On which day of the cycle is frozen embryo transfer done?

The day of the embryo transfer in the frozen embryo cycle depends a lot on whether you are taking hormones or you are in the natural cycle. The idea is that we need to synchronize the age of the embryo, which is usually frozen on day five with the day of the progesterone because a day five embryo should be transferred on the fifth day of progesterone, so the length of the cycle is not so relevant. You can start the progesterone on days 10, 15, or 16 of your cycle. Usually, once the endometrium has reached the right size in the first phase and then the only thing that we do is that the patients start the progesterone, and we transfer the embryo on day five of progesterone to make sure that there is this synchronization between the endometrium and the embryos.

Basically, the embryo transfer is planned after supplementing the progesterone and after priming the endometrium with estrogen. So basically, I have the estrogen level that has made the endometrium lining thicker and thicker, and then I need progesterone supplementation to help with the implantation potential. Arbitrarily speaking, we say on day 5 we need 5 full days of progesterone supplementation. And then we transfer.

However, if after 1-3 times it’s still didn’t work, then we have to look further. And how do look further into the problem of good embryos not implanting? If there is an issue of the implantation window which could be shifted right or left, we need to address it with a simple test called ‘ERA’ (Endometrial Receptivity Array) where you take a simple biopsy from the lining of the womb in an artificial cycle mimicking exactly as if we are going for an embryo transfer. So we give you estrogen, we give you progesterone for 5 days and then we take a biopsy. Obviously, there is no transfer then. We take a biopsy and it takes roughly two weeks to analyse it. And then it gets me an answer whether 5 days is enough or whether I should give you less or more?

If, for example, it is post receptivity, that means I should give you more. And then, in the actual analysis, I would recommend maybe you need 7 or 8 days of progesterone. Then, in that case, we would be guided by the recommendation and hope for the best – if this is detected. So this is simply the way it works.

The preparation for the frozen embryo transfer starts on the second or the third day of the period. Typically, as I said ,the patient would start taking estrogen tablets on the second or third day. They would continue these tablets for about 12 days, come back to the clinic for a scan to see if the lining has built up and if the lining is ready, then we start the progesterone injections or or pessaries depending on what’s been prescribed and on the sixth day of taking progesterone, the blastocysts will be defrosted and transferred into the uterus via a conventional embryo transfer and of course after the embryo transfer is done the patient will continuously take the estrogen and progesterone that has been prescribed as part of the treatment up to the pregnancy test. Pregnancy test would be done 10 days after the embryo transfer and of course if it’s positive then they continue taking those hormones for a while.

What is the indication for a frozen embryo transfer? This can happen because we have frozen embryos because we have done an initial transfer that hadn’t worked and we have some remaining embryos and we need to do a frozen transfer. If we have ovarian stimulation where the hormones, the progesterone goes quite high which is the case, usually, in the polycystic ovaries syndrome, or, sometimes, during endometriosis – we prefer to freeze all the embryos so that we can reduce the chances of hyperstimulation and then proceed with frozen embryo transfer.

Frozen embryo transfer (FET) is nowadays done thanks to the process of vitrification which is an excellent technique that gives us almost equal chances to fresh transfer. It is quite often used, even in our unit. In some cases, we have even better chances of success with frozen rather than fresh embryo transfer.

Regarding the question on which day of the cycle we can do the frozen transfer. This depends on the way that we prepare the endometrium. Frozen embryo transfer can be performed in a natural cycle, a seminatural cycle, or a medicated cycle. Usually, when it is a medicated cycle, we prefer to give a minimum of 12 days or a maximum of 18 days of estrogen before we start giving progesterone. Then, if we have blastocysts, the embryo transfer happens 5 days after the initiation of progesterone. If we have day 3 embryos, the embryo transfer happens 3 days after the initiation of the progesterone.

In total, the embryo transfer happens about 16-20 days after the beginning of the cycle. But, sometimes, we can prepare the lining of the womb in different ways. Sometimes, we need to give an initial injection which is called GnRH analogues. Then, the whole process may last a bit longer. Generally, the timing depends on what way we prepare the endometrium, whether it is a natural cycle or a medicated cycle.

Embryo transfer is usually performed between days 17 to 21 of the cycle, it depends. In a natural cycle, the body tells us when the best time is for embryo transfer. In an artificial cycle, we can choose the day. It’s better for planning. The most important is the time between the first day of progesterone and the transfer. It is five days and something, usually 120-125 hours after the first intake of progesterone. It is a very important thing. Patients ask me why last time we did the transfer on day 17, and now we the transfer on day 20. What is important here is five days after the start of progesterone.

At this time, the implantation window opens, and the endometrium is able to accept the embryo. If we do it wrong, for example, three days after the start of progesterone or seven days after progesterone, there will be no success. Some patients have an implantation window later or earlier, and it’s a problem. But fortunately, 80% of women have implantation window in good time. So only 20% of women have implantation window in a different time than usual. Then we can test it by biopsy, but it’s invasive and expensive.

We start to follow the natural cycle when we see 17 millimeters of the follicle. We give the patient one injection and 36 hours after this injection we expect the patient to ovulate. This time is considered to be day zero and five days after we are planning the embryo transfer – this is for the natural cycle.

