By fertility experts from Spain.
In this webinar, Dr Diana Obidniak, Head of ART of Birth Clinic in St. Petersburg, in Russia, talked about recurrent implantation failure (RIF), its causes, diagnosis, and available treatment options that she believes can help all those suffering from it. In 2012, Dr Obidniak started her more in-depth study on recurrent implantation failure.
‘I faced so many patients with ineffective IVF attempts that I dedicated all my time, energy and inspiration to create approved practical guidelines. 9 years later, my team has 4 international awards from the American Society of Reproductive Medicine, 2 patents for invention and viable protocol’.
Dr Obidniak started by explaining how the implantation process works and why it is so crucial. The very beginning of your pregnancy starts with implantation. It is the process of a delicate interaction between an embryo and the endometrium. It was 9 years ago, it was discovered that ‘cumulus cells, microenvironment and various growth factors play an important role contributing or hindering successful mediation’. Before this data, all the investigators, physicians worldwide knew that there were just two players: the embryo and the endometrium.
Now, we know that there are much more players involved, Dr Diana explains that concomitant pathology also plays a great role in contributing to the pregnancy or hindering the risk of miscarriage or ineffective implantation.
Dr Obidniak emphasized that it is common for the aneuploidy rate to be high in human beings. Even at a very young age, half of the embryos are abnormal. Dr Obidniak shared a slide from Excemed Congres held in 2017, where the topic discussed was: ‘The prevalence of aneuploidy and the morphological evaluation of embryos’.
The embryos are called excellent, good, average or poor quality embryos according to their morphological appearance. Even among the excellent quality embryos, just 56% of them are normal and close to 45% are abnormal with either single or double or complex aneuploidy. All abnormal embryos are not recommended for embryo transfer. If an abnormal embryo is transferred, there are 3 possible outcomes.
The first one, there will be no pregnancy. Another one can be even worse, for example, the fetus starts to develop, but it has to be interrupted because of some medical indications, sometimes the pregnancy stops itself when there are some genetic abnormalities in the embryo. What can be done in such a situation? Dr Obidniak assures that Pre-Implantation Genetic Testing (PGT-A) has to be recommended. It’s a very safe procedure, and it is performed in 90% of the cases at the Art of Birth Clinic. Several years ago, all the fertility specialists considered that pre-implantation genetic testing shouldn’t be recommended in egg donation programs because egg donation gives good results. Egg donors are young and screened, unfortunately, it doesn’t guarantee good fertilization results and embryo development.
Dr Obidniak presented a trial called: ‘Major factors involving an implantation rate of PGT-A euploid embryos in egg donation program over 35 years old’. The investigators compared two groups. In group A, there were 182 egg donation programs with PGT-A, in group B, 58 without PGT-A. Even though these groups are not similar, we have enough programs to evaluate, and we can rely on this result. In group A, the implantation rate was 46%, which’s not that high, taking into account that it’s an egg donation program, but in group B the investigators demonstrated a 20% of implantation rate. That shows that when we implement pre-implantation genetic testing, even in egg donation programs, we get better results, we see a double elevation of implantation rate, that’s why in Art of Birth Clinic, we recommend pre-implantation genetic testing. It is only not recommended when there is a very young woman. Usually, it’s close to 90%.
Dr Obidniak also added that sperm morphology should not be omitted, the male factor plays a great role in this process as well. Another trial was to evaluate the impact of sperm morphology on aneuploidy rates in oocyte programs. According to the data, diminished sperm quality is correlated with the aneuploidy rate in pre-implantation embryos. That’s why even when we perform an egg donation program, and we have major defects in sperm, we always have to recommend pre-implantation genetic testing to select the good embryo and prevent implantation of an abnormal embryo.
Unfortunately, we still are unable to fix the genetic problems in embryos. All we can do is select a good embryo that can turn into a pregnancy and a healthy baby. There are several ways to select the perfect embryo. The first line is the so-called embryoscopic time-lapse cultivation of embryos, it’s a specific incubator where we don’t have to take the embryo outside this incubator to assess its morphology. Nowadays, we can observe embryo development without causing any risk to it.
