Multiple embryo transfers without success can feel overwhelming — but there may still be answers, options, and hope. After multiple failed embryo transfers, what should happen next? In this expert-led Ask Your Doctor Live Q&A, fertility specialists Prof. Panagiotis Drakopoulos and Dr Federica Moffa discuss the latest evidence on Repeated Implantation Failure (RIF), helping patients understand when further investigations are needed—and which tests and treatments truly matter.
Featuring:
Prof. Panagiotis Drakopoulos, IVF Specialist & Founder of Drakopoulos Reproductive Medicine, Greece.
Dr Federica Moffa, MD, PhD, Medical Director of Fertilab, Spain.
Hosted by: Dr Shabana Bora, MBBS, MRCOG, Consultant Gynaecologist, Fertility Specialist & Co-founder of ALMA Fertility, UK.
Repeated implantation failure, often abbreviated as RIF, is one of the most difficult and emotionally demanding situations in fertility treatment. For patients, it can feel confusing: the embryos may have been described as “good quality,” the endometrium may look normal on ultrasound, and yet pregnancy does not happen, or implantation occurs only briefly and ends in an early loss.
The guests’ message was clear: before diagnosing repeated implantation failure, doctors first need to understand the real expected chance of implantation for each embryo. A failed transfer of an untested embryo from a patient over 40 is not the same as a failed transfer of a genetically tested euploid embryo. The first step is therefore not to assume that the uterus is the problem, but to assess whether the embryo transferred had a high probability of implanting.
Dr Federica Moffa explained that, when an embryo does not implant, the starting point should be the expected implantation chance for that embryo.
In other words, doctors should ask: What was the probability that this embryo would have implanted in the first place?
It is not the same situation if the failed embryo came from the eggs of a 42-year-old patient and had not been genetically tested, compared with the failure of an embryo that was tested and confirmed to have normal chromosomes.
Dr Moffa referred to the guideline from ESHRE, the European Society of Human Reproduction, which uses a threshold of 60% expected cumulative pregnancy rate. When a patient should have reached this probability after embryo transfer and pregnancy has not occurred, it may be justified to begin investigations.
For example, if a euploid embryo is transferred, Dr Moffa explained that the implantation rate per embryo transfer is around 55% to 60%. Therefore, even one failed euploid embryo transfer may reach the threshold where further investigation is reasonable.
However, if embryos are not PGT-A tested and come from a patient over 40, the picture is different. In that situation, Dr Moffa said it may take five or six embryo transfers before repeated implantation failure is suspected and investigations begin.
This distinction is important because not all failed transfers mean the same thing.
Prof. Panagiotis Drakopoulos stressed that many patients are labelled with repeated implantation failure even though they have never transferred a euploid embryo.
This matters because embryo morphology alone does not confirm that an embryo is chromosomally normal. An embryo may look good under the microscope but still have chromosomal abnormalities that reduce the chance of implantation or increase the risk of early loss.
In cases where a patient has had multiple failed transfers of morphologically good embryos, Prof. Drakopoulos said that the first step may be to consider IVF with PGT-A, especially if PGT-A has not previously been performed.
He explained that if doctors can transfer euploid embryos, the prognosis becomes clearer. According to Prof. Drakopoulos, evidence shows that if up to three euploid embryos are transferred, the cumulative success rate is around 95%.
As he explained:
If we fail with euploid embryos, then we should talk about recurrent implantation failure.
This was one of the central messages of the webinar: true repeated implantation failure should be discussed in the context of embryos with a strong implantation potential, particularly euploid embryos.
A PGT-A normal embryo, also called a euploid embryo, has been screened for chromosomal abnormalities. However, Dr Moffa and Prof. Drakopoulos both explained that this does not guarantee pregnancy.
PGT-A screens for chromosomal abnormalities related to pregnancy loss and implantation failure, but it does not test for every possible disease or every possible genetic or biological factor.
Prof. Drakopoulos noted that some patients believe PGT-A screens for all conditions, but this is not the case. It screens for chromosomal abnormalities, not everything that may affect embryo viability or implantation.
The implantation rate for a euploid embryo is around 55% to 60%, not 100%. This means that even a genetically normal embryo can fail to implant.
In the future, Prof. Drakopoulos suggested that if techniques develop to evaluate more genes within embryos, the success rate per euploid embryo transfer may increase. But based on current knowledge, a euploid embryo still does not guarantee success.
Dr Moffa discussed a common and sensitive scenario: patients who have only one or two embryos available after several IVF cycles. These embryos are often described as “golden embryos” because of the effort, time, and emotional investment required to create them.
