In our recent event, we discussed ways to boost your chances of a successful embryo transfer. The discussion went beyond the traditional focus on the endometrium, exploring additional factors that play a crucial role in optimizing outcomes.
Our panel of experts included:
Dr Joaquín Llácer – Medical Director of Ginefiv, Spain
Dr Marcel Štelcl, PhD – Chief Physician of ReproGenesis, The Czech Republic
Dr Eleftherios Meridis, PhD – Scientific Director of IVF Serum, Greece
The event was hosted by: Dr Alan Thornhill, Fertility Expert & Coach; Founder of The Fertility Guy
Dr Joaquín Llácer, Ginefiv: The endometrial preparation is, nowadays, the key to the situation. Some years ago, endometrial preparation was the same as ovarian stimulation during fresh embryo transfer. However, nowadays, approximately 80% of embryo transfers in our clinic are frozen embryo transfers. This allows us to think about the best way to prepare the endometrium for embryo transfer.
We must take into consideration different factors, including the efficacy of the treatment and the comfort of the patient. It is important to plan the embryo transfer in a way that maintains a balance between family life, work life, and treatment. One of our priorities when preparing a patient for an embryo transfer is to ensure that the patient can continue with their normal daily life without significant restrictions. This is crucial because the efficacy of the treatment is not significantly different among the various methods.
Dr Marcel Štelcl, Ph.D, ReproGenesis: First of all, I would like to say that I prefer a natural cycle if it is possible. There are cases where this is not possible, for example, women without spontaneous ovulation or when preparing women from France where everything, including flights and accommodation, must be arranged. In these cases, I prefer artificial medication.
Why do I prefer a natural cycle? Because the efficacy is similar, patients sometimes believe that medication is better, which is not true. The safety during late pregnancy is also better after a natural cycle than after an artificial cycle. If it is possible, I use a natural cycle with only progesterone supplementation. I usually use 400 milligrams per day of vaginal progesterone.
In artificial cycles, there are three ways to administer estradiol: orally, vaginally, or transdermally. I like the vaginal method very much, but there is a disadvantage—if there is any inflammation in the vagina, it is impossible to continue with this application.
Dr Eleftherios Meridis, MD Ph.D., IVF Serum: We have to decide if we’re going to speak about the medication we’re going to give for transferring fresh embryos or what preparation we’re doing for transferring frozen embryos. It’s a different situation. When you have fresh embryos, you have just come from a stimulated cycle or a natural cycle, so you have already been given some medication. You have ovulation, and then a few days later, you decide you’re going to transfer day two, day three, or day five embryos. You are basically following a stimulation cycle or natural cycle, but you have fresh embryos, and there is a kind of preparation you can give for the transfer of fresh embryos.
On the other hand, there is another preparation, which can be kind of similar but also different, when you have to transfer frozen embryos. Each decision has its advantages and disadvantages. There can be variations in the medication you’re going to give. If you have frozen embryos, and you want to transfer them to a patient, you also have the choice of transferring them in a natural cycle or a down-regulated medicated cycle.
There are some advantages and disadvantages, and it depends on the patient to decide what protocol will be more suitable for the needs of that patient. For example, if you have frozen embryos and a patient you want to transfer the frozen embryos to, and you know there is a problem with endometrial thickness, you cannot always depend on the quality of the endometrium that is going to be grown during a natural cycle. You have to assist by giving some estrogen to improve the thickness of the endometrial lining. Sometimes, this is not enough. If you have a patient with a severe lining issue, you may need to down-regulate. You need to down-regulate the patient so that after she has her period, you can start medicating with estrogen. Then you have the luxury of having more days of estrogen supplementation to reach the ideal thickness of the endometrium. You are not in a hurry because you think the patient is going to ovulate, and you don’t rely on the estrogen produced by the ovary. You have the extra advantage that you can delay your transfer. Furthermore, you can give estrogen for 14, 16, or 18 days before you achieve the desired endometrial thickness, and then you start the luteinization process.
Dr Eleftherios Meridis, MD Ph.D., IVF Serum: There is a consensus. The magic number is 7 millimetres.
Dr Joaquín Llácer, Ginefiv: In this case, the pattern of the endometrium is also quite important. If you have a trilaminar endometrium, even with a thin endometrium of 6-7 mm, it could be okay. If you don’t have a trilaminar endometrium, and you have a thin endometrium, it’s time to stop and do a hysteroscopy or a 3D scan to evaluate the cavity before proceeding with the treatment.
