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.
Embryo freezing protocol
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.
- the embryos remain frozen at minus 196 Celsius degrees in liquid nitrogen until the woman or the couple decides to use them
- the embryos paralyse their physiological activity so that in the future, they can be thawed and can resume all their functions
- the embryo can be in storage for an indefinite time without losing the characteristics it had at the time of verification
- it’s important to classify the embryos before vitrification, it’s crucial to apply the classification criteria correctly to freeze the good quality embryos, otherwise, the chances of having a good survival rate could be decreased
Freeze-all strategy – recommendations
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:
- early OHSS: 3-7 days after the trigger injection
- late OHHS: 12-17 days after the embryo transfer and is induced by the production of endogenous HCG during the pregnancy
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.
- there are no differences in the cumulative live birth rate between fresh and frozen embryo transfer cycles
- there is a potential benefit to the freeze-all strategy on cumulative live birth rate, in specific clinical scenarios, such as high-responders
- there are no differences in the miscarriage rate between fresh and frozen embryo transfer
- there are no differences in the risk of delivery before 37 weeks of gestation (preterm delivery) among pregnancies resulting from freeze-all compared to fresh embryo transfer cycles meta-analysis
- no differences have been reported between freeze-all and the fresh embryo transfer strategies regarding other pregnancy outcomes, such as gestational diabetes, placenta previa or antepartum haemorrhage, congenital anomalies or perinatal mortality
- women in the freeze-all strategy might have an increased risk of hypertensive disorders during pregnancy, it could be related to the endometrial preparation during the artificial, frozen embryo transfer cycle but, based on the results of the latest studies, it’s unclear whether endometrial preparation is associated with increased risk of hypertensive disorders of pregnancy or whether there could be another explanation
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.