Free IVF Magazine 2022.
Download and read articles by top IVF experts worldwide.
Download and read articles by top IVF experts worldwide.
Esther Marbán, MD
Gynecologist & Fertility Specialist at Clinica Tambre, Clinica Tambre
Category:
Advanced Maternal Age, Embryo Transfer, Genetics PGS / PGT-A
During this webinar, Dr Esther Marbán, Gynaecologist & Fertility Specialist at Clinica Tambre, Madrid, explained what freeze all strategy mean, what’s the evidence behind it, and when it’s indicated.
Dr Marban started her presentation with the definition of the freeze-all strategy, where all the viable embryos obtained after ovarian stimulation are cryopreserved. The embryo transfer takes place in a different cycle after ovarian stimulation. It means that the patient will undergo the ovarian stimulation first, and the embryo transfer will be done in a different cycle, which can be postponed for 1 month or even more. The improvement of the vitrification technique has been crucial to making this a daily practice in many IVF laboratories all over the world, since it increases the survival rates and permits a similar implantation rate compared to fresh embryo transfer.
Dr Marban, later on, explained how the IVF procedure is conducted and described the embryo freezing protocol. We need to stimulate the patient’s ovaries that stimulation normally lasts for 10 days, during this stimulation, we perform several ultrasounds and some hormonal tests to check how the ovaries are responding. Then we do the egg retrieval in which we take the eggs from the ovaries, fertilize those with the partner’s sperm or sperm donor sample and wait for 5 days, in a normal protocol embryo transfer takes place 5 days late of egg retrieval. However, in many patients, we recommend freezing all the embryos, the embryo transfer doesn’t take place at that moment, and it can be delayed until it takes place in a different cycle. How does it work?
Embryo vitrification is an ultra-fast freezing technique in which the presence of high concentrations of cryoprotective molecules and very rapid cooling is required. Through this technique, the dehydration of the cell is promoted to avoid the formation of ice crystals inside the cells, which could damage the internal structures and cause cell death.
Why and when is a freeze all recommended? One of the most important causes is ovarian hyperstimulation syndrome (OHHS). It’s a complication in assistive reproductive techniques due to an excessive ovarian response to the stimulation that may threaten the patient’s life. There are 2 types of OHHS:
The risk factors for OHHS are PCOS, low BMI, high ovarian response to stimulation, and high estradiol levels on the trigger’s injection day. Because of that, patients that are at a high risk of developing that syndrome are good candidates to freeze their embryos to avoid that syndrome. The OHHS syndrome could be mild, moderate or severe depending on the symptoms and blood alterations.
In patients that suffer from a mild OHHS syndrome, they may have a quite bloated belly, there may also be some kind of abdominal pain, and normally it could be an increase in them in the waist size. The blood parameters are fine, so we don’t find many alterations in the blood, but they can also have a more important syndrome-like moderate or also severe one.
In patients who have moderate syndrome we could also find some alterations in the blood tests, such as a tendency to have clots in the blood, some patients might have difficulties in breathing, and on the ultrasound, we may see that there is liquid inside the patient’s belly, so we see quite a high amount of liquid surrounding the ovaries and also the uterus. Fortunately, it’s not very frequent to have patients affected by a severe ovarian hyperstimulation syndrome because nowadays, according to our protocols and thanks to the vitrification technique, there is a minimum risk of having a complication. We prefer to freeze all the embryos and do the embryo transfer afterwards than risking and doing the embryo transfer knowing that, in the future, the patient may have this problem.
Another example of why and when we should freeze all embryos is in patients who are undergoing pre-implantation genetic screening (PGT-A). When we want to test the embryos for several reasons, such as genetic illnesses that should be discarded in the embryos, also potential alterations in the karyotype that we want to be discarded in the embryos. In general, all patients undergoing PGT-A need to freeze their embryos. The main reason is that apart from doing the stimulation of the ovaries and undergoing the treatment as a normal patient, we need to test the embryos, so we need to do a biopsy of the embryos. We normally fix the cells and send those cells to the genetic laboratory. We get the results in around 10 days, and depending on them, we can move forward with the embryo transfer. It’s quite normal to have all the embryos frozen to have time to receive the report from the geneticists, and with the results after that, if we have healthy embryos, we can move forward for the next embryo transfer as usual.
Another reason to freeze all the embryos is when we find a patient who has high serum progesterone levels on the trigger day. We know that having an increase in the progesterone on the day when we are using the trigger injection or also on the day when the patient is starting the progesterone intake could also be an issue in terms of implantation. We know that certain progesterone levels are related to a lower implantation rate, so it means that when a patient is undergoing ovarian stimulation and if we find high progesterone serum levels it is highly recommended to freeze all the embryos to have good chances of having an ongoing pregnancy afterwards.
