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.
The very first step described is implantation, which is characterized as a delicate process of interaction between the embryo and endometrium, yet it was later discovered that cumulative cells and various growth factors also have an important role in contributing to or hindering successful implantation.
Moreover, based on the session, it is important to highlight the main role in the implantation of the embryo, the endometrium, and concomitant pathology.
In the human being species, there is a particular prevalence of aneuploid abnormal embryos. Therefore, even considering the external morphological evaluation of embryos and the PGT-A (pre-implantation genetic testing), in several high-quality embryos, only half will be normal.
It was also mentioned that even in an egg donation program, PGT-A should also be implemented as 30% to 45% of abnormal embryos are present, so it is a must in recurrent implantation failure. Evaluation of sperm morphology is also significant in the examination program.
One of the studies presented in 2019 showed 188 egg donation programs that were performed with PGT-A testing in the 1st group, while in the 2nd group, 58 egg donation cycles were performed without PGT-A. Implantation rates in the first group were 46%, while in group 2nd, it was 20%.
Traditionally, endometrium was considered to be a passive factor that was thought to have nothing to do with implantation. Nonetheless, throughout the investigation, a new era arose in which endometrium is widely considered a microenvironment with a crucial role as a biosensor in embryo quality. A fragile balance is also involved, which involves the receptivity and selectivity of embryos. This balance can be altered by morphology and functional alterations. For instance, speaking of infertility, low receptivity, and high selectivity are commonly associated.
The most common problems associated with endometrium are inflammatory processes, also known as chronic endometritis. It is believed to be difficult to diagnose because of a lack of symptoms apart from subtle changes in menstrual bleeding. Other problems include Hyperplastic processes and Intrauterine synechiae.
A condition involving the breakdown of the peaceful co-existence 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.
Data on chronic endometritis and prevalence reveals significant variations in this data, emphasizing the influence of study groups. In the general population, prevalence is around 10%, but it rises to 28% in unexplained infertility cases and can reach 45.5% in patients with poor prognosis, such as recurrent implantation failure. Recurrent pregnancy loss patients are a key focus group due to the condition’s association with chronic endometritis and is between 60.6%-66%.
Compromised window implantation is at the forefront when we’re talking about functional alternations because the synchronization of the process of embryo development and the maximum endometrial receptivity is necessary. Unfortunately, only 65% of women have a normal implantation window, while another 35% of individuals seem to have a delay in this synchronization.
Nowadays, there are 2 tests available that allow us to investigate the window of implantation, these are the ERA test and the Be Ready test.
Personalized embryo transfer requires attention to detail. We should consider three study groups: one focusing on frozen embryo transfer, the second on fresh embryo transfer, and the third on personalized embryo transfer. Observing the clinical pregnancy rate per embryo transfer, it’s evident that the personalized embryo transfer group exhibits remarkably high rates, reaching 80% and 85.7%. However, within this group, there is a miscarriage rate ranging from 8 to 12%. Despite this, the initial clinical pregnancy rate remains notably high. Unfortunately, at present, we cannot entirely prevent miscarriages. Nonetheless, pre-implantation genetic testing of embryos can help minimize this risk.
Unfortunately, patients experiencing recurrent implantation failure often receive numerous recommendations to consult with specialists such as hematologists and endocrinologists.
The primary concern for patients with recurrent implantation failure is hereditary thrombophilia. Dr Obidniak presented a study from 2006, which indicated that having two or more thrombophilia factors may lead to fertility issues, although it was later (2017) narrowed down to favouring the V mutation, MTHFR homozygous mutation. Additionally, the MTHFR homozygous mutation can also contribute to fertility problems, but it may be treatable.
Various studies show that APS increases the risk of implantation failure threefold. It’s important to emphasize that this data is reliable. Unfortunately, as per Dr Obidniak’s experience, she noticed that the diagnosis of APS is sometimes not verified according to actual guidelines. It’s crucial to understand that evidence-based medicine provides strict indications and criteria for prescribing laboratory tests for APS. Even if there are abnormalities in lab tests, control tests should be done no earlier than 2 weeks after the initial investigation.
The prevalence of celiac disease varies from country to country and is not associated with ethnic differences but with diagnostic guidelines.
The third factor to consider is autoimmune hereditary issues, such as uncompensated problems with the thyroid, ovaries, and uterus. There is a strong immunological association when there are menstrual problems, indicating a high chance of uterine issues. Therefore, screening tests before planning treatment and a few days after embryo transfer are necessary.
In the presence of severe problems, the competence of oocytes, the functional capability of cumulus cells, and the effect of the ovarian stimulation protocol are taken into account, However, the male factor of the DNA fragmentation and genetics disorders of the embryo can also cause fertility difficulties.
Case 1 – a 41-year-old, who had undergone 27 embryo transfers with endometriosis IV and severe activity and autoimmune component, she already had multiple recommendations to proceed with surrogacy.
Her hormonal levels were relatively good for her age, and her ovarian pattern was magnificent. The patient wasn’t ready to pursue the surrogacy route. It was recommended to proceed with IVF with her own eggs and PGT-A program, a new stimulation protocol tailored to her needs—medications she had never used before. Two normal embryos were obtained, and it was necessary to investigate her uterus further.
During hysteroscopy, numerous endometrial polyps were found, some of which were not apparent on ultrasound due to their small size. This underscores the importance of hysteroscopy as the gold standard for diagnosing uterine issues. These polyps were removed, and the implantation window was investigated. Subsequently, a delayed embryo transfer in a natural cycle was performed, considering the results of the implantation window investigation. The patient also had gone through PRP therapy to address the autoimmune component of chronic endometritis.
The result? A clinical pregnancy and the delivery of a healthy boy. Recently, she underwent her 29th embryo transfer and is now pregnant with a girl.- Questions and Answers