In this session, Dr Ksenia Khazhylenko, Obstetrician-gynecologist, Fertility Specialist & Geneticist at IVMED – Fertility Center discussed 1 complex case about a couple with previous IVF failure and diagnosed with recurrent implantation failure. Dr Khazhylenko explained the tests performed and the treatment plan in detail that allowed the couple to achieve a pregnancy and a healthy baby finally.
Dr Khazhylenko started her presentation by emphasizing that the definition of recurrent implantation failure (RIF) is one of the most complicated and most controversial in reproductive medicine because there is no consensus between experts, society, and countries when it comes to defying it. Some consider recurrent implantation failure as some unsuccessful attempt, some that are at least 2 or 3, 4 failed attempts. Many questions arise in regard to embryo quality. Does it mean that the embryo has to be of high-grade morphologically, or does it need to be genetically tested? Should we keep in mind the age of the patient over 40 if it’s genetically tested? Therefore, there are a lot of questions and not as many answers to this.
There are a lot of different situations which cause implantation failure and starting with gamete quality and uterine factors as well as thrombophilia, etc. We need to keep in mind that not all these factors are evidence-based. Some of them are just logical, others are more controversial.
The case presented by Dr Khazhylenko described a case of a young patient who came to the clinic (IVMED) when she was 32 years old. She never got pregnant, and she was diagnosed with unexplained fertility, which means that she didn’t have any problems with ovarian function, fallopian tubes or uterine anatomy, her partner had a normal semen analysis, and they had normal coital frequency.
When she started the treatment, she was 32 years old, so she had a good prognosis. The couple decided to start IVF, and on the first attempt, she got 12 eggs and 5 good quality blastocysts, 1 of them was transferred in a fresh cycle, but she didn’t become pregnant. They tried with the second transfer, and she became pregnant, but she miscarried very early on. After that, the couple decided to genetically test the embryos. Two of the three embryos were euploid, which was a good result. Before the next. transfer, the doctor decided to do a diagnostic hysteroscopy, and it is uterine was normal, and the endometrial biopsy was negative. They also did an endometrial scratch before the transfer, and then 1 one euploid blastocyst was transferred, but she didn’t become pregnant again.
Before transferring another embryo, they did additional tests on thrombophilia, and even though this patient didn’t have any individual or family risk factors, they found prothrombin 2 (an inherited condition that increases your predisposition to develop abnormal blood clots in the veins and lungs), that was the reason for previous failures. They repeated the frozen transfer where they transferred a genetically tested blastocyst, and they prescribed Low-molecular-weight heparin (LMWH) plus aspirin, but the patient didn’t become pregnant. This was their 4th transfer and the last frozen embryo.
Therefore, the couple started their second IVF attempt, but before stimulation, her husband had done a DNA fragmentation test, which was normal. During the egg retrieval, 15 eggs were obtained, 5 blastocysts were biopsied and frozen, and out of 5 embryos, 4 were euploid. Their doctor decided to do additional tests, and they wanted to check the patient’s window of implantation, it turned out that it was displaced, it was 1 day later, which means it was the day after a conventional implantation window. When we take the endometrial biopsy to check the window of implantation, they also studied NK case levels in the endometrium, and it was discovered that they were also elevated in this patient. Therefore, again transfer number 5 was performed with 1 euploid blastocyst was transferred, before the transfer, the patient was prescribed immunoglobulin infusion (IVIG), but the result was also negative.
The 6th frozen transfer was done, again they prescribed immunoglobulin infusion (IVIG), Prednisone was added, taking into the account thrombophilia prothrombin 2 mutation, they also added low-molecular-weight heparin (LMWH) plus aspirin, however, the result was negative.
After this attempt, the couple came to our clinic (IVMED) with their 2 remaining embryos. We summarized all the previous attempts to understand the reasons for the failures.