In any case, the preparation depends on the lifestyle of the patient. If the patient lives nearby, you have more opportunities to prepare the endometrium in the best way. You can start with a natural cycle. If you need to cancel the natural cycle, you can move to another cycle. You can look for the best thickness and everything. But, for example, if the patient is in another country and has just 3 or 4 days, or 1 week, to do the treatment, taking the risk of premature ovulation or a thin endometrium at the moment of the embryo transfer puts you under pressure to plan the embryo transfer. This is not a good idea.
Sometimes, we prefer to do a mock cycle before planning the real cycle to be sure that, at the time the patient is in your city, everything is okay. You can anticipate a bad endometrium and perform a hysteroscopy or another preparation before starting the real preparation and before the patient plans the trip to your clinic.
Dr Marcel Štelcl, Ph.D, ReproGenesis: I usually do mock cycles only when I expect that there will be low endometrium, and usually when there is some distance between me and the patient. Patients from our town come for the transfer cycle, and if everything is okay. For me, 7 millimeters is a good minimum, and 6 millimeters is an acceptable minimum. But usually, I try preparation again, maybe with a higher dose of estrogen. I don’t do mock cycles every time—maybe 10%, but no more.
Dr Eleftherios Meridis. MD Ph.D., IVF Serum: This is something you can do in any part of a woman’s cycle. What you’re doing is trying to test the cervical patency, right? To see if the cervical channel is open, or if at the time of the real embryo transfer, when you have embryos in the lab waiting to be transferred, you’re going to have a serious issue and a problem and won’t be able to transfer the embryos at the end of the day.
At Serum, we always do a mock embryo transfer. We have integrated the mock embryo transfer into a procedure that involves the evaluation of the cavity. We do something like a HyCoSy—infusion of normal saline in the cavity—at the first initial consultation of the couple or the woman. So it’s part of the routine basic investigation. Sterile normal saline is infused inside the cavity during the process of a mock embryo transfer. If there’s going to be a problem during the transfer eventually, this is the time that you realize it. Then you can refer this patient for a hysteroscopy.
At the same time, when you have a successful Aqua scan, you can visualize and evaluate the cavity for polyps, fibroids, adhesions, or the shape, like an arcuate uterus. There are other things, this procedure is very useful to diagnose before you transfer the embryos.
Dr Joaquín Llácer, Ginefiv: I would prefer not to do an invasive exploration in case the scan is absolutely okay. If we have a trilaminar endometrium with a normal thickness from the previous cycle. We reserve to do a HyCoSy or hysteroscopy in the case that the scan is not okay. We prefer to check if the endometrium is trilaminar with good thickness. We don’t do a mock transfer. Considering the probability of encountering special problems at the moment of the embryo transfer is very low, if any, you must have discomfort for 1,000 patients to save one single embryo transfer. So, this is the idea, but I respect the decision to check the cavity with a hysteroscopy before the first embryo transfer. In my view, we reserve this kind of exploration when we have a non-normal scan. This is my opinion.
Dr Joaquín Llácer, Ginefiv: This is a special moment, and the patient must be sure that everything is okay with the embryo transfer because considering that we have a 40-50% probability to fail, this is the probability that we can have an embryo transfer. The maximum probability of having a pregnancy is 60% or more, and we must be sure that in case we fail, it’s because we are not lucky, not because the embryo transfer was suboptimal. This is the reason that sometimes we don’t do mock transfer but do it after lowering the embryos in the catheter after being sure that you are inside the cavity with the ultrasound.
Dr Eleftherios Meridis, MD Ph.D., IVF Serum: I believe that my colleagues are doing the transfers with abdominal ultrasound scanning. We have developed a method that we do it with internal vaginal. When you do it like that, you have an incredible view of the cervical canal, and the uterus, and you can leave the embryos exactly where you want. It’s magnificent to see.
Dr Marcel Štelcl, Ph.D, ReproGenesis: Sometimes I do it as well, but only in cases when the transfer is difficult like you can feel it in your fingers that there is some problem, and it’s not visible by the abdominal way. I feel like an octopus when I do this.
Dr Joaquín Llácer, Ginefiv: I have some experience with the vaginal scan guiding the embryo transfer or transrectal scan, and the image is fantastic. It’s beautiful the way that you can see the embryo transfer, but sometimes it’s uncomfortable for the patient and uncomfortable for the gynecologist because it’s more hands. But the results are reassuring, taking into account that the studies say that the probability of pregnancy is not different between the vaginal or abdominal, but it’s for sure that with the vaginal, the image is fantastic, and sometimes the patient is more comfortable, taking into account that she can see the scan.
