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Elena Santiago, MD
Fertility Specialist at Clinica Tambre, Clinica Tambre
Category:
Embryo Implantation, Embryo Transfer, IVF process
In this webinar session, Dr Elena Santiago, Fertility Specialist at Clinica Tambre, Madrid, explained what tests can be performed and what can be improved to increase the chances of successful embryo transfer.
Dr Elena Santiago started her presentation by explaining what she’d like to discuss during this webinar. She started with the definition of the endometrium. After that, she focused on different types of preparation for fresh embryo transfers and frozen embryo transfers. She finished by explaining the meaning of endometrial tests that can be done to see when it’s indicated or not.
The endometrium is a tissue that we have inside the uterus, it is the innermost layer where the embryo implantation and the fetus development take place. This tissue is special in women’s organisms because it changes depending on the timing of the ovarian cycle. So there are different moments where we get different types of the endometrium, but everything is thought so that we can get pregnant. Due to the ovarian hormones produced during a natural cycle, the endometrium is changing. First, the oestrogens are the highest levels of hormones, and they help the lining to thicken for a potential pregnancy. Afterwards, we also need progesterone, which is produced after ovulation, and this hormone helps supply the lining and stimulates the glands to grow and nourish the early embryo. This is a very important part of a woman’s organism during her fertility treatment. There are different ways in which we can prepare the endometrium for an embryo transfer.
We can prepare the endometrium for a fresh embryo transfer during an IVF and for a frozen embryo transfer, in which there are 2 basic options of preparation. It can be during a substituted cycle with hormonal treatment, or sometimes we can also do a natural modified cycle.
What are the requirements for a fresh embryo transfer to take place?
We shouldn’t proceed with fresh embryo transfer if, for example, we’ve been having loads of follicles growing during the simulations, more than 15 follicles of 16 millimetres on the day of the trigger, it’s better to freeze the embryo and do a transfer later on so that we don’t get that risk of hyperstimulation syndrome.
Also, hormones are going to help us to know if there is an added risk. So not only we are going to see the progesterone levels, but also the estrogen levels. If they are higher than 2,500 or 3000 pg/ml, it means that probably that woman has quite a risk of developing an OHSS syndrome afterwards when she gets pregnant, if the embryo implants.
Finally, we have to check the number of eggs that we retrieved because if we have more than 15 eggs, it’s better to freeze the embryo and go ahead with an embryo transfer at another cycle so that we get rid of the risk of OHSS.
Nowadays, frozen embryo transfers are much more common than fresh embryo transfers. We are using PGT-A testing on the embryos, therefore, we need to freeze the embryos after the biopsy, so that we can wait for the results. There are different ways of preparing the endometrium.
The first option will be with a substituted cycle. It’s the most common preparation used because it’s easier to plan, and we need fewer ultrasounds during the preparation.
We start with the oestrogens’ treatment from the start of a cycle, and this medication can be taken orally, transdermal with patches or creams or even vaginally. How does it work?
If we are using the vaginal progesterone, it’s important that 1-to 2 days before doing the transfer, we check the progesterone levels again to see if they are correct. A lot of patients can get under 10 mg/ml levels of progesterone, which is considered not enough for proper embryo implantation or a developing pregnancy. Therefore, if we don’t have at least 10 ng/ml, we add subcutaneous progesterone to the vaginal one so that we are sure that our levels are going to be correct in a modified cycle.
2. Natural modified cycle
The steps in a natural modified cycle:
The ovaries are also producing the progesterone on their own, so there is no reason to test progesterone levels with this type of protocol.
The pros are that we are going to use less medication, and oestrogens are not needed at this point, therefore, without the oestrogens, we can have fewer side effects.
It also has its cons, we can only use it in women with regular cycles. We are going to have less planification, which means the transfer will need to be scheduled. We also need to do more ultrasounds to follow up on the natural cycle, and there is more probability of cancellation due to spontaneous ovulation.
The endometrial tests are not necessarily done on every patient. It depends on the case, but some options allow us to look at the endometrium a bit more and have more information.
The window of implantation is known as the period when the endometrium has the best conditions for the embryo implantation to occur. We say that the endometrium is receptive at that point. Normally, it lasts for around 3 days only. It should be more or less the same for each woman, but lots of research and lots of DNA testing of the endometrium showed that around 30% of the patients have a different window of implantation. Therefore, they will need to change their preparation protocol.
There are several tests that we can use. One of them is called the ERA test. Another one is called the TIME test. Both of them do the testing of numerous genes to see if the endometrium is at the point when we are doing the biopsy. If it is at the point, that means it is receptive.
