Causes of repeated implantation failure

In medicine, there are no healthy people, they are just badly examined. My mom was a professor of gynecology, and it was her famous phrase to students: how do you know that at the age of 46 you generate a healthy embryo, you generate embryos, which are A, B, AB of morphology, but to tell you if they are healthy or not, the only way to do it is PGT-A, it’s to take 1-5 cells out of each embryo and send it to the genetic lab and see if it’s healthy or not health. If you’re telling me, you are 46, and you had 3 or 2 embryos, you had probably good quality embryos defined morphologically, but nobody has checked them genetically.

If you want to be a mom, I’ll be more than happy to talk to you in person tomorrow. If you are 46, my colleague nurses will be more than happy to send you a chart with the number of genetically normal embryos that we generate in different age groups, and then, we’ll need to decide if we do one cycle with your own eggs and genetic testing of them or embryo banking because your AMH is low or you’ll say, statistically at the age of 43-46 less than 10% of generated embryos are healthy, they’re good-looking, they have good morphology. I don’t know if your embryologist told you that those embryos have the potential of implantation, but they were not verified genetically, which is the most common implantation issue that we face in advanced maternal age.

We do not perform it. There are different papers published about HCG. We do HCG injections after transfer because this increases the lining receptivity, this is something that we do. I wouldn’t say that we do it routinely. 3-4 four years ago, there was a paper published about HCG effect and receptivity. Before I would treat you with HCG, I would like to define if you have healthy embryos or not. I would like to know your implantation window because if you transfer genetically unhealthy embryos, and you transfer them outside of the implantation window, no matter how much HCG you’re going to put, it’s not going to work. Before I go ahead with this kind of unconventional medicine, I would need to know your euploidy rate and implantation window.

No, not at all. My first contact in reproductive medicine was about 15 years ago in the Detroit area where we were developing embryos to day-3, and I don’t believe that I’m going to say it, but I will say that we were transferring 3 embryos under day-3 of development because we knew that at the age of 40, 1 of them could be health, so through transferring more embryos, we were hoping to increase pregnancy rates. Now, it’s a history of medicine, now we wait till day-5 of the embryo development and do PGT-A testing on them as we know that through proper embryo selection. If you transfer one single embryo after PGT-A or egg donation, your pregnancy rates at 70%. We try not to transfer 2 embryos at all. We select them that well, which modern reproductive medicine wants us to do.

I used to take hydroxychloroquine myself for systemic scleroderma, an autoimmune issue, and for me, it didn’t work at all. Some clinics use hydroxychloroquine for TH1 and TH2 ratio abnormalities. I can tell you that we used to use Humira, which was a problem to administer because those are injections. Now, for TH1 and TH2 ratios. If you do have it and I do diagnose it in your uterus lining biopsy, not in your blood, then I would give you Prograft or Tacrolimus, which are a lot stronger and are strong medications in reproductive medicine, so before I give it to you, you have to haveTH1, and TH2 imbalance and I’m not sure if hydroxychloroquine is not too weak. Hydroxychloroquine used to be used as an anti-malaria medication when you were travelling to African countries. I used to do tropical medicine for 3 months in a student exchange program in São Paulo in Brazil, so then we were given hydroxychloroquine. Now, it’s slowly becoming a history of medicine. It’s given in some autoimmune diseases, and there’s no strong evidence-based medicine, there are no strong numbers behind hydroxychloroquine in reproductive medicine, in my opinion.

If you have an NK cell issue, I do recommend it.

I believe you’re asking me if a modified natural cycle is better than a substitute cycle. When you have a small office, you can allow yourself to transfer embryos in a natural cycle because you can control your patient as much as you want to. If your office grows, you cannot do it that well anymore. I had a chance to meet in person professor Bruce Shapiro in Las Vegas, and he was the first doctor in the world who published that we have higher success rates in substitute artificial estrogen cycles than in fresh ones.

The majority of the cycles, so 99% are done with estrogens. There are artificial estrogens that are used, 15 days of Progynova, 5 days of Progynova and Progestan. There are patients that no matter how much estrogens you’re going to give them, do not have Asherman’s syndrome, do the hysteroscopy, and the wall does not have adhesions, they are called estrogen resistant. Their lining does not grow through artificial hormones, and this is the only reason we give people a low dose of Gonal-F. It is given to stimulate 1-2 follicles to let your endometrium grow with a natural estrogen that you’re going to produce. As I was a professor’s Shapiro student, I have to say that I have better success rates with artificial cycles than natural ones.