Nowadays, the endometrium is a microenvironment, it plays a great role as a biosensor of embryo quality. Naturally, all women can assess the embryo inside. If the embryo is good, all the capabilities of a woman are inclined to make successful implantation. However, if the embryo in natural life is abnormal, endometrium prevents implantation of such an embryo. In a normal situation, receptivity and selectivity create inferential balance. Unfortunately, when we have some functional or morphological alterations of the endometrium, its function also suffers. If we have elevated receptivity and diminished selectivity, it results in recurrent pregnancy loss. A woman accepts all the embryos she produces, even if the embryo is abnormal, but the pregnancy has a bad prognosis and usually stops developing. On the other hand, if selectivity is too elevated, receptivity is diminished, and then we see recurrent implantation failure or infertility.
What are those morphological endometrium alterations? The main endometrium alterations were considered to be morphological, and we discussed chronic endometritis, hyperplastic process and intrauterine synechia.
‘Chronic endometritis is a condition involving the breakdown of the peaceful coexistence 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.’
When the patient is suffering from chronic endometritis, inflammation in the endometrium doesn’t cause any pain or elevated temperature. General inflammation in the body is not absorbed, but we see that as a chronic process. Usually, there are some morphological changes, for example, micro polyps or synechia. They will notice that their menstrual bleeding quality changes, for example, the bleeding becomes more brownish, that the bleeding lasts longer than usually those 3-4 days and the last days are not that intensive, but it is more brownish.
In the general population, chronic endometritis can be found in approximately 10%, but if we look at more difficult cases, for example, with several failed IVF attempts, we will see that chronic endometritis is present in 30%. If we look at recurrent implantation failure with good quality of transferred embryos, chronic endometritis will be identified in 60% of cases. In a group with recurrent pregnancy loss, we observe chronic endometritis in most patients in 66%. Therefore, the treatment plan should include a diagnosis of chronic endometritis. If we verify it, we should treat chronic endometritis and prepare endometrium properly.
Nowadays, we understand that the uterus is not sterile at all, and we have a lot of microorganisms, we have a normal microbiome and abnormal ones inside the uterus. The uterine microbiota plays a great role because your uterus is like your apartment for your pregnancy. Embryos prefer good conditions from the first day, that’s why if they don’t find the good condition inside, they will never implant. We divide all the microorganisms into residents, tourists and invaders. Invaders are the riskiest group, we have a lot of trials concerning microbiome in recurrent pregnancy loss and repeated implantation failure. There are a lot of papers concerning uterine microbiota which are rather difficult to understand. There are a lot of microorganisms, but normally we have so-called lactobacillus dominant. If the microbiome consists of lactobacillus dominant, there are good conditions for implantation. Sometimes, specifically in inflammation, we have another microorganism that prevails, and the implantation doesn’t occur.
On the other hand, we have functional alterations, so-called compromised window implantation. In natural life, the embryo development and the receptivity of endometrium are synchronized, that’s why if the processes of embryo development and reaching maximal endometrial receptivity are de-synchronized, we will never obtain a pregnancy. Therefore, we now have 2 tests which are called ERA tests and the BeReady test. Both of them use the same technology, they give us their personalized perfect time for embryo transfer, and it results in a great outcome. Both of those tests have very similar results, and we use and implement them in our practice.
On the slide, there are three groups where they compare frozen embryo transfer with fresh embryo transfer and so-called personalized embryo transfer. The number of embryo transfers was 1.7, so sometimes they transferred two embryos, sometimes one embryo, but they tried to transfer just one embryo. CPR means clinical pregnancy rate per embryo transfer, we see that when the team of investigators implemented frozen embryo transfer, the result was 61%, fresh embryo transfer 60%, but when they use personalized embryo transfer, the CPR ( clinical pregnancy rate) was 85%, which is a great result. Dr Obidinak said that her team was the first team who started this personalized embryo transfer in Russia because we work with the most difficult cases, and so far, we had an impressive outcome.
