During our patient meeting with Dr Harry Karpouzis, Founder & Scientific Director of IVF Pelargos Fertility Group, we discussed and answered key questions about recurrent implantation failures and personalised treatment plans. Dr Karpouzis provided expert insights, addressing patient concerns directly.
Hosted by Jessica Bourke, The Fertility Detective, who has nearly 20 years of experience in helping overcome fertility challenges and pregnancy loss. With her guidance, we created an interactive environment where patients received personalized answers and support.
The issues have changed many times. The most recent definition states that we say a woman is having recurrent implantation failures when we cannot achieve a clinical pregnancy after the transfer of at least 4 good-quality embryos in at least 3 transfers, fresh or frozen. This definition might change, though, and it might lower the number of transfers when we are talking about PGT-A embryos or when we are talking about egg donation.
In some of the most recent definitions, when we have 2 failures of chromosomally normal embryos or egg donation embryos, we can say that we have recurrent implantation failures. In women over 40 years old who do not have good-quality embryos, 2 or even 3 failures are something that is not uncommon.
No, it’s in total the four. According to the definition, we say that after the transfer of 4 embryos, it can be 2 and 1, for example.
But when you transfer four good-quality embryos in women under 40 years old, and you cannot achieve a clinical pregnancy, you fall into the definition of recurrent implantation failures.
Not really. When you have a euploid embryo, it means that it is chromosomally normal. We will talk later and explain that this is not completely accurate because it depends on the definition of what we say is a chromosomally normal embryo. In most laboratories, euploid means embryos that do have mosaicism, but the mosaicism is less than 20%. They do have some abnormal cells, but these are less than 20%.
Even euploid embryos have some abnormalities. If you transfer a euploid embryo in a woman who is 42 or if you transfer it in a woman who is 35, if they don’t have any difference in other factors like the endometrium or anything else, the chances should be equal. The only difference is in the extreme age limits where we are talking about egg donation, for example, and situations like that. We have noticed that when you get close to the 50 or over 50 age group, the success rates are lower, even though we are talking about possibly chromosomally normal embryos or egg donation.
Many times, it’s due to blood flow, the thickness of the endometrium, or a hypoestrogenic state that some of these women have experienced for a long time, which might affect hormonal balance. Additionally, there are uncertain factors that play a role. We do notice differences in success rates even with euploid embryos in these age groups.
First, it’s the embryo. If you transfer embryos without knowing the chromosomes, that’s often the main factor. The embryo can relate to the egg, sperm, or their combination. So, you need to investigate if it’s a quality issue with the egg, the sperm, or both. In sperm, there are hidden factors like DNA fragmentation or oxidation that aren’t always evident in standard analysis. Next is the endometrium, which may not get thicker, may stay thin, or even if it thickens, the embryo might not implant. It could involve immune or autoimmune factors, general health issues, or even localized endometrial factors. The implantation window is complex, and various factors, still not fully understood, can affect it. Infections or conditions like endometriosis and issues with the implantation window are also factors. Generally, the main categories include the egg, sperm, embryo, endometrium, and general health factors.
I usually start with the embryo, the most common reason. First, I check if the embryo is chromosomally normal. If you continue transferring embryos that aren’t chromosomally normal, it can keep failing, and you won’t know why. This leads to investigating rarer conditions without knowing if the embryo is the issue. So, my first step is PGT-A to confirm the embryo’s chromosomal normalcy. If it fails despite a normal chromosomal profile, we can then evaluate other factors.
Yes. For a single unexplained failure, we typically suggest a hysteroscopy. Sometimes, a hysteroscopy reveals hidden reasons that an ultrasound might not show.
Absolutely. Some patients want to test everything before transferring their remaining chromosomally normal embryo. This is entirely reasonable.
If we’re talking about recurrent implantation failure, defined as at least three failed transfers with good-quality embryos, then yes. In someone around 33, the frequency of chromosomal abnormalities is lower, so we might first check for thrombophilias, do a hysteroscopy to detect any structural issues, or look for chronic endometritis. However, if all these are ruled out, then PGT-A can still be valuable, as knowing the embryo’s status is crucial to avoid recurring failures.