I’d say progesterone is never too much, now we have a luxury because we can check it, so people start with Utrogestan 800 milligrams, then they go higher 1200, then if they still have level 9 of progesterone on the day of a transfer, you can still give them injections of Prolutex, and there are very few people that do not recover progesterone with vaginal Utrogestan high dose and one injection of Prolutex. I had a couple of cases like this where you need to add second Prolutex injections.

So progesterone is never too much unless the patient’s thresholds in the blood are suggesting that. The implantation window is not about the level of progesterone in your blood, it’s when you start it. If you started 5-7 days before your transfer to open your implantation window. In classical reproductive medicine, it was like 10-15 years ago where blastocyst day-5 embryo was transferred to an endometrium with 5 days progesterone preparation, I have seen that only 70% of all the patients have receptivity with five days.

The other 30% need 6, or 7 or days of progesterone, so it means that before the first embryo transfer, you need to start with 7 days of progesterone. When you have confirmed implantation window with 7 days, we put 5- day blastocyst on top of this, and in selected cases confirmed with uterus lining biopsy, we know that this is the best for you. This is case number 2 that I showed you on my slides. We had a young patient who did PGT-A who had unsuccessful pregnancy, a negative result, and then uterus lining biopsy verified that her implantation was not 5 days, it’s 7 days and then what we did was we put 2 embryos, and we had twins.

We have cases like yours where even though you are 40 where statistically you should have a 20% euploidy rate, we see you are not the case. This world is very small, we know each other professionally, so I know that the next couple of papers on PGT-A that will be published is about euploidy rate. Not only it is age-dependent but not to discriminate against anybody, it’s also race-dependent. You are 40, you should have 20% of good embryos, but you don’t.

This is the best moment to understand that no matter what you’re going to do at the age of 41-42, it will be even more difficult to produce healthy embryos. If you have time, money, hope, you can allow yourself for embryo banking to generate more embryos and look for euploid ones, or you have to move on and go for egg donation. I now have a patient who had an IVF cycle with PGT-A somewhere in Spain, now she came to us and somewhere in Spain all embryos were genetically abnormal, she believed that we’re going to do it better, she has 1 embryo, and it’s mosaic.

The mosaicism means that one of the chromosomes that it has is not recommended being transferred, so this is the moment where we probably have to let go and switch the strategy, and it’s probably allowing ourselves psychologically to talk about egg donation. Today, I was talking a lot about science, but there is a whole support group of people that help women psychologically all around the world to learn how to live with an egg donation child, how to communicate it to the child, and how to be happy in this life, so I’ll be more than happy to see you in person tomorrow on a patient meeting that we are planning.

The recommendation of the Spanish Society of Reproductive Medicine is to treat people until they are 50 years old and 11 months. If you are older than 51, we have to see your case individually, you have to present a lot of medical documents from an internal medicine doctor, we’ll have to do a lot of ultrasound, we need to make sure that you are healthy, not just biologically you are the 52-year-old girl, who looks, and behaves like 30, then have the doctors in your country who will support you, then we can negotiate if we can treat you, even though you are older than 50. There is no maximum age for any treatment.

There are certain indications to see you individually. Depending on your age, we’ll just have to decide if we go for IVF or we go for egg donation. When you are older than 43, it will be a lot easier for us to work with an egg donor but let’s see it individually, drop me an email, write a medical history, tell us what you want, let us see each other face to face and then let us plan your treatment.

There is no golden recipe, we use multivitamins, we do not have any like a special brand that I can recommend, but the best vitamin for good quality of your embryo is to generate them before you are 40. The best vitamin for healthy embryos is PGT-A, it’s just the genetic testing of them because that way we’ll know if it’s healthy or not.

There are American studies that we use a lot of CoQ10 in the States, we use DHEA, we used to use a touch of a growth hormone. I would need to see your age, AMH, and medical history, and then we can decide if it’s going to help you or not. At the age of 46-47, no matter how much CoQ10 you take, it will have to be the egg donation treatment for you.