In these cases, Dr Moffa said her approach is proactive.
Before transferring such embryos, especially in patients of advanced maternal age or those with a history of previous failures, she would usually recommend:
Even when ultrasound appears normal, hysteroscopy may help assess the uterine cavity more directly.
An endometrial biopsy may be used to check for asymptomatic endometritis, meaning inflammation or infection of the uterine lining that may not cause symptoms.
Dr Moffa also mentioned screening for thrombophilia and autoimmune parameters.
In some patients, HLA profile screening may also be considered.
The aim is to reduce preventable risks before transferring a limited number of valuable embryos.
A recurring theme throughout the discussion was the importance of checking the uterine cavity, particularly after failed euploid embryo transfers, abnormal bleeding, or before transferring very limited embryos.
Dr Moffa said that, when there is only one or two embryos available, she would perform hysteroscopy even if the ultrasound appears normal.
Prof. Drakopoulos also recommended hysteroscopy in several scenarios, including when there is irregular bleeding before transfer.
The purpose is to check for possible uterine factors that may interfere with implantation, such as structural abnormalities, inflammation, or other cavity issues that may not always be visible on ultrasound.
In patients with recurrent implantation failure, hysteroscopy can be part of a broader investigation rather than a standalone answer.
Both experts discussed endometrial biopsy as part of the evaluation after repeated implantation failure, especially after failed euploid embryo transfers.
Dr Moffa mentioned an endometrial biopsy to rule out asymptomatic endometritis before transferring “golden embryos.”
Prof. Drakopoulos said that in Greece, when a patient has had two failed euploid embryo transfers, one standard approach is to perform an endometrial biopsy and test for:
Chronic endometritis may be silent, meaning it may not cause obvious symptoms. For this reason, a biopsy may be considered even when the ultrasound looks normal, and the patient does not report specific symptoms.
Dr Shabana Bora asked whether EMMA, ALICE and microbiome testing are being used more frequently in recurrent implantation failure.
Dr Moffa explained that, in her practice, when they do an endometrial biopsy, they also perform microbiota testing. She acknowledged that if doctors want to strictly follow guidelines and evidence-based practice, the evidence is not very strong.
However, in true implantation failure, she said, EMMA, ALICE or microbiota testing can be considered.
Dr Moffa clarified that she was referring to endometrial microbiome testing. She also said that sometimes vaginal microbiome testing may be done to avoid the discomfort of a biopsy.
Prof. Drakopoulos said that studies have not been conclusive regarding microbiome testing in general. Personally, he uses endometrial microbiome testing rather than vaginal microbiome testing, although he noted that he does not have strong evidence to support one over the other.
The overall message was balanced: microbiome testing may be used in selected RIF cases, but the evidence is not definitive.
Immune testing was one of the most frequently discussed topics in the webinar.
The specialists agreed that immune factors may be considered in selected cases, but they were cautious about using immune treatments without a clear reason.
Dr Moffa explained that in cases of failed euploid embryo transfers, her team may perform HLA profile screening, including KIR genes and HLA-C profile. This is used to look at the patient profile, the embryo profile, and compatibility.
She said that this approach is influenced by the immunologist in her team and may reflect the Spanish approach to immunological evaluation.
Prof. Drakopoulos said that in Greece, after two failed euploid embryo transfers, his standard approach would include endometrial biopsy to test the microbiome, endometrial immunological profile and chronic endometritis. Sometimes HLA profile is also performed, and treatment is recommended based on the results.
One patient asked about Intralipid after two failed transfers of euploid blastocysts, with antiphospholipid syndrome and elevated peripheral NK cells. One immunologist had recommended cardioaspirin, enoxaparin and Plaquenil, while another had suggested Intralipid.
Dr Moffa said that for complementary treatments, she refers patients to a specialist. In her experience, in such a situation, treatment may include aspirin, heparin and Plaquenil as an immunomodulator. However, she does not usually treat with Intralipid because, in her view, the pros and cons are not balanced and the treatment is not evidence-based enough to justify its use.
Prof. Drakopoulos explained that Intralipid is legal in Greece, but he gives it only to a very small minority of patients. It may be used in patients who have had MatriceLab or IMAP testing, which evaluates the immunological profile of the endometrium, and only if there is a clear indication.
A patient with lupus asked whether immunosuppressive treatment, immunosuppressors or prednisolone should be used before embryo transfer.
Dr Moffa said that with an immune disease such as lupus, the patient should have some immunosuppressive treatment.
The experts were clear that they do not support giving multiple immune or blood-thinning medications blindly, without a diagnosis or rationale.
