During this webinar session, Dr Tomáš Frgala, PhD, Head Physician at UNICA Clinic – Brno, started with short topics he’s been focusing on during his presentation. Dr Frgala explained the procedure itself and discussed the regimen after transfer. He started with two major characters, the endometrium and the uterine lining, in which we place the embryo and then the embryo itself, where the quality of both plays a crucial role in the process. Later on, he switched his focus to the patient and talked about the holistic approach and what can be done or supported throughout the process to increase the chances.
One of many possible definitions of embryo transfer is the insertion of the selected embryo into the uterine cavity, but what makes it exciting, and kind of stressful, is the fact that this is usually the grand finale of the assisted reproduction treatment. The stimulation of the patient herself, fertilizing her own eggs with the sperm cells of the partner and the embryo transfer, then the following care or a cycle where donated eggs are fertilized. The embryo is transferred into the recipient’s uterus, where we have to prepare the endometrium, the uterine lining to the best of our knowledge or the third category, the frozen embryo transfer. We are not placing the embryo directly into the endometrium, but rather very gently and carefully between two layers of the uterine lining.
The lining that we need to prepare for the embryo, so it has a good chance to go through the implantation process, start the communication with the mother’s organism and then develop further and prosper. Dr Frgala explained that the endometrium has to have a certain character, certain type and a certain height, this goes hand in hand with the natural process throughout the natural cycle when in the first half throughout the proliferative phase where usually the dominant follicle grows, it provides estrogen hormones and under the influence of the estrogen hormones the lining grows. We want it somewhere between 7 and 12 millimetres for the transfer, anything between 7 and 12 millimetres appears to be sufficient, anything between 8 and 10 might be labelled perfect, but it’s individual. Following the ovulation, around the midpoint of the cycle – day 14 where the ovulation happens. Following the ovulation, the follicle rebuilds and the cells of the follicle start to produce a second crucial hormone for the cycle, progesterone.
Under the influence of progesterone, the blood flow in the uterine lining increases, it becomes softer, a little wet, and it becomes perfectly ripe and ready for the embryo to nest. While the first phase and the effect of the oestrogens, the proliferative phase may vary in length, and we can play with it a little. Sometimes, it’s a little shorter than 14 days, sometimes it may be a little longer than that. The second phase, the secretory phase is very sensitive to the timing because following approximately 5 days of progesterone which is the standard, that’s the time when the endometrium is just right or where the implantation window opens up, and the lining is perfectly ready for the embryo.
There are still discussions going on whether that implantation window is quite short 24 hours, 36 hours or whether it’s much wider up to 4 days, we don’t exactly know, it can also vary from patient to patient. Around 2 days should be right, regardless of the procedure undertaken. We always check at least once, usually around the day 10 to 12, if the endometrium is growing, if it has the right structure and if it has the right thickness.
The second major participant and seemingly the most important one is the embryo and its quality. The embryo usually develops for 5 days in the lab, and throughout this embryogenesis, it should actually divide, then compact, and then eventually develop into the blastocyst stage. There are various blastocyst stages, all of them are fine for day-5, an early blastocyst, blastocyst, expanded blastocyst or a hatching blastocyst. There is still a discussion on the point of embryo development, it is perfect for the transfer. Usually, it’s one of the two variants, either day-3 of the development or day-5 of the development.
Nowadays, most clinics move towards day-5 for the embryo transfer, at Unica, we do the same thing because we feel that way we can learn a lot more about the embryo until day-3 at least, that’s what one of the embryological hypotheses says, the embryo develops mainly from whatever the egg brings to the cooperation. From day-4, it’s about the quality of the genome from both gametes, from both sides, that starts to show. Also, that’s the phase where many embryos stop their development. We feel that if we transfer on day-5, we give a chance to the truly viable embryos, that’s the time we pick for transfer and cryopreservation of the other embryos.
