In this webinar session, Dr Elias Tsakos, FRCOG, Medical Director at EmbryoClinic, Thessaloniki, Greece, talked about recurrent implantation failure, and available treatment options, and once again all was based on the examples of patient case studies.
Implantation failure is the failure of IVF (In Vitro Fertilization), as there wouldn’t be a failure without an artificial treatment (IVF or ICSI). Dr Elias Tsakos mentions that the widely accepted definition of RIF is failure after three attempts at implantation of high-quality embryos. In other words, RIF means a failed IVF at an early stage, in which there’s a starting pregnancy that does not move on to become a viable pregnancy to produce a healthy child.
The failure of RIF could either be in the biochemical phase. Therefore, it could happen at the stage where the pregnancy is only identified by the HCG hormone test, the hormone pregnancy test, or the beta HCG, or it could be a clinical miscarriage.
Dr Tsakos shares three cases of implantation failures that he vividly remembers.
Dr Tsakos, before the lockdowns, offers an online consultation to provide second opinions to patients from all over the world who can also send details about their medical notes. He tries to identify and unravel the mystery of a possible diagnosis that has been missed. Dr Tsakos remembers about this case a very nice and longitudinal view of a uterus and scans where everything looked normal, yet he couldn’t identify from the notes what was going on.
The woman moved on to egg donation before attending the clinic. As she was in her early 40s, it was thought that maybe the miscarriages were due to chromosomal anomalies associated with her age, even though she never had a couple’s karyotype or a karyotype analysis of the products of conception nor PGT-A. It was also considered that it was associated with ovarian quality and her age; nevertheless, she also had implantation failure with egg donation.
When she arrived after having around 7 failed IVFs, 2 failed and 5 had early miscarriages. All the investigations looked normal, yet it depends on how they’re all defined. Dr Tsakos, later on, said the following:
Under no circumstances can we ever, ever, be sure that we’ve done everything.
Many patients, from the US or Australia who tend to be over-investigated, ask Dr Tsakos to do everything, and he clearly states that:
at no given point we can claim that we’ve done everything, there’s always a little bit missing.
The patient returned and Dr Tsakos investigated a little bit more for solid possible factors after the transverse section of the patient’s uterus he identified a huge uterine diaphragm that has been missed which was also associated with her vaginal diaphragm. Uterine Diaphragms are congenital anomalies that women are born with and have no effect on the period and cycle of menstruation, and there is no pain during sexual activity. If they’re missed, they’re present in either miscarriages or implantation failures.
This patient had a big congenital disorder which was picked up on the scan. Dr Tsakos performed the hysteroscopy successfully and created a roomy uterus. He divided the vaginal diaphragm and did an ultrasound scan to ensure that the urinary tract was in good shape, as there are anomalies associated with the urinary system. The patient went on with egg donation, and it was successful for the first time.
Dr Tsakos recognizes that the uterus was taken on a transverse plane, and sometimes it can be missed. It can also be missed if there’s a uterine diaphragm which is not exactly central or if there’s one normal cavity of the two, probably in a lady with a fairly large body frame. He urges colleagues and patients to ask about the chance of a congenital anomaly of the uterus.
As scanning cannot be completely certain, except in a big diaphragm, he generally insists patients undergo some sort of imaging of the uterus, in the form of HSG or hysteroscopy or both. The first take-home message from Dr Tsakos is to:
make sure that the uterus has been checked properly before digging deep into rare factors such as immunology, killer cells, implantation windows or phospholipid syndromes and so forth.
Hydrosalpinx is a condition in which the tubes are damaged, usually due to infection, and it’s generally asymptomatic (no symptoms). There was no history to indicate that the woman has hydrosalpinx. Sometimes, if hydrosalpinges are big they’re picked up by scan, but some of them may not be picked up on scan. The only way to be picked up is by a formal HSG test.
This patient underwent salpingectomy in England and had successful IVFs in his clinic on two separate occasions. She produced two healthy infants two to three years apart. Dr Tsakos emphasizes remembering about women’s tubes.
Another take-home message from these first two cases is to remember the basis of pregnancy and the importance of the environment of the uterus and the tubes. There’s a misconception that the tubes aren’t important in IVF. This is true as long they’re not hydrosalpinges.