A patient asked about using prednisolone, Plaquenil and low molecular weight heparin in recurrent implantation failure and recurrent pregnancy loss, even without confirmed thrombophilia.
Dr Moffa said she does not like to give completely empirical treatment, especially combined medication without a rationale. Her team includes an immunologist who evaluates each case individually.
Prof. Drakopoulos agreed. He said that heparin and cortisone are routinely prescribed by some physicians even though there is no convincing evidence to support their use in all cases.
He also warned that treatment without indication can cause problems. For example, some patients take aspirin or heparin for no clear reason and then bleed at 6 or 7 weeks of pregnancy. At that point, doctors must decide whether to stop and restart treatment, creating uncertainty and anxiety.
His message was that every treatment should have an indication.
Thrombophilia was another important topic, especially in patients with recurrent implantation failure, recurrent pregnancy loss, Factor V Leiden, lupus anticoagulant or antiphospholipid syndrome.
Dr Moffa said that her clinic usually screens for:
These include anticardiolipin antibodies and lupus antibodies.
These include Factor V, Factor II, protein S, protein C, antithrombin and homocysteine.
Dr Moffa also mentioned that panels are now available for patients.
Prof. Drakopoulos said his practice is similar. He screens for congenital and acquired thrombophilia, although he added that in most cases it is unlikely to find an abnormality, and results often return normal.
In the case of Factor V Leiden, Prof. Drakopoulos said that a haematologist would usually recommend heparin, sometimes even before transfer. He advised that patients with this condition should be managed together with a haematologist.
One patient asked about multiple blastocyst implantation failures in the context of Factor V Leiden thrombophilia and diabetes, while currently taking Mounjaro.
Prof. Drakopoulos said that for Mounjaro and GLP-1 agonists, there is not a lot of data, although available data is reassuring in the context of IVF.
In most cases, he said, the medication is stopped one month before starting treatment.
The most important point is that diabetes should be well-controlled. This should be managed with follow-up from an endocrinologist, because diabetes control is not only the responsibility of the fertility clinic.
For Factor V Leiden, he again advised consultation with a haematologist and ensuring the patient is on appropriate heparin treatment before transfer if indicated.
A patient asked whether a prolactinoma could affect implantation when hormone levels and uterine lining appear optimal.
Dr Moffa explained that if the prolactinoma is controlled by an endocrinologist, hormone levels are normal, and ovulation is present, it should not normally affect the result.
She added that it depends on whether the embryo transfer is planned in a natural cycle or an artificial cycle. Hormone levels should be carefully controlled, but in general, a controlled prolactinoma should not affect implantation outcomes.
Some patients experience cramping or premenstrual-type pain after embryo transfer. One patient described contractions from day three or four after transfer and had already tried Atosiban and Buscopan.
Prof. Drakopoulos said this is not seen often. Sometimes patients have uterine contractions immediately after transfer, and in such cases the transfer may be done under sedation. Usually, this kind of problem resolves with Atosiban and Buscopan.
For cramps after transfer, he suggested increasing progesterone supplementation, sometimes by adding or changing to a subcutaneous route if the patient is using only vaginal progesterone.
Dr Moffa said she had seen a few patients like this, often with adenomyosis. She agreed that increasing progesterone, particularly subcutaneous progesterone, may help because of its relaxing effect on the uterus.
She also advised avoiding intercourse, because it can trigger uterine contractions. Patients do not need to rest completely, but a more relaxed lifestyle may be advised.
The experts also noted that cramping after transfer may not necessarily be the reason a pregnancy test is negative. It may be unrelated.
Progesterone was discussed as an important factor, especially in hormone replacement therapy cycles.
Prof. Drakopoulos said that progesterone levels are important and that there is now enough evidence to support testing in certain situations.
For HRT cycles, he said progesterone should be tested. For modified natural cycles, progesterone should not be tested because evidence suggests progesterone levels do not play the same role. For completely natural cycles, he described the evidence as a grey zone.
In his practice, he prefers modified natural cycles because they are easier to organise and have clearer evidence regarding progesterone levels.
Dr Moffa said her clinic tests progesterone before transfer and corrects it if it is below their threshold. Their threshold is 11, partly because they work with international patients and cannot always perform testing at their own clinic.
If correction is needed, they use subcutaneous progesterone. Neither specialist reported using intramuscular progesterone routinely.
A patient asked how high thyroid levels and low iron levels may affect embryo implantation.
Prof. Drakopoulos explained that, based on available evidence, if thyroid function is within the normal range, it should theoretically not affect implantation or pregnancy. However, he prefers TSH to be below 2.5.