It doesn’t mean day-3 embryo transfer would be wrong, but that’s just a clinic preference, and day-5 is our preference and has been for quite a long time. There’s always an argument saying if you insert the embryo on day-3, you’re putting it in the uterine cavity, the best incubator for the embryo there is. However, if you look at it from a different angle, you might say that the embryo, while it develops, is moved through the fallopian tube and enters the uterine cavity towards the end of day-4 or at the beginning of day-5. Somewhere around that time, so around day-3, it’s still in the fallopian tube, it’s not in the uterine cavity. Either way, it’s fine, and the success rates are comparable.
The next thing that Dr Frgala focused on was the preparation of the patient. Dr Frgala emphasized that preparation is not only about the technicalities, such as the quality or height of the endometrium, the quality, and viability of the embryo, and the patient state of body and mind.
This is where it gets tricky, and this is where it gets somewhat difficult sometimes, it’s also individual, it’s different for every patient. Everybody needs something else, some patients prefer their usual regime, they go to work as if nothing serious was going on and then just stop by for the transfer and continue saying, if I focus too much on this, I’m going to go crazy, this did happen to me in the previous cycle I don’t want to think about what’s going on right now.
On the other hand, many patients prefer to slow down a little, take some time off, we try to discuss it with them, support them and offer options that might lead them towards the more holistic approach, such as yoga instructors, acupuncturists, nutrition specialists, there’s a psychologist.
We don’t force these on everybody, but there are options that the patient can choose individually, one or the other or a combination, just to see what works for her best. It’s not just a question of the patient, and all the members of the support team, but also her family, friends. Someone doesn’t like to reveal that much to their surroundings, somebody else likes to share, once again, this is individual, there is no right way to do that. There is no procedure that we would force or could force on anybody, we just need to listen, we need to try to adjust, and as we go, we need to tailor sort of the approach and the whole preparation to the needs of the specific patient. The patient’s coordinator plays a very important role in that, and her physician as well.
One of the most popular approaches as a part of a holistic approach or the methodology is acupuncture. Once again, there is no right way to do that. There is no guideline or regime that we would dictate or even recommend. If I were to pick, I would probably go for at least 1 session a week throughout the transfer cycle and the transfer itself. It’s usually timed around day 20-21 of the cycle, so that gives you 3 sessions, maybe more. We are also able to provide an acupuncturist on the day of transfer at the clinic. The patient can have a 20-minute session immediately before the transfer and then once again immediately after the transfer if she wishes to do so.
Dr Frgala once again reassured that it is about the team effort even though the patient herself plays the major role, she shouldn’t feel that all the responsibility is on her shoulders. Everybody plays a role, and ultimately we always need a little luck, we always need a little help from nature herself.
I just feel heartbroken when the patients ask me what have I done wrong, and maybe I shouldn’t have done this. I always say you have done nothing wrong and nobody else there, maybe the embryos weren’t viable enough, or we just were not lucky enough, but if we keep trying, we usually and a very high percentage of patients persevere and reach the goal.
There are some very interesting technologies as well being used throughout the process. Embryoscope or generally so-called time-lapse technique where the embryos are cultivated individually in wells and each well has a camera, and that camera takes a picture every 10 minutes in infrared light as not to disturb the embryo. These pictures are lined up in the computer, and the embryologist can follow the embryo throughout its whole development without ever having to manipulate it, without ever touching it. There are still discussions going on at the meetings about whether Embryoscope or time-lapse technique is the future of embryo selection or just a luxurious cultivation box. We might not have all the answers just yet, but according to Dr Frgala, even if it is just the luxurious incubation box, let’s go for it, the embryo deserves it, and the embryo appreciates it.
Another thing is PGT-A and PGT-M testing. The pre-implantation genetic testing for aneuploidies previously called genetic screening (PGS). Another test is called PGT-M, the pre-implementation genetic testing for monogenic diseases where there’s a specific problem that we’re looking for. These are also being discussed and argued about. There are situations where they’re very helpful, there are situations where their use might be less important or even questionable. It’s always best to talk to your specialists and get through the consult. It’s important to try to be quite open, even if, in some cases, there are no clear-cut answers yet, but that’s a very interesting direction.