Dr Eleftherios Meridis, MD Ph.D., IVF Serum: Sometimes it might be difficult for a 44-year-old patient to reach the blastocyst stage, so we know, that while waiting for day 5 to reach blastocysts, you may have no embryos to transfer. Embryos could be fine because there is no better cultivator for embryos than the uterus. If you have embryos that look fine, and they have reached day 2 or day 3, but you are worried that they may not reach day 5, and you have a 44-year-old patient, you don’t have like 10 embryos, usually you may have like 2, or 3. And on day 2, you see that one is good, and the other one is not so good. You have to decide if you’re going to transfer on day 2 or day 3, or you take the risk of not having any embryos at all to transfer on day 5.
We perform 100% of day 5 embryo transfer. When the woman says, “Well, I would prefer to transfer them on day 3.” We can transfer the embryos on day 3, but the results on day 5 transfers are very reassuring. Taking into account that in the last ESHRE meeting in the Netherlands, a randomized control study comparing day 3 to day 5 showed that the cumulative birth was the same, so it’s logical to think that we don’t lose embryos in the culture in the lab that we have nowadays. We can say to the patient that in case the embryo fails to arrive on day 5, it’s because the embryo is not able. And the decision to transfer the embryos at day 5 is, in my opinion, the dominant strategy.
Dr Joaquín Llácer, Ginefiv: We speak with the patient and say, “Well, you are 44, and this is the last opportunity.” We are going to transfer on day 2, and the woman agrees. For me, it’s perfect because you are not going to have a lower probability of pregnancy, but sometimes we transfer an embryo on day 2 or day 3, and the embryo fails to implant. The woman may think that her body rejected the embryos. Okay, and sometimes they start with an adjunct therapist, immunology treatment, or something like that because they understand or think that they reject the embryos. Sometimes it’s an embryo that fails to arrive at the blastocyst stage, and we must put everything into balance. It’s very respectable to transfer on day 2 or day 3, but in my opinion, the dominant strategy is to arrive at day 5 to check that, well, you fail because the embryo failed to arrive at the blastocyst stage, not because you reject the embryos.
Dr Marcel Štelcl, Ph.D, ReproGenesis: Yes, I fully agree. Patients can understand when the embryo does not progress in the uterus; they might attribute it to issues with immunology, a faulty transfer, or assume they made a mistake. However, when there is no embryo, the situation becomes clear for them. Eventually, they may become more open to considering egg donation when they realize that after three cycles without an embryo, we proceed with a transfer each time. Moreover, I completely concur regarding immunologic tests and hysteroscopy, among other procedures.
Dr Marcel Štelcl, Ph.D, ReproGenesis: Yes, but not in the first line. Usually, after 2 or 3 negative transfers, it should be good-quality embryos. But sometimes, it’s very difficult to explain to the patient that embryos are of good quality. But I use the receptivity test, and I have a good experience with it. If there is some recommendation for a different day, I usually have a very good experience with it. Therefore, you would be a candidate for this test.
Dr Joaquín Llácer, Ginefiv: This is a complicated situation and when you have doubts, you must be honest with the patient. You are desperate, and the patient is desperate, but we have the will to explain to the patient the real evidence and to go ahead with another treatment. In case the patient prefers to go to the immunologist, we respect the opinion of the patient. And in case the immunologist has some add-on therapy, we understand that we can use this add-on therapy. But we must explain to the patient that we have a good-quality embryo. In the last paper published in Human Reproduction by Philipov Valdi and his team, they say that in the first 5 embryo transfers with a chromosomic normal embryo, the probability of success is not different from the 4th to 10th and the 2nd to 10th. We must try again and have the confidence of the patient to try. After ruling out that the problem is with the uterus and after discussing with the patient the probability of use and add-ons, to go to the immunologist or immunologist. But we are desperate, and we can respect all the opinions.
Dr Eleftherios Meridis, MD Ph.D., IVF Serum: I just want to say that what you were describing was recurrent implantation failure. In my opinion, there is no such thing as unexplained recurrent implantation failure. The term “unexplained” describes our inability to find a reason why this patient does not get pregnant. If you continue doing the same thing, you’re going to get a negative result again and again. If you don’t change something, if you don’t investigate more to find what is the cause of this implantation failure, and if you just keep transferring embryos, you’re just going to get the same negative result.
There is a spectrum of tests you can do. You can test for natural killer cells, for example. Another thing you can do is you can test for subclinical infections. Chronic infections could be there for many years and the patient does not have any symptoms at all, like pain or abnormal discharge, whatever, and they may not be the main reason that someone cannot get pregnant with very, very good embryos. There is a spectrum of tests you can do. As it was mentioned, the ERA test is something that could be very useful for some patients. You can do the microbiome, as I said; you can take a sample from the uterus, and you can test it for possible bacteria that could ruin your chance to get pregnant.