Exactly. Endometritis is an inflammation, and screening for pathogenic factors is also part of the evaluation. These steps are essential, though genetic testing of embryos can add cost and time, and the research shows some debate about its benefits.
The cost of PGT-A can be significant. However, if you balance everything, PGT-A might be more cost-effective in the end. PGT-A typically happens on day 5 embryos, and we know we cannot do a day 6 transfer due to reduced chances, so we freeze. If you do PGT-A and don’t have a chromosomally normal embryo, especially in a medical tourism scenario, you avoid coming back for an embryo transfer, paying for the transfer, and paying travel costs again and again. In the end, PGT-A might be more affordable than repeated transfers and the associated costs.
It’s something we discuss with the patient. PGT-A used to be called PGS, meaning selection. If you have only one embryo, there’s nothing to select. The important part here is to discuss it with the patient and explain: with one embryo, they can choose to transfer without PGT-A and risk unknown reasons for failure, or they can do PGT-A to check for any issues. We’re here to inform them about all sides, and the decision is theirs. If they choose to transfer without PGT-A, they should be aware of the increased risk of miscarriage compared to a PGTA-tested embryo. If it fails, they won’t know the cause.
The more eggs you retrieve, we have evidence nowadays that the chances of achieving the one egg that will be successful increase. Reaching day 5 is a good step, but it doesn’t mean that a day 5 embryo will have normal chromosomes. Depending on the woman’s age, this plays a crucial role.
Not all embryos from day one make it to day 5, so you likely have had some that didn’t reach that stage. If your age is over 40, the more eggs retrieved, the more blastocysts you may end up with due to an average conversion rate of about 50%. Most likely, you’ve had a good egg yield with good sperm, allowing them to reach day 5. But ultimately, it’s a matter of chromosomes.
In the age range of 40 to 42, for example, the literature suggests we may need about 15 to 20 eggs—or even 25, in some reports—to have a chance of finding just one chromosomally normal egg. Also, consider that if the male factor is good, this might help the embryo grow to day 5. However, this doesn’t guarantee normal chromosomes, as this mostly depends on the age of the egg.
Usually, by definition, we are talking about clinical pregnancies, and a biochemical pregnancy isn’t exactly included in that definition. However, biochemical pregnancies are still significant, as they give us some information. For instance, if someone has two or three biochemical pregnancies, this situation needs to be investigated further.
We’re missing some important information, particularly the patient’s age. Additionally, I don’t know the quality of the embryos. If we’re discussing good-quality embryos and the woman is under 40, I would suggest trying again, especially if they are good-quality blastocysts. However, this is a decision that needs consent and understanding, as the chances of egg donation would certainly be higher.
If the patient wants the best possible chances, egg donation would be a 70% success rate. With their own eggs, chances will be lower, and previous failed transfers reduce that chance even further, though it wouldn’t be zero. It’s worth investigating more thoroughly, as there might be issues that haven’t yet been explored. However, the patient needs to be realistic about her chances.
es, by definition, it could cause implantation failure and even miscarriages. For those unfamiliar, lymphocyte antibodies are an immunological condition that could affect implantation. According to some studies, it might not be the only cause, so other factors also need investigation. Immunological status is a critical factor in cases of recurrent implantation failures, though it’s rarer. If we have healthy embryos that aren’t implanting, we need to investigate other immune conditions as well. Reproductive immunology is extensive, and there’s much to consider.
First, the main advice for someone who is 42 and wants to do IVF with her own eggs is to expedite things. Preparing well before IVF is essential, but there’s no guaranteed way to improve egg quality. Various treatments may have some positive effects, but none are miraculous. For example, vitamin D, coenzyme Q10, and folic acid have solid evidence supporting them, as well as melatonin.
A healthy lifestyle—avoiding smoking and drinking—also helps prepare for IVF. Comprehensive testing and choosing a personalized IVF protocol is key, as is having an advanced laboratory that can yield good results. Every situation is unique, so success will depend on factors like AMH.
