By fertility experts from Spain.
Find out how to prepare for embryo transfer and learn how important the implantation window is for embryo implantation. Watch the video recording from our webinar with Dr. Roksolana Semchyshyn, Ph.D., M.D., from Intersono Clinic.
In IVF it is widely understood that for successful implantation to occur, a good quality embryo needs to be transferred. Whilst it certainly plays a hugely important role in achieving a pregnancy, embryonic health isn’t the only factor.
In this webinar Dr Roksolana Semchyshyn, a fertility doctor and head of the IVF department at Intersono clinic, Ukraine, explains the importance of a healthy endometrium, outlining the window of implantation and describing what happens after an embryo is transferred.
Before explaining why the uterine lining is so important, Dr Semchyshyn advises that patients need to understand the process of implantation, and how the partnership between the endometrium and the embryo works.
Following the fertilisation procedures of IVF, an embryo is transferred into the female’s uterine cavity. Implantation does not take place immediately and, once in utero, an embryo will start searching for the right place to implant. As it does, it transmits signals which the endometrium reads and then uses to understand whether, or not, the embryo is good enough to implant. However, this all-important communication, between the embryo and the uterine lining, will only take place if the endometrium is healthy and has a normal structure. For any embryos permitted to implant, that usually happens around four to five days after the transfer.
The main function of the endometrium is to provide the most suitable conditions for an embryo to implant. Abnormal inclusions, such as polyps, can be a factor of unsuccessful implantation, as can IVF itself.
Due to the medically induced suppression of the endometrium during the down regulation process, a woman’s body is sometimes unable to read the signals emitting from the embryo. In order to check whether the endometrium is fully healthy to receive the embryo, regular ultrasounds are crucial.
Screening is also imperative to check on the thickness of the uterine lining in advance of the transfer. Dr Semchyshyn advises that an appropriate measurement of the endometrium is essential for increasing the chances of pregnancy. For an embryo to implant properly it needs enough space to embed into the endometrial lining. If this lining is too thin there will be a decreased blood flow to the uterus and the embryo may not be able to implant correctly. On the other hand, if the lining is too thick this could make it more difficult for the embryo, and could also lead to hyperplasia; a continued, abnormal growth of the endometrium.
According to Dr Semchyshyn a lining which measures between 8-14mm is ideal or, when undergoing a cryo (frozen) cycle, from 7mm.
For women who have repeatedly failed to become pregnant, following the transfer of healthy embryos, a hysteroscopy may be recommended. In this procedure a camera is used, in utero, enabling medical teams to see the uterine cavity more clearly than on an ultrasound. Intersono clinic has noticed a higher pregnancy rate in patients who undergo this procedure, however, there is no evidence that it is a benefit for all patients undergoing IVF, and hysteroscopies should not be routinely advised for everyone.
Whether conceiving naturally or by IVF the window of implantation is critical for a successful pregnancy.
Every woman is different but, on average, this window typically takes place around day 20-24 of a woman’s cycle, which is circa 6-8 days after ovulation. It lasts for 48 hours. In IVF, the window of implantation is effectively the timeframe when embryos need to be transferred into the uterus; it’s when the endometrium is at its most responsive.
If IVF with good quality embryos has been unsuccessful then an ERA (Endo Receptive Array) test may be recommended. An ERA is used to detect when the endometrium is at its most receptive.
By conducting this type of biopsy, medical teams are able to look at the genes responsible for implantation, determining when they are at their most active. This will then tell doctors when the transfer should take place.
For a woman to conceive her body needs to be “baby friendly” which, in part, means having good immunological health. Dr Semchyshyn describes the body’s immune system as the “bodyguard of our organisms,” and advises that clinics should run immune testing on female patients who have suffered repeated IVF failure or recurrent miscarriage.
NK (Natural Killer) cells are thought to prevent implantation. These are activated when viruses or bacteria are present in the body’s organisms, rejecting any virally infected cells. When a woman becomes pregnant the pregnancy creates a conflicting situation for the immune system, as the embryo is not natural to the body’s cells. If the immune system doesn’t function properly then these NK cells can become highly aggressive and detrimental to implantation, and /or ongoing foetal development. Immunogram testing can checks for NK levels within the blood or the endometrium cells. The more information medical teams can learn from each patient, the more they can understand whether the immune system is operating correctly. If any immunological issues are discovered, then clinics can surgically treat and / or medicate, which gives any subsequent pregnancies additional help to proceed.