Dr Eleftherios Meridis, MD Ph.D., IVF Serum: From my clinical experience, sometimes you end up doing a hysteroscopy on a patient who has implantation failure. You did the hysteroscopy, and you see that clinically, this patient has an obvious endometritis. Sometimes, it can be severe endometritis.
My view on this topic is that you cannot carry on doing embryo transfers until you treat this endometritis. Then you cannot just use empirical treatment of random antibiotics. To treat endometritis, you have clinical views during hysteroscopy. You cannot do a standard protocol, empirically. You have to take a sample and send it for PCR to know exactly what are the specific bacteria that’s causing this. Then you can give targeted antibiotics.
Dr Marcel Štelcl, Ph.D, ReproGenesis: It’s clear with chronic endometritis. I inquired at the university if changing the microbiome is possible. You administer antibiotics for 14 days, then suggest lactobacillus, hoping for improvement. However, I doubt it’s possible to effect change this way. They responded that the microbiome is occasionally genetically determined, making alteration challenging. So, if an imbalance is detected, can it be rectified? Thus, it might be preferable to advise everyone to try a vaginal lactobacillus transfer cycle twice a week. Perhaps the outcome will be similar.
I think that with lactobacillus, it’s clear because the strongest microbiome is the intestinal microbiome. However, improving it takes time. The patient is asking for a transfer now, not after 6 months. This is why I use vaginal lactobacillus when I use it.
Dr Joaquín Llácer, Ginefiv: I don’t recommend these kinds of therapies to my patients. I only consider using this medication if the patient specifically requests it. We must recognize to the patient that we don’t have a clear understanding of the cause of the failure, and we must respect their opinion. However, we prefer not to use this kind of therapy because the evidence for these treatments improving pregnancy probability is the same as for them potentially impairing it. I prefer not to use these medications unless the patient insists.
Heparin or baby aspirin are medications with fewer side effects. But even with these, the evidence is limited. For more complex treatments like intralipids IVIG, or steroids, I prefer not to use them. We must remember that once you start adding treatments, it’s challenging to stop. If you fail with heparin, then add steroids and fail, then add immunomodulators, and fail again, you end up with a patient continuously on multiple medications without clear evidence of benefit.
I prefer not to start this spiral of additional medications with no solid evidence. However, we must acknowledge that both the patient and we, as doctors, can be desperate, and we can discuss the use of these medications.
Dr Eleftherios Meridis. MD Ph.D., IVF Serum: I think the add-ons are not for everyone, but if you have a patient with specific clinical indications, it might be considered. It would be a mistake not to give this additional medication, even if there isn’t always conclusive evidence of its efficacy. For example, if you have a patient who has thrombophilia or antiphospholipid syndrome, it is debatable whether these conditions interfere with implantation. However, for me, it would be necessary to supplement this patient with low molecular weight heparin. If the patient has antiphospholipid syndrome, I would also add aspirin.
If you have a patient with very high natural killer cells, it would be mandatory, after the embryo transfer, to supplement this patient with 25 milligrams of prednisolone. You would also need to consider administering IVIG or intralipids. These are special medications, not for everyone, but for specific patients who need them.
Dr Joaquín Llácer, Ginefiv: I used it some years ago but decided not to continue because it’s a bit expensive, and no differences were seen. However, nowadays, after the guidelines of the ASRM on recurrent implantation failure suggested that nothing else works but EmbryoGlue, I offer it to patients. I explain all the possibilities and one of them is the possibility of using EmbryoGlue.
Dr Eleftherios Meridis, MD Ph.D., IVF Serum: We use it. We believe it’s working.
Dr Marcel Štelcl, Ph.D, ReproGenesis: It depends. In cases of only endometriosis, I use the same protocol. Usually, if it is more severe endometriosis, I recommend a freeze-all strategy and transfer later. If adenomyosis is present, it’s much more difficult.
Dr Joaquín Llácer, Ginefiv: In cases of endometriosis, sometimes I prefer a freeze-all policy and prepare the endometrium under different conditions, not during the embryo transfer cycle. The evidence is not very strong, but we prefer to do a frozen embryo transfer and not a fresh embryo transfer in patients with endometriosis.
Dr Eleftherios Meridis MD Ph.D., IVF Serum: If you have active endometriosis, it depends on the stage, of course. If you have active endometriosis, it’s always a good clinical strategy to downregulate the patient, wait three months, and then transfer frozen embryos.
