Oocytes vs. Embryos vs. Pregnancy vs. Live birth guarantees
When it comes to infertility treatment, it is generally believed that a personal approach and treatment adjustments are the key to success. How can then guarantees be possible? Is it possible to predict treatment success or a failure already from the beginining? What are the risk factors and how to avoid them? To solve these riddles, we did #IVFWEBINARS with Dr Tomas Frgala [UNICA Clinic] where he tried to explain IVF with Donor Eggs and Guarantees.
Dr Tomas Frgala starts with quite a pessimistic but still realistic remark: unfortunately, not all IVF treatments end with a positive outcome. There are many factors that can negatively influence the results of the procedure. Even though after every cycle doctors do analyse it thoroughly, looking for blanks to fill and improve on, there are cases when patients experience repeated implantation failures or repeated miscarriages. According to dr Frgala, then it is time to consider alternative solutions.
When looking for reasons for repeated implantation failures or miscarriages, doctors always start with the basics. Firstly, they analyse the quality of sperm and egg cells as there is strong evidence that it is the quality of the embryo that influences the success (or failure) of IVF cycle. Supposedly, an embryo carries about 80% of the responsibility. The other 20% includes factors such as the condition of the uterus, endometrial receptivity, hematology, immunology, etc.
In the case of previous attempts without any success or when indications are quite obvious, egg donation is considered. Treatment with donated oocytes is recommended when a woman does not produce her own eggs (either if she does not have her own eggs or suffers from POI – premature ovarian insufficiency) or if the eggs are of poor quality. There are also cases with severe endometriosis or clear genetic recommendation which may lead to the conception of unhealthy embryos. Last but not least, it is the woman’s age – the factor that is the most important when it comes to the good quality eggs from one’s own ovarian reserve.
A woman’s advanced age is generally connected with all the above-mentioned factors. And the habits in society do change. Dr Tomas Frgala recalls the statistics showing that 18 years ago in the Czech Republic the average age of women getting pregnant was around 30. Nowadays it’s over 35 years old. Although women choose to get pregnant later, the evolution doesn’t hold a step here. The egg quality is still the best at 19-30 years of age. Then it starts to drop and around the age of 40, it becomes complicated to get pregnant from a woman’s own eggs.
When a woman is pushed towards the cycle with donated eggs, it is important to consider the basic rules in the country where she plans to undergo the treatment. And the rules might differ from country to country. We should pay attention to the fact who the donors are, how they are selected and matched with a recipient as well as if egg donation is anonymous or not. It is also good to learn the reasons underlying the donors’ decision of donating own eggs. Dr Frgala admits he was quite intrigued and pleasantly surprised by the study conducted by ESHRE (European Society of Human Reproduction and Embryology), issued in 2017, showing that 50% of donors gave pure altruism as the sole and only reason for their decision about donating eggs.
The whole process of egg donation for the recipient is quite simple. It is the donor who goes through a series of check-ups including ultrasounds and applies hormonal injections on a daily basis. Then she undergoes egg retrieval under complete anaesthesia. The retrieved eggs are fertilised with male patient’s sperm and the embryo is cultivated. For the female patient, the whole procedure usually includes one visit to a clinic for the embryo transfer. Patients are often interested in what medications they will have to take in order to prepare the endometrium (the lining of the uterus) for receiving the embryo. Dr Tomas Frgala says these are mainly estrogens (in the first initial two weeks to build up the endometrium) and then progesterone to make the endometrium ready for the embryo. The lining evolvement in the uterine cavity is checked by ultrasounds usually around day 10, 11 or 12 of the estrogen application. Doctors qualify endometrium as optimal when it has acquired a trilaminar or triple-line structure. The ideal endometrial thickness is 7-10 mm.
However, as dr Frgala said before, the most responsibility for the successful embryo transfer is carried by the embryo itself. There are several options when to transfer the embryo – it’s either on day 3 or day 5 of the cultivation. According to what the embryologists claim, up to day 3 it is usually the quality of the egg that is the most decisive and has the largest influence on the development of the embryo. From day 4, the quality of the genome from both the egg and the sperm starts to show. It is usually around day 5 that many of the embryos show their potential and either slow down or stop completely. Dr Tomas Frgala highlights that it is not a mistake to transfer the embryo after 3 days but, at the same time, he admits that a lot more can be learned about the embryos by transferring them on day 5. An embryo in vitro culture is a selection process. One has to remember that each embryo’s progress is evaluated thoroughly and then the decision is taken on which day it is most likely to implant successfully.
