Recurrent implantation failure (RIF) – success stories

Elias Tsakos MD, FRCOG
Medical Director , Embryoclinic

Embryo Implantation, Failed IVF Cycles, Success Stories

From this video you will find out:
  • What is the definition of Recurrent implantation failure?
  • What are the most common possible causes of RIF?
  • What kind of investigations and treatment options are there to treat a patient with repeated implantation failure?
  • What is the role of the endometrium in Recurrent Implantation Failure?

Successful pregnancy outcome in women with recurrent implantation failure

In this webinar session, Dr Elias Tsakos, FRCOG, Medical Director at EmbryoClinic, Thessaloniki, Greece, talked about recurrent implantation failure, available treatment options, and once again all was based on the examples of patient case studies.

Repeated Implantation Failure – Patients’ Stories

- Questions and Answers

I’m currently doing embryo banking at a clinic abroad. I’m 41, and I got 2 frozen embryos when I was 40. Next year, we will proceed with the transfer, I have a small endometrial polyp measuring around 5 millimetres. Do you recommend removing it before the transfer, or is it not necessary? I want to ask if there is any risk when doing repeated stimulation cycles. I have a family history of breast cancer and was wondering about the risk these hormones entail if taken repeatedly?

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.

What is your opinion about endometrial scratch? Do you believe it has a role to play in increasing implantation chances? How would you include it in a cycle, and how long before embryo transfer?

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.

In place of hysteroscopy, would saline sonogram work?

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.

In my country, we do not have access to the ERA test. How else can we determine if we are in the right implementation window? Is there a minimum number of hours of progesterone intake before blastocyst transfer?

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.

Does implementation failure get worse with age? After how many attempts should you stop? Is PGS testing worth it?

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.

Related to the implantation failure with donor eggs, is PGS testing worth it?

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.

When do you suggest uterine surrogacy after many recurrent implantation failures without a known factor?

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 had an egg collection in the UK. I’m 39, we have had 2 failed cycles. My question is what to do or ask to ensure the best possible transfer this time? If we are lucky enough to have day-5 blastocyst, what can I do to improve the chances of implantation?

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.
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Elias Tsakos MD, FRCOG

Elias Tsakos MD, FRCOG

Dr Elias Tsakos, FRCOG, is a Medical Director of Embryoclinic - Assisted Reproduction Clinic in Thessaloniki, Greece. He has received extensive and certified training in the United Kingdom and is a Fellow of the Royal College of Obstetrics & Gynaecology. Dr Tsakos is also a Board Member Representative of the Royal College for Greece and Cyprus and a Board Member of the Hellenic Society of Assisted Reproduction. He is a Member of the British, European and American Fertility Societies (BFS, ESHRE, ASRM). Dr Tsakos has been living and working in Thessaloniki, Greece, since 1999.
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Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is managing MyIVFAnswers.com and has been hosting IVFWEBINARS dedicated to patients struggling with infertility since 2020. She's highly motivated and believes that educating patients so that they can make informed decisions is essential in their IVF journey. In the past, she has been working as an International Patient Coordinator, where she was helping and directing patients on their right path. She also worked in the tourism industry, and dealt with international customers on a daily basis, including working abroad. In her free time, you’ll find her travelling, biking, learning new things, or spending time outdoors.