Regarding iron, he said that if haemoglobin and haematocrit are good, he does not see how low iron levels alone would affect implantation. However, if iron is low, supplementation is simple and relatively low-cost, so it may be reasonable to correct it.
Dr Moffa said her clinic tests thyroid function in everyone and uses a cut-off of 2.5. They also screen for thyroid antibodies, including anti-TPO.
If thyroid function is normal but antibodies are abnormal, they do not give thyroid treatment automatically, but they monitor the patient. She explained that sometimes TSH can rise above 2.5 or 3 just before transfer or after progesterone starts, even if baseline TSH was normal.
Prof. Drakopoulos said he also tests thyroid function and antibodies, but he does not treat anti-TPO antibodies if TSH is normal or below 2.5.
The specialists discussed endometriosis and adenomyosis in the context of embryo transfer planning.
One patient was 40, had lean PCOS, lupus anticoagulant, donor sperm, clinical endometriosis, irregular bleeding, and three euploid embryos after several retrievals. She was planning a modified natural frozen embryo transfer.
Prof. Drakopoulos agreed with a modified natural frozen embryo transfer using ovulation induction, trigger and progesterone. Because of the irregular bleeding, he recommended hysteroscopy and biopsy before transfer.
Regarding endometriosis, he said he generally prefers downregulation. His approach is usually one month of downregulation, followed by a test to confirm whether downregulation has been achieved. If it has, the transfer can proceed in either an HRT cycle or a natural cycle.
He said he uses a similar approach for adenomyosis, tending to downregulate before transfer with either a GnRH agonist or a progestin pill.
Dr Moffa also recommended hysteroscopy and biopsy in this case, due to the bleeding, and she agreed with downregulation.
She added that the presence of a corpus luteum may help placentation and reduce obstetric risk. In some patients, she downregulates and then uses mild stimulation to reach ovulation and trigger, creating a type of suppressed natural cycle for embryo transfer. If possible, she prefers not to use an artificial hormone replacement cycle when ovulation can be induced.
A 47-year-old patient asked whether implantation rates are affected by the age of the mother or womb, and whether surrogacy would offer better odds.
Prof. Drakopoulos explained that the evidence is conflicting.
For euploid embryos, age appears to play some role. For example, in a 38-year-old with a euploid embryo, success may be close to 60%. In a 45-year-old with a euploid embryo, success may be lower, around 50%.
This suggests that age may affect receptivity, especially after 45.
However, he emphasised that age alone is not an indication for surrogacy. He would not recommend surrogacy purely because of advanced maternal age.
He noted that in Greece, the law allows embryo transfer up to age 54. In egg donation cycles after 50, success rates remain very high, although not as high as in patients aged 42 or 43.
The message was that age may have some effect on implantation, but it should not automatically exclude embryo transfer or push a patient toward surrogacy.
One patient had failed three transfers using embryos created from donor eggs and donor sperm. One transfer was implanted but ended in pregnancy loss at six weeks. The embryos were described as PGT-A tested normal, with a 10 mm lining.
The patient wondered whether the issue could be the donor combination and whether the donors should be changed.
Dr Moffa said that hysteroscopy would definitely be the next step.
Regarding “incompatibility,” she explained that this would not usually be understood as real incompatibility with the donors or donor mix. Instead, the HLA profile could be explored to assess whether the patient has a high-receptivity or low-receptivity profile.
The patient also mentioned using prednisolone for only four days. Dr Moffa said that if steroids are used, her clinic continues them until the pregnancy test and then until six to eight weeks, followed by tapering.
Prof. Drakopoulos said his practice is similar, continuing steroids until around six or seven weeks of pregnancy.
The discussion suggested that, before changing donors, the uterine cavity, immune profile and treatment protocol should be reviewed.
A patient asked whether treatment would still be possible after eight implantation failures and no implantation, with previous clear tests such as hysteroscopy, EMMA, ALICE and blood tests.
Dr Moffa said treatment can continue, but probabilities may be narrow. If there have truly been eight failures with euploid embryos, she would question whether the lining is good and whether a uterine factor is affecting the endometrium. If all testing is normal, she would refer the patient to an immunologist.
Prof. Drakopoulos agreed and added that the male partner should also be tested.
The patient later clarified that only two embryos were euploid and that she was 39. This changed the interpretation, because it was not eight failed euploid transfers. At age 39, the patient may still be able to create more embryos and try again.
This discussion reinforced an important principle: the number of failed transfers should be interpreted in the context of whether the embryos were euploid or untested.
Although the discussion focused mainly on the embryo and uterus, Prof. Drakopoulos also highlighted the importance of sperm testing.
