WHAT IS THE ‘IMPLANTATION WINDOW’ IN FERTILITY TREATMENT AND HOW TO IMPROVE IT?
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How to manage successful embryo transfer after recurrent implantation failure?

Diana Obidniak, MD
Fertility Specialist

Category:
Embryo Transfer, Failed IVF Cycles, Miscarriages and RPL

RIF patients- how to manage them?
From this video you will find out:
  • What the process of implantation looks like?
  • Are abnormal (aneuploidy) embryos prevalent in human beings?
  • What is the implantation rate in egg donation with and without PGT?
  • What is the right endometrial environment for implantation?
  • What are the morphological alterations of the endometrium?
  • How prevalent is chronic endometritis?

 

What are the steps after implantation failure?

In this session, Dr. Diana Obidniak, the Head of ART of Birth Clinic in St. Petersburg, Russia, and also, a Russian Representative of ESHRE Community has been talking about RIF patients, and how to manage successful embryo transfer.

The very beginning of your pregnancy

The very first step described is implantation, which is characterized as a delicate process of interaction between the embryo and endometrium, yet it was later discovered that cumulative cells and various growth factors also have an important role in contributing to or hindering successful implantation.

Moreover, based on the session, it is important to highlight the main role in the implantation of the embryo, the endometrium, and concomitant pathology.

The embryo

In the human being species, there is a particular prevalence of aneuploid abnormal embryos. Therefore, even considering the external morphological evaluation of embryos and the PGT-A (pre-implantation genetic testing), in several high-quality embryos, only half will be normal.

It was also mentioned that even in an egg donation program, PGT-A should also be implemented as 30% to 45% of abnormal embryos are present, so it is a must in recurrent implantation failure. Evaluation of sperm morphology is also significant in the examination program.

One of the studies presented in 2019 showed 188 egg donation programs that were performed with PGT-A testing in the 1st group, while in the 2nd group, 58 egg donation cycles were performed without PGT-A. Implantation rates in the first group were 46%, while in group 2nd, it was 20%.

Embryos in terms of good clinical practice
  • Proper embryo selection
  • RI Witness – control system to detect and monitor all activity in the IVF Laboratory
  • Embryoscope (Time-lapse cultivation of embryos) – which allows the embryologists not to disturb the embryos during the whole process of cultivation, providing a very delicate observation.
  • PGT-A and PGT-M (Preimplantation genetic testing for monogenic/single gene defects)
  • Artificial intellect (Embryoscope big data), which provides a specific algorithm to select the perfect embryo for transfer

The Endometrium

Traditionally, endometrium was considered to be a passive factor that was thought to have nothing to do with implantation. Nonetheless, throughout the investigation, a new era arose in which endometrium is widely considered a microenvironment with a crucial role as a biosensor in embryo quality. A fragile balance is also involved, which involves the receptivity and selectivity of embryos. This balance can be altered by morphology and functional alterations. For instance, speaking of infertility, low receptivity, and high selectivity are commonly associated.

Morphological alterations of endometrium

The most common problems associated with endometrium are inflammatory processes, also known as chronic endometritis. It is believed to be difficult to diagnose because of a lack of symptoms apart from subtle changes in menstrual bleeding. Other problems include Hyperplastic processes and Intrauterine synechiae.

Chronic endometritis

A condition involving the breakdown of the peaceful co-existence between microorganisms and the host immune system in the endometrium, resulting in a special type of chronic inflammation in the endometrium, characterized by non-apparent clinical signs.

Data on chronic endometritis and prevalence reveals significant variations in this data, emphasizing the influence of study groups. In the general population, prevalence is around 10%, but it rises to 28% in unexplained infertility cases and can reach 45.5% in patients with poor prognosis, such as recurrent implantation failure. Recurrent pregnancy loss patients are a key focus group due to the condition’s association with chronic endometritis and is between 60.6%-66%.

