embryo transfer, it is called the ERA test and ER map test. This test allows us to check the perfect moment to place the embryo, so we can synchronize the embryo transfer and the lining for perfect implantation.

Another crucial part of implantation is immunology. This needs to be balanced, there are some factors in the endometrial lining that allow the implantation to happen. Once the embryo comes inside the womb and is prepared for the implant, some factors called HLA antigens need to be present. Some Natural killer cells have some KIR receptors that allow this embryo to be accepted, and they trigger a chain of changes in the lining that allows the implantation. These immunological factors can be very important and very challenging in terms of implantation. When we look at those immunological factors, we know that the NK cells, TH1, TH2, T17 and T cells (Treg lymphocytes) and B lymphocytes are the most significant in the implantation, and each one of those has importance.

The NK cells are there to work, they check if that structure that’s common to implant is suitable for you, and if they are so, they are triggered before the implantation and allow the embryo to implant. If they are too high in concentration, there can be a problem for the embryo to implant properly. If they are too low, this interaction might not take place, and if it doesn’t, this triggering of the implantation is not going to take place.

The TH1, TH2, and TH17, and these regulatory T cells are immunological cells that need to be seen in combos. TH1 and TH2 together, TH17 and Regulatory T cells together. The TH1 and TH17 are cytotoxic, they are a bit more aggressive. If there is some imbalance between them, there might be some issues for the embryo to implant, the embryo can be rejected.

B lymphocytes are responsible for producing antibodies that are there to protect the womb and the embryo from bacteria to all those things that can create an infection. If they’re too high, it can again cause a problem for embryo implantation. Depending on the issue, there are some suitable therapies for that. If NK cells are too high, intra lipids can be used, and if they are too low, then you will be beneficial with Ovitrel therapy, for example.

KIR-HLAC genotyping determines the compatibility between KIR uterine receptors and the ‘foreign’ HLA-C presented by the embryo. If the HLA and the KIR of the NK cells do not match, then the NK cell is not going to activate itself, which is not going to let the embryo implant. Therefore, if there isn’t an HLA compatibility between donor eggs, own eggs, partner’s sperm or donor’s sperm and the woman who’s taking the embryo, this might reduce the chances of implantation.

Conclusions

The main embryonic causes are aneuploidies and DNA fragmentation which can be solved with the PGT-A or sperm selection techniques, other solutions are sperm donation, egg donation or embryo adoption. The endometrial issues could be associated with a displaced implantation window, the solution for that is performing an ER Map or ERA test and synchronization with a frozen transfer. Immune cell abnormalities can be checked with immunological testing of the lining and immunotherapy. The KIR/HLA incompatibility can be avoided by KIR/HLAC genotyping, and if needed performing an immunomodulatory treatment.

- Questions and Answers

I had 4 embryo transfers of donor eggs without implantation in the Czech Republic. I had very good quality embryos, I used EmbryoGlue every time. I am 48. Any advice?

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.

In the case of egg donation, is it recommended to do KIR-HLA compatibility? The donor is anonymous.

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.

I have had 7 euploid transfers made with my own eggs and my partner’s sperm, all with no implantation. We have been investigated extensively, karyotype testing, thrombophilia screen, autoimmune antibody screen, Hysterosalpingography, hysteroscopy, laparoscopy, ERA/ALICE, CD138, NK, and full blood immune testing. The only abnormality that might account for the implantation failure is a complete DQA1 match between my partner and me, I have not responded to LIT. Will this ever work for me? What am I missing? Should I move to surrogacy or keep trying? We have 12 euploid embryos remaining, (no issue with making embryos at all).

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.

I am 38, I used donor egg, semen was excellent, we created 2 blastocysts 4AA grade. We had a failed transfer. I had a Hysterosalpingography and hysteroscopy – all was clear. No endometriosis. I was taking blood thinners, aspirin, progesterone, and estrogen. Why would it fail?

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.

I have used donor eggs twice, both times failed implantation. How is that possible?

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.

We completed our batch cycling, I have just undergone NK cells, and TH1/2 testing to see if I’ll need IVIG or other immunology treatment. What’s your opinion on IVIG or just using prednisolone to treat immunology to help with maintaining a pregnancy? The last transfer was in June, it was the first pregnancy I’ve ever had, but it turned into chemical. The good thing was that I did get pregnant, do you think Prednisolone 25 mg is good to use?

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.