Another immunological factor which can hinder implantation is HLA (Human Leucocyte Antigens). In simple terms, antigens are the surface of the blood cells in the human body. When creating a healthy pregnancy, any offspring need to inherit half of the antigens from the mother and half from the father; both sets need to be different. If the inherited genes are too similar then the mother’s body will not recognise the pregnancy, meaning her immune system is unable to trigger the immunological response which is required to protect and preserve the pregnancy. Dr Semchyshyn explains that, again, clinics can test to determine whether tissue compatibility could be the reason for failed embryo implantation.
Medical teams should also analyse the thyroid gland of patients who are struggling to conceive, even with assisted reproduction techniques. Thyroid glands are usually hidden from the body’s immune system and it’s only when the immune system isn’t working properly, that it starts to notice the thyroid gland and attack it. Or, in the cases of pregnant women; attack the baby. If the correct tests are conducted, then any problems can be diagnosed and treated in advance of the embryo transfer. Once a pregnancy is established, medication can also be administered to provide ongoing prenatal thyroid support.
“Unexplained fertility generally means that the physician failed to find the true cause of infertility” said Dr Norbert Gleicher and Dr Semchyshyn agrees..
Greater reproductive knowledge is continually amassed, and further testing and analysis can now be carried out to help couples find out exactly why they are struggling to conceive. With correct clinical procedures and medical guidance, patients should be offered a diverse range of protocols to prepare for individualised embryo transfers, most suited to their particular needs. Medical teams have a duty to patients to be thorough in their screenings, recommending specialised regimens based on medical and fertility treatment history, alongside current, comprehensive test results.
When it comes to preparing the endometrium, regular and detailed ultrasound and hormonal monitoring are absolutely key. Combine a good quality embryo with a healthy endometrium and immune system, and the probability of successful implantation leading to a healthy pregnancy and live birth is greatly improved.
As for me cramping it is not connected to the embryo transfer. If I am understanding what do you mean by cramping?
I can’t understand what is cramping.
Yes, sometimes, you mean the uterus cramping? Okay, normally you don’t feel the cramping of the uterus. But sometimes if you have very painful periods, this means that the uterus cramps. After an embryo transfer is not connected with the cramping of the uterus. The uterus, this is a muscle, and for a muscle this is the normal situation when it’s cramping. So, if you feel pain sometimes when we use progesterone, the progesterone can influence the intensity. So sometimes these painful feelings, these are not due to the uterus, but due to the intestines and due to the reaction of the progesterone.
If the endometrium is not thick enough, hysteroscopy will not help us. Why? Because hysteroscopy is a diagnostic just to see what is going on inside, and not to correct the thickness. Hysteroscopy can show us polyps, can show us including into, inside the uterus, can show the endometrium, but not help make the endometrium thicker. What can we do? We have two options. First of all, we can choose the protocol without agonist so we can try not to suppress your body and to start with oestrogen. Also, nowadays we are using the medicine which can stimulate endometrium growth. This is the growth factor that we put into the uterus and the endometrium starts to gro. We use those factors maybe a few days before the embryo transfer 2 or 3 days before. In Europe, this is called Neupogen. This is a growth factor which we put inside the uterus. When we are inserting then we do ultrasound scan in 2 or 3 days and we can see that one millimetre or even 2 millimetres. We can see the growth of the endometrium.
And also, once again, we can have a thin endometrium when we have an inflammatory process in the individual. So maybe the option is when you receive the results of the biopsy, just to understand what is going on inside the uterus. If they have an inflammatory process, we can just correct the inflammatory process inside the uterus and maybe we will get the normal thickness of endometrium.
No, sorry for that there is not any food or drinks that can help us to thicken our lining. We understand that in some foods there is oestrogen but this is like a legend more than really help for us.
IVF attempt can’t create polyps, but if they have very small polyps inside the uterus during IVF procedures, we use hormones in a higher dosage then your body provides. So sometimes when we use IVF protocols with a stimulation, we can see that the polyps are growing so the polyps can grow during IVF procedures.