The patients who are undergoing dual stimulation should also freeze their embryos. Dual stimulation is a different stimulation in which we stimulate the ovaries in 2 different moments of the cycle. The first stimulation will take place with the menstruation, as usual, so we will stimulate the ovaries as we normally do, we do the egg retrieval, and then 5 days after, it’s possible to restart a new stimulation. The dual stimulation aims to get a higher number of eggs in 2 different moments of the cycle. The dual stimulation is specially indicated in patients undergoing PGT-A in terms of having a higher number of embryos to be tested in a shorter period.
Any problem that may affect the uterus in terms of affecting the uterine cavity will also play a role in implantation, and for those patients, we should at least offer them the chance to freeze all the embryos. Sometimes, when we are stimulating the ovaries, we may find a polyp inside the uterus or some causal fibroids and some other alterations, such as thin endometrium or some issues in the endometrium. If that happens, it’s recommended to freeze all the embryos in terms of having a good chance of implantation afterwards. If we see a polyp while we are doing the stimulation, it’s possible to end the stimulation, retrieve the eggs, and keep the embryos in the laboratory. Then have the chance of undergoing a hysteroscopy to remove the polyp.
The same happens with the hydrosalpinx, which is an alteration in the fallopian tubes where those tubes would have some liquid inside them. It’s not so infrequent to start a stimulation without having any kind of notice about that problem, and then during the stimulation, we can see that there could be some liquid inside the tubes. If that happens, the liquid could be toxic for the eventual embryos we are transferring. Because of that, we prefer to freeze the embryos, do the surgery to try to remove the tubes to avoid any unnecessary risk and then move forward with the next embryo transfer.
The last indication for freezing all the embryos could be adenomyosis, which is a kind of endometriosis in which the uterus is highly affected. In many patients who suffer from that kind of issue, it’s highly recommended to do the stimulation, then keep the embryos and use a special medication to try to down-regulate the hormones, in terms of trying to deactivate the adenomyosis a bit and increase the chances of implantation. Therefore, we recommend freezing the embryos and then waiting for 2 or 3 months and increasing the chance of using some medication to try to lower the chances of having very active adenomyosis, which could also decrease the implantation rate in the end.
Due to the good vitrification technique, we know that the survival rate of the embryos is high, which is also important to consider. Because of that, we prefer not to take any unnecessary risk in terms of moving forward with the fresh embryo transfer because we know that we have the chance of doing frozen embryo transfer with good results.
There have been many papers that have shown that the results are good, and because of that, it’s something that we also should consider.
A freeze-all strategy is currently an option in patients at higher risk of worse outcomes after IVF (risk of OHHS syndrome, endometrial issues, etc.) and those who undergo PGT-A. The improvement in the vitrification technique has been crucial to obtaining good results afterwards. In general, there are no differences in the obstetric outcomes between fresh and frozen embryo transfer cycles, so it’s a daily practice nowadays to perform frozen embryo transfers.
We consider high progesterone levels over 1 ng/ml because then we know that the implantation rates could be reduced, and that is the reason for freezing the embryos.
First, it’s important to exclude potential factors that could play a role in terms of the endometrium. Sometimes it could be infections inside the uterus, also patients that have undergone previous surgeries on the uterus could have issues with the lining. Therefore, so start by trying to improve the results, increase the estradiol doses, and if it doesn’t work, we normally recommend doing hysteroscopy or a 3D scan to check if there is something wrong inside the uterus at that moment. We can exclude any kind of problems inside the uterus, and it’s also recommended to perform some tests to discard potential infections inside the uterus.
Sometimes, it’s difficult to make the endometrial lining to be thicker, many patients could also be good candidates in terms of trying to change the preparation we normally do. We normally use oestrogens, but some patients can do a natural cycle, and it can work quite well, in some others, we can use gonadotropins similar to the ones that we use to stimulate the ovaries but in a lower dose to get 1 or 2 follicles and for them to grow properly. We need to add aspirin, a low dose of vitamin E, and sometimes, also some kind of medication that can improve the blood flow in the uterus. It can be very difficult to have a good endometrium even when we do our best, but sometimes it’s a matter of finding the main cause and then finding the best way to prepare the uterus for this particular patient.