Functional alternation, compromised window of implantation

Compromised window implantation is at the forefront when we’re talking about functional alternations because the synchronization of the process of embryo development and the maximum endometrial receptivity is necessary. Unfortunately, only 65% of women have a normal implantation window, while another 35% of individuals seem to have a delay in this synchronization.
Nowadays, there are 2 tests available that allow us to investigate the window of implantation, these are the ERA test and the Be Ready test.

Personalized embryo transfer

Personalized embryo transfer requires attention to detail. We should consider three study groups: one focusing on frozen embryo transfer, the second on fresh embryo transfer, and the third on personalized embryo transfer. Observing the clinical pregnancy rate per embryo transfer, it’s evident that the personalized embryo transfer group exhibits remarkably high rates, reaching 80% and 85.7%. However, within this group, there is a miscarriage rate ranging from 8 to 12%. Despite this, the initial clinical pregnancy rate remains notably high. Unfortunately, at present, we cannot entirely prevent miscarriages. Nonetheless, pre-implantation genetic testing of embryos can help minimize this risk.

Concomitant pathology

Unfortunately, patients experiencing recurrent implantation failure often receive numerous recommendations to consult with specialists such as hematologists and endocrinologists.

The primary concern for patients with recurrent implantation failure is hereditary thrombophilia. Dr Obidniak presented a study from 2006, which indicated that having two or more thrombophilia factors may lead to fertility issues, although it was later (2017) narrowed down to favouring the V mutation, MTHFR homozygous mutation. Additionally, the MTHFR homozygous mutation can also contribute to fertility problems, but it may be treatable.

Immunological factors
  • APS (Antiphospholipid syndrome) syndrome
  • Unverified celiac disease
  • Autoimmune thyroiditis, Uncompensated hypothyroidism

Various studies show that APS increases the risk of implantation failure threefold. It’s important to emphasize that this data is reliable. Unfortunately, as per Dr Obidniak’s experience, she noticed that the diagnosis of APS is sometimes not verified according to actual guidelines. It’s crucial to understand that evidence-based medicine provides strict indications and criteria for prescribing laboratory tests for APS. Even if there are abnormalities in lab tests, control tests should be done no earlier than 2 weeks after the initial investigation.

The prevalence of celiac disease varies from country to country and is not associated with ethnic differences but with diagnostic guidelines.

The third factor to consider is autoimmune hereditary issues, such as uncompensated problems with the thyroid, ovaries, and uterus. There is a strong immunological association when there are menstrual problems, indicating a high chance of uterine issues. Therefore, screening tests before planning treatment and a few days after embryo transfer are necessary.

Factors associated with gametes and embryos

In the presence of severe problems, the competence of oocytes, the functional capability of cumulus cells, and the effect of the ovarian stimulation protocol are taken into account, However, the male factor of the DNA fragmentation and genetics disorders of the embryo can also cause fertility difficulties.

Real-life case

Case 1 – a 41-year-old, who had undergone 27 embryo transfers with endometriosis IV and severe activity and autoimmune component, she already had multiple recommendations to proceed with surrogacy.

Her hormonal levels were relatively good for her age, and her ovarian pattern was magnificent. The patient wasn’t ready to pursue the surrogacy route. It was recommended to proceed with IVF with her own eggs and PGT-A program, a new stimulation protocol tailored to her needs—medications she had never used before. Two normal embryos were obtained, and it was necessary to investigate her uterus further.

During hysteroscopy, numerous endometrial polyps were found, some of which were not apparent on ultrasound due to their small size. This underscores the importance of hysteroscopy as the gold standard for diagnosing uterine issues. These polyps were removed, and the implantation window was investigated. Subsequently, a delayed embryo transfer in a natural cycle was performed, considering the results of the implantation window investigation. The patient also had gone through PRP therapy to address the autoimmune component of chronic endometritis.