The first patient had eight embryo transfers with PGT-A done at different clinics, but the couple never had a positive pregnancy test, and we just performed one test, and then we performed embryo transfer which resulted in pregnancy, and the pregnancy went very well with no complications, no risks and great delivery with a healthy boy. Then we had 10 or 11 cases ending in positive results, that’s why it’s our routine practice nowadays, and we use personalized embryo transfer very often.
On the analysis report of the BeReady test, we see this scale of receptivity, and the normal rate is 100 points. If we have more than 100 points, as in the first picture, we can see that this is a post-receptive endometrium, so we should perform the embryo transfer a bit earlier. If we have less than 100 points, we consider that endometrium is pre receptive, so we should perform the embryo transfer later than it was.
When we talk about recurrent implantation failure, we cannot avoid talking about hereditary thrombophilia. When the study started in 2006, there was a reflection that hereditary thrombophilia always results in recurrent implantation failure or problems with pregnancy. Everybody thought that two or more thrombophilia factors affect it. In 2012, we had more information, and then we understood that if there is just one isolated factor, for example, antibodies for just one factor, it doesn’t affect it, and it doesn’t provide any clue to perform a treatment. We now know that only factor V, MTHFR homozygous mutation impacts the outcome, all others are not that significant.
Antiphospholipid syndrome (APS) is one of the difficult conditions, but it’s a rather rare situation. According to a systematic review of 29 studies that included more than 5000 patients, we know that APS increased a three-fold risk of implantation failure. The good news is that we know how to treat it and prevent these bad outcomes. The idea is to verify the right diagnosis because sometimes we observe a diagnosis of APS. After all, there are very strict instructions and indications to verify APS syndrome. We have to make several tests, not just one positive test of antibodies, but we have to repeat this test because sometimes they give us false-positive results. At this time, we fix APS, we can fix complications associated with APS in most cases, but sometimes we see that we have to neglect this diagnosis, and additional diagnostic tests are required to make sure there is no APS syndrome.
Unverified celiac disease and autoimmune thyroiditis also play a great role in implantation failure. That’s why we collaborate with a specialist in endocrinology and dietology. Most of our patients have at least one or two consultations with the dietician because it’s important to have a healthy diet. When it comes to food, our habits are associated with the microbiome, and the microbiome can create a complication in our health.
According to our algorithm after embryo transfer, we always perform screening tests on TSH to control the function of our thyroid because there is strong evidence that after embryo transfer when we have implantation, we see that the thyroid function alters, and it lasts just for a very short period, but it can result in a so-called biochemical pregnancy. This alteration, in theory, results in miscarriage at a very early stage. That is the reason we have implemented screening tests on TSH on the 2nd or 3rd day after the embryo transfer so we can control it, and if there are high levels of TSH, we fix it and prescribe additional medication.
More and more trials and investigations are focusing on trying to enhance the quality of oocytes. Unfortunately, science doesn’t provide technology that can increase the quality of the oocyte. We know that time in the reproductive area is crucial.
Several years ago, nobody took DNA fragmentation seriously because there were different assessment methods and the results of these methods were very different, and they didn’t correlate with each other. We know now that DNA fermentation is strongly associated with recurrent pregnancy loss. The key factor contributing to this unbelievable outcome is the elevated DNA fragmentation in sperm.
The first case is one of Dr Obidniak’s favourite, where she had a patient who was 39-years-old, and she already had eight embryo transfers in different clinics, all with PGT-A, and she never had a positive outcome. We performed a hysteroscopy, she had a very severe form of endometriosis, so we had a long period of conservative treatment of endometriosis, and Dr Obidiniak insisted on trying a natural pregnancy, and she asked the couple to give her 3 months, and it resulted in a pregnancy. Non-invasive prenatal tests (NIPT)was performed as she was 39- years old, so we took into account the elevated risk of genetic disorders in embryos, but non-invasive test described that everything is well and we had good delivery. Sometimes the problem is very tiny, and we do not need to do a lot of work, we just need to find the problem and fix it, and sometimes we don’t even need to perform IVF. Still, it’s a rare situation.