I would suggest having those embryos tested first. Seven blastocysts are great, I would propose performing the test on the embryos as you are 43, the potential chances of having a healthy embryo for transfer is around 12%. It means that 1 of all those 7 blastocysts could be healthy, or more, but in the end, I would recommend at least defrosting the embryos, doing the biopsy and then freezing them again to get the results from the geneticists in terms of having a better chance of implantation. You can keep on trying several times.
If the embryos have good quality, it’s possible to do it. It’s not the ideal situation, but in terms of implantation rate, in terms of chances, and of course, in terms of time to pregnancy, we can do it. If the embryos are of good quality, they can tolerate the procedure of defrosting, then doing the biopsy and freezing them again, of course, it also depends on the quality of the embryo, as I mentioned, it’s really important to classify the embryos properly. First, we need to classify the embryos, and then, as I mentioned, it’s possible, although it’s not the ideal situation, we can do it.
I’m afraid there isn’t, I mean, it’s impossible to know exactly when the ovulation may happen. We normally use a special medication to make the ovulation happen at a specific moment, but it’s impossible to exactly know when the egg will go out from the ovaries and will be taken by the fallopian tubes. We go directly to the ovaries, take the eggs, fertilize the eggs, everything that should happen in the fallopian tube will happen in the laboratory, and then we put the embryo back. I’m afraid there is no new technique that could do that.
As I mentioned, the highest production level should be 1 ng/ml, the main reason is that it has been proven that when progesterone is over that level, the chances of implantation are reduced. In the past, we didn’t measure that, and we didn’t know that it was important, now we are completely conscious of that, and we always measure it.
The moment it should be measured is the day when the trigger happens, so it’s normally 2 days before the egg retrieval takes place. If the embryo transfer takes place in the blastocyst stage, it would be 1 week before the embryo transfer. Generally, we test progesterone and estradiol, at least at Clinica Tambre, at the beginning of the treatment and then when we are doing the trigger injection. There are many studies that I can give you, but it’s quite easy to find online, you’ll find more than 10 or 20 papers.
Sometimes, it can be detected with a normal scan that can be performed at a consultation, or through hysteroscopy. We may perform a hysteroscopy for a different reason, and we find small implants of endometriosis inside the uterus. The most common situation is that we do a 3D scan, and we can see that as a small implant of implants of adenomyosis. When there is mild adenomyosis, we can also see the muscle of the uterus that is quite thick, and because of that, the uterine cavity could be reduced. It’s not only having potential adenomyosis but it’s also related to the place where we are leaving the embryo.
It has to be big enough to accept that embryo, and because of the adenomyosis, if the uterine and the muscle are thick, sometimes the uterine cavity could be quite reduced as well. Therefore, we should consider doing surgery to try to widen that cavity. Normally it can be detected with a vaginal scan, a normal one.
I’m afraid, they don’t. EMMA/ ALICE will give you the information in terms of potential infections inside the uterus and what we call the microbiome, which is the good bacteria that should be inside the uterus. However, they don’t detect potential adenomyosis, so sometimes, as I mentioned, it’s a matter of doing a special scan or a normal scan. If the patient suffers from endometriosis, we should consider that the endometriosis is affecting the uterus.
We recommend dual stimulation in patients with low ovarian reserve because we don’t expect a high number of embryos at the end of the protocol. It’s highly recommended in patients that for any different reason may expect a low number of embryos at the end of a day of the stimulation. Indeed, the luteal phase works more or less the same as the initial phase, but we have many patients that obtain better results in a luteal phase. In the end, it’s a different way to stimulate the ovaries in a different moment of the cycle, and we don’t know the main reason, but in the end, what we see is that some patients obtain a better and higher number of eggs in the luteal phase than in the previous one.
We are quite used to doing that stimulation to our patients, and we are happy with the results. If the ovarian reserve is really low, we wouldn’t expect a complete change, but in the end, we can retrieve a higher number of eggs and potential embryos in a shorter period, which is also important for our patients.
No, it just starts 5 days after the retrieval, so if the egg retrieval takes place, let’s say today, which is Tuesday, the dual stimulation and the second stimulation should start on Sunday, which is 5 days later. Then 3 days after, the ovarian stimulation happens.
It’s not only a matter of being 44 or 40 years old, the main risk is related to the quality of the embryos. If the patient is 44 years old, but the embryo has a good quality and the chances of having a good survival rate are high. Apart from the quality, it also depends on the laboratory expertise, and how the stimulation went, so it’s not only a matter of age. We should consider the quality, how the laboratory works, its protocols and so on, but in general, the quality of the embryo is most important.