The result? A clinical pregnancy and the delivery of a healthy boy. Recently, she underwent her 29th embryo transfer and is now pregnant with a girl.

Related reading:

- Questions and Answers

Do you offer your guarantee packages only with your donors or with IPs that pass the screening? If so, what are those parameters? Do you offer surrogates and guarantee ‘live birth’ packages as well? (not just a pregnancy guarantee as there could be miscarriages even if there is a pregnancy guarantee ?) What are these costs?

Given our possibilities and our equipment to tell you the truth, we provide different packages with a guarantee for all the patients. It depends on your status because at first, we should take your data into account, and after this, we will provide you with personal types of treatment, all of them are with guarantee.  If the resources of your ovaries are exhausted, we never tell that we can create healthy embryos from nothing, but I guarantee that at first we always struggle to have good embryos from their eggs.  The only limitation is medical issues if there is a chance to have the embryo from your own eggs. If we’re talking about egg donation, there are no limitations, we are talking about the preparation of the uterus. When it comes to the surrogacy program, for sure, we are talking about a live birth guarantee. You can send me a message, and my team will provide you with full information, there are many packages, and I always insist on making the treatment individualized.

Are donors anonymous in Russia?

In Russia, there are anonymous or non-anonymous donors. In our clinic (ART of Birth), most of the donors are non-anonymous because we have great psychological support. When we’re talking about international patients they are ready to have a meeting with the donors personally. Nowadays, in this lockdown situation, we provide skype or Zoom consultation meetings. We can also provide the pictures of the donors with a portfolio, and if our intended parents want to have some personal information or do a video meeting with the donor for sure, we can provide that.

Do you believe only antibiotics can cure endometriosis in 99% of the cases? Or a new biopsy will be important after treatment? I had Asherman’s syndrome that has been removed, and I got endometritis.

Generally, yes. We should understand that antibiotics are the first-line treatment for endometritis, but it can be caused by infection and talking briefly by endometriosis, so also inflammatory disease but which is active and which is caused by non-infectious issues,  so the treatment should be pathogenic.  If endometritis is caused by a kind of inflammation, for example,  acute inflammation after pregnancy loss or after some surgical interventions or as a kind of complication of some incident in a gynecological life, our first-line treatment will be hysteroscopy. With approval performance of surgical treatment and after that, we do a  complex therapy, taking into account the histology result and immunohistochemistry investigation.  We need a morphological evaluation to assess the activity process. After that, we provide one of the three algorithms for treating endometriosis. The first line is antibiotics, but sometimes you also make injections to prevent adhesions formations connections or the tissue endometrium. In endometritis cases, it is associated with endometriosis. We should cure, and we should treat the main problem, there is no doubt it is endometriosis. To answer this question, the treatment should be defined by the cause. First, we should understand which is the primary cause of this inflammation, and only after that, we should do the pathogenic treatment. Regarding a new biopsy, it will be reported after treatment. Asherman’s syndrome is the result of chronic endometritis,  this is a severe and very tough connection between layers of the endometrium. At this point, Asherman’s syndrome is one of the most severe situations, and antibiotics aren’t useful because the main thing is that the tissue of the endometrium was so compromised that it is poorly regenerated. In such situations, we usually recommend using means of regenerative medicine, which is called PRP – platelet-rich plasma therapy, it’s safe, and it’s approved with good results. However, regeneration of endometrium, unfortunately, doesn’t work in 100% of cases. If we’re talking about a very long history of Asherman’s syndrome, sometimes we’re talking about several surgical interventions to fix this problem. In these cases, unfortunately, sometimes, even PRP therapy doesn’t work. There are some investigations, some trials investigating stem cell therapy. There is some data about good results, but unfortunately, stem cell therapy at this moment is not approved. It is still considered an experiment. We are waiting for this, and our team is also working on it, but at this time to tell you the truth, we usually don’t use antibiotics in the situation because it’s not an active inflammation, we’re talking about the complications, the result of this inflammation. We usually implement regenerative medicine, but unfortunately, in the toughest cases, we have to talk about a surrogacy program.