I’m 36, I’m doing IVF with PGT-A to avoid passing on the genetic condition I’m a carrier for. I’ve been pregnant naturally once before but we decided to terminate it in the second trimester due to the baby inheriting this genetic condition. Our first good grade day 6BB euploid embryo led to early chemical pregnancy. I’m getting ready for FET 2 with another day 6 BB euploid embryo, but I’m worried about getting the same outcome. Could the chemical pregnancy with my first FET have just been bad luck, and if we keep transferring good great euploid embryos, are we likely to achieve a live birth? I’ve had 2 normal saline sonograms, normal fertilization, microbiome and infection testing, and normal TSH and vitamin D levels. My husband has been found to have high double strand fragmentation, but it wasn’t so high that we couldn’t use the FertileChip, and we used ICSI.

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.

I have a 6-year-old through C-section naturally conceived and 1 miscarriage previously. I am trying for a sibling, I have had 7 failed IVFs, which started when I was 36, 4th round ended in a missed miscarriage, and others failed with good embryos. I had 2 DE rounds which failed with excellent embryos. ERA showed receptive, Chicago test was fine, and I have had 2 hysteroscopies, which were fine. I have 1 embryo left so I am unsure what is the problem. For our last round, we used MACS.

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.

We are both 35, we’re trying to conceive for the past 2 years. My husband’s sperm is great. HyCoSy was normal, I ovulate regularly, and my AMH is 6.1 pmol/L. We’ve decided to go for IVF given the time we’re trying to conceive, I’ve never been pregnant, 1st cycle, 4 follicles, 1 egg retrieved, 4AB blastocyst (transfer was painful as uterine fundus hit by the inexperienced practitioner). In my 2nd cycle (with androgen priming and max dose of FSH) there were 4 follicles, 3 mature eggs, and 3 blastocysts. Fresh transfer 4AB, which was much better. I am due to do a frozen embryo transfer with 4BB, I still, have another blastocyst after that (4BC). I was offered TRIO biopsy if I want, but I was told that 2 failed transfers are fairly normal, and the doctor advised me to carry on. Do you agree, I’m nervous that endometriosis is affecting implantation, and we will waste good embryos when I already have a history of poor ovarian response, and I may not get many more.

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.

Will PGT-A testing help with choosing the right embryo? I have 5. I have read that this test does not help.

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.

I just had a 4th failed egg donor embryo transfer with a third donor, one 5AB blastocyst, I had a fresh cycle, and it was a chemical pregnancy. I have 2 6BB that my doctor wants to transfer next time, and he wants me to do an ERA test. My BMI is 32. What tests would you recommend? I have hypothyroidism which is under control.

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.

Can the work environment affect toxicity,e.g., dentist or hospital? Also, how long to reduce or get rid of toxicity in the body?

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.

What about the technician doing the transfer, to what extent might their expertise consequence implantation failure?

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.

I have transferred 6 euploid embryos. I have a five-year-old from the first frozen embryo transfer, had 3 failed transfers and then success when adding Medrol and Levonox in January. We lost the baby at 12 weeks due to SCH causing a placental abruption. Our transfer after that wasn’t successful, and we only have 1 embryo left, we’re preparing to transfer in November. Would this be considered recurrent implantation failure? Is the SCH related to immune issues? Should we change my protocol? My RE is having me suppress with Provera 10 mg 2 x day leading up to transfer, he doesn’t think Lupron is necessary.

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.

I had a miscarriage at week 8 due to aneuploidy in chromosome 4, it ended up in provoked thrombosis, I am looking therefore to change the clinic. Do you in your clinic have treatment options for patients with one episode of Thrombosis? I need to start again from scratch, e.g, stimulation.

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.

What are the advantages of Comprehensive Chromosome Screening (PGT-A/ CCS) for Advanced Maternal Age patients (+38)?

Non-Invasive Prenatal Testing (NIPT) following IVF or IVF+PGT-A, beneficial or not?

How important is male factor and how to overcome that?

PGT-A Success Stories Explained: Outcome vs total cost of IVF treatment

IVF & fertility treatment for women over 40 – what are your chances?

What to do after failed cycles and miscarriages?

Authors

Dr Héctor Izquierdo

Dr Héctor Izquierdo is a Gynaecologist at IVF-Life Group, Alicante (Former Clinic). He graduated in Medicine from the University of Valle (Colombia) and the University of Heidelberg (Germany). Later, he specialized in Gynaecology and Obstetrics at the University Hospital for Women of Würzburg (Germany), and in Assisted Reproduction at the University of Salamanca (Spain). In addition to his extensive knowledge and his experience, Dr Izquierdo is highly appreciated for his excellent professional and close relationship with patients.

Event Moderator

Caroline Kulczycka

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

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