Salpingectomy is a technique to remove the tubes, and salpingotomy is a different technique where we do like a small hole in the tubes to avoid the liquid to spread out. Currently, all the protocols say that it’s much better to remove the tubes to get rid of the problem, otherwise, if we make a small hole in the tube, the liquid can go back again, and in the end, we’ll be starting from the beginning. If the patient doesn’t have a very high risk of undergoing surgery, we prefer to do a laparoscopy and have the chance of removing the tubes.
It depends on the patient, if we are talking about patients that want to get pregnant in a short period, I would suggest freezing embryos rather than eggs. The main reason is that eggs are more fragile because they are just one call, and the vitrification could also do more damage. In terms of implantation, it’s better to freeze the embryos, as they may have a higher survival rate.
If we are talking about a patient who doesn’t want to get pregnant, we recommend freezing eggs without any doubt. For patients undergoing fertility treatment because they want to get pregnant at this moment, we recommend freezing the embryos because the chances and the results are much better.
If someone has 10 healthy embryos, it could be great, but of course, I’m the gynaecologist, and we are always in touch with our laboratory staff, who classify the embryos based on their development into the blastocyst stage. Since the eggs are fertilized, the embryologists check the embryos. When we talk about quality, we talk about the potential the embryos may have, how regular the cells are, how are the cells divided, and when they reach the blastocyst stage, we classify the embryos depending on how the blastocyst expanded. The more expanded blastocyst, the better quality.
Apart from that, we also classify how the inner cell mass is, The embryologists give us some advice in terms of classification and let us know which embryo should be the first to be transferred. They also give us a list of embryos to be transferred from the first one, and so on.
If the embryo is of good quality 1, it can tolerate the biopsy procedure, but it’s indeed an invasive technique, and in the end, it also has its risks, so it’s not possible to guarantee 100% that the embryo won’t be damaged. If the embryo is of good quality, the chances of having good chances of tolerating that procedure are quite high. The embryologist will tell you if that embryo is suitable to be tested or not if the quality is not high.
Here, there is a different factor which is shipping the embryos, so if that transportation is done, for example, in the same city, it’s quite a safe procedure, but if the oocytes have to go from the UK, let’s say Denmark, the risk will be higher. If it’s from Europe to the U.S., there is a risk, that something can happen during the shipping of the embryos or the eggs. Then it could be an issue because if the temperature suddenly rises or if there is any kind of problem with the transportation, it can also affect the quality and the survival rate.
I would suggest moving forward with the fresh embryo transfer. I think we are not adding any benefit of freezing the embryos unless you want to have the embryos genetically tested, so I would recommend doing a fresh embryo transfer without freezing the embryos because we are not adding any benefits to the treatment.
Mosaics are embryos that, after being tested, have some normal and some altered depending on the chromosomes affected and also depending on the number of cells affected by alteration. On many occasions, we can also transfer those embryos, having some alterations in the external part of the embryo doesn’t mean that the embryo is also impacted. Many babies were born after being mosaic embryos, and it seems that the inner cell mass keeps the healthy cells and pushes the non-healthy cells to be in the placenta, and the end, ends in a healthy baby, and they don’t need to be part of the baby itself.
We find the mosaics while we are testing the embryos, but if the chromosomes impacted are not high-risk chromosomes such as sex chromosomes, chromosome number 21, 13 or even chromosome number 18, we move forward with the embryo transfer with good expectations.
When we do the PGT test on the embryos, we are not thinking about the mosaics, we are thinking about the potential of aneuploid embryos, so not healthy ones. Many patients are quite concerned about the potential risk of doing the transfer with an altered embryo that may be affected by many genetic problems, but many of them can be transferred. The risk is there, but we know that this is not related to age, so it doesn’t matter if you are 40 years old or 30 years old, the mosaic rate is the same. It’s not the same with the non-healthy embryos, in the aneuploid embryos, the rate increases as the patient gets older.
Normally, it takes 3 weeks between when the menstruation comes and the embryo transfer, but not all patients indeed are the same. The idea is that we need to check the uterine lining, it takes 10 days to 2 weeks to have the endometrium ready, and then depending on the embryos, we may decide when to do the transfer. If the embryo is 3 days old and is not a blastocyst, we need 3 days of progesterone, however, if the embryo is a blastocyst, we need 5 days, so it will be also added to the other day that we were doing the endometrial preparation.
It’s also important to consider if the patient has undergone any kind of tests to have more information about the window of implantation. The day of the embryo transfer could be changed, so we might need to add some more hours of progesterone, or we should remove some more hours of progesterone, it could also be related to the result of the test. Some patients undergo a standard protocol, but on many occasions, we have to change it.