Dr Joaquín Llácer, Ginefiv: This kind of protocol is practically mandatory in my clinic for patients with adenomyosis. For patients with endometriosis, if there is an implantation failure, we use this kind of protocol with long downregulation.
Dr Eleftherios Meridis MD Ph.D., IVF Serum: My opinion is that there’s not a lot you can take to improve your egg quality. But there is something that you can do, and this is called ovarian PRP.
We do it regularly for this kind of group of patients, and we have seen quite an improvement. Also, in the number of eggs that we collect after a stimulated cycle, we have seen an improvement in the quality of the eggs we get. PRP stands for platelet-rich plasma. It is a procedure where we take a small amount of blood, about 60 ml, from the patient. This blood is processed and centrifuged to create a solution very rich in platelets other growth factors and bioactive proteins. You then have the option to inject this PRP solution into the ovaries if there is an issue with ovarian quality or the number of oocytes, or you can infuse the PRP solution into the endometrium if it is thin or of poor quality.
Our clinical experience so far with PRP has been very favorable. We have seen pregnancies and reductions in FSH levels, as well as improvements in AMH levels. It doesn’t work miracles—it’s not going to turn two eggs into ten eggs, and it won’t work for everyone—but we have seen it work for some patients.
Dr Joaquín Llácer, Ginefiv: The present evidence is very, very weak. There are different uses for PRP: one is for thin endometrium and recurrent implantation failure, and another is for ovarian rejuvenation. The evidence for ovarian rejuvenation is very weak, but sometimes we try it in situations with very low ovarian reserve before moving to egg donation. The other possibility is using PRP for recurrent implantation failure and thin endometrium, where we have had good results.
We offer PRP to patients, explaining that it is an experimental treatment. While the evidence is weak, we try it in specific situations to see if it can help.
Regarding supplements, I think that a normal, healthy woman doesn’t need to take any special supplements. However, we must take into account another aspect that we sometimes overlook: lifestyle. Sometimes, we encounter women with implantation failure who have been prescribed a lot of medication, but they are overweight and do not have healthy habits.
We must recommend correcting these habits and maintaining a normal weight, or at least not being especially obese. This is fundamental because sometimes we use medications without evidence, while there is clear evidence that being overweight contributes to failure. The probability of success is higher when we obtain a better lifestyle. So, we think that we must discuss this with the patient in the office before considering special medications or supplements.
Dr Marcel Štelcl, Ph.D, ReproGenesis: I never recommend transferring more than one embryo. The last time I did it was a unique situation. The patient was from the USA, and we did a day 5 fresh transfer with 1 blastocyst and 1 morula. I transferred both. She was 40 years old. This kind of case happens maybe once per year. It’s very rare.
Dr Eleftherios Meridis MD Ph.D., IVF Serum: I think it depends on the clinical scenario you’re facing. If you have someone who’s 34 years old, and it’s their first IVF with good embryos, these patients are usually very concerned about the possibility of having twins. They’re happy to transfer 1 embryo. There’s no question about transferring more.
However, if you have a woman over 40 who has had a few embryo transfers before and her embryos are not that good, you can consider transferring more. In such cases, you might transfer 2 embryos. Actually, in Greece, we can transfer up to 4 embryos after the age of 40.
It’s not an easy question to answer. Even for the latter scenario, there are some patients who, despite the recommendation to transfer more than 1 due to poor embryo quality, are scared about the possibility of twins or triplets and would still prefer to transfer only 1. As a specialist, you give your clinical advice, but you also have to respect their opinion. At the end of the day, it’s their cycle and their life. It depends on different clinical scenarios, and it’s always helpful to discuss with the patients. You give them the advice, and they decide what they want to do.
Dr Joaquín Llácer, Ginefiv: I transfer just 1 embryo in practically all scenarios. We never recommend transferring more than 1 to the patient. Sometimes, we transfer 2 if the patient prefers to transfer 2, and I accept, but only after more than one conversation. I have been working in IVF for more than 25 years and have seen enough horrible twin and triplet pregnancies in my life. I try to have just 3 kinds of patients under 35, and over 35 with PGT-A and egg donation. In these scenarios, the probability of implantation is high, and I transfer just 1 embryo.
Dr Eleftherios Meridis MD Ph.D., IVF Serum: I wouldn’t support it, to be honest. I think if after the embryo transfer, the patient remains in bed for about half an hour, this is more than enough for us.
Dr Marcel Štelcl, Ph.D, ReproGenesis: Same, I think that it can be harmful to stay in bed for 14 days. It’s very bad for health and doesn’t help implantation.
Dr Joaquín Llácer, Ginefiv: Yes, I agree.