In case they are, accumulation of fluid and toxins within the tube may be associated with implantation failure, miscarriage, ectopic pregnancy and so forth. It could also be a source of infection which can produce problems for the woman at a later stage, even if it’s not notorious.
Most laparoscopies have been done on women in the late 40s or 50s, after their reproductive period has finished, with pelvic infection secondary to hydrosalpinx. Apart from the effects of IVF, hydrosalpinx should be ruled out and treated by salpingectomy for the sake of the good health of women.
He reviewed investigations and the patient had very thorough uterine checks with scans, 3D scans, HSGs, hysteroscopies and laparoscopy to exclude endometriosis. She also had all sorts of biochemical testing, hormonal testing, infection testing and ERA testing.
Her partner had extensive investigation with the DNA fragmentation index and everything looked normal, as well as the karyotype of the couple and the genetics of the embryo. The embryo looked fine in the photographs provided by the previous units and, indeed, there was no obvious reason.
This case took the doctor a few hours. The patient flew over, and they did 4 exams, repeated some tests to identify factors that may have been missed and went on repeating some thrombophilia testing and there was nothing they could identify. Dr Tsakos decided to look at the implantation protocol.
He then states something to take into account:
There are at least 100 points where a protocol can go wrong, in the stimulation, in the trigger, in how we fluctuate the hormones in the times that we administer the drugs, in the times we do the egg collection, in the times that we allow the culture of the embryo, after and before thawing and, of course, in the technique of embryo transfer. Each one of us has a different success rate on embryo transfer. That’s why we tend to let the most senior person in the unit perform the embryo transfer in especially difficult cases.
Dr Tsakos later on identified an issue in the administration of progesterone. This patient, in the first few cycles, had three transfers, so on the first transfer, the progesterone was administered in line with the implantation window associated with the day-3 transfer. For some reason, this protocol has been done again for the later transfer (blastocyst transfer).
In the first few attempts, as it had an embryo transfer of questionable quality because they were day-3 embryos but with good protocol in line with day-3 implantation, on day-5 of embryo implantation she was given two days less progesterone than she should’ve been given. For this reason, the endometrium was for a day-3 transfer and she had a day-5 transfer.
Dr Tsakos expressed that it was a critical issue which was diplomatically addressed to the patient. The same embryos were used, but the protocol changed. This ended in a successful pregnancy for the lady. This is a very fine example of the importance of the finest detail in the management of patients, and how important it is for patients to be empowered by knowledge. Dr Tsakos asks kindly for patients to challenge them in every decision and step they make. He then states that one of the promises he’s made over the years it’s that, hopefully with simple forms of AI, they can very soon have patient control software, so patients can have control of their treatment on very basic stuff.
He also expresses that:
We’re having lots of conferences discussing the value of various drugs of stimulation, the value of different routes of administration, of various protocols, and then we can just fail because we don’t give the progesterone long enough, or we don’t start it on the right day.
Dr Tsakos explains that the reasons for a current IVF failure could be either uterine or, so to speak, environmental. They could be male factors, embryo factors, genetics and it could be the protocols they use. He further discusses that the environment of implantation is normal and, as a simple rule, he always requests a very high-definition ultrasound scan of the internal organs of the female, usually, coupled with some sort of imaging.
He’s a great fan of hysterosalpingography, even though it’s a bit old-fashioned technique, he states that it gives them a good second opinion apart from their scanning diagnosis, usually coupled with the hysteroscopy. He then states that he does not perform laparoscopies very often, although there’s some evidence that there may be some factors which can be identified by this procedure as well as implicate IVF. However, laparoscopy is a noninverted procedure.
According to Dr Tsakos’ opinion, hysteroscopy is part of the baseline investigation and, of course, more valuable in current miscarriages. He looks out for congenital anomalies of the uterus, polyps, myomas, adhesions, and evidence of infection and he likes to ensure that the uterus has been thoroughly checked, at least two to three months before the implantation.
Another factor of RIF includes thrombophilia. There is some evidence that there may be an association between antiphospholipid syndrome, thrombophilia and recurrent failures.
Moreover, according to Dr Tsakos, male factors need to be investigated although, with the use of ICSI, they can ensure to pick the top-quality sperms. Currently, there’s a new technology coming out helping them to identify the best quality sperm. The embryo quality is also very important. The culture media, the culture techniques and the culture technology have improved over the years.