Another interesting issue is the number of eggs to retrieve. As dr Tomas Frgala puts it, the process of fertility treatment is complex and at every step, some of the strength in numbers may be lost. Firstly, not all the eggs collected will be mature and suitable for fertilization. Secondly, not all the mature eggs will be successfully fertilised in spite of using ICSI method. Lastly, some embryos will fail to develop correctly during the initial 5-day in vitro cultivation. That’s why it is a priority to start with the sufficient number of eggs that would lead to a promising number of healthy embryos on day 5 – both for the transfer and for cryopreservation.
Dr Frgala admits that the success rates with egg donation are generally quite high. That’s why many IVF clinics nowadays offer guarantees for egg donation treatment. The guarantees have much to do with both previously mentioned statistics and biological processes and the advancements in technology, such as e.g. vitrification. The latter is a modern cryopreservation method that ensures blastocyst survival (with the same unchanged quality) up to 99%.
There are different types of guarantees, such as a guarantee of oocytes or embryos as well as pregnancy or live birth guarantee. As it is the embryo that carries the most responsibility for the success of IVF treatment, dr Tomas Frgala advises seeking for offers with embryo guarantees and not oocytes guarantees. And even more crucial is to look for guarantees with embryos at the blastocyst stage. However, according to dr Frgala, it is best to seek guarantees with clinical pregnancy. The reason is the risk of early miscarriages between weeks 5 and 8 of the pregnancy. Fortunately, in egg donation miscarriage rates are much lower after heartbeat confirmation than in IVF with own eggs.
The novelty are programmes with live birth guarantees. They represent a sort of risk sharing between a clinic and a patient. Patients are refunded part of the money spent if programmes are unsuccessful. Dr Frgala admits that although live birth programmes are quite expensive, they make a lot of sense. They give patients a feeling of security – both in a psychological aspect and a financial one. Generally, guarantees have much to do with giving patients peace of mind, motivation and new hope.
Questions from the event
I would like to know what do you think about giving a Decapeptyl Depot injection in the cycle before the transfer? Is it possible that this injection is responsible for implantation failure?
We stopped using it a long time ago. Actually, even 10 years ago we preferred small doses of Decapeptyl administered daily over that one depot injection. Even though a depot injection represented a strong alternative. But we completely skipped that step in the past 5 years or so. It didn’t seem to have any positive effect on the outcome, it didn’t help us much in planning the cycle. It was not popular with the patients because it was rather expensive. We have tried all the various protocols with a single Decapeptyl shot, with small dose shots, even with the antagonist. But since approximately 5 years ago, we have used the protocol where estrogens doses of 6 millilitres are applied from day 2 of the cycle. This dose in itself has a down regulatory effect on the ovaries so we do not need to worry about the dominant follicle growing and eventually disturbing the preparation of this cycle. I wouldn’t go as far as to say that the injection might be responsible for the failure, I don’t know if there is any data for that. But it’s expensive and we do not use it anymore. There are other alternatives.
I had my first IVF cycle at the age of 34. It is possible that my eggs were poor quality because of endometriosis at this age?
It is really hard to say to what extent endometriosis influences not only the ovarian reserve, the number of the eggs but also the quality of the eggs and eventually, the receptivity of the endometrium. There are some studies and there is some data that suggests that endometriosis has a derogatory effect on many levels. It might be a part of that equation. But I don’t think it’s simply endometriosis. And I don’t think you should give up at this phase, after the first IVF cycle. Maybe there can be some adjustments made to the protocol, like a higher number of eggs that you could use. So I would try again. On the other hand, it is really hard to exclude that. It may play a role but I wouldn’t be able to express that in percentages.
Do you select donor eggs basing on their morphology? Do you rate them? What is your score?