We do preparation, no matter what type of protocol we use, but when we are going to do the embryo transfer, we are doing an endometrial biopsy, which is normally done at the consultation. Several days after, we get the results to see if this woman is receptive at that point, or if we need any changes in the protocol of preparations.
What are the indications for these tests?
We can do those tests at the same time as the endometrial biopsy. EMMA, ALICE and META tests are used to look at the microorganisms that we have inside the endometrium. It’s normal to have bacteria over there, but the normal bacteria that we require for implantation to take place and developing pregnancy to take place is called the Lactobacilli species. There are other good bacteria species there, but this is the basic one.
There could be pathogenic deviations in the dominant microbiome. If we don’t have that normal level of Lactobacilli required, the normal is more than 90% of this type of activity, we could have some infertility problems such as implantation failure or miscarriages. We can check this, it’s a DNA study of the bacteria we have inside our endometrium.
On the graph shown, in a patient with ongoing pregnancies, the population of Lactobacilli is completely dominant over the rest of the bacteria. In patients with recurrent miscarriages or implantation failures, there is also that type of bacteria, but other bacteria are coming out as the result of the DNA testing.
It’s not only going to tell us if our microbiome is fine, the same biopsy is going to tell us if there are any pathogens or bad bacteria that could be causing chronic endometritis. This is an infection that could be long term inflammation of the endometrium that doesn’t give any symptoms. If this occurs, we need to start an antibiotic treatment to try to stop the infection or inflammation.
When do we consider that we need to look at the microbiome?
The endometrium is extremely important for fertility treatments. A good endometrium may increase the implantation rates. Apart from the basic examination regarding the lining of the thickness, we also have several endometrial tests that we can do to have much more information rather than only the ultrasound image. The main goal is to improve reproductive outcomes.
It’s not something that needs to be increasing all the time. Normally, it’s something that should be more or less stable from the moment you started the progesterone supplements in 24 hours if you are taking the same medication, it should be stable. We have to take into account where you’ve done the tests because if you do them at a different lab, you can get different results. The evidence says that we have to check blood levels to assume that we are having correct levels for embryo transfer, and therefore, implantation to take place.
If you have less than 10 ng/ml of progesterone level in your blood after at least 24 hours of your treatment, then go ahead and put subcutaneous progesterone. However, normally with that added progesterone to the pessaries, it should be enough. If you have more than 10 ng/ml, it should be enough. You also have to take into account the time you are doing those blood tests, it may vary on the time of the day as well.
There are different types of progesterone. Normally, the subcutaneous ones are daily. It should be 1 or 2 shots per day, depending on the protocol, or if we are adding it up to the vaginal progesterone, normally twice a week. It’s another type of medication, it’s intramuscular progesterone. That’s why the protocol is different, too. At first, intramuscular progesterone is valid, but it is not something we use a lot in Spain. That’s why, I didn’t mention it, but I know that in other countries, such as the US, they use it a lot. You can get very good levels of progesterone with a protocol, even if it is only twice-weekly.
It’s difficult to advise with the information I have here. If the fibroid is not affecting the endometrium, maybe it’s not at a point of the uterus where it could affect the egg retrieval to take place vaginally, and that could happen. If it’s not very big, and it’s intramuscular, that shouldn’t be affecting the chances of implantation. There are too many things that have to be considered in your case. I don’t have all the information to be confident in telling you that it doesn’t affect it.
The endometrium needs to be checked before embryo transfer, that is for sure. It shouldn’t be something that we find afterwards. If you want to be confident about your endometrium, I do advise you to do the tests we were talking about before going for the frozen embryo transfer.
As they are day-3 embryos, normally to have maximum chances per embryo transfer, it is better to put 2 together. It depends on your medical conditions, if you have any problems, your age, this is something to be considered by your doctor because by putting 2, we do increase a bit the risk of twins, and this is something that needs to be considered. In terms of lower chances, it’s better to transfer 2 by 2, and normally protocols will be to go first with the 2 best ones, then decrease all the quality for each embryo transfer. It doesn’t mean that the best ones are going to the implant for sure, and the other ones won’t. It’s a way of selecting embryos in order.
The most effective way is to use Lactobacillus probiotics directly with vaginal pessaries of these probiotics. There are concrete preparations that they sell at the pharmacies or even online. You can get them, sometimes, it’s not a medication itself. It’s better if those probiotics are vaginally rather than orally.
I didn’t mention that because there is not enough evidence to prove that it is going to improve or give better chances of implantation. It’s not something that we normally do. If your gynaecologist suggests using it, just to do something else or something different, it’s not so invasive, so why not try that. For me, it’s much more valid doing the endometrial tests that we’ve talked about because we will have much more information with that rather than scratching.