Another case report is a patient who was 41, she had 27 embryo transfers. She had severe endometriosis and chronic endometritis with severe activity and even autoimmune components. She had multiple recommendations for egg donation and surrogacy programs, and she even tried egg donation, but there was no result, and she came to us with no hope. She just wanted to try everything. We did stimulation with own eggs program following PGT-A, then we did hysteroscopy where we removed lots of micro polyps. Then there was a conservative treatment of chronic endometritis and frozen embryo transfer in natural cycle with PRP therapy. The result was the clinical pregnancy and delivery of a healthy boy on the second attempt. In 2020, we did another embryo transfer, it was her 29th attempt, and it was also successful, and she now has a baby girl.
A successful implantation rate in surrogacy when embryo transfer is already approved is close to 80-85% per one embryo transfer. Unfortunately, we still don’t know everything, but we expect a very high per cent of success. It’s one of the programs where we guarantee pregnancy in 3 attempts no matter what. There’s a very small chance that something goes wrong, and implementation will not occur.
Yes, unfortunately. Even with such a great success rate as we have in our clinic, it’s still not 100%, it’s more likely to be positive than negative. Even 10 years ago or in some clinics nowadays, the success rate is just around 30-40%, so it’s more likely to be negative than positive, it’s not normal in 2021. IVF clinic should provide not less than 65% success. It’s not possible to guarantee a good result on the first attempt, but we have lots of chances and opportunities to help you from the first attempt, and we aim to perform one embryo transfer and have one healthy baby.
We can verify and confirm chronic endometritis with the immunohistological examination, it’s not just a biopsy of the endometrium, we should always examine it properly. We have the scale that helps with assessing chronic endometritis. It tells us if it’s an active form of chronic endometritis or ongoing chronic endometritis. Depending on the type of chronic endometritis, we have different algorithms of treatment.
If the inflammation is very active, we have to use antibiotics. If we’re talking about chronic endometritis, which is present for many years, we usually do not observe intensive activity, so antibiotics won’t help but harm. That’s why we usually implement PRP (platelet-rich plasma) therapy as a tool of the regenerative method to recover the endometrium.
When we will have stronger evidence on the microbiome, I’m sure that it will be the key solution in this situation.
We diminish inflammation with anti-inflammation therapy antibiotics, and sometimes we even do some injections. If it’s a long-existing inflammation, we usually do not see any active microorganisms, and that’s why we should fix the outcome of this inflammation, synechia, polyps, fibroids. There is no room for antibiotics in this situation. We treat chronic endometritis individually for each type of it. It’s the only accurate method.
Our recommendation is to do hysteroscopy before the previous cycle or two cycles before you’re planning embryo transfer. This is the gold standard of assessment of endometrium. Unfortunately, ultrasound diagnostic doesn’t provide 100% objectivity and sensitivity, and we have so-called blind places in the uterus which cannot be investigated by routine ultrasound. That’s why we should perform hysteroscopy and prepare your uterus.
When you’ll be preparing for embryo transfer, you will have menstrual bleeding, it’s one of the stages of preparation for embryo transfer. You will notice the difference between the quality of menstrual bleeding you had and the quality of menstrual bleeding you will have after hysteroscopy. My recommendation, without a doubt, is to do a hysteroscopy, a biopsy of the endometrium, even if your physician says that everything is good, you should confirm it.
Even if you have a micro polyp that doesn’t do any harm to your organism, it will diminish your chances of a successful embryo transfer.