This is changed cells of an individual when we have abnormal growth of endometrium cells. They are dividing incorrectly and, in that place, when we have the incorrect division of the cells, we have multiplication of those cells and those cells grow into polyps. Polyps are an incorrect division of the cells.
So menopausal, this means that our body produces hormones in an incorrect way, but still our uterus is ready for implantation if we will provide the uterus with a normal level of hormone. So, if you have menopausal patients, we just work with them with long protocols and we prepare, at first for maybe three or four months, then with oestrogens and prepare the endometrium prepare the uterus for the normal cycling on the hormones and then we can start with IVF procedures with a long protocol and we can do the embryo transfer.
After IVF procedures, we recommend, on the same day, stay at the clinic. After the embryo transfer, we recommend to stay one hour at the clinic and you can fly the next day. But sometimes patients fly the same evening.
First of all, you need to rest. You need to have a good mood because this is very important to have a good psychological condition and to be convinced that everything will be okay. About the lifestyle, I understand this is a good option for the lifestyle during the preparation for IVF attempt and that’s all. You need to take vitamins you need to be active and you need to have a normal weight because also if you have a higher weight this is not good for our IVF attempt.
I’ll measure the window of implantation from the first day of the progesterone.
After embryo transfer you’ve the small discharges maybe a week after embryo transfer. Why? Because during the implantation when the embryo implants into the endometrium we can have some brownish discharges. If we have a good implantation, and we after 14 days, after the embryo transfer, we do the RCT test and we understand that we are pregnant. If we are pregnant the bleeding is not normal. When we have bleeding, this means that something is not good and at the embryonic sac is not correctly implanted into the uterus. So, in that case we recommend to have lighter regime of lifestyle. Don’t have intercourse, and to take some medicines just to prevent it from bleeding.
No, we don’t do ERA test for the surrogacy mother. Why? Because the surrogacy mother has already had babies. So, she doesn’t have infertility problems, and we understand that there is no problem in the receptivity of the endometrium. What we are doing for our surrogacy mothers is, we monitor the hormones, we monitor the immune system, we monitor her general health, but not ERA test.
It depends on the patients. If we are talking about frozen embryo, when we have, for example, egg donation programs or we have embryo adoption. This means that the main process will be only during the embryo transfer and before the embryo transfer this is only preparation and ultrasound scanning. So, we can do it distantly. We are preparing the protocol, and you are doing in your country ultrasound scanning and just send it to our doctor. If we are talking about fresh stimulation, this means that you will be stimulated. We have also two options, if you have the opportunity to buy medicines in your country and to have ultrasound scanning in your country, you can do it in your country, and come here only for the egg collection or for the embryo transfer. If you don’t have the opportunity to buy the medicines in your country, then you need to be to be here. But you also have the option that we can help you with the medicines. We can prescribe it, and with our prescription you can go to the pharmacy and to have the medicines.
Up to 48 hours, if we are doing the ERA test. We do it, as usual, on the day 6 of progesterone, and we received 3 variants by the endometrium is receptive. This means that we can do the classical embryo transfer on day 6 of progestin. If we find that the endometrium is pre-receptive, this means that we need to wait one more day. Usually, they are waiting for how many days to the embryo transfer, they recommend one or two. If this is post receptive endometrium, they also show the time, how many days you need to do the embryo transfer before that test.
If we have a long protocol, and the period started earlier, this is not a problem. Because, when you are on a long protocol, your hormones are supressed, and we can start the stimulation later. So, the agonist, three shots, are present for 28 days in our body. So, this is enough time to have a delayed work (break in transmission.) This doesn’t make a big influence on our stimulation. If you have a delay of the periods, we plan the embryo transfer within 14 days of preparation. But we see that from 12 days this is enough for the endometrium to grow So we have 3 days 3, 4 days to just, to move in with our stimulation if they have a delay for 3 or 4 days, this is not a problem. If they have a delay for a week, then it can be a problem because we need to move our embryo transfer.
If you are going through egg donation programs, and you have high NK cells, we recommend the use of intravenous immunoglobulin. What is this? This is a medicine that has an influence on the immune system. When immunoglobulin is in your blood, they just come in contact with NK cells, and NK cells start attacking immunoglobulin, and during this, your pregnancy starts to implant and starts to grow. If we’re talking about immunoglobulin, then we have no influence on the antigens because we are using an immune correcting therapy. And also, we have problems with actually antigens only in 2.3 percent of the patients. So, it’s a very rare problem, so the chances that our donor egg women, our donor and the husband will have the same actual antigens is very low.