In his practice, sperm DNA fragmentation index and sperm oxidative stress are tested in all couples before embryos are created.
He noted that some patients come from other clinics where the male partner has never had DFI testing, so in those cases, he screens the male partner as well.
This is important because implantation failure is not always only a female or uterine issue. Embryo quality also depends on sperm contribution.
The session ended with a strong emphasis on evidence-based care.
Dr Moffa said that the first step is to make sure that the embryo transferred is euploid.
Prof. Drakopoulos advised patients to trust their doctors and trust the evidence behind treatment, rather than relying on “magic” solutions or treatments that promise to dramatically improve success rates.
After multiple embryo transfer failures, the experts’ approach can be summarised as follows:
A failed transfer of an untested embryo is not the same as a failed transfer of a PGT-A normal embryo.
Hysteroscopy may be useful, especially with abnormal bleeding, failed euploid transfers, or before transferring limited embryos.
This may include testing for chronic endometritis, microbiome and, in selected cases, endometrial immune profile.
Screening may be considered, but treatment should usually be guided by a clear indication and specialist input.
The specialists were cautious about using heparin, steroids, Plaquenil, Intralipid or other immune therapies without a rationale.
Sperm DNA fragmentation and oxidative stress may be relevant before embryos are created.
This may include attention to progesterone levels, cycle type, endometriosis or adenomyosis downregulation, and whether modified natural transfer is possible.
Repeated implantation failure is not a single diagnosis with one simple solution. It is a clinical situation that requires careful interpretation of embryo quality, embryo genetics, uterine factors, endometrial health, immune and thrombophilia markers, hormonal preparation, and sperm factors.
As Prof. Panagiotis Drakopoulos and Dr Federica Moffa explained, the first question after failed transfers should be: what was the expected chance of implantation for the embryo transferred?
Only after this can doctors decide whether repeated implantation failure is truly present and what investigations are justified.
For many patients, the most important step is not to add more treatments blindly, but to return to evidence-based assessment: confirm whether embryos are euploid, evaluate the uterus and endometrium, investigate selected medical factors, and personalise the next embryo transfer plan.
Dr Federica Moffa, PhD, Fertilab, Spain: When we face implantation failure of an embryo, we have to start by knowing what the expected chance was for this embryo to implant.
It is not the same to face implantation failure of an embryo from the eggs of a 42-year-old patient without any genetic testing or PGT-A screening, compared with implantation failure of an embryo that has been tested and shown to have normal chromosomes.
The definition and guidelines of ESHRE, the European Society of Human Reproduction, give us a threshold of 60% expected cumulative pregnancy rate in embryo transfer. When we are supposed to reach this probability, and we do not have a pregnancy, then it is justified to start investigations.
For example, if I transfer a euploid embryo, the implantation rate per embryo transfer is around 55% to 60%. So already, one failure reaches this threshold.
But if I am transferring embryos that are not PGT-A tested from a patient above 40, I would face repeated implantation failure after five or six embryo transfers before I am supposed to start investigating.
Prof. Panagiotis Drakopoulos, Drakopoulos Reproductive Medicine, Greece: We do not have the full picture. When the patient says “good-quality embryos,” she probably refers to morphology. Especially in France, they do not perform PGT-A. So I think it is completely different to know whether these embryos have been genetically tested compared with embryos that have not been genetically tested and only appear normal morphologically.
For me, the first thing I would do would be to recommend IVF with PGT-A. I can see that the patient has already undergone several exams, including tests to evaluate the immunological profile of the endometrium. But the first step would be to know whether we can achieve a genetically normal embryo.
Of course, this depends on many factors, including the age of the patient.
I would also add something important for all patients. We now have evidence. It is not like 10 or 15 years ago. We know that if we manage to have euploid embryos and transfer up to three embryos, the success rate is around 95%. This is evidence. In other words, recurrent implantation failure remains for a limited number of patients.
Unfortunately, even now, I see patients labelled with this diagnosis although they have never had a euploid embryo transferred.
If we fail with euploid embryos, then we should talk about recurrent implantation failure. This is an important message for all patients.
Dr Federica Moffa, PhD, Fertilab, Spain: This is a scenario that we face more often now. First of all, we have to make sure that we are going to transfer an embryo with a high probability of implantation.
But what should we do when we have only one or two embryos? We call them the “golden embryos.” These are patients of advanced maternal age who have done several rounds of IVF and have only one or two embryos available.
In those patients, we are proactive.
We definitely do hysteroscopy, even if the ultrasound appears normal. We do an endometrial biopsy to make sure there is no asymptomatic endometritis. We also do a screening for thrombophilia and autoimmune parameters. In some patients, we can also screen the HLA profile of the patient.