We should also take into account the quality of sperm because if there are some defects, it’s better to do pre-implantation genetic testing, even if you have good quality embryos. When we have created good conditions, there is a very tiny difference between the success rate when we transfer two embryos or one embryo. The difference is just several per cent, so my idea is to prepare your uterus properly to investigate the embryos. Given the fact that you’re a very young woman, your husband’s or your partner’s sperm is of good characteristics, I think that you should pay more attention to the endometrium. If you haven’t done a hysteroscopy, I would advise you to do it.
In most cases, even if patients had multiple ineffective attempts, we should go through a specific algorithm such as performing hysteroscopy, paying attention to the endometrium’s microbiome or implantation window, assessing and preparing a good embryo, and everything will be well.
We should understand why at such a young age, we have diminished the quality of eggs. At this point, we should do a blood test on Ca125 to assess if there are some points for endometriosis. Endometritis and endometriosis are different diseases. Endometriosis would affect the quality of eggs. In this situation, I would take a break for about 3-4 months and give your body time to recover before another type of stimulation.
A routine embryo transfer can be performed in a fresh cycle on day-5 after egg retrieval or as a frozen embryo transfer. Nowadays, in most cases, we perform frozen embryo transfers on a specific date. Usually, we do it 5 days after we start to give progesterone, so we do the embryo transfer on the day- or day-6 of progesterone administration.
When they investigated the window of implantation, we got the information that only 65% of women have standardized time frames for the window of implantation. The implantation window is connected to the process of embryo development and reaching maximum receptivity.
In most cases, the implantation window is delayed or can occur earlier than these five days. That’s why when we transfer the embryo inside the uterus, and the endometrium is not ready or is over matured. This connection between embryo and uterus just doesn’t occur properly, and we see no result. The idea is to make the trial preparation cycle, and on the day when we wanted to do embryo transfer, we do a biopsy of your endometrium, we do not perform the embryo transfer on that cycle, but we investigate this sample of the endometrium to assess and detect the perfect time for embryo transfer precisely. In the following cycle, we perform embryo transfer not according to a standardized protocol and not on day-5 but the perfect time for you, and it gives a great result. It’s one of the instruments which resulted in such a high success rate in clinics.
According to all the international guidelines, the normal range for TSH is 2.5, but some papers demonstrate that it’s better to have it even lower, so we talk about the so-called aim level when it’s better to have a norm of 1.5 to 2. It’s not a problem if TSH is even lower than 1.5, but we start to do a so-called prophylactic dosage when TSH is at 2.5 and higher. There is a risk that it can increase just after the embryo transfer.
I agree with your physician, it’s better to do hysteroscopy to check, and after that assess the condition inside the uterus, we should take tissue samples in any situation because, unfortunately, we cannot assess it during the procedure properly. We should take a sample of the endometrium and assess it in the lab. For sure, I would recommend doing a microbiotic test because otherwise, we will not have a complete understanding of it. Keep in mind that patients with pregnancies, even when we talk about miscarriages, have a better prognosis, than women with no pregnancy at all.
It doesn’t do any harm, but there are no great benefits of IVIG. It gives a very small room for implementation, it can be beneficial in APS syndrome and some very severe autoimmune diseases. However, it doesn’t provide any benefits in routine practice for a recurrent implantation failure.
The thing is that the injection of IVIG should be performed only inside the clinic because one patient from one country told me that she’s ready to do it at home, please don’t do it by yourself, only according to the administration of your physician.
Normally, you should have lactobacillus as a dominant microorganism. In your situation, you have Enterobacteriaceae and Gardnerella vaginalis, for sure, you should treat it and then repeat the test till we have a normal microorganism, which is lactobacillus dominant type of microbiome. I would recommend not to do embryo transfer till you have a good result, it does play a crucial role in our work. It means that there is dysbiosis, abnormal relationships between the concentration of microorganisms. In normal situations, lactobacillus is dominant, but there are plenty of microorganisms. We call it normobiosis when lactobacillus is dominant, we have aerobic or anaerobic dysbiosis dependently on which type of microorganism is dominant. In your situation it is rather a simple type of treatment, you should check it after the treatment to be sure that it is fixed and you have a normal type of microbiome.