In this webinar session, our next expert Dr Héctor Izquierdo, Gynaecologist at IVF-Life Group, Alicante, explained the main common causes of implantation failures and possible solutions.
Dr Izquierdo started his presentation by explaining what implantation is, how it works, and how it should work. This is crucial to better understand the main causes of recurrent implantation failures. The causes may be divided into three groups, the causes related to the embryo, the womb or other causes.
The first part of this process begins with transferring an embryo and getting it in the womb in the endometrial lining. Once it’s there, and that happens on day 5 or day 6 of the embryo development, the embryo starts expanding and contracting until it has enough energy to break the capsule, that’s holding it and then starts to wander outside. First, is the trophectoderm, a structure outside the embryo, which is the future placenta, and this structure goes and starts rolling in the lining. At the very beginning, the embryo presents itself to the womb, to the lining and all factors, such as NK cells, lining, blood vessels, arterial, venous, and immune systems, have to communicate with each other. If this communication is taking place appropriately, then the embryo is letting the trophectoderm start digging in the lining. In the end, a whole new structure called the placenta is produced from the embryo, which is going to provide all the blood supply that they need, and from the side of the lining, it is going to nourish the lining that gives a lot of blood to this embryo.
Recurrent Implantation Failure (RIF)
There are two ways to approach Recurrent Implantation Failures (RIF). The first one is that all patients above 40 years old should be treated like patients with repeated implantation failure because the opportunity of producing good quality embryos is much lower than in patients much younger. If the problem is the number of embryos available, we need to try to evaluate these causes of not succeeding from the very beginning. If there are 3 or more good-quality embryos transferred and none succeeded, we call such a situation recurrent implantation failure.
One of the solutions to deal with that is performing IVF with PGT-A, PGT-M or PGT-SR testing. That way we can exclude the embryos that are not genetically healthy and therefore avoid the transfer of unhealthy embryos that won’t implant.
Some data shows that when IVF is performed with PGT-A, in 35 and younger women, the chances of implantation and pregnancy are around 62%. Above 35 and up to 40, those chances reduce dramatically from 62% to 18%. Therefore, if we do the genetic testing on the embryos, we overcome this and will have a much higher rate of implantation.
We shouldn’t forget about the male factor in this matter as well. One of the most important factors is DNA fragmentation. We need to remember that 40% of infertility cases are due to male factors. Sperm is just a genetic career, the rest of the sperm structures are meant to do the fertilization, and the rest stays out, but the DNA is inside the embryo.
Nowadays, there are ways to test and see how many of these sperm that are produced in the sample are DNA fragmented. In case the DNA fragmentation rate is high, we can use some techniques to isolate or take sperm that are DNA fragmented and use them for fertilization via ICSI or any type of treatment.
When we talk about those embryonic factors, there are some other solutions available if you cannot proceed with your eggs due to bad egg quality, and when you cannot produce a healthy blastocyst, there are two possibilities that we can be offered. It is embryo adoption or an egg donation or double donation if needed as well if the sperm quality is also an issue.
One of the things that affect the chances of implantation is the implantation window (WOI). What does it mean? We know that the thing that triggers the moderation of the lining itself is not the beginning of the cycle, but the beginning of the ovulation. The beginning of ovulation is marked by the production of progesterone. The progesterone is what triggers the moderation of the lining itself. If an embryo takes around 5 days to be ready to hatch and wander inside the womb and implant, the lining should be prepared to receive the embryo after 5 days of progesterone. However, some things can happen along the way, sometimes the eggs require a bit more time to get to this blastocyst stage and on day 6, for example, they need more time to get to this moment where they can hatch and implant. That’s why one way to help patients with implantation failures is to do a frozen transfer. It allows us to freeze the embryo and capture the moment when it’s ready to implant, and in the meantime, confirm that your lining is ideally prepared for an embryo transfer after 5 days of progesterone. When you do a frozen transfer, it’s possible to put back the embryo at the perfect moment and make it more likely to implant.
The window of implantation (WOI) is very important and usually happens between days 19 and 21 of the cycle, but it can be normal or displaced. Alterations in the window of implantation can cause implantation failure or early pregnancy loss. There is a test that helps to estimate the best moment for the embryo transfer, it is called the ERA test and ER map test. This test allows us to check the perfect moment to place the embryo, so we can synchronize the embryo transfer and the lining for perfect implantation.
Another crucial part of implantation is immunology. This needs to be balanced, there are some factors in the endometrial lining that allow the implantation to happen. Once the embryo comes inside the womb and is prepared for the implant, some factors called HLA antigens need to be present. Some Natural killer cells have some KIR receptors that allow this embryo to be accepted, and they trigger a chain of changes in the lining that allows the implantation. These immunological factors can be very important and very challenging in terms of implantation. When we look at those immunological factors, we know that the NK cells, TH1, TH2, T17 and T cells (Treg lymphocytes) and B lymphocytes are the most significant in the implantation, and each one of those has importance.
The NK cells are there to work, they check if that structure that’s common to implant is suitable for you, and if they are so, they are triggered before the implantation and allow the embryo to implant. If they are too high in concentration, there can be a problem for the embryo to implant properly. If they are too low, this interaction might not take place, and if it doesn’t, this triggering of the implantation is not going to take place.
The TH1, TH2, and TH17, and these regulatory T cells are immunological cells that need to be seen in combos. TH1 and TH2 together, TH17 and Regulatory T cells together. The TH1 and TH17 are cytotoxic, they are a bit more aggressive. If there is some imbalance between them, there might be some issues for the embryo to implant, the embryo can be rejected.
B lymphocytes are responsible for producing antibodies that are there to protect the womb and the embryo from bacteria to all those things that can create an infection. If they’re too high, it can again cause a problem for embryo implantation. Depending on the issue, there are some suitable therapies for that. If NK cells are too high, intra lipids can be used, and if they are too low, then you will be beneficial with Ovitrel therapy, for example.
KIR-HLAC genotyping determines the compatibility between KIR uterine receptors and the ‘foreign’ HLA-C presented by the embryo. If the HLA and the KIR of the NK cells do not match, then the NK cell is not going to activate itself, which is not going to let the embryo implant. Therefore, if there isn’t an HLA compatibility between donor eggs, own eggs, partner’s sperm or donor’s sperm and the woman who’s taking the embryo, this might reduce the chances of implantation.
The main embryonic causes are aneuploidies and DNA fragmentation which can be solved with the PGT-A or sperm selection techniques, other solutions are sperm donation, egg donation or embryo adoption. The endometrial issues could be associated with a displaced implantation window, the solution for that is performing an ER Map or ERA test and synchronization with a frozen transfer. Immune cell abnormalities can be checked with immunological testing of the lining and immunotherapy. The KIR/HLA incompatibility can be avoided by KIR/HLAC genotyping, and if needed performing an immunomodulatory treatment.