EmbryoGlue is one of the methods that we still collect the data. The studies are still coming in, which are supposed to show whether it has a strong significant effect on the embryo’s chances to nest or if it’s just a marginal method. We’ll see, but it looks promising, it doesn’t hurt. It’s a cultivation medium with growth factors and other goodies for the embryo. It’s cultivated for several minutes, 15-20 minutes before the transfer and then it’s taken with this media and transferred like droplets with microliters of the media into the uterine cavity.
Whenever the transfer is performed under the control of the ultrasound, a patient should come with a full bladder because then it’s easier to see on the ultrasound. Plus, if we look from the side, the uterus kinds of bent forward, in the so-called anteversion, and the bladder is right underneath the body of the uterus. Getting through this curve with the catheter is not always easy, however, with the full bladder, the body of the uterus gets lifted, and the way for the catheter is straight and then makes it easier.
2. The doctor will insert the embryo into your uterus through a soft, thin catheter.
It’s not actually that easy but it’s not that problematic of a procedure, it’s not painful, you don’t need to worry about it, anaesthesia is not necessary. We always perform it under the control or the guidance of the ultrasound and usually in 2 steps to keep it most comfortable and quick for the embryo. At first, we just take the cover of the catheter with a thin probe, and it has a memory effect, so if the uterus is shaped in a let’s say less than the typical way, we can point it in the right direction, watching it on the ultrasound. We go into the right depth, and when everything is set and perfectly ready, only then do we call for the actual soft catheter, and they bring it with the embryo from the lab, and the catheter just slides through that cover into the uterine cavity. The procedure takes just seconds, and it’s comfortable.
Dr Frgala added that it’s better not to use any deodorant or any strong soaps on the day of transfer, it’s only because the embryo is brought in an open catheter, and the molecules of like the strong smell might be a little aggressive to the embryo. There should be no smoking before the transfer but also no intense perfume. After the transfer, you can do anything you want, and it’s not going to have any effect on the embryo anymore, this is only a question of the moment where they bring the embryo in the catheter.
This could be a whole lecture and a very interesting topic, but the short answer to this question is just one. It’s been over 10 years when even the legislature in The Czech Republic was adjusted to motivate the couples to transfer just 1 embryo, the procedures, the success rates have been going up, and what used to be a necessity to put more embryos in to increase to support the chances, it’s just not only not necessary anymore, it becomes irresponsible and risky. Multiple pregnancies carry more risk for the woman, and the babies, who are often born prematurely and stress the whole family. A twin pregnancy should not be the goal of the treatment, specifically not in cycles with egg donation because the success rates there are around 60%, and if you transfer 2 embryos, you increase your chances only very slightly, but the risk of multiple pregnancies is significant, 45% of couples with two embryos used to end up with twins.
The couple does have the right to decide if 1 or 2 embryos are transferred. Unless there’s a contraindication such as a scar on the uterus, for instance, C-section, then 1 embryo is recommended. There are exceptions, when there’s a woman over 40, and she’s doing a cycle with her own eggs, the chances are very low, so sometimes we agree with 2 embryos. In The United States, they still transfer 3 embryos sometimes just to increase the chances in these specific situations, but generally, 1 embryo per transfer should be the decision, and that’s our recommendation.
How long does the actual transfer take? For the embryo, it is just a couple of seconds, for the patient, the physician, a couple of minutes. The complete visit to the clinic, including everything, the preparation, the paperwork, etc., takes about 30 to 60 minutes, and it doesn’t hurt.
After the transfer, we recommend a normal regime, normal activity. Bed rest is not necessary, it’s not forbidden, but studies were showing that the length of bed rest after the transfer does not have any major or any influence at all on the success rates, so it’s not necessary. We recommend taking it a little easy for the 7 days after the transfer and refrain from heavy physical strains, so no heavy lifting, no sports and no sexual intercourse for about 7 days.- Questions and Answers