Taking into the account that if you do an endometrial biopsy, the cycle previous to the endometrial preparation, you are also doing a scratching. It’s absolutely the same. The endometrial biopsy itself is doing a scratching in the endometrium, but I don’t think that this is the reason outcomes may improve after doing the endometrial testing.
Normally, this is the basic treatment, but to thicken the lining in women who don’t respond to this treatment, sometimes we have to use other types of medication such as vitamins, for example, vitamin E, and aspirin. Other times, maybe if the woman has regular cycles, we can use gonadotropins as if we were doing an ovarian stimulation instead of putting oestrogens. There are different options depending on each patient, but let’s say that the basic one is the one that we’ve talked about.
The supplements that increase blood flow to the uterus are vitamin E or aspirin, anti-clotting, let’s say treatments, but it’s not always considered to be useful in every patient. It depends, on each case.
There are lots of cases where recurrent implantation failure is due to the immune system. It doesn’t have to be related to Psoriatic arthritis & Psoriasis by itself. This depends on each case, but normally it’s true that if you have already an autoimmune disease, you can get some other factors going on during the implantation that could be affecting you.
My advice would be, if you have implantation failure in your case, go ahead and have a special consultation with an immunologist, the specialist that will consider all your medical records, see what tests you need to do and see if you need any other medication, add it up to, let’s say the basic protocols that we’ve talked about.
The scientific evidence doesn’t show significant improvement in pregnancy rates. It’s something that we don’t have the experience with because we decided at a point that we are not going to use it as it doesn’t improve the results.
The proper labs that do all these endometrial testing will tell you that the window of implantation is going to be the same for each patient. If it takes a long time from when the test was done until the embryo transfer, let’s say several months or years, the window of implantation can be altered. However, it doesn’t mean that it will change from one cycle to another. It’s true that when we’re doing this type of testing, they recommend doing it in a cycle just before the embryo transfer.
I’m not sure if that would cause non-implantation. All the factors count, but it doesn’t mean that if the medication wasn’t in the fridge, it doesn’t work for sure. Many other factors interfere with the implantation, so I can’t tell you it was the cause.
It all depends on the location of this fibroid. If it is subserosal, it means it is outside the part of the uterus, and these types of fibroid shouldn’t affect the implantation unless there is more than 50% of that fibroid affecting the muscle of the uterus.
I don’t believe that double embryo transfer is going to help you. If you’re having an embryo at the blastocyst stage of good quality, I do recommend doing a single embryo transfer. Double embryo transfer is not going to increase your chances. On the other hand, it will increase the risk of having twins, which can create and increase the risks of other problems. If your doctor suggests IVIG, intralipids or prednisone in your particular case, then go ahead. It’s very difficult to scientifically prove that these work, but if there is any indication, it is better to use them rather than not.
Regarding the ERA/EMMA/ALICE tests, I think that those are easy to perform before the other embryo transfer, I do recommend them as they will give you more information before the transfer.
Normally, age is not something that makes the endometrial preparation more difficult to take place. I don’t think it is something that could affect the endometrium. Menopausal women indeed have less blood flow in the uterus, and it is more difficult, but it is not the cause.
Regarding BMI, it could influence the proper effect of the medication we’re giving, and it may not work as good. The problem appears to impact the implantation rates and developing pregnancy rather than endometrial preparation.
It depends, I don’t know when it could occur. If you have a low level of lactobacillus, it could not only affect the implantation but also can increase the miscarriage rates. It would normally be a miscarriage during the 1st trimester.
When we’re doing the window of implantation check-up, we always need to do a mock cycle. For EMMA/ALICE/META tests, we don’t need a mock cycle if we’re not adding the ERA/TIME tests.
Even if you have premature ovarian insufficiency, it doesn’t mean that your endometrium won’t be well-prepared. If you’re not having regular cycles right now, I recommend going ahead with a substituted cycle, so adding oestrogens from the beginning. It can work the same way even if you’re not having periods.
It’s very difficult to give a percentage as it all depends on the woman’s age, the quality of the embryos etc. However, in general, the embryo and the endometrium are the most important factors.
That is not something that we normally use. I supposed it is another option, but I am not used to doing this type of preparation, so it is hard for me to advise on that.
Let’s say that the preparation will take around 3 weeks in total, but it shouldn’t take more than 4-5 weeks. You can try to add more medication if you see that after 10 days after taking medication, the endometrium is not thick enough, then do another check-up a week after that. If nothing happens, it’s better to cancel it and start over again rather than go for a longer treatment.
I have lots of patients that go straight for IVF without doing IUI, it depends on each case. In my opinion, if you are over 38 and go directly for IVF, you will have a much higher chance of success, rather than doing IUI cycles. The time is crucial, and I also have patients that go straight to egg donation because of age, maybe it is not your case, but I suggest going for IVF directly.
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