I used to use a lot of Pergoveris, and I used to love it, and the situation has changed where the price of Pergoveris changed here in Spain, and then the majority of patients couldn’t pay for it. There is a moment in your life that no matter how many drugs you’re going to use, your ovary is not going to generate more eggs. When I came from the States, we used to use like 600 units of recombined FSH, LH, and at that time, I used to work here with a colleague that was trained in Sweden, and she used to use 225. Believe it or not, we compared our results after 1 year with my 600 and her 225 and then the results with all the respect at that time, I was doing 600 cycles, and she was 600 cycles, so that’s like 1200 cycles, and my numbers were very similar to hers, maybe I had one more egg. The number of your eggs is your AMH dependent, of course, cycle with LH, in the second half of a cycle, go better.

You can only see the quality of my embryos is better when they develop them to the blastocyst, so day-5 embryo, AB quality, genetically tested. The very fair answer to your question will be how many euploid embryos we generate with Pergoveris and how many with Gonal-F. Sometimes, what can surprise you is that maybe the number of eggs is lower. There are more blastocysts, and there are more genetically normal ones. You never know it. Better results when you are referring to the quality, quality means euploidy, and there are no papers published to compare different drugs and seeing your euploidy, your number of genetically normal embryos.

I would do the uterus lining biopsy to see what’s going. It looks like your receptivity issue is not there, but maybe immunologically, some cells see embryos as a foreign body, or there is an inflammation, which we can treat. Then, in the next cycle, I would have to see your AMH, AFC, and then depending on your AMH, I would decide if you do one cycle with PGT-A or 2 embryo banking cycles. When your AMH is between 7 and 14, your units which are 1 into my unit, so if your AMH is under 1, it’s going to be super difficult to make it happen, but still, I would like to have your AMH result to tell you which direction is the best for you to go. Get yourself an AMH check when you are in the UK,  sign up for a free first consultation, and let’s discuss it with your medical history form and your AMH.

It would be better to know the results after each cycle, of course, but who’s going to pay for it. In the genetic lab, if we test genetically 1-2 or 8 blastocysts, the price is the same. Of course, we want more embryos. In reproductive medicine, we have the highest success rates when we have 6 or 8 blastocysts. Statistically, I know how many genetically normal embryos I have. For me, the more embryos I have, the higher number of genetically normal embryos. For the genetic lab, it is also the price issue.

The price is about 3 000 EUR, and they don’t care if they switch a machine for you for 1 embryo, or 8, but you personally, it makes a difference, it’s a lot easier to find healthy embryos out of 6, than out of 1.

I like challenging cases in my life. I had a patient from Belfast that had a trachelectomy, which means she had a cervix amputation because of cervical cancer a couple of years ago, so she almost had no cervix. So one of the doctors and I, in the partner clinic, had to like to negotiate what we were going to do, and how we were going to take care of her during her pregnancy. We use transvaginal ultrasound to do a transfer, it’s not commercial, but we have a very special, very thin catheter that comes almost through every cervix, so you know a compromised cervix.

Somewhere in the world, the transfers are done with a very stiff, old-fashioned catheter and trans abdominal skin, this could be challenging there, but when you’re coming here with the transvaginal scan when I’m very close to the uterus with a very thin, Japanese catheter. 99.9% of all the transfers are done without any complications, maybe, once a year I have to say, please do a hysteroscopy because no matter what I’m doing, I cannot come through, so it’s very seldom that somebody has that compromised cervix. Then on the day of our first appointment, everybody gets a transfer test, so with the same catheter that I do a transfer on the day of the transfer, I do a transfer. On the first appointment day, I do a transfer test, so come for the first appointment, let us do the transfer test.

It’s not necessary, but it makes your time pregnant as short as possible, and it gives you a lot of security. In the United States, so many cycles are performed with genetic testing. The reason for this is that when we transfer good-looking embryos, and we believe that they are of good quality, and they implant and you have a miscarriage with them, and you’re going to go back to me and say, listen I’ve miscarried with this embryo that you’ve transferred, and this embryo is genetically abnormal, you can sue me. The reason for you not to sue me and for both of us to sleep well is the genetic testing of your embryos because I know that at the age of 40, out of 10 embryos, 8 of them are bad and 2 of them are good, and I want you to be pregnant now with good ones only, healthy ones.

This is the reason why the majority of cycles we do is with PGT-A. We have the lab, the team, skilled people that do trophectoderm biopsies only, so you have to have a team of people who know how to test embryos genetically, how to design this kind of cycle, not to be afraid of hyperstimulation, freeze the embryos, biopsy them and freeze, so we have embryologists that are coming here from different parts of the world, they spend 2-3 years here, they learn Spanish, and they go back home, and they know how to biopsy embryos. It’s high-technology medicine.

