In this webinar, Dr Foteini Chouliara, Gynaecologist & Fertility Specialist at Assisting Nature discussed day 3 embryos, and when such sources can be considered for transfer.
Dr Chouliara started by explaining how the embryo develops in nature, as soon as ovulation occurs, the oocyte is released by the ovary and is picked up by the fallopian tube. It’s passively moved towards the uterus, if sperm is there and the conditions are optimal, fertilization occurs. At first, the embryo consists of a single cell called the zygote, and then through a series of divisions, it develops into a two-cell organism, a four-cell organism, an eight-cell organism and so on. As the embryo is passively moved along the fallopian tubes, it will spend a few first days of its life inside the fallopian tube. By day 4-5, the developing embryo enters the uterine cavity, and by day 5, if everything goes well, it will form a blastocyst stage on day 5 to day 6. The embryo will hatch out of its protective layer, called the zona pellucida and start the implantation process.
In the IVF setting, the equivalent event to ovulation is the triggering shot and the oocyte pickup. In IVF, instead of the fallopian tube picking up the oocyte, it’s the fertility specialist that is picking up the oocytes, and then is safely passing over the oocytes to the embryologist, who then fertilizes them and places the fertilized eggs into designed culture media and state-of-the-art incubators to allow the embryos to develop and culture further.
Embryo transfer refers to the process of transferring the cultured embryo into an appropriately prepared and receptive uterus. This can take place at any time after fertilization, it can take place on day 2 up to day 6 of embryonic development, but usually, it takes place either on day 3 or day 5. These days are not picked out randomly, they are special days because the embryo reaches special stages of its development, and it’s also the time when it’s possible to grade the blastocysts.
Day 3, or a cleavage stage embryo, consists of 4 to 8 cells. It’s still enclosed in its protective layer, the zona pellucida, and it uses the energy and the chemical components provided by the egg to reach this stage. A blastocyst consists of a lot more cells, which are organized into the inner cell mass and the trophectoderm. The inner cell mass is a group of cells that are going to give rise to the embryo, and the trophectoderm is the outer layer of cells that is going to give rise to the placenta. Almost all embryos can reach day 3, but only a third or half of the embryos can develop into a blastocyst. This is because blastocyst formation requires genomic activation for further growth and differentiation.
Embryo grading takes place on day 3 and day 5, those embryos that have got the best implantation potential are selected. Day 3 embryo is graded by the number of cells, symmetry, and degree of fragmentation. A very good day 3 embryo is graded 8A. Whereas, in a blastocyst, the embryologists look at the blastocoele degree of expansion. Another important thing is the degree of expansion of the cells, inner cell mass compaction and trophectoderm cell number. A very good quality blastocyst would be 4AA or 5AA, however, it’s significant to remember that the embryos continue to develop, and change. The grading has got its limitations because, at the end of the day, it is based on morphological features, so it can look beautiful, but in reality, it could be chromosomally abnormal.
Nowadays, there is a variety of culture media, and they can emulate in vivo conditions a lot better, and they can accommodate the changing embryonic metabolic and nutritional needs. Culture media can help the embryos to reach the day five stage. At the same time, thanks to the evolution of incubators with separate chambers that could offer more stable conditions as well as time-lapse incubators, which can additionally offer continuous embryo surveillance, there are better laboratory conditions. They improve the embryo traits and can also offer more information to improve embryo grading and the prediction of those embryos that have got better implantation potential, and in the end, improve live birth rates, which is the ultimate goal.
Having all these things in mind, considering when to transfer the embryos having in mind the advantages of highly designed culture media, having very good incubators, and having highly skilled embryologists, it seems best to transfer day 5 embryos. Most studies and reviews have shown that a day 5 embryo transfer is superior to any earlier embryo transfer. It allows for a better selection of viable embryos, which might have looked similar on day 3. It also allows transferring of fewer embryos back into the womb and perform single embryo transfers, therefore, minimizing the risk of higher-order pregnancies and all the obstetrical and neonatal complications that go along with it.
Additionally, by transferring on day 5, there is a better synchronization of the embryos with endometrium and the implantation window, even the uterine contractility is reduced, which allows for the embryos to stay exactly where they’ve been placed. By transferring embryos with higher implantation potential, the implantation rates are increased, which in turn means increased pregnancy rates as well as decreased early pregnancy losses. Another reason to transfer day 5 embryos is transparency.
When we are allowing our embryos to cut to an extended culture when we allow them to grow further and reach day 5, we make sure that we can offer our couple the embryos of the best potential possible. That’s transparency, and at the same time, if the embryos do not reach the blastocyst stage, we avoid any futile and unnecessary embryo transfers, so save our couple from necessary heartache and pain.
It’s also very useful for diagnostic purposes, especially in couples with repeated implantation failures. It is possible to see if the embryos are competent enough to reach the blastocyst stage. If they are not, it helps to explore other therapeutic options sooner and find the reason for the failures. Are there any drawbacks to transferring day 5 embryos? The first one is the fact that there is a higher cancellation rate, and although it helps to avoid unnecessary embryo transfers, it could also have a financial impact on the couple as well as psychological stress that the couple is experiencing. To perform a day 5 embryo, an experienced and skilled embryologist is crucial, as well as extended culture in a state-of-the-art lab.
A day 3 embryo transfer might be a good idea if there are poor laboratory conditions, in such cases, it’s preferable to transfer early even though the embryo is not in the appropriate environment as the day 3 embryo should be still in the fallopian tube, not in the uterus, so it is exposed into a more adverse environment. However, it’s a lot better than leaving the embryo in suboptimal lab conditions and leaving a very good day 3 embryos to waste. Day 3 embryo transfer might also be a good idea for couples with fewer embryos available for transfer. For example, couples who are going through natural cycles, poor responders or advanced maternal age. Leaving such embryos to culture further, there is no additional selection advantage. In these cases, it’s also important to remember that it is usually necessary to transfer 2-3 embryos rather than 1.
Deciding when to transfer is not always a straightforward answer, many factors need to be taken into account like the embryo quality, embryo grading, the embryo quantity, how many embryos are available for transfer, the couple’s particular circumstances like the patient’s age, the couple’s history, the risk of multiple pregnancies and the current lab conditions available. Considering all those factors, an individualized choice needs to be made amongst the couple, the treating physician and the embryologist.- Questions and Answers