What is the name of the test that I could ask my doctor to rule out thrombophilia?

It’s not just one test, there are several lab tests, and I need to know your medical history to provide you with a list that is necessary for you. There are many lab tests, and we need to clarify those according to your medical history.

Do you feel a fresh transfer is better than a frozen transfer? I have had 2 fresh transfer failures, and I have 3 frozen embryos, but I’m concerned that the percentage of success is less with a frozen transfer?

I bet that many patients have the same concerns, but today the truth is that there is nothing to worry about. We expect better outcomes when we’re talking about frozen embryo transfer. I will explain why because when we talk about the fresh transfer is just like an old-school tactic because if we implement preimplantation genetic testing,  we will have delayed embryo transfer.  We cannot just make a fresh cycle.  If we’re talking about severe endometriosis,  we also have to make an embryo transfer, which is delayed. If we’re talking about egg donation usually, I also have to mention your husband, partner’s indication if there are some problems with sperm. As I have told you,  during the recent 3 years, we have implemented widely, like a must for egg donation programs, we also perform preimplantation genetic testing, and we have great results.  The thing is that when we talk about the fresh transfer in an egg donation program, the problem can come from two sides: the endometrium, and we should assess the quality of the endometrium, the pattern of the endometrium, and we should expect the problem from the embryo because if we talk about fresh transfer,  we cannot provide preimplantation genetic testing. Generally, when we are talking about the effectiveness of fresh versus frozen embryo transfer, there is no difference. Sometimes, when we’re talking about the stimulation cycle and frozen embryo transfer, the outcomes will always be better than in the first cycle. When it comes to the egg donation program,  it’s usually no difference, so I  think the problem is certainly not associated with the status that the embryos were frozen and then refrozen.

Do you test for the balance of good and bad bacteria within the uterus at your clinic? Do you believe an incorrect balance can affect fertility? How would you go about fixing a bad balance of this? For example, I have only 2% of the good bacteria and have been told it should be 90%.

This is the question about microbiota in the uterus. It’s very interesting that in the 70s  of the last century, there was an understanding that the uterus is sterile,  so they’re no bacteria inside the uterus.  By this time, just 50 years after that,  we know that there are a lot of bacteria, different types of bacteria like defenders tourists. We usually give them some funny names, but I know that it’s rather new information, and not all physicians trust this data. I was involved in this study, and I know from different sides that we are talking about specific bacteria in most cases, which is called bacterial vaginosis. For sure, we have to exclude this problem because we have a strong correlation between ineffective IVF attempts and that disbalance over microbiota. The thing is that we can’t fix it. Sometimes, it doesn’t take a very long period, for example, 2 or 3 months. It’s because microbiota has an association with the activity of the whole organism. Sometimes, we work also with the intestine, we work with microbiota in different organs,  but it is worth working on it, and we should try to fix it. I cannot provide you with the treatment plan because I don’t know what kind of bad bacteria you have in that 90%, but I expect the so-called conditionally normal bacteria in a more quantity than we expect.  You can send me more information, and I will check if I need some more details. I or my manager will contact you, I  will try to prescribe something if it is possible according to the data.

Do you have experience treating patients with endometriosis with intralipids to reduce inflammation in general before the transfer? I have one embryo already, and the doctor does not believe in 3 months of Lupron and thinks this is harmful to me. But, I have some hope in Intralipids. What else would you recommend?

We do have the practice of intralipids, I want to explain to you that Intralipids are never considered, as the treatment of endometriosis, so I agree with your physician. It’s not any line of treatment for endometriosis. Some years ago, intralipids were considered a method of therapy or immunological conditions. Intralipids are a very difficult medication, and it should be performed only in terms of the hospital. Last year, they were overestimated. However, we have another tool,  it’s like a human immunoglobulin. We usually use a human immunoglobulin G (IgG), and there are different types of it,  depending on the country you’re from. When you have problems with your immune system or recurrent implantation failure in your medical history,  there is a basis for prescribing the human IgG, but the intralipids are out of the recommendations.