We use intravenous immunoglobulin.
In our program will have three attempts. We offer it until the heartbeat. Also, this is to six weeks of pregnancy.
We will be in the conference in London in November as doctors but not as consultants.
For us a suitable TSH level is less than 3. If they have a level of TSH higher than 3.5, there is an option for an endocrinologist to lower the TSH level.
Earlier we would do to the embryo transfer on day 3. But nowadays mostly maybe in 98% of our transfer, this is day 5, blastocyst stage transfer. Why? Maybe a few years ago there was an idea that at that moment, this is the best option for the embryo, and if they have a poor-quality embryo, or we have very few embryos, then it’s better to have day 3 embryo transfer than to have the day 5 transfer. Nowadays, we understand that on day 3 our embryo is not in the uterus, it is still in uterus tube, and the situation in the uterus tube is quite different than in the uterus. So, it makes no sense to put the embryo on day 3 into the uterus, and to say that it’s a better condition for the embryo. So, we prefer to stay on the blastocyst stage embryo transfer. In this case, we can understand that we have good quality embryo. Then we receive a good quality embryo and we have a good chance for implantation. Especially in the case of the male’s factors and thus during when we have problems with the sperm quality and the male factor start to affect the embryo on day 4. So, we can have a good quality embryo on day 3, and then have a bad quality embryo on day 5. So, our policy is just to wait and to understand that we put a quality embryo inside the uterus.
As for the first question we use progesterone injection and suppositories or use both. We use, in the morning, injections and in the evening, we use suppositories. Injections, we can have intramuscular or subcutaneous. Nowadays we have very good medication, named Prolutex. This is progesterone, which we use subcutaneously. So, you don’t have painful feelings, as when we use intramuscular progesterone. About Meprednisone, we don’t use it without immunological testing.
No, if you’re talking about the receptivity, this means that you have no implantation. When we have pregnancy loss at the terms of 5 or 6 weeks, in most cases this is either bad chromosomes, or either in immunology factors.
We do the endometrial biopsy and we also do the histochemical tests for the bio type tissue. Just to see if we have inflammation inside. We also think that this is an important issue, especially if we have a thin endometrium, or we have a failed implantation before and we also use antibiotics when we perceive inflammatory process inside the uterus.
No, there is no evidence.
Yes, if you have immunological problems, we can use several options. First of all, we can use methylprednisolone this is hormonal medicine. Also, we can use intralipids or we can use intravenous immunoglobulin. Intravenous immunoglobulin, is are the most expensive and methylprednisolone this is the cheapest one. So, intralipids is between them. But the most effective, this is intravenous immunoglobulin.
In Ukraine we use electronic microscopy test. We search for pinopodes, those cells which are responsible for the implantation. We also receive the answers if the endometrium is receptive or not. When those pinopodes are present in the endometrium. When we do electronic microscopy of the endometrium. We do a biopsy, but we do three biopsies. On day 6, on day 8 and on day 10 of progesterone. So, it’s a little bit longer than ERA test. When we do ERA test, we also can do ERA tests in Ukraine, then we do only one biopsy on the basis of progesterone. We receive not pinopodes, we receive the information about the expression of the genes which are responsible for the implantation. The difference is between the information that we receive. In the ERAs we received information about the genes which are responsible for the implantation and in electronic microscopy we receive the cells which are responsible for the implantation.
Nowadays the new trends in the IVF field this is “freeze all” technique. Why? We really have better result with frozen embryo transfer than with fresh embryo transfer, but it depends also on the reason for infertility of the quality of the embryos, the quality of endometrium. If we have the same quality of good quality embryos, good quality oocyte (egg), and then it passed from the quantity of oocyte. If we have more than 15 oocytes, this means that we have very high oestrogen in our body and our endometrium is over stimulated, and it has a worse receptivity than in cryo cycle. So, in the case that we have, or high progesterone before that, the egg collection. Or we have more than 15-20 oocytes during the egg retrieval then we prefer also result if we have 5-6 oocytes then we do a fresh embryo transfer.
Neupogen the name of the growth factor is Neupogen.