To have an idea of what an IVF lab looked like 30 years ago, he says to look at the phone or car used 30 years ago compared to a current one. This is also how technology has evolved in the IVF lab.
Another important factor of RIF is the human factor in performing the ICSI. He states that they do not do body ICSI yet, although he wouldn’t be surprised if they start doing it at some stage but they still need highly skilled laboratory colleagues, not only to perform the techniques but also to ensure that the environment of the lab, media, loading of the needle, embryo transfer in a uterus that has been prepared is perfect with the largest possible attention to detail.
Even though evidence is not brilliant with current implantation failures, Dr Tsakos generally suggests the addition of aspirin and low molecular heparin. He considers that these cheap drugs with no major side effects, in a small proportion of cases, can be helpful especially when we have some question marks with regards to immunology and other factors.
Dr Tsakos moves on to say to make sure there’s no infection. There are a lot of high-tech ways to check for infection; therefore, he insists to ensure that the environment does not contain any infective factors. He states that he wouldn’t disagree with some of his colleagues in the use of empirical antibiotics before the implantation.
Patients with recurrent implantation failure are the most valuable patients they have. They have patients in who they test their trust, connection, openness and understanding. He considers that they are not only the most challenging cases but also the cases in which his trust and his medical knowledge are challenged. Dr Takos later on emphasizes the following:
I would like to personally thank all my patients who failed multiple times with us and kept on coming, kept on trying, kept on working with us, kept on hoping with us and gave us the strength to give them a little bit extra, a little bit extra, next time, and I’m very grateful to them and in particular, I have a darling patient. This is Emily. Thank you so much after so many failures with us, you kept trying, you kept your faith and thank god you’re a few weeks pregnant…
Related reading:
Firstly, yes, keep on banking the embryos. Just make sure that these are good quality blastocysts. I would encourage that. When we feel that we’re confident with the outcome, the question is your age, we would need a good number of embryos, and again that depends on whether these embryos are PGT-A tested or not. On the other hand, do not delay the embryo transfer too much. Although the success rate depends on the quality of the blastocysts, unless we’ve done genetic scanning, we’re not sure of the quality of the blastocyst. Unfortunately, the rate of chromosomal abnormality and DNA anomaly of the embryos at your age could be as high as 50 or 60%.
In regard to the polyp, absolutely, yes. Go ahead and remove it but do it soon before you do the embryo transfer, don’t delay this too much because we’re always a little worried about polyps in women over the age of 40. The chance of malignancy and cancer is extremely low, but it is not 0, so it is not just for reproductive reasons, it’s also for your own health. I would strongly suggest having a hysteroscopy.
When it comes to your family history, my team and I are very sensitive, a breast assessment is one of our obligatory tests to have a formal breast assessment before. Our Breast specialist in our team happens to be my wife, and she has threatened to divorce me if she ever found out that we did IVF on anyone without a formal breast assessment. I’m also very sensitive about breast cancer because I lost my mother to breast cancer, and this is the reason I became a doctor, unfortunately, breast cancer is very common. The rate in western societies could be as high as 1 in 7, 8 women. Whether it’s associated with IVF or not, there’s good evidence now to recommend that there’s no association. In other words, there’s no causative association that IVF cause breast cancer. However, if someone has a small lump and that lump is undiagnosed, and if that person undergoes IVF, this lump will grow, but it will also remain undetected during pregnancy and breastfeeding. I’m very sad to share with you the fact that in my unit, we pick up 2 to 3 cases of breast cancer before IVF through our screening program. Have a very thorough breast exam. I know that the European scenario is that in the majority of the European countries, official breast screening offered free doesn’t start before the age of 40 or before the age of 45 in some countries that doesn’t mean that this is justifiable because, unfortunately, about 50% of breast cancers occur in women under the age of 40.
Make sure you have your breasts properly checked, and when I say properly, I mean check it with mammography or ultrasound or both. Breast self-examination, even medical examination, would not be showing enough before starting IVF. Breast cancer and family history is a very long discussion. However, the definition of family history of breast cancer is that if you have 1 or 2 relatives who develop breast cancer at a younger age, younger than 50 or 45, and the majority of breast cancers are not genetically linked, so in other words, they’re not associated with the genetics. The BRCA gene is associated with high-risk breast cancer, so have your own doctor give you a risk assessment. Your grandmother or aunt who developed breast cancer at the age of 60 does not count as a family history. Having said that, have a formal assessment of your risk for breast cancer based on your family history, other associated factors like alcohol and smoking, previous possible issues on breasts, and please make sure that you have a recent accurate breast assessment before starting IVF.