Morphology is the built of the cell and eventually of the embryo as well. It’s pretty much the main factor in evaluating eggs. I have to admit that I’m not quite familiar with details with the scores that embryologists use. I could comment on the scores for the embryos during their development. I know that eggs also have their scores but I couldn’t give you an example or averages. But the answer to that first crucial question is: yes, it’s their morphology. But there are many things that play a role. For example, are they ripe? Is the polar body showing and expressed? Do they have fragmentations? Usually, these are described in great detail in the embryological protocol. Only the ripe eggs of perfect quality are used for fertilisation in these cycles.
In relation to progesterone, you stated this was used to help the lining become receptive. Do you have tests to ensure receptivity or is it just assumed that the medication will work?
Yes, we basically work with tons of data made available previously. That is actually built on the physiology of the typical run of the menstrual cycle. The implantation window, the phase where the endometrium is perfectly ready, usually comes 5-6 days after the ovulation. It has been tested many times that usually it’s 120 hours of progesterone before the endometrium is just right. Of course, there are still arguments of how wide the implantation window is. Is it one day, two days before the endometrium grows old or overripe? There are some tests but they are quite elaborate and quite expensive. You may have heard about the ERA test or ER (Endometrium Receptivity) Essay that is performed in Valencia in Spain. In that case, the endometrium is prepared just like for the transfer, including the progesterone application, and then, instead of the transfer, a biopsy is performed. In Valencia, they run the analysis of that probe from the endometrium to detect gene activation. As a result, they show whether the lining was receptive or not ready yet. Maybe next time it will need a couple more hours of progesterone or a little less. It is still fairly new and it is not an easy test to make. So I have to admit: yes, we actually build on the previous experience and on the data available and accepted all around the world: 120 hours of progesterone prior to the transfer. Of course, there is one experience that is really important: if the patient did have a positive HCG test in one of her previous cycles, we always look at that cycle and the length of the progesterone application prior to that transfer. This might serve us just as well as the ERA test, showing when and whether the endometrium was receptive.
A French gynecologist advised my friend against IVF with egg donation in Ukraine because of the possible bad effects of the Chernobyl disaster on the donors’ health and the possibility that she could have a sick baby. What do you think about that?
That’s the question I do not have a brief and exact answer to, I’m sorry. I do not want to hurt my colleagues in Ukraine suggesting anything directly. Of course, there might be effects but I’m afraid it’s not only over Ukraine. It might be over the whole of Europe from that unfortunate time. I don’t think that anyone will be able to really express that in studies and show whether that is the part of, let’s say, the poorest spermiograms that we have seen in the past couple of years. Or to what extension it is a significant part of that. Honestly, I cannot answer that question. But just as everybody else, I am concerned about the health of us all and our kids. Hopefully, bad experiences like that will be avoided in the future. But I cannot give you any numbers, I’m sorry.
Up to what age are you able to offer a guarantee program? I would like to proceed with own eggs, I am 43.
The guarantee or live birth programme is shaped and started and I believe the age level will be 45. However, the programme is specifically designed for patients with egg donation. In the cycle with your own stimulation, we can try and we can give our best but there’s no guarantee whatsoever. The success rates in the age group between 40 and 45 are very low. I’m very sorry to say that but the success rates are usually between 1 and 3 %. So there’s absolutely no guarantee we can give for stimulation with own eggs. This is the true answer to the question.
What do you think about scratching of endometrium in the cycle before the transfer? Is it possible that natural killers cells are higher because of scratching?
Is it possible? Yes. Is it guaranteed? I don’t think it is. The initial study on a relatively small group of patients was promising. But after that, there were numerous studies that failed to confirm that effect. So I don’t think it hurts, I don’t think it lowers your chances but we don’t believe it’s so effective that we would incorporate it in our protocols. If the patient wants to have that or she has it recommended by her gynaecologist, we’re not against it. But we do not proactively recommend that.
What is the maximum stimulation and the maximum number of oocytes obtained that you recommend?