After reviewing the case, Dr Khazhylenko emphasized that the patient got pregnant after the second transfer, which could mean that she had a prolonged window of implantation. According to Dr Khazhylenko, a patient who previously had a pregnancy after standard transfer could have a normal window of implantation. Regarding the NK cells, it could be a temporary situation. Sometimes, in some patients, high NK cell levels can be just temporary, it doesn’t mean that in the next cycle, the NK cell level will be the same. Another thing is that after the ultrasound, it was found that the patient had adenomyosis, and in this type of situation, estradiol in ART cycles is not recommended because estradiol can increase the development of adenomyosis. Generally, patients with adenomyosis and endometriosis need some pre-treatment before going ahead with embryo transfer. We know that adenomyosis is a very strong inflammatory environment for the embryos during the implantation process, and we know that adenomyosis increases sub-intermediate contractility in the patient, especially after the transfer, and it can cause cavity deformation and the progesterone resistance.
After the reevaluation, the next approach was to use a long preparation with agonist gonadotropin (GnRH) releasing hormone, and Atociban to decrease the sub endometrial contractions, and taking into account possible high NK cells to use intralipid infusions before the embryo transfer, plus additional progesterone for luteal phase support because it’s well known that progesterone can decrease the NK cells levels in a patient with high levels. We also proposed to avoid taking estradiol due to her Prothrombin 2 level mutation. We also wanted to do it in a natural cycle.
The result was finally positive, fortunately, she had an uncomplicated pregnancy, and she gave birth to a baby boy.
Related reading:
I meant it is not a good idea to do PGT-A on frozen embryos because to do the biopsy, we need to thaw them, then do the biopsy and on the same day freeze them again. This is a very stressful procedure, 2 procedures in one day, it needs double precision with thawing, biopsy and freezing the embryo again. It is evidence-based that after this type of biopsy, the embryos are usually quite weak on the next transfer, and we know that the next transfer can be unsuccessful just because of this biopsy.
I don’t know where you are from, but it is a good example. In that case, it would be worth checking the chromosomal status of the embryo, I mean a product of conception. It’s very important because, in the case of NK cells or other immunological parameters, it is very important to analyze the chromosomal status of the embryo. Then we do something to support pregnancy. We have to know that this embryo is healthy because sometimes the reason for miscarriage is different. You can have a high level of NK cells but, still, have a normal pregnancy.
Unfortunately, every next miscarriage increases the risk for another one. I want to help all the patients with a miscarriage. The best thing is possible to try to get another consultation. Look for a second opinion first, and due to the COVID pandemic, online consultations became much easier than two years ago. Maybe you need some online consultation to hear a second opinion about what to do because ten mystery miscarriages are sad enough, and it carries a very high risk for the next. In case of repeated failure despite treatment, there is an additional risk. You should check the endometrium, for example.
Yes, there are a lot of signs of adenomyosis in conventional ultrasound. Conventional ultrasound is the best way to see adenomyosis, and there are different types of adenomyosis. There was one picture with ultrasound signs of adenomyosis. This is a typical sign of focal and dynamic diffuse of adenomyosis, and in this patient, miscarriage is a risk factor. Often these patients have diffuse adenomyosis with high uterine wall thickness, and one wall is thicker than another, but some of them have focal adenomyosis very similar to myoma or fibroids, but they’re different. There are some different ultrasound signs, but it’s well visible in conventional ultrasound.
I didn’t explain all the possible reasons for implantation failure, but hydrosalpinx is one of the most common reasons. There is a lot of evidence that there is an association between hydrosalpinx and implantation failure. The recommendation to do surgery after an IVF failure is logical to me. Sometimes I can do the transfer in patients with hydrosalpinx or even two transfers, firstly explaining the possible problems. Especially, if we have enough good embryos, not one or two. If we have good quality embryos, we can try a first or even second attempt and then go back to hydrosalpinx if these attempts are unsuccessful, but sometimes some patients have successful pregnancies even with this hydrosalpinx. I think two IVF failures is an indication of the surgery.