During the procedures, during your natural cycle, you have hormones that are affected by the nervous system. So, if you have stress, your hormones also react to that stress and you have, you can have the possibility to have disorders in your cycle. When we do IVF procedures you have your hormones blocked, and we are putting our hormones in a stable dosage. So, you won’t experience those drops of hormones due to stress. Therefore, you can fly and everything will be ok. All our foreign patients fly, and everything is ok.
Yes, hyaluronic acid doesn’t have an effect on the embryo transfer. The question is only about your general condition. If your inflammatory process allows us to do the embryo transfer then yes, but hyaluronic acid doesn’t influence our process.
We also advise to stop training because when you train, you can have cramps in the uterus. During the implantation, it’s better to have a relaxed uterus, which prevents cramps. Because when you have contractions in the uterus, the embryo can move through the cavity and sometimes even can drop into the uterus tube, and we can have an extra-uterus pregnancy. So, it’s better to be relaxed during the two weeks of embryo transfer to have better chances. But there is no evidence and no investigation which shows that training or not training is better for the implantation.
About the scratching, contraceptive pills and scratching, they do not correlate. We use contraceptive pills just in case, to have your cycle plans and that’s all. About the scratching, we don’t use stretching in all cases of frozen embryo transfer. Why? We use scratching only in the cases when we have thin endometrium when we have negative (unsuccessful) attempts and we when we have a suppressed immune system. We don’t use scratching for all patients, because if they have an aggressive immune system, stretching can even affect implantation, but not help.
During IVF attempts we have standard progesterone dosages after the embryo transfer. They are checked by numerous tests and those level of progesterone can’t affect the implantation. The progesterone is for implantation, just to support the implantation.
I guess so. We do immune testing for all our patients before IVF attempts. Even before the first IVF attempt. In Ukraine, the patients are paying for their IVF attempts by themselves, so our main thing is to detect all factors, the most that can influence the IVF attempt, and just correct them so our patients all do immune testing before IVF attempts.
For us one protocol, this is the golden standard, but we need to understand that each first each patient is individualized. So, if we understand that the patient had problems with the thickness of the endometrium, and had a thin endometrium before. Then it makes no sense to have the long protocol. If we understand that the patient has a good endometrium and antagonist shot will not decrease the thickness of endometrial then it’s better to have the one protocol.
Dipherlene 3.75 mg works for 28 days.
It can be true if the dosage was 12 mg.
Bioven is intravenous immunoglobulin, which we use in Ukraine, and we use it at the date of embryo transfer.
We always discuss the number of embryos with the patient during the embryo transfer because it depends on the quality of the embryos and the age of the patient, and the situation also with her weight, for example, with her pathology. If she is healthy or has additional pathology. In your case, and we discussed, that if we will transfer two embryos, yes maybe we will have a slightly higher chances for the pregnancy. When we are pregnant with twins, it’s harder to carry twins, and we have the higher risk of preterm labour and complications during the pregnancy. When we have singleton pregnancy, yes, the chances for the pregnancy are a little bit lower but still we have the higher chances to have a healthy baby. So, we recommend, let’s start with a transfer of one embryo and then when we try the next attempt, we discuss two embryos.
If you are 46 years old and you have periods, we don’t need to do the preparation. We need to do ultrasound scanning and to see the condition of the endometrium, the thickness of the endometrium, the structure of endometrium and to do the investigations which are needed to go for IVF procedure. If we have a menopausal woman, then we need to prepare the endometrium for at least three months, just to have the good receptivity of the endometrium.
Yes, because of age and I suppose because of your ovarian reserve. If we have above the embryo quality. The embryo quality, on the embryo quality influences the quality of the oocyte, we understand that the most high-quality embryo is at age, up to 35 years. Between 35 and 40, the woman is in a so-called grey area. This means that we have half and half. Half of the embryos will be healthy and half of them can have chromosomal disorders. So, after the age of 40 we have a crucial bad quality of the oocytes and we can have up to 80 percentages of chromosomal abnormalities in the embryo. So, if you want to have your own stimulation and you have good enough ovarian reserve so it’s better than PGS screening, this means that we can use preimplantation diagnostic and diagnosed the embryos for the chromosomal abnormalities, and only in case that we have the good quantity and healthy embryo we can do the embryo transfer. If you don’t have the possibility to do this due to a mesh level, the low ovarian reserve or due to financial questions then is better to have the egg donation program.