Endometrial scratch was very popular until some years ago. A couple of years ago, some evidence showed that it’s possibly not associated so much with success. However, I think it’s an opportunity to get some more information about the uterus, and I usually suggest hysteroscopy and endometrial biopsy before IVF in women over 40. I would not suggest hysteroscopy for women under 40, with normal scanning, no previous history of miscarriages and no risk factors of endometrial pathology. However, in women with recurrent implantation failure, I would very much like to have hysteroscopy at least 6 months before another implantation.
Now, scratching could be performed either with hysteroscopy, or it could be performed independently. In either case, I think it’s an add-on that may give us some more information. Although I don’t expect miracles from it, I generally wish to have some evidence from the endometrium and the substance we remove from the endometrium, I would like it to be checked both histologically, and I would like an infection test on it.
I’d like to share a recent case of a lady in her early 40s, she’s only 41-42, she had 2 implantation failures, she had a small fibroid of 3 centimetres not touching onto the cavity so much. We’ve done hysteroscopy, and there was mainly normal endometrium on the scans, we’ve done hysteroscopy, mainly to ensure that the fibroid was not distorting the endometrial cavity. The cavity looked fairly normal, I took a biopsy, and the biopsy showed sarcoma malignant, which is a very dangerous type of uterine cancer. The lady went on and had a hysterectomy, and that confirmed the diagnosis, she moved on to surrogacy after that, and that lady had her life saved, basically because we did that. It’s a rare case, it’s a case report we’re going to present soon, thankfully, it’s very uncommon. The women we’re dealing with are more often than over 38-40 years old, so the chance of uterine pathology is fairly high, especially in women with a current implantation failure.
Yes, the answer is yes. However, the diagnostic accuracy is lower compared to hysteroscopy. A saline sonogram is an ultrasound imaging of high quality, so this cannot replace by any means the direct visualization of the uterus.
Neither in Greece and to be honest, in my practice, I don’t use it at all. I’m not convinced with the evidence so far. Designing the protocol is an art, and that has to do with the quality of the embryos, the stage of the embryos, sometimes the hours are important, the type of progesterone we use, the type of estrogen we use, how we monitor that in terms of both. Also, the effect on the endometrium, we do hormonal tests to ensure that there’s no progesterone rise before we start counting the progesterone days and all that. There are a lot of little hidden mysteries.
We can either do a fresh or frozen cycle. In the first half of embryo transfer, I’m very particular about the progesterone levels, I’d like the progesterone levels to be low, I measure progesterone quite frequently, and I become a little nervous when progesterone before the trigger is higher than 1 nanogram. I always perform progesterone levels on the day of the egg collection. When I’m considering a fresh embryo transfer, I need to make sure, and I need to be sure, that I’m happy with the progesterone levels being low enough and not even being anywhere close to the grey zone. It’s because I understand that the accuracy of our assays and our measurements is not brilliant for progesterone at those low levels. If that’s the case, then I move on to fresh embryo transfer as long as I have a good ultrasonic appearance of the endometrium.
If I’m in doubt, I do freezing, the decision of freezing also depends on other factors like the quality and the number of the embryos. If I have one precious embryo, perhaps I would save it for a frozen embryo transfer, where I would feel more confident that the progesterone would be lower. There are a lot of ways to do the protocols, many people don’t do down-regulation. In 90% of cases, they’re right, however, in my practice, I perform downregulation with a single depot injection of GnRH analogue before frozen embryos transfer. If I decide on a medicated cycle, sometimes I choose a natural cycle, and I always measure the hormones, not just the progesterone but also oestrogens and LH trying to correlate and trying to understand as closely as possible when the implantation window is going to occur.
In general, for blastocyst transfers, I like to have 5 days of full progesterone, but it’s not just the progesterone, it’s how we administer it and how good is the environment of oestrogens that we had.
