In this session, Dr Pavel Otevřel, Head Doctor at Reprofit, Brno, the Czech Republic has been talking about all factors that cause implantation failure and what can be done to get a successful IVF attempt.
Dr Pavel Otevřel started his presentation by explaining what implantation failure is and it’s simply a negative pregnancy test after the embryo transfer. There can also be unexplained or repeated implantation failure when a good quality embryo fails to implant at least 3 times without any reason. It’s a very challenging situation, the implantation is a highly complex process, in literature, you can find the name embryonic maternal crosstalk, and there are a lot of different aspects, and all players need to be involved 100%. Even if one missing aspect could negatively affect the process, and we can see only a very small part of this process, our knowledge is still limited. We can split the problem into 2 parts, the embryo problem and the endometrium or uterus problem.
When we are talking about the embryo, approximately 60-70% of implantation failure has genetic incompetence of the embryo. The other 30-40% respond to the uterine side, such as the window of implantation, uterine cavity issues, thyroid gland issues, infections, microbiome, etc.
The question of the highest importance is: how old was the egg from which the embryo has been created? The age of the egg is the most important thing, and as shown in the diagram, even in the group of young, healthy women, approximately one-quarter of embryos carry some serious genetic issues, and these embryos are not going to implant. As the age increases, this proportion is increasing as well. A typical IVF patient is 39 years old, and implantation failure is approximately 50-50? Therefore, if the issue is more likely on the embryo side, it is recommended to offer PGT-A (Pre-implantation Genetic Testing for aneuploidy).
The idea of genetic testing is to take a few cells from the embryo, it’s mostly done on embryo day 5 or 6, and we investigate those cells and their DNA profile as a representative of a whole embryo. Performance of this method requires a skilled expert, but generally, worldwide, it’s considered to be quite a safe part of the process. Thanks to that, we will obtain information about the embryo.
However, there are some questions regarding this method that we can’t answer for sure, for example, what if we receive a false-positive result? What if the representative lies and shows only part of the truth? What if we did harm the embryo? What if the originally aneuploid embryo was able to heal itself? Therefore, PGT-A is a very good and sophisticated method, and the benefits have been proven in patients in the age group 40 plus and very likely in patients older than 37. It brings fewer futile transfers and fewer miscarriages, and of course, it shortens the time to pregnancy. However, PGT-A is not able to:
The next thing discussed by Dr Otevřel was the investigation that can be done when the reason for implantation failure is connected to another side, either there is a problem with endometrium or other things. This is usually the case where the embryo was genetically tested, and despite this, it didn’t implant.
The first thing that can be looked at is lifestyle changes. For example:
All of those things can negatively affect egg quality. Supplementation of some vitamins can also be quite beneficial. Especially important are:
There is a lot of scientific proof that these 3 substances are useful in the prevention of miscarriage and improving the implantation rate.
After implantation failures, very often it’s recommendable to check the cavity. We can do that through hysteroscopy, and thanks to this method, we can exclude:
Sometimes, laparoscopy can also be recommended. The goal should be to exclude damaged tubes and to remove such tubes because if they’re damaged, and there is fluid in the tube for a long time, the presence of such a chronic inflammation could negatively impact the environment in the cavity, and it could kill the embryo. Some Scandinavian studies showed that the removal of hydrosalpinx could double the chances of successful implantation.
Another thing that can be the reason for failure and is recommended to check is a window of implantation (WOI). Normally, the endometrium needs to be on 5 days (120h) under the influence of progesterone because, in humans, there is no pregnancy without progesterone. It is a very important hormone, but the timing is important as well. The endometrium needs to be ready, and normally, it is ready in 120 hours. The very first contact of the endometrium with progesterone is either through a natural production of progesterone after ovulation, it could also be vaginal progesterone gel, oil, or injection.
After 5 days, the endometrium is on the maximal point of receptivity. Approximately 85% of patients need 120h to prepare for receptivity. However, there is approximately 15% of patients have genetically different timing, it could be between 80-140 hours. This should be checked after at least 2 unexplained implantation failures. The most popular test is called the ERA test (Endometrial receptivity array), which is done in Spain, but it’s quite expensive (1000 EUR). However, there is quite a lot of scientific voice that doubts this test shows the whole truth. Despite that, it looks very promising, this is not the first-choice test.
We have to always exclude infections, but it’s important to note that:
The microbiome plays a more important role than we estimated. Generally, the microbiome in the uterine cavity must be:
Those two tests are not first-choice tests, but should be considered in patients with repeated failures.
As mentioned before, progesterone hormone is essential for successful implantation, and it has to be high enough at the time of implantation and later, not before.
In 2019, HFEA presented a light chart light and put reproductive immunology tests and treatments in the red part as there is still no evidence of their effectiveness of it. This topic is complicated and remains questionable. What can be tested?
- Questions and Answers
From my experience and our approach at our clinic, after the first implantation failure, stay calm. The nature of human reproduction is low implantation. After 2 failed implantations, still, stay calm, it could only be bad luck, trust your specialist. After 3rd implantation failure, it could be the first sign that something is wrong, and it makes sense to consider investigating both the embryo and mother’s side. I can imagine there are couples or people who prefer to do all possible investigations before the first embryo transfer, but from the nature of human reproduction, it is probably wasting time and money.