When we think of the dosage for stimulation, we take many things into account: the estimated ovarian reserve based on anti-mullerian hormone (AMH) levels and antral follicle count (AFC) as well as the age of a patient, her previous experience, etc. There are many studies showing that the maximum initial dose of follicle-stimulating hormone (FSH) applied via injection during the stimulation is 300 units per day. And that if you go any higher, you won’t really increase the chances of the patient for a healthy pregnancy. You might increase the number of eggs obtained or well-dividing embryos but ultimately, the take-home baby rates are the same. By the same token, sometimes we did not achieve the goal with the specific patient and 300 units per day. The number of follicles and eggs was low. Sometimes we do start higher but never over 400 units per day. I don’t think it makes sense to start with 450 or 500 or higher because I do not think it’s going to bring anything else. The maximum number of eggs is quite individual. There are women who, regardless of age, will have only 2 or 3 follicles and eggs. However, in every cycle, there are some who will have 23 or 24. Usually, the optimum number is 10-15 eggs. However, now in the age of cryopreservation, if there’s a risk of hyperstimulation, the embryos can be effectively and safely cryopreserved. The ovaries are left to rest and only when it’s safe, the transfer comes. This, of course, may result in the cryopreservation of 7-11 embryos. This is actually preventing the patient from any future stimulation because she will have enough embryos for all the pregnancies she might wish for. This isn’t strictly divided now but usually, 10-15 oocytes is a sufficient and reasonable number.
How many times is donor donating eggs in her life usually?
Not many of them want to do it repeatedly because it’s not an easy procedure. It’s usually up to 5 times, not more than that. This is also for the donor herself to concern because we cannot be sure what long-term effect it may have on her ovaries. We’re also distinguishing between a donor who has two children and doesn’t plan any further pregnancies and a donor who didn’t have any children yet. But usually, after 5 stimulations, we do not recommend any further ones for her own sake. Besides, donors who want to donate repeatedly are rather rare.
What do you think of PGS? Do you do that at your clinic? Does it have to be done while the embryo is frozen?
It’s a very broad issue and a very interesting topic. It’s shaping up to be a very interesting tool. The recommendations might vary in different clinics, countries and different groups of patients. With own eggs, it’s a tool to select the embryos for the transfer. We do recommend it – some say over 33, other – over 36 years of age. There are some conflicting data and it involves a lot of discussion. Summing up: we say yes to the stimulation with own eggs. In the cycle with egg donation, generally, we don’t recommend it. It’s costly. You would have to freeze the embryos. So yes, we do that at our clinic if the couple wishes so or if it’s necessary. For instance, it is advisable in the situation when there are donated eggs because of an age factor in the woman and a specific genetic problem in the man. Then, of course, it wouldn’t be PGS ( or as it is now called “PGT-A”) but it would be PGT-M for specific diagnosis. We do have that available, too.
About the last question: PGS is not done while the embryo is frozen but the embryos have to be frozen after the biopsy is performed. So on day 5, in well developed embryos, the biopsy is performed, the cells are actually collected and then the embryos have to be cryopreserved. They wait in the cryobank for the outcome of the test which sometimes takes a month or two or a little more. Only when we get the results from the genetic lab, we know which embryos are the healthy ones. Those are then prepared for the transfer.
How does your team match donor to recipient? Would you look at photos of the recipient’s body type and facial structure? Do you consider factors other than hair and eye colour? Dimples and a nice smile are important features?
That’s such a sweet question, my favourite one 🙂 . Since it’s an anonymous process, there are very strict rules and regular checks from the Ministry of Health of the Czech Republic. There are only two people in the whole clinic that have access to the database and to that matching process. I’m not even one of them. What I know is that the head coordinator indeed uses the photos of the recipients, the body type and the facial structure definitely. We always motivate the patients to send some typical photos of the couple, not only of the patient. And it is taken into account. Unfortunately, we are not able to show the photos of the donor to the couple. It has been discussed at length with the lawyers and they said it might represent the intrusion and actually break the anonymity law. What are the factors other than eye and hair colour? Do we consider dimples and a nice smile? Of course, these are very important but I do not think that the genome and genetic predispositions will have a crucial influence on the looks, the visage and the aura the child is going to carry. I think the upbringing and the influence of the mother and the family, both during the uterus phase and after birth, have actually much stronger influence. But we will surely have to look into dimples more 🙂 .