Prof. Panagiotis Drakopoulos, Drakopoulos Reproductive Medicine, Greece: I would add another important point for patients.
With PGT-A, the idea is to screen embryos for chromosomal abnormalities, but we do not screen for everything. Sometimes patients believe that by doing PGT-A, we can screen for all diseases. This is not true. We only screen for chromosomal abnormalities that are related to pregnancy loss and implantation failure. The success rate per euploid embryo transfer is approximately 55% to 60%, so it is not 100%.
Maybe in the future, if we have the techniques to evaluate more genes in embryos, we may increase the success rate per euploid embryo transfer even more. Perhaps we may get closer to 80%, but we do not know.
Prof. Panagiotis Drakopoulos, Drakopoulos Reproductive Medicine, Greece: For Factor V Leiden, I suppose the patient refers to a mosaic state. In this case, a haematologist usually suggests heparin, even before the transfer.
For Mounjaro, we do not have a lot of data. However, the data is reassuring regarding the use of Mounjaro and GLP-1 agonists even in IVF. In the majority of cases, it is stopped one month before starting.
What is important is to know that the diabetes is well controlled. This is the most important step, but of course, it is not our job alone. The patient should also have follow-up with an endocrinologist to ensure that the diabetes is well-controlled. For Factor V Leiden, I would recommend seeing a haematologist and making sure that the patient is under heparin before the transfer.
Dr Federica Moffa, PhD, Fertilab, Spain: Normally, if it is controlled by an endocrinologist and the hormone levels are normal, and there is ovulation, it should not affect the results. It also depends on whether we want to transfer in a natural cycle or an artificial cycle.
Hormone levels should be controlled very carefully, but normally, it should not affect the result.
Prof. Panagiotis Drakopoulos, Drakopoulos Reproductive Medicine, Greece: That is an interesting question.
We do not see this often. We may have patients with uterine contractions just after the transfer. In this case, we may do the transfer under sedation. Usually, this type of problem resolves with Atosiban and Buscopan.
What you can try is to increase the dose of progesterone supplementation. Sometimes I try the subcutaneous route if the patient is only using vaginal progesterone. To the best of my knowledge, there is no other medication that has been shown to improve this type of problem.
I have had cases like this. In one transfer, the pain disappeared, and the patient got pregnant. I have also had patients who had this type of pain or cramps and still got pregnant. So I do not have anything else to recommend.
Dr Federica Moffa, PhD, Fertilab, Spain: I have had a few patients like this. Normally, our patients had adenomyosis.
I agree that increasing the progesterone level may help, especially using subcutaneous progesterone, because it may have a relaxing effect on the uterus. I would also advise avoiding intercourse, because patients may not always know that this can provoke uterine contractions.
They can have a more relaxed lifestyle. This does not mean that patients have to rest completely, but they should avoid anything that may trigger contractions.
Dr Federica Moffa, PhD, Fertilab, Spain: For these cases, we have an immunologist in the team.
I do not like to give totally empirical treatment, especially this kind of combined medication, without a rationale.
However, sometimes if we do not see things, it does not mean that there are not slight alterations of the immune system or coagulation system that are not evident in the clinical workup. Basically, I would not suggest empirical treatment. We have an immunologist who evaluates each case individually.
Prof. Panagiotis Drakopoulos, Drakopoulos Reproductive Medicine, Greece: We see this in everyday practice. Heparin and cortisone are routinely prescribed by physicians, although there is no convincing evidence to support their use. I agree that each case needs to be evaluated by a specialist, in this case by an immunologist, to decide if something should be added.
I also do not like to add empirical treatments if there is no indication. Sometimes we may even cause harm.
It has happened many times that patients come to me taking heparin or aspirin for no reason. Then they come at six or seven weeks and have bleeding. Then what do you do? You stop the aspirin or heparin, and then you need to decide whether to restart it or not. We need an indication for all types of treatment.
Prof. Panagiotis Drakopoulos, Drakopoulos Reproductive Medicine, Greece: The evidence here is conflicting.
For euploid embryos, we know that age plays a role. For example, if a 38-year-old patient has a euploid embryo, the success rate is almost 60%. For a patient of 45 with a euploid embryo, the success rate is lower, around 50%.
So yes, age may also affect receptivity. However, age is not an indication to go for surrogacy. My suggestion would not be to go for surrogacy because of age alone. We see more and more that age, especially after 45, may have an effect on receptivity. We also see this in egg donation cycles.
In Greece, the law allows embryo transfer up to the age of 54. We see that in egg donation cycles after the age of 50, the success rates are still very high, but not as high as in patients aged 42 or 43.