It is a recommendation of my German colleague who has most publications about intralipids use, and her recommendation is to use 100 or 200 milligrams firstly before transfer – 3-5 days before transfer, but then they recommend repeating this infusion if the pregnancy test is positive. Regarding the history of the patient, sometimes they repeat this infusion every 2 weeks till 10 or 12 weeks of pregnancy, especially in patients who have had a miscarriage before. Sometimes we use intralipid infusion just once – before the transfer, and sometimes we repeat this until the positive test, like in my case today. After getting a positive test, we can do blood tests on intralipid level, and if it becomes normal, we don’t provide the next infusion.
Anti-phospholipid syndrome is one of the main reasons for miscarriage, and the treatment of antiphospholipid syndrome is not just well-known, but also is very effective. It’s known that a patient with antiphospholipid syndrome can have a successful pregnancy and take home a baby without treatment, just in no more than 15-20 per cent of all these cases. But, if you treat them, we can have a successful pregnancy in almost 80 per cent, so it means like in a healthy woman. So, the treatment of antiphospholipid syndrome is using low molecular weight heparin plus aspirin.
We don’t use any hormones, such as Prednisone, we don’t use immunoglobulin infusion, just conventional and quite effective low molecular weight heparin and aspirin. I want to stress that antiphospholipid syndrome means quite strict criteria for this syndrome. It’s not enough if you have a high level of antiphospholipid antibodies one time to make this diagnosis. We need to have a high level of antiphospholipid antibodies twice over at least 12 weeks between the first and the second test, and also it can be positive lupus anticoagulant additionally. So if these criteria are met plus clinical evidence like a repeated miscarriage (two or more miscarriages) occurs, it means you have the syndrome, but if we don’t have the clinical criteria or just weak laboratory results, it may not be antiphospholipid syndrome. It’s very, very important.
In my opinion, a natural cycle for transfer is the best idea. With my patients, I use this type of preparation in 80% of all transfers. It’s a good idea for everything. I just don’t use a natural cycle in patients who never had ovulation. It can be quite difficult to induce, so if the patient has natural ovulation, it’s always a good idea not to use estradiol. Thyroid problems and NK cells level in a natural cycle and artificial cycles will be similar. I only suggested an additional progesterone prescription after the ovulation to decrease these levels but not estradiol.
If you mean fresh cycle, you mean cycle of stimulation, because usually in a stimulated cycle, NK cells level will be generally higher. There is some publication comparing the level of NK cells in endometrium and the blood of a patient in fresh embryo transfer. By fresh, I mean a cycle of stimulation, because cycles with the transfer of frozen embryos in the natural cycle is a frozen transfer in a natural cycle. But fresh transfer means that it’s a stimulated cycle. In this type of cycle, you can transfer the embryo if you have high NK cells. In the stimulated cycle, the NK cells level will be higher.
It’s a difficult question because RIF is difficult not just for young women, but at any age. Usually, young patients have a mostly good prognosis, and when despite the good prognosis, they became RIF patients, it’s very sad. But when we are talking about age, it is mostly a problem for chromosomal pathology. With age, we must take into account a high number of chromosomal pathologies in the embryo. If these embryos are genetically tested, it doesn’t matter what the age of the patient is.
So when it comes to additional tests, you’re right. Sometimes when I get one or two embryos from a 40 plus patient, or even younger patients 30-38, before transferring this embryo, I sit with my patient and explain that we could transfer, and it can be normal and it will be following the protocol. We can transfer in a natural cycle. But if the result will be negative and we won’t have any embryos later, we can be very disappointed. We can think why didn’t we do some additional tests before this transfer. So sometimes if you have a few embryos, I can discuss with patients some additional examination. Sometimes it can be really important, for instance, testing for chronic endometritis if a woman has had a miscarriage or some complicated pregnancy before. Then we plan a transfer of just one embryo she has, so it will be better to do something just to get her some insurance.
It is a difficult question again. Most patients don’t have any immunological reaction to the implantation, they don’t have any signs. Sometimes I can suspect something when the patient, for instance, has some autoimmune condition, autoimmune thyroid or some other general conditions with immune antibodies.