Do you think a small size of less than 5 cm fibroid can affect the implantation?

It is an all small size when it’s less than 4 centimetres. The fibroid, which is more than 4 centimetres are considered to be harmful and is considered to be an indication for surgical treatment, so all the fibroid which are more than 4 centimetres are considered to be an indication for surgery, no matter what’s their location and the type of fibroid.  The size more than 4 centimetres, it’s not small, it’s the direct indication for surgery.

I’m 45 and had 9 round own egg / own sperm IVF cycles over the last 7 years with different clinics. All were good embryos, and I only had implantation once, which ended in a missed miscarriage at 10 weeks (age 39). We moved to donor egg / own sperm last year (from a proven 21-year-old egg donor). This resulted in 6 excellent/good quality embryos, which we froze. I have had 5 embryo transfers with these, and still no positive result. We have one DE embryo left (grade AB). Should I have any tests before we transfer this final embryo? In the past, I already had hysteroscopies, laparoscopy, and the ERA test, as well as thrombophilia tests and immune tests (NK cells / TNAlpha, etc.). There were no issues. I had PGS testing on one of our own egg / own sperm IVF rounds. The embryo result was ‘normal’ but this did still not implant.

When we talk about the miscarriage factor at 10 weeks, it’s a very significant point for diagnosis because if this pregnancy stopped at 10 weeks stage, for us,  we need to exclude Antiphospholipid syndrome (APS). If the pregnancy stopped earlier but unfortunately, the diagnosis was verified only at  10 weeks, we should think about genetic problems with genetics in the embryo. If it stopped at 7 weeks, please,  briefly tell me about the quality of the sperm because in those 10 weeks when we’re talking about the good quality of embryos in the egg donation program, there wasn’t preimplantation genetic testing in this egg donation program. For sure, I need all your details from your medical history but talking briefly, I think that it’s very likely that there was a problem with the embryo but after this miscarriage at 10 weeks because you have told me that the embryos stopped at 7 weeks and unfortunately during 3 weeks this embryo with non-viable tissue was in the uterus.  Just imagine that during 3 weeks,  there was the trigger of inflammation. Usually, after the pregnancy loss or interruption of the pregnancy, there is a high chance for chronic endometritis.  At this point, hysteroscopy is just the mode of diagnosis, so for sure we should find the signs of chronic endometritis, but then, we treat them, otherwise, for sure there will be ineffective attempts even when we place aneuploid to the uterus, it doesn’t matter if it was an embryo from your own eggs or egg donation. If you haven’t done preimplantation genetic tests on the last egg donation embryo, do this test. Also, pay more attention to the endometrium, your menstrual period,  menstrual bleeding with your physician. If there is some brownish bleeding because it’s a very significant and very important sign in our clinical practice. Sometimes,  chronic endometritis is under-diagnosed and under-treated.

I’m awaiting the results of PGS for embryos In Ukraine. They guarantee2 embryos for transfer. Would you recommend only 1 embryo for transfer?

Yes, without a doubt, after preimplantation genetic testing, when we have the approval of the embryos, we strongly recommend transferring just 1 embryo.  Remember that we aim to have a healthy baby, and when we have good preparation, and I  believe that you have good preparation, and we place 2 embryos after preimplantation genetic test, we have extremely high chances to obtain multiple pregnancies,  which is associated with elevated risk for both,  the baby and the mother. I strongly recommend doing a selective embryo transfer.

Are high FSH doses bad for egg quality? What does is the most effective? Could an egg resulting from stimulation with too high FSH produce embryos with abnormal chromosomes?