If the patient is using a donor embryo or donor egg, the age of the mother is not necessarily a reason not to proceed with embryo transfer. The success rate is still very high. It may not reach 70%, but it is still very high.
So age alone is not an indication to go for surrogacy.
Dr Federica Moffa, PhD, Fertilab, Spain: For these kinds of complementary treatments, we always refer the patient to the specialist.
Here, there are two immunologists and two different approaches. In our experience, in this situation, we are more likely to give aspirin, heparin, and Plaquenil as an immunomodulator. We do not treat with Intralipid because we think that the pros and cons are not balanced. For us, this treatment is not evidence-based enough to justify its use.
Prof. Panagiotis Drakopoulos, Drakopoulos Reproductive Medicine, Greece: In Greece, Intralipid is legal, but we give it to a very small minority of patients. It is really for patients who have done MatriceLab or IMAP tests that evaluate the immunological profile of the endometrium.
If there is an indication there, then in very few patients we may give Intralipid.
Dr Federica Moffa, PhD, Fertilab, Spain: In those cases, we also do the HLA profile to screen for KIR genes and the HLA-C profile, and to see the egg and sperm profile, the embryo profile, and compatibility. This is what we do because of our immunologist, and probably because of the Spanish school.
They screen the patient for this HLA profile. Related to the profile, for example, a double A profile is associated with low receptivity.
They may also give other immunomodulators, such as Neupogen.
Prof. Panagiotis Drakopoulos, Drakopoulos Reproductive Medicine, Greece: In Greece, if I have a patient with two failed euploid embryo transfers, what we usually do is an endometrial biopsy. We test for microbiome, the immunological profile of the endometrium, and chronic endometritis.
For me, this is the standard.
Sometimes we also do the HLA profile. Based on the results and findings, we may recommend treatment. Of course, DFI, meaning sperm DNA fragmentation index, and sperm oxidative stress are also tested in all couples before creating embryos.
Sometimes patients come from other clinics and have never had DFI tested, so in that case, we also screen the male partner.
Prof. Panagiotis Drakopoulos, Drakopoulos Reproductive Medicine, Greece: It is a bit strange that from 71 mature eggs, we finish with only 11 blastocysts. This really requires some investigation.
She has three euploid embryos, one day-five and two day-six. I suppose they will prioritise the day-five embryo. I would agree with a modified natural frozen embryo transfer: ovulation induction, trigger, and progesterone. Because of the irregular bleeding, I would also do a hysteroscopy and biopsy, just to be sure there is nothing there.
I suppose she would also be on aspirin or heparin because of the lupus anticoagulant. Otherwise, if it is a first transfer, I would try with one euploid embryo.
Regarding endometriosis, I generally prefer downregulation. I usually use one month of downregulation and then do a test to evaluate whether downregulation has been achieved. If it has, we start either an HRT cycle or a natural cycle. I have the same tendency with adenomyosis. I tend to downregulate before transfer, either with GnRH agonist or with a progestin pill.
Dr Federica Moffa, PhD, Fertilab, Spain: Because of the bleeding, I also suggest hysteroscopy and endometrial biopsy, as well as downregulation. It is proven that the presence of a corpus luteum can help placentation and reduce obstetric risk.
In those patients, I downregulate and sometimes do mild stimulation to reach ovulation and trigger. It is a kind of suppressed natural cycle for embryo transfer. If possible, I prefer not to prepare with an artificial hormone replacement cycle if we can induce ovulation.
Dr Federica Moffa, PhD, Fertilab, Spain: There were 3 transfers of blastocyst embryos proceeding from two donors, and PGT-A tested normal embryos.
Definitely, I would go for hysteroscopy. That is for sure. She already received treatment with heparin and corticoids, and extra immune support. Regarding the question of incompatibility, in this patient, we could explore the HLA profile. It is not a real incompatibility with the donors or donor mix. It is more to see if her profile is of high receptivity or low receptivity.
Dr Federica Moffa, PhD, Fertilab, Spain: If we give steroids, we continue them to the pregnancy test and then up to six to eight weeks. Then we taper off.
Prof. Panagiotis Drakopoulos, Drakopoulos Reproductive Medicine, Greece: We do the same. We give steroids for 6 or 7 weeks of pregnancy.
Prof. Panagiotis Drakopoulos, IVF Specialist & Founder of Drakopoulos Reproductive Medicine, Greece: Based on the available evidence, if the thyroid is in the normal range, theoretically it does not affect implantation or pregnancy.
Nonetheless, I prefer to have TSH below 2.5.