If they do not have an impact on the uterine cavity, they do not affect it at all. I have to be sure that your fibroids are not in the uterus lining, which we verify. I was studying two medicines, German and American ones, so a majority of verification if fibroids have an impact or not are done in the office through hydrosonography. We put a fluid to your uterus, we see how it expands if the fibroid has an impact, or not. If it doesn’t have an impact amazing, there’s nothing we have to do. If the fibroid has an impact. It means you need to have a hysteroscopy to remove this fibroid or if we see, and we have this kind of cases if we see that the fibroid is too big, and no matter what kind of operative hysteroscopy we’re going to do and how well we’re going to shape the embryo, it’s still going to stay. In selected cases, we have to do the myomectomy, the one with an open belly, laparoscopic one.

It depends only on you and a good cycle it’s always where we see the follicle growth through the transvaginal scan, and we also can see your hormonal results in blood like estrogens, progesterone. I like to trigger when I have more than 2 000 units of estrogens, then I know that eggs are mature and it’s day 10, in some cases, it’s day 12, so it only depends on your ultrasound result and your hormonal results. In one cycle, it can be day 10, and in the other cycle, it can be day 12, so it’s very individual.

No, it does not matter at all. The only thing is that Decapeptyl stops you from being hyperstimulated, and Ovitrelle not. How do I trigger only depends on how many eggs you have, what kind of estrogens in blood you have? If you have more than 2 000 units of estrogens in the blood, of course, I have to trigger you with Decapeptyl because if I trigger you with something else, I’ll hyperstimulate you, but for banking the Decapeptyl is fine.

It has nothing to do with what I think, it’s what has been published, and so in reproductive medicine, the TSH has to be under 2.

We have to see if in a donation day-3 cycle embryos were transferred, or day-5 embryos were transferred. We also need to know if your receptivity has been checked or not. If you want to have a good quality egg donation treatment, do it in Spain. I have to see your medical history to see what has happened before to offer you something better. We do not only offer you a certain number of eggs, but we also offer you a certain number of blastocysts, day-5 embryos, and if you fail 3 transfers with day-5 embryos, which we usually have out of 12-16 eggs, then we have to look deeper into your immunology and match your embryo, your donor immunologically.

We have to see when the ERA test was done. Usually, the receptivity is good for a year, and then the fourth donor has to be matched to you immunologically and trust me, we are having this kind of case like yours. In some cases, I have to say that we would suggest a double donation, so sperm and egg donation, but before I do it, I will have all the evidence on the table to show you where the problem is. Sometimes, in cases like yours, if we see your immunology, we stimulate a donor for you, which we know has the highest success rates, who generate HLA embryos. We will make your immune system, and your NK cells calm down, which will not stimulate NK cells to an immune response. Then, in selected cases, this kind of donor when we have eggs from her fertilizes 50% of them with the sperm of her husband and 50% with the sperm donor.

The sperm donor is also phenotypically and immunologically matched to your husband with a certain HLA. I can tell you that there’s only one clinic in Alicante that does it, and there’s only one sperm bank in Spain that does it, so drop me an email. After 20 years in gynaecology, I like challenging cases, and I do like to tell people where the problem is, and 97% of patients have children after treatment. I will be able to tell you if the problem is your immunology, if there is something in the receptivity of your lining, or if there is some chronic inflammation that we have to work on.

I don’t want you to give up, but if you show me 2,3 cycles with all genetically abnormal embryos, we’ll both understand that you are out of statistics. At the age of 40, around 20% of your embryos should be good or not, or maybe you’re going to surprise me, and you will have 1 genetically normal embryos. Sometimes, I have like cases where the embryo banking was done, there were 2 cycles, people generated 2 embryos at the age of 42, and 1 of them was healthy. Before COVID-19, I used to have like 20 international flights every year, once a month I used to be in London, then 3 to 4 times a year I was in Germany, and I had a patient today like you, she’s Japanese, and she plays in a philharmonic orchestra somewhere in Germany, she’s married to the German man, she did this kind of cycle at 39-40 years old with 2 embryos, with a very low ovarian reserve and 1 of them was healthy, and she says: you know what, we know that in March you are going to fly to Berlin for kinderwunsch tage, let us go out with you and let us have dinner, maybe I can play something for you, so you have this kind of stories in your medical history, in your career, let me show your results, I’m not a fortune-teller, I need to know your age, I need to see your AMH, AFC and then give me your medical history, and then we can decide if it’s better to try with your own egg or a donor egg. It’s a lot easier to say go for your own eggs when you have somebody with an AMH 14, and you know that she is an egg making machine, you will have 20 eggs, 10 embryos, 2 will be healthy, but if you have somebody who already failed PGT-A cycles or has AMH of 0.08, and she’s still trying, it’s a lot harder to make it happen. Let me see your case individually to do the best out of it.