Age is one of the factors associated with implantation failure, and when it comes to age, there are two elements. One is the age of the oocytes, and the other is the age of the carrier. They could both have an effect, the biggest effect is the oocyte age. Age is important, so is obesity, smoking, stress, so any lifestyle factors may also affect implantation. If someone is between 40-45, which is the most common age group for implantation failures, and they’re using their own eggs, to be honest, after 2 or 3 implantation failures, I would encourage the use of PGS. The chromosomal DNA anomaly is one of the major factors of implantation failure in that age group. With the help of PGS testing those embryos, I avoid the question mark of the possible reasons for failure, so this is a take-home message, over the age of 40, I have a very low threshold in performing PGS.
If someone is producing PGS normal embryos up until the age of 45 and if all the other factors we can perhaps think of are normal, I would keep going. In theory, PGS euploid embryo could produce a healthy child, so medically, you could keep going. It all depends on how you feel about egg donation, how much support you have from your partner, your environment, your clinic, and how quickly you want to become a mother. This is not a very quick way, so if you feel tired after trying for years, and if you want to get there and shorten the time to pregnancy, then possibly you should consider egg donation. With the egg donation the tables are turned, the chance of success provided everything else is normal provided sperm is fairly normal, and you don’t have any serious associated factors, you could be talking of a success rate of up to 70% per cycle and more than 90% per cumulative pregnancy rate per egg donation cycle.
When to stop is something very personal. You would need the advice of your team and the support of your family members towards that decision. There are a lot of factors to take into account, but by all means, I would highly suggest PGS testing of embryos over the age of 40, especially with IVF failure history.
In my opinion, no. Provided the sperm is normal, the male has normal Karyotype, and there’s no reason to suspect any sort of male chromosomal abnormality, and we’re using a young donor under the age of 30, the chance of chromosomal abnormality on the embryo is extremely low. In my opinion, it’s not worth doing PGS testing.
Scientifically, the value of PGS increases over the age of 35. However, with egg donation cycles, because miscarriages do happen, the overall chance of miscarriage in my unit with egg donation is in the region of 10 to 15%, which is fairly low. If you think that we’re talking about women over the age of 40 where the natural pregnancy or the own oocytes’ miscarriage rate could be as high as 50 or 60%. We need to eliminate the other factors I was talking about before, the uterine factors, male factors, environment factors, haemophilia infections, and so on.
With surrogacy, anyone can get pregnant because, as we all know, they don’t need the uterus, they don’t need the sperm, they don’t need the ovaries, they don’t need the oocytes. In surrogacy, we can use foreign genetic material, and I think this is an absolute miracle. I have a lot of patients coming to us for surrogacy, who haven’t tried egg donation or who have had multiple IVF failures in the early or mid-40s or late 40s, and they feel that service is the way forward without even trying carrying a child through egg donation themselves.
The way to surrogacy in this pyramid is after trying your own eggs, try egg donation, make sure you optimize all the factors that could affect a healthy pregnancy, so make sure your uterus is well checked, make sure you have your hormones, your infections checked, and a male factor is tested, karyotype, cystic fibrosis, you’ve done all alterations to your lifestyle that could be associated with better results. I think there’s a very small proportion, maybe 5% of women who fail when everything else is normal after 2 or 3 egg donation attempts. For that 5%, I would possibly consider embryo donation because some of these couples may produce embryos of questionable quality due to male factors. Then I would use the double donation, embryo donation, and if that failed, I would probably move on to surrogacy. I would also move on to surrogacy if there are limiting factors in the uterus. If someone has multiple fibroids or huge adenomyosis or adhesions, we hate adhesions in the uterus because there’s very little we can do at the moment to treat them. If they’ve had multiple D&C, multiple operations on the uterus, and so forth, then I would move on to surrogacy quicker.
As long as a female under the age of 50 has a fairly healthy uterus and a fairly healthy endometrium, and they’re willing to use egg donation or sperm donation or both, there’s a very small proportion of those patients, less than 5% that would need surrogacy.
I will give you some simple advice, try to improve your lifestyle factors, so smoking, alcohol, exercise, diet, stress, those 5 factors. Secondly, try to create blastocysts and try to have the most experienced person on the team do the embryo transfer for you, and I think that’s it. Day-5 embryos, blastocysts, need five days of progesterone. Follow the advice, have a look at the protocol, and hopefully, you will make it. At 39, if you produce 3 or 4 good quality blastocysts, you have a good chance of success, so go for it.