You’re talking about your stimulation work cryo cycle and egg donation. Because if you are talking about your situation, we will start stimulation with the FSH hormones. These hormones will cause the growth of your follicles, and the hormones don’t affect your weight and don’t affect your health. These are the same hormones that are produced by your body, but we input them in a higher dosage. So, your body is producing for one follicle, and we will work input for 10 follicles. Some of these hormones don’t, in fact, affect the weight they influence only on the follicle growth. If we are talking about cryo cycle, and not your ovary stimulation, so you will be taking only oestrogen, and also in the low dosages. So, that medicine also can affect your weight and can affect only what you are eating and that’s all.
If you have polyps, the best option is to remove them. You can use the option of hysteroscopy for removing the polyps, and the best option is to do IVF attempt in the next cycle after hysteroscopy. The maximum – this is up to three months after the hysteroscopy.
It depends what kind what type of adenomyosis you have. How it is spread over the uterus. When you have adenomyosis, it slightly reduces our chances, but it has a straight correlation between the stage of adenomyosis and pregnancy.
Yes, we use Bioven instead because we have higher results, better results, on intravenous immunoglobulins, than on the intra lipids and that’s why we’re using Bioven.
We can use aspirin during the pregnancy. When you have pain, it depends what kind of pain you have, and why you feel the pain.
Immunogram the test name is immunogram, and we search for NK cells, or maybe you have a separate test for NK cells. In Ukraine, we don’t have for the separate test for NK cells. We have the general immunogram in which we detect NK cells, maybe in your country, you have just NK cell testing.
If you have a positive test, then first of all, yes. If you have severe bleeding, you do need to go to the emergency and to have the medicine to stop the bleeding. The next step is to doublecheck the RCG level, and to understand if it’s increasing or not.
It depends on the case. If you have only having the first attempt, we recommend to do the NK cells test, and to screen the thyroid gland. If they have several negative tests, then in addition, we recommend to do SLA tests.
To remove further polyps, you need to remove the polyps and this will be the option to increase your chances for IVF.
If we have aggressive scratching. How does scratching work? When we do scratching, we are just injuring the endometrium, and immunocompetent cells increase in the endometrium. So, we are activating our immune system if you have already Hashimoto after immune disease this means that your immune system is already aggressive. So, it makes no sense to do the scratching, because we already have your immune system aggressive. We need to suppress your system not to activate it.
I don’t know if they are registered, and the name of them in Ukraine is tranexamic acid. In most cases, we use tranexamic acid.
It depends, if we have fibroids that are not in the cavity, then we can just leave them alone. If you have the opportunity to have the surgery for fibroids then we use the options to do the surgery for fibroids. If the fibroids are very big and we can’t do the surgery then we just leave them.
In the instruction to the medical limitation is written that the diphereline works for 28 days, and when we plan the cycle, we calculate that the diphereline works for 28 days.
If you have a small size cyst, no. If you have a big cyst, it can have an influence, because if you will give oestrogen it can slightly grow. So, it’s better not to have cysts before the stimulation, or if we have a cyst not more than three centimetres. It will not influence the stimulation of the endometrium, but it can just grow and cause problems when you are pregnant.
In your case ERA tests are diagnostic. So, if you have negative attempts, we need to understand what is going on. So, in your case you need to choose, you have risks, or you have benefits. In your case ERA test is a benefit, because you will know exactly the situation what is going on with your endometrium. Also, ERA test is like scratching, because you are putting the catheter inside and making movements inside the uterus causing trauma to the endometrium. But you can use options that you will do ERA test and you can, for just one month, have a rest, and have the program on the next cycle. In addition, if you have a higher NK cell count, we can use Bioven intravenous immunoglobulin and just correct the influence of the immune system.
Yes, we have a courier service. We can propose the option that our courier will come to the clinic, take the sperm, and bring it to Ukraine. So, it’s not a problem.
Yes. Several cases when we have very thin endometrium. We have one pregnancy at endometrium 5. One pregnancy was in endometrium 5.5. Several within endometrium 6. So, sometimes if they have a good structure good, triple lining endometrium but thin, sometimes we do embryo transfer. Just understand if it’s your maximum and we can’t get a higher one, we really have problems.