In this webinar, Danny Daphnis, Scientific Director at Mediterranean Fertility Institute, Chania, Greece talked about PGS as an approach for repeated implantation failure (RIF) patients.
IVF is a technique which depends on multi-parameters, we need ovarian stimulation, egg retrieval, embryo culture and embryo transfer, but the most important thing is the actual implantation. It’s possible to deal with poor-quality sperm or poor-quality eggs, it is still possible to create embryos, but it’s impossible to implant them, there is no technology for that. The best embryo needs to be put into a very good, receptive individual.
Repeated Implantation Failure (RIF)
RIF is defined by ESHRE as the absence of pregnancy in the form of a gestational sac after at least 3 embryo transfers with very good quality embryos or blastocysts, or after the transfer of 10 or more embryos in multiple transfers. If you have not got pregnant after this, then you fall into this category. The RIF patients are a challenge for every clinician and embryologist because it’s multifactorial, and depend mostly on embryo quality but also receptiveness of the endometrium.
The selection of the best embryo to transfer is the most difficult task to face. Embryos are chosen according to morphological grading criteria, which can vary, so this morphologic grading criterion is not enough, it’s just looking at how nice an embryo looks like, but we cannot be sure of the actual quality of the embryo. There are a variety of non-invasive methods like time-lapse, morphokinetics, and metabolomic studies, and all these have tried to assess embryo quality, but we’re still not able to find the best quality embryo to transfer.
Doctor Daphnis explained that PGT-A (Preimplantation Genetic Testing for Aneuploidies), previously known as PGS, has enabled chromosomal analysis before embryo transfer. Many studies have demonstrated that aneuploidy (the presence of chromosome abnormalities) is one of the most reasons why IVF fails, and by using PGT-A we can select chromosomally healthy embryos.
PGT-A was originally made and invented to detect specific chromosome abnormalities like cystic fibrosis, myotonic dystrophy and even BRCA genes, but lately, it has found a way in trying to select the best embryos, which are chromosomally normal that, in turn, could reduce implantation failure and increase IVF chances and increase the chances of a healthy baby.
PGT-A – the procedure
How are the samples obtained? There are 3 different types, there is a polar body (PB) biopsy, which is when you look at the mature egg and it’s like a very small ball outside the egg, it’s the less invasive of all, however, it only provides information about the maternal genetic material and not what happens after fertilization. Then, there is the cleavage stage biopsy, which takes place on day 3 of embryo development (the embryo is between 6 and 8 cells), 1 or 2 cells are removed and sent for genetic analysis. It has been found that during that time, there is an increased likelihood of mosaicism. All studies with the PGT-A and the genetic analysis of embryos showed that not all the cells in an embryo are of the same chromosome content. That means you might have a normal cell and an abnormal cell within the same embryo. When that happens, such an embryo is called a mosaic because they have 2 different chromosome lines.
The third method is a blastocyst (trophectoderm – TE) biopsy. It takes place on day 5 of embryo development, when the embryos have more cells (150 to 200 cells). The advantages are that you take more cells so you reduce the level of mosaicism, and also the cells are taken from the trophectoderm, which is the part that’s going to give rise to the placenta, it’s not the part that’s going to give rise to the actual embryo, therefore, the embryo is not touched. Lately, everyone is turning to blastocyst biopsy rather than the other 2 biopsies.
PGT-A & RIF (Recurrent Implantation Failure)
Chromosome abnormalities do contribute to women who are not abhorrently able to have implantation, so these are ladies who have good quality embryos, but they don’t have a pregnancy regardless of maternal age.
One study performed in 2005 aimed to evaluate the role of PGT-A for women over 40 with RIF and women between 41-44. They tried to find out how helpful PGT-A is with repeated implantation failures. They separated the patients into 2 different groups, and it did show that in patients where PGT-A was performed, and they had repeated implantation failure, they had a higher live birth, however, they did mention that’s not statistically significant.
In science language that means that maybe PGT-A is not helpful, however in real life that means that maybe 1,2 or 10 women did get pregnant because they did PGT-A because they were able to have some good quality embryos, so we shouldn’t say that because it’s not statistically significant that is wrong.
Another study performed in 2014 tried to find the clinical pregnancy rate after transferring just 1 euploid embryo, which means chromosomally normal blastocyst after aCGH in young patients with RIF. There were 3 different categories of patients with repeated implantation failure that did PGT-A, patients with RIF who did not do PGT-A and patients that did not have repeated implantation failure. It turned out that 68.3% of the patients had PGT-A and had been diagnosed with repeated implantation failure, compared to the 22% of patients who had been diagnosed with repeated pregnancy rate but did not do PGT-A and had the clinical pregnancy rate.
PGT-A was able to distinguish better quality embryos, and they did find that if you do PGT-A if you are a repeated implantation failure patient or if not, then you get a higher percentage, and you get better quality embryos. It showed that if you are one of these patients, then maybe PGT-A can help you and increase your chances of getting pregnant.
- patients with repeated implantation failure (RIF) are very distressed, they don’t know what to do but even the scientists and the clinicians opposite them don’t know what to do, so it’s a very difficult group of patients need to be taken care of and we need to treat them accordingly
- chromosomal abnormalities are the most significant cause of implantation failure
- although not all repeated implantation failures cases are due to embryonic defects, the ones that are problematic PGT-A can help them because many patients have different chromosomal abnormalities and the extension of these anomalies increases with the number of previous IVF cycles