Normally, it starts after 5 days, but it’s true that at that moment, what we find in ultrasound is the corpus luteum from the previous cycle. We see a Haemorrhagic ovarian cyst (HOC) from the previous egg retrieval. Sometimes, it’s really difficult to see small follicles, but in patients that we know are undergoing dual stimulation, we try not to do the egg retrieval from the smallest follicles so that we can let them grow in the next stimulation. We do a scan 5 days after the stimulation, and then, if it’s possible, we do a new stimulation. Sometimes, it’s not possible to start in some situations, but in general, if we see that the ovaries are doing fine, we can start. At the same time, the small follicles grow during the dual stimulation the big ones that are like the rest of the other pregnancy start decreasing in size, it’s quite normal for us to see that.
It’s quite likely that your embryo transfer takes place between a day 19 and 21, which is like 3 weeks after your period start, so it’s quite likely that it happens at that moment. The ERA test will give you information about the window of implantation, so we are not talking about lining, we are talking about the genetic expression of your endometrium related to implantation, but normally the embryo transfer takes place 3 weeks after the menstruation.
If you decide to do the ERA test in a cycle with an artificial cycle, you should do the embryo transfer the same way. The same happens with the natural cycle, so if a patient wants to undergo a natural cycle, do the ERA test as the results are related to how the preparation took place, it’s really important to follow the same protocol that the patient followed to do the mock cycle for the ERA. Not necessarily it has to be done with medications, it can be also done with a natural cycle.
The embryologists may have more information about the embryos, when we are using the time-lapse device, we have the chance of knowing more about the embryos, so they can classify embryos that maybe were not classified as good quality, seeing when the cells are dividing, they know how the cells are doing every day as the embryos are in the lab.
Not all of them, what we know is that they’re like different waves of follicular growth. In the past, we thought that the follicles don’t grow after the proliferative phase, and now there are different waves of follicular growing, so in the end, it means that some follicles will die for sure but not all of them. If the follicles have not been pre-selected because they are not reacting to the medication, they will be there, and they can be selected afterwards.
The quality is the same because blastocyst 5AA is the top quality blastocyst, but the implantation rate is higher in a patient that is 30 years old. The embryo in a patient that is 30 years old is stronger, and it has a higher chance of implantation. Apart from the quality, the potential rate of embryo implantation will be higher in a younger patient.
After doing the retrieval, the patient should wait until the period comes, so at that moment, they can start the preparation, the mock cycle to prepare for the ERA test and then what the laboratory suggests is that the closest to the embryo transfer, the better. The results are indeed quite reliable, even after 1 year of having done the biopsy, but if the patient is planning the embryo transfer, let’s say in December, I would suggest doing the ERA test in October or November, not before because the results will be more reliable.
Disclaimer:
Informations published on myIVFanswers.com are provided for informational purposes only; they are not intended to treat, diagnose or prevent any disease including infertility treatment. Services provided by myIVFanswers.com are not intended to replace a one-on-one relationship with a qualified health care professional and are not intended as medical advice. MyIVFanswers.com recommend discussing IVF treatment options with an infertility specialist.
Contact details: The European Fertility Society C.I.C., 2 Lambseth Street, Eye, England, IP23 7AGAnalytical cookies are used to understand how visitors interact with the website. These cookies help provide information on metrics the number of visitors, bounce rate, traffic source, etc.
Cookie | Duration | Description |
---|---|---|
_ga | 2 years | This cookie is installed by Google Analytics. The cookie is used to calculate visitor, session, campaign data and keep track of site usage for the site's analytics report. The cookies store information anonymously and assign a randomly generated number to identify unique visitors. |
_gat_UA-38575237-21 | 1 minute | No description |
_gid | 1 day | This cookie is installed by Google Analytics. The cookie is used to store information of how visitors use a website and helps in creating an analytics report of how the website is doing. The data collected including the number visitors, the source where they have come from, and the pages visted in an anonymous form. |
Necessary cookies are absolutely essential for the website to function properly. This category only includes cookies that ensures basic functionalities and security features of the website. These cookies do not store any personal information.
Any cookies that may not be particularly necessary for the website to function and is used specifically to collect user personal data via analytics, ads, other embedded contents are termed as non-necessary cookies. It is mandatory to procure user consent prior to running these cookies on your website.
Other uncategorized cookies are those that are being analyzed and have not been classified into a category as yet.
Cookie | Duration | Description |
---|---|---|
_gat_FSQM52 | 1 minute | No description |
cf_ob_info | No description | |
cf_use_ob | No description |