There are limitations, and generally, we shouldn’t use more than 450 IU daily.  It’s a high dose if we use more than this dosage, for sure,  we expect that sometimes we obtain a worse and worse egg quality.  We understand that we use high doses when there are problems, usually, we talk about patients of advanced age or with obesity,  so with severe risk factors for egg quality.  That’s why we don’t have evidence that high doses of more than even 450 will have a bad impact on egg quality, it’s more likely that the reasons we have to administer high doses of stimulation will result in bad quality eggs. Generally,  we never do the administration of more than 450 IU in one day.

Are there any major genetic screening diseases that IPs should consider avoiding when considering surrogates?

Regarding surrogate mothers, according to all the guidelines, even karyotype is not obligatory for screening.  As we have said, there is no genetic connection between the surrogate mother and the baby. That’s why the main aim of screening, which is very large and multifactorial, is not considering genetic issues because there is no connection. There is no basis for hereditary from surrogate mother to the embryo. We are not talking about epigenetics, which is another thing, and epigenetics cannot provide the embryo problems within. There is no genetic connection between the surrogate mother and the embryo.  The genetic screening of a surrogate candidate is usually not applicable because it doesn’t make any sense.  We do a very deep and very accurate genetic screening for egg donors, but doing the same for surrogate mothers doesn’t make sense.

I had immune tests done. My NK cells and other levels cd3, NKD (natural killer cell deficiency), and T-cells (Tregs) are off. I was on hydrocortisone for over a year, and it didn’t change very much at all. What are the chances for a successful ICSI round with the use of intralipids? I have had 5 ICSI rounds, 2 of the attempts didn’t result in viable eggs. My husband had a vasectomy. We did a biopsy test. I have also had ICSI with a sperm donor, and I only got 1st blastocyst ever with the donor sperm. After 1st round of ICSI, I fell pregnant, but I miscarried at 8 weeks. I am 37.

All these figures that you’ve provided are not considered as our indication for hydrocortisone. Especially for such a long period.  We do not think that they will affect the quality of embryos and especially the rate of fertilization. You have already been pregnant, and I think that there can be some problems with egg quality, for example, endometriosis. I do not believe that immunological factors are leading to that quality in your situation, even at your age. I  don’t think that intralipids will make any difference in fertilization rate or blastocyst rate. We should consider and find the real reason for the compromised egg quality. This result should be an indication of the therapy as preparation for ICSI. As well as, assisted reproductive technology cycle, but I don’t recommend to use intralipids. I don’t see any basis to improve the outcome because of the intralipids. There is no correlation and association between intralipids and fertilization rate or blastocyst rate.

Is there a possibility of a successful pregnancy with severe diffuse adenomyosis at your clinic? My myometrium thickness is around 30 mm.

The secret of success in endometriosis is preparation. Sometimes it takes about  3  to 6 months, you don’t have to be in the clinic during this time. However, we do need to stay in touch distantly, it’s extremely important. When we’re treating endometriosis, we need to be patient.  We need to follow the demanded time frames for endometriosis treatment. Especially, when we’re talking about severe adenomyosis.  We have many successful pregnancies, but it’s always a long period of preparation. Our idea is to do one embryo transfer, one successful one. That’s why when we talk about a severe form of endometriosis,  given the specific features of the treatment of endometriosis,  it always takes a long period, but you just have to be patient and prepare properly, and everything will be good.
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Authors
Diana Obidniak, MD

Diana Obidniak, MD

Dr Diana Obidniak, MD is the Head of ART of Birth Clinic in St. Petersburg, Russia. Dr Obidniak is a Fertility Specialist, Affiliated Professor at St. Petersburg State University. She is also a member of the American Society for Reproductive Medicine and the European Society of Human Reproduction and Embryology (ESHRE). She is also a National Representative of Russia at the ESHRE Committee.
Event Moderator
Caroline Kulczycka

Caroline Kulczycka

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