I’ll explain what we do at Pelargos IVF. First, even immunological testing needs to be personalized. In some clinics, if there are repeated failures, they may just suggest taking steroids or intralipid without a clear reason. There’s a well-regarded review by a French immunologist, which we try to apply in our practice. It emphasizes the need for personalized immunology.
What happens in the blood doesn’t always reflect what happens in the endometrium. Natural killer cells in the blood differ from those in the endometrium. Endometrial natural killer cells aid implantation, but when they become too toxic, they cause problems. You can have hypoactivity, hyperactivity, or a mixed immune condition. If the immune status isn’t clear, giving steroids may cause the opposite effect.
In cases like this, we prefer to check the endometrium with a biopsy, particularly after hormonal replacement treatment, as hormones can alter the immune status in the endometrium. Testing at a random cycle stage would yield different results than after using estrogen and progesterone, since both hormones influence endometrial immunology. After conducting the biopsy, we assess various cell categories in the endometrium, such as TH1 vs. TH2, interleukin-15, interleukin-18, and cytotoxicity markers like CD54. Each one requires a specific approach.
When dealing with hyperactivity, steroids or medications like Plaquenil can be beneficial. In some cases, we might use intralipid or IVIG; however, IVIG is not permitted in Greece. If we unknowingly treat hyperactivity with steroids or intralipid, it could worsen the condition. In such situations, balancing estrogen doses, administering more progesterone (which also influences endometrial immunology), and even using endometrial scratching may be necessary. Everything we do has a purpose.
Our testing involves both a biopsy within the endometrium and general immunological tests for conditions like lupus or SLE, including blood tests and endometrial biopsies.
Yes, the issue usually comes up when we’re discussing thin endometrium. Ideally, the endometrium should be more than nine; more than eight is okay. Less than eight reduces the chances, and less than seven lowers them significantly. A trilaminar endometrium generally appears healthier. If it’s trilaminar, that’s better, of course. If it isn’t trilaminar, you should check for ovulation. We always check progesterone levels, as they’re important, and we’ve seen that without this, things can be missed. We personalize it in cases like that.
Now, regarding the upper thickness, it’s a challenging question. If it’s trilaminar and measures 14, I would proceed without concern. But if it’s very thick, we need to be sure that we aren’t overlooking something like a polyp or a polypoidal endometrium, so we would investigate any underlying causes for why it might be so thick.
Adenomyosis is a very difficult condition. Unfortunately, there is no treatment for adenomyosis itself. A large percentage of cases with adenomyosis are also associated with endometriosis, so when we have or suspect adenomyosis—often, we suspect rather than confirm it—we need to thoroughly investigate for endometriosis as well, as they are frequently connected.
Endometriosis is when the lining of the uterus exists outside the uterine lining. It can be found anywhere in the abdomen, such as the ovaries or ligaments, and typically causes painful periods, pain during sex, or both. Endometriosis can also lead to chocolate cysts. Adenomyosis, on the other hand, involves a thickened uterine muscle. It’s not a fibroid, though it can look similar to fibroid tissue and is spread diffusely. Adenomyosis can be close to the uterine cavity or even within it, and in some cases, there may be endometriotic spots inside the cavity, which can be seen via hysteroscopy or ultrasound.
In these cases, treatment is challenging since there is no direct cure. However, down-regulation before embryo transfer with GnRH agonists can sometimes be beneficial. Surgical treatment for adenomyosis, specifically for fertility, is a very conflicting issue. There isn’t a clear answer; some studies suggest removing adenomyotic tissue might help, but it’s a complex surgery with associated risks, which we usually avoid unless necessary.
iIt’s not an easy condition to manage. In extreme cases, I’ve seen some patients consider surrogacy. It’s indeed a tough one to handle.
There is a lot here. From what I gather, these embryos are not chromosomally tested. Since the embryos are already frozen, it’s generally not advisable to thaw, biopsy, and refreeze them, as this process could compromise their viability. There’s clear evidence that re-freezing can increase the miscarriage rate, even if the embryos are normal.
So, since they are already frozen, the focus should be on investigating other factors that might cause implantation failure, including addressing any immunological issues. However, if the embryos are chromosomally abnormal, even with immunological adjustments, success is unlikely.