If we prepare the endometrium and suppress the ovulation with hormonal tablets, we start to give the tablets on the second day of the menstruation. The patient takes the tablets for at least 13 days and 13 days after we call her back to check her uterus with an ultrasound, and if needed, with a biochemical test to check if she is ovulating or not. This day is considered as day zero and five days after, we are planning the embryo transfer. It means that this artificial cycle is about 18-19 days until the transfer from the beginning.

The indications for frozen embryo transfer are two things. Until a couple of years before, for all patients, we normally used to consider fresh embryo transfer but, according to some studies, many IVF centers started to quit performing fresh transfers and consider all patients frozen transfer candidates. This is because when you compare fresh to frozen transfer, the frozen transfer was considered to be more successful. But, two or three years after, they saw that there’s no big change, so now we do both.

The only strict indication for the frozen embryo transfer is the hyperstimulation risk. Hyperstimulation risk occurs in patients who have more than 20 eggs collected or with some hormonal levels that signal to us that they are hyperstimulated. Hyperstimulation can manifest in swelling of the ovaries, some fluid accumulation in the lungs and the abdomen. In order to prevent hyperstimulation in those patients, we freeze all embryos and call those patients 1-2 months after for the frozen embryo transfer.

In terms of the day of the cycle, it varies. Again for the frozen cycle, it very much depends on the stage of the frozen embryos. If the embryo was frozen on day 2 or day 3, then that should be taken into consideration. The embryo transfer will be transferred at a different time compared to an embryo that has been frozen on day 5.

Normally, we would give some progesterone, to match the stage of the embryo. So just to make things a little bit clearer. If you are on a medicated cycle, and your lining is fine, it’s ready over 7-8 mm, then you have a day 5 embryo. Then we would start the progesterone. Then after six days of progesterone, we would transfer the embryo. Because that is the time when if you were to conceive naturally, you would have had already 5-6 days of exposure to progesterone. And also, it’s the time when in natural conception, the embryo actually travels from the fallopian tube inside the uterus. It’s very similar to the natural conception of what we do when we transfer a day 5 blastocyst. That’s why probably, it is one of the reasons why the blastocyst transfers are very successful.

If your embryo is a little bit behind so day 2or day 3, then again we will give 3-4 days of progesterone before transferring the embryo. The idea is that the lining, the uterine cavity should be timed and synchronized with the age of your embryo. So that’s the idea behind it.

Regarding the indications for frozen transfer, some patients have frozen embryos transferred because, for example, during the fresh cycle, they have experienced ovarian hyperstimulation syndrome. That is one of the main reasons to freeze embryos because by delaying the pregnancy, we reduce almost to zero the chances of being ill. That is one of the indications. Another indication is if, for example, during the first cycle we discover polyps, which can actually grow during the stimulation. Polyps can affect implantation. Again, in this case, it is good advice to freeze, get rid of the polyp, and then transfer the embryo when the uterine cavity is healthy again. Another reason could be other gynecological problems like hydrosalpinx, which is when the tubes are swollen. And sometimes these tubes become swollen during the stimulation. Again, freezing is recommended.

There’s been also quite a trend in the last few years of actually freezing embryos anyway. Because there’s been some belief that by transferring the embryo in a frozen cycle, you have a little bit more control of the preparation of the endometrium of the environment, and there could be better timing for that. That might increase the chances of becoming pregnant. But there’s been a large study done, multinational studies showing that there is no difference, at least for the general population. Some categories of patients would still benefit from freezing. But the general population wants one benefit. So yes, indications for frozen embryo transfers are mainly the reasons why the embryos were frozen to start with.

So this depends a bit on the type of preparation cycle we are carrying out on the endometrium. And the type of preparation differs; they can be done with a natural cycle or with a medicated cycle. In a natural cycle, we are going to use the follicles growing in our ovaries and this is going to produce progesterone that is going to make the lining grow as well. Then when we think that everything is accurate, we will trigger the ovulation or wait for it after which we will be able to start the transfer which will depend on the day of the ovulation. If we have a day three embryo, three days after the ovulation we will do the embryo transfer, if we have a day five blastocyst, the transfer will take place five days after the ovulation.

On the other hand, if we do a medicated cycle, we would need hormonal treatment to make the endometrium lining grow as the ovaries are not going to work.  When we see that the endometrial lining is correct, we can then start the progesterone and program to have the transfer done 5 days later, 10 days later, or 15 days later. The timings are more flexible in this case because we are not depending on the ovulation of the natural endometrium and this happens normally 3 weeks more or less after starting the menstrual cycle as it will depend on the patient.  In some specific cases, we need to put up some preparation beforehand like agonists to inhibit the ovarian function. All these factors depend on and are specific to the case of a patient.

In general, the transfer is done 3 weeks after the menstruation and normally this process lasts 3 weeks. During the treatment, it’s important to note that patients will need to do some check-ups such as an ultrasound and a blood test. Normally between one and three check-ups just to be sure that everything is correct and ready for embryo transfer.

The exact day of the cycle that we are transferring the embryo is not important because if it is a hormone replacement therapy cycle, we will wait until the endometrium is thick enough, normally over 7 mm, and then we will add the same days of progesterone as the embryo has developed. For example, if we are transferring a blastocyst, we will add 5 days of progesterone so that the endometrium and the embryo will be on the same day of development. If it’s a natural cycle, it happens in the same way: we will wait 5 days for the first day of the progesterone for being developed the same day.