Regarding iron, to the best of my knowledge, if the patient has good haemoglobin and haematocrit, I do not see how low iron levels would impact implantation.
Of course, this is similar to vitamin D. If we can supplement the patient and it is easy to do so, why not?
If we find a patient with low iron, why not give iron for one month? These are things we can modify and that do not really increase the cost for the patient.
Answer: Dr Federica Moffa, PhD, Fertilab, Spain: We test thyroid function in everyone, and our cut-off is 2.5. We also always screen for thyroid antibodies, including anti-TPO.
If someone has normal thyroid function but abnormal antibodies, we do not give thyroid treatment, but we monitor.
Many times, in these patients, if we test TSH just before transfer or when we start progesterone, sometimes it goes over 2.5 or 3, even if the baseline TSH was normal. We sometimes observe this, probably as very subclinical hypothyroidism.
Prof. Panagiotis Drakopoulos, Drakopoulos Reproductive Medicine, Greece: We also test, but personally, I do not treat anti-TPO antibodies if the TSH is in the normal range or below 2.5.
Dr Federica Moffa, PhD, Fertilab, Spain: Normally, we screen for anticardiolipin antibodies. We screen for lupus antibodies. We screen for Factor V, Factor II, protein S, protein C, antithrombin, and homocysteine. Today, there are also panels that we can offer to patients.
Basically, we screen for antiphospholipid parameters. As mentioned, we also screen thyroid antibodies, including anti-TPO.
Prof. Panagiotis Drakopoulos, Drakopoulos Reproductive Medicine, Greece: For thrombophilia, it is the same. We screen for congenital and acquired thrombophilia. I have to say that it is highly unlikely to find something in the majority of cases. Most results come back normal.
But yes, we do the screening as well.
Dr Federica Moffa, PhD, Fertilab, Spain: Of course, we can treat and continue with new rounds, but the probabilities are narrow. If she had 8 implantation failures with euploid embryos, I would wonder whether the lining is good and whether there is a uterine factor that is affecting the endometrium.
Again, if all blood tests and immunological screening are normal, I would refer the patient to the immunologist.
Prof. Panagiotis Drakopoulos, Drakopoulos Reproductive Medicine, Greece: I agree. Maybe also test the male partner. Eight implantation failures with euploid embryos is something I have never had in the past. But we also need to know whether all eight were really euploid embryos.
We also need to know the age of the patient. If she is over 40, it is different.
Prof. Panagiotis Drakopoulos, Drakopoulos Reproductive Medicine, Greece: Absolutely. Progesterone levels are important, and we now have enough evidence to support this. This is especially important for HRT cycles. For natural cycles, it is still a grey zone.
In my practice, I prefer modified natural cycles because in that case, we know that progesterone levels do not play a role, and this has been proven.
If patients undergo HRT cycles, progesterone should be tested. If they undergo modified natural cycles, progesterone should not be tested.
For natural cycles, it is still a grey zone. Personally, I do not do completely natural cycles because timing and organisation are quite difficult.
Dr Federica Moffa, PhD, Fertilab, Spain: I totally agree. We test progesterone levels before transfer, and we correct them if the level is below our threshold.
Our threshold is 11, because we have patients from other countries, so we cannot always perform the test in our clinic. We use this threshold and correct with subcutaneous progesterone. We do not use intramuscular progesterone.
Dr Federica Moffa, PhD, Fertilab, Spain: With an immune disease like lupus, the patient should have some immunosuppressive treatment.
Dr Federica Moffa, PhD, Fertilab, Spain: In our practice, when we do the endometrial biopsy, we also do microbiota testing. If we want to follow guidelines and evidence-based practice, the evidence is not so strong. But I think that in real implantation failure, we can also do EMMA, ALICE, or microbiota testing.
I am referring to endometrial microbiome testing. Sometimes we do vaginal microbiome testing to avoid the discomfort of a biopsy for the patient.
Prof. Panagiotis Drakopoulos, Drakopoulos Reproductive Medicine, Greece: Studies have not been conclusive regarding the use of microbiome testing in general. Personally, I use endometrial microbiome testing and not vaginal microbiome testing.
I prefer endometrial testing, but I do not have strong evidence to support the use of one over the other.
Dr Federica Moffa, PhD, Fertilab, Spain: As we said at the start, first of all, make sure that you transfer euploid embryos.
Prof. Panagiotis Drakopoulos, Drakopoulos Reproductive Medicine, Greece: Trust the doctors and trust the evidence behind the treatment. Do not believe in magic filters or treatments that will exponentially improve your success rate.
As Federica said, testing and transferring a euploid embryo is the most important step.