Considering the age factor, especially for a woman over 40, the remaining embryos may be of slightly lower quality as the best embryos are typically used first. But there’s still a chance with these remaining embryos, and she can go ahead with the transfer if she wishes.
If this attempt doesn’t work, I would recommend considering another IVF cycle, but this time with PGT-A testing. I’m a strong advocate of PGT-A, especially for women over 40, as we see success rates with chromosomally normal embryos.
Yes, that’s a consideration. In some countries, like Greece, there might be specific regulations about discarding embryos, but that doesn’t apply in Ireland, so you have flexibility. In Spain, for example, once embryos are PGTA-tested and found chromosomally viable, you are required to proceed with them.
As far as we are concerned, we usually test on the day we start progesterone and on the third day of progesterone as well. This way, we can have the levels before the transfer. If the levels are lower, we can administer some injections to bring them up. Usually, if the levels are okay at the time of the embryo transfer and you continue with the same doses of medication, they are maintained. We rarely check after the embryo transfer, but in women who have recurrent implantation failures, it can sometimes be attributed to progesterone resistance. Some theories suggest that women with endometriosis may also have progesterone resistance, so higher levels of progesterone are needed. We do check after the embryo transfer as well. Common practice is to check on the day the progesterone starts and three days later, before the embryo transfer, to ensure we can increase the levels. This practice is not standard protocol in Ireland, so it’s important to request monitoring, as it often isn’t done.
I would say no unless there is a specific reason for the patient to do that. I wouldn’t compromise embryos like that because evidence suggests it doesn’t affect implantation rates but does increase miscarriage rates. It’s different if you have a day-three embryo and can defrost it, let it reach day five, and then biopsy it, compared to having a day-5 embryo, thawing it, biopsying it, and refreezing it.
Recurrent implantation failures, as described, need to be investigated. A hysteroscopy is necessary to rule out any issues. I would also recommend a DNA fragmentation check because we now have evidence that, in addition to antioxidants, techniques like Zymot or MACS might help in selecting the sperm. After all that, I would also recommend PGT-A for the next attempt. It’s a tough journey, and the Zymot and MACS techniques refer to sperm selection methods that can be beneficial.
Yes, endometriosis is associated with miscarriages, but it is not the main cause. I wouldn’t attribute it as the main reason if they get implanted. There might be other reasons as well. Some studies suggest a connection between endometriosis and miscarriages, mainly through the progesterone resistance mechanism I mentioned before. However, I would check for other reasons as well. Given she’s 36 and has 3 frozen embryos left, I’m not sure if she’s had it before.
Not really. Unless we are talking about severe endometriosis, chocolate cysts, active disease, or anything like that, and unless it is associated with symptoms like pain, I wouldn’t recommend it. You can monitor it when we have endometriosis in the frozen protocol. We always do regulate, and if we are talking about mild disease, that should be enough. I wouldn’t put her in a situation of having to do something more invasive.
She has done a lot of things that she should do. First of all, I don’t know what exactly was tested regarding the natural killer cells, etc. Blood tests, biopsy—I don’t know if she has ever tested the implantation window or chronic endometriosis. Endometriosis is associated with bacterial issues, but it is also associated with chronic endometriosis. Even though they are different things, endometriosis is an infection, and endometriosis is what we described before. Many times they are associated. I would check for chronic infection as well. Antibiotics sometimes might be a reason. I would check for a possible implantation window, even though the most recent research and studies have not given a lot of credit to it. We do have cases that have done very well with it. I would ask her what exactly her immunological status is.
Regarding the protocol, given that we are talking about endometriosis and adenomyosis, I would downregulate, as downregulation might help with adenomyosis. It’s difficult, though. I need to know more things about the case to discuss the protocol and what would be best. I cannot give this answer just based on the information provided. If most of those things had been done and accounted for, I think the main concern is that, obviously, with downregulation, they want a medicated cycle because you’re shutting things down. It’s hard for the ovaries; you need the extra help. However, the concern is that research indicates better pregnancy outcomes for non-medicated cycles.
