How to manage successful embryo transfer after recurrent implantation failure?

Diana Obidniak, MD
Head of ART of Birth Clinic, ART of Birth Clinic

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.

What are the steps after implantation failure? - 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.

Authors
Diana Obidniak, MD

Diana Obidniak, MD

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

Caroline Kulczycka

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

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