Why not. Now, there is a lot of papers published about an infection, Lactobacillus where they say you have higher success rates when you have high Lactobacillus than the lower one.

There’s not a lot of like data about it, but when you have a low Lactobacillus, you have a potential to be colonized with Gardnerella vaginalis and all these other bugs that not only make your sex life unpleasant but also painful, so it’s a lot better to have low PH, which means a lot of acids, Lactobacillus in the vagina than the other way around.

You can apply for immunological matching of your donor, and probably in this kind of case, we need to test your embryos genetically. Do the PGT-A and your egg donation embryos, and after this kind of cycle, even if you show me that you had done an ER map, I would like to do an immunological study of lining again, not only to check for immunology but also receptivity. As I told you, I had a patient 3 years ago who was receptive with 8 days of progesterone, I couldn’t believe it, but I did transfer, and she got pregnant. After complicated stories and your story is complicated, there is no trust in you anymore, everything has to be double-checked again. My solution for your case would be performing uterus lining biopsy for immunology receptivity, inflammation, and immunological matching of your donor. Then a PGT-A, testing of your embryos. It is a super high technology cycle.

Yes, they do. When patients are coming to us, and they’re not sure if they have polyps there or not before we thaw the embryos for them, I do an ultrasound, and sometimes I cancel cycles because there are polyps inside. In American medicine putting an embryo into a womb with the polyp is considered a failure, you can sue me for that. Polyps need to be removed, and they can be confirmed or excluded through hydrosonography. We can remove them through hysteroscopy. The polyps before any transfer must disappear, like fibroids that affect the uterus lining cavity.

It only depends on your AMH level. When your AMH is more than 2, it is 20, between 1 and 2, 10. If it is under 1, it is difficult to say. But, I don’t know exactly in your case, I have to see the cycle individually.

I’ll tell you even more before transfer cycles, we inject Decapeptyl, which puts you artificially into menopause for 1-3 months. It depends on the kind, which we used to have you completely under control. The point is that your hormonal levels before the transfer do not matter to me at all because I can have them under control. What matters to me is your implantation window. I would probably do the uterus lining biopsy to see when you are receptive. I would check the progesterone level on the day of the embryo transfer, which matters to me because I want it to be more than 10. If you have frozen embryos in your country that you want to transfer, go for it. At the age of 42.5, you deserve PGT-A to see if your embryos are healthy or not, so finish the cycle that you’re about to do, measure your progesterone in blood on the day of your embryo transfer, and if it doesn’t work, drop us an email.

They are developed to a blastocyst, and if they are not biopsible, that means they are of poor quality. Sometimes, it’s better to transfer what you have and maybe focus on what we can do better in the next cycle.

It should be, and the lab director and people that are responsible for finances should not hear this, but we guarantee 5 blastocysts, and we used to say with normozoospermic results, but now we also guarantee it to patients where husbands have worse results. If you fail 2 full egg donation cycles, it means that we gave you 12-16 eggs with the first donor, and nothing happens, we do the same with the 2nd donor, and there’s no blastocyst, we know that the problem is the sperm quality of your husband, and then we have to move on to a double donation. We use 2 donors, we give you a guarantee of 5 blastocysts, and we do not say husband sperm or donor sperm, so it’s a lot of security after this kind of cycle, it’s in your favour in this case.

It does. When people are coming to us, and they are very tense, it doesn’t happen, they’re not getting pregnant. You have to be relaxed, and you have to allow us to do our job. We have an amazing team of people who do acupuncture, Reiki, that allows you to deal with stress. When you have an IVF cycle with PGT-A, and there is 1 embryo, there’s a lot of pressure, so after acupuncture, people are usually getting relaxed, and they’re fine, but if you have an egg donation cycle, you have 5 goals because we offer you 5 embryos. There’s a lot less pressure on you, so don’t get nervous, see what is offered, and see how we can help you with the stress.