That’s why they’re asking about the modified natural cycle. On one hand, you have adenomyosis and endometriosis, and on the other hand, you have what you said. I don’t know if she has been investigated regarding the things I mentioned earlier. If we do the implantation window in a natural or semi-natural cycle, it’s a bit more difficult to arrange and synchronize everything. Timing is difficult, making it hard to give a definitive answer.
We usually give a smaller dose of melatonin in a supplement that includes other things. Melatonin has a main issue: you need to take it in the evening because it can cause sleepiness. It’s a sleep hormone.
It works in an antioxidant way, like all other antioxidants. Some reports give good evidence behind it. Regarding the dose, I believe it’s around 1 to 3 milligrams. For context, if you were trying to recover from flying transatlantic, you might see doses like 10 milligrams, which is much higher. Provided it’s taken in the evening, right before bed, it’s considered safe. Always check with your caregiver.
That’s a lot to absorb. Before discussing endometrium, immunology, and other conditions, all these things need to be investigated. 39 is not 42 or 43, and you achieved some euploid embryos before, so I wouldn’t jump straight to egg donation. Regarding the sperm, DNA fragmentation can play a role. It’s good to manage it with sperm selection techniques or antioxidants. With sperm, you can select the better sperm; with eggs, you typically use what you have. Better sperm improves the chromosomes possibly of the embryo and the conversion rate to day five. I wouldn’t jump to donor sperm; I’m not convinced this is the main reason. At 39, chromosome abnormalities can occur, but you had a euploid embryo before, so maybe you can achieve another one. Check all other reasons first. Egg donation would provide better chances, but if someone doesn’t want to move to egg donation, they have every right to try with their own eggs.
Staying immobile or resting doesn’t have evidence behind it. We advise, especially for people travelling from abroad, to take it easy for the next three to four days while implantation happens. Mild exercising is fine; avoid over-exercising. Reducing stress, acupuncture, and a healthy lifestyle with a good diet help. I wouldn’t stay in bed. Just avoid overactivity in the following days.
An infection in the embryos? I didn’t understand the infection’s location. The lab results showed a vaginal infection, and it seems that the embryos themselves were infected. Vaginosis can sometimes cause miscarriages, and it needs treatment with probiotics or other things, but it doesn’t directly affect the embryos. The embryos will not stop growing because of the vaginal infection.
At 35, with 9 embryos not in PGT-A, things can change in 2 years. Why not an outpatient hysteroscopy? It wouldn’t cause any issues and would provide information regarding endometritis and other conditions. If possible, I would repeat it.
Not really. If you do have the embryo, first of all, these hot flashes and everything need to be checked to make sure that they are not medication-derived. Then you can do a hormonal profile to ensure that you are entering perimenopause or not because you can see that from FSH levels and things like that. If the embryo already exists, women in menopause or perimenopause still have chances; you just need hormone replacement treatment to achieve the right thickness and to prepare the endometrium.
Where was the interleukin 6 found? In the blood? I can guess which doctor this person saw for that blood work. So yeah, with that, seeing some Plaquenil because of that, I would imagine she probably had the repro flow or Chicago blood done.
You can keep trying with the Plaquenil, but it doesn’t mean that your interleukin 6 is the only reason why it is not working. Many times we look at the rare things. You don’t know if there are other issues like the chromosomes or the embryo. For sure, but, at this young age, something is going on, and this person needs to keep pushing.
If we are talking about 9 miscarriages, that most probably means that she started quite younger with this situation. Things at the age of 44 are very difficult. The chances of success with own eggs to start with are very low, less than 5%. Egg donation will take out the egg factor, which is the main thing right now. However, because we’re talking about 9 miscarriages that most probably started from a younger age, something else might be there as well. There needs to be a good investigation about everything because we are talking about recurrent miscarriages here. It’s a big issue. You know, thrombophilias, immunology, and other conditions as well. Otherwise, even if she goes with egg donation, it might fail again.
While egg donation can be a very good option in some cases, it doesn’t guarantee success. Nine miscarriages, presumably over the late 30s and early 40s, is unlikely to be just the egg. There’s got to be other stuff going on. I know you mentioned hypothyroidism, so make sure to relate Hashimoto’s as well, because I often see that being overlooked.
