Causes of repeated implantation failure

Natalia Szlarb, MD, PhD
Gynaecologist & Fertility Specialist at UR Vistahermosa, UR Vistahermosa

Category:
Embryo Implantation, Failed IVF Cycles, Miscarriages and RPL, Success Stories

From this video you will find out:

What are the necessary “ingredients” to have successful embryo implantation?
What is the percentage of failures caused by the male factor?
Can PGT-A be a solution?
Why do doctors recommend embryobanking?
When egg donation is recommended?
How to wisely manage egg donors to ensure the best results for the recipient?

Causes of repeated implantation failure

Why the embryos keep not implanting?

In this session, Dr Natalia Szlarb has been discussing the causes of repeated implantation failure and provides options that can help you improve your chances. Dr Szlarb started by explaining the definition of recurrent implantation failure, which is a lack of pregnancy after at least 3 transfers with good-quality embryos. The definition does not specify if embryos of good quality should be on day-3 or day 5 of development. The first thing we have to have is a healthy embryo, in egg donation cycles, the eggs come from a young, fertile donor, so in the majority of cases, there is no need to perform genetic selection, but in patients of advanced maternal age, so people who are older than 35 years old, it’s always best to transfer only euploid blastocysts. Therefore, the first thing we have to focus on is embryo quality. The second thing to solve the problem of recurrent implantation failure is the uterus lining, the endometrium. There was a study published in 2015 where 60 000 blastocysts from all around the world were genetically examined, and it showed that 60-70% of all donor embryos are euploid, and in other age groups the number of genetically normal embryos is age dependent. At the age of 35, statistically, every other embryo is healthy, at the age of 40, 20-30% of embryos are healthy, and at the age of 43, less than 10% of your embryos are healthy. Therefore, in patients of advanced maternal age, the genetic selection of an embryo is the only way to diagnose a healthy embryo. In 1950 or 1955, 30% of all the mothers were 20-24 years old, now there is only 14% of mothers at the same age. In 2017, the majority of women having children in England and Wales are between 25 and 35 years old. Also, 20% of women have children between 35 and 39 years old, and as we know, the quality of the eggs between 35 and 39 drops dramatically.

Mother’s age & ovarian reserve

To assess your ovarian reserve, we need to check your AMH and Antral Follicle Count (AFC). AMH levels show your overall ovarian reserve, it can tell us the number of eggs or embryos we can expect if we were to perform a cycle. When your AMH is higher than 2 ng/ml, we expect around 20 eggs in a mild IVF cycle. Antral Follicle Count (AFC) is a transvaginal ultrasound where doctors specialising in reproductive medicine or their sonographers see how many antral follicles you have in both ovaries. The mother’s age is the main factor in implantation issues. As the woman gets older, there is a higher risk of genetic abnormality. The most common risk of Down syndrome is Trisomy 21, there is 1 chromosome in position 21 too much, and this can cause mental retardation. The second common abnormality is Trisomy 18, called Edward’s syndrome, and Trisomy 13 is Patau syndrome. These are the most commonly described age-related abnormalities that women’s eggs are generating.

Male factor

Most infertility issues that men have started in their 50s, and 60s, and it’s due to erection issues, but that can be solved easily through medication like Viagra. At a certain age, testosterone production drops. However, it’s important to mention that around 40% of infertility cases are due to male factors. It is very often recommended for men to not only take vitamins and start to ejaculate more frequently, but also some men and their hormonal adults allow using injections the same as female FSH/LH-based medication to support sperm production. Every man, on the day of the first appointment, gets a sperm analysis. According to World Health Organization criteria from 2010, here are the norms: Total sperm count in ejaculate: 39–928 million Ejaculate volume: 1.5–7.6 mL Sperm concentration: 15–259 million per mL Total motility: 40–81% Progressive motility: 32–75% Sperm morphology: 4–48% Another test that is also routinely done is DNA fragmentation, if there is a high DNA fragmentation, a high dose of vitamins C, and E treatment and high ejaculation frequency and fertilization with fresh sperm are recommended. Magnetic-activated cell sorting (MACS) is also advised if the DNA fragmentation is more than 30%.

IVF & PGT-A

In IVF and PGT-A, when the biopsy is performed, 5-6 cells are taken out of each embryo, and it is sent to the genetical testing lab, and the results will show how many genetically normal embryos we have. Sometimes, we can retrieve16-20 eggs if a woman has a good ovarian reserve and is 30-35. When we generate 16-20, some other complications like infection and post-egg retrieval bleeding can happen, therefore, every patient gets medication to prevent inflammation to support their blood clotting after the egg retrieval. After 1-2 hours after the procedure, the patient can go home. Then, the embryos are genetically tested and frozen. To avoid recurrent implantation failure, the first step in your treatment is to define how many eggs and genetically normal embryos we will be able to generate, depending on your age and AMH. Then your eggs are going to be processed, and after the genetic testing, the embryos will be frozen. Step number 2 is to go back for 1 day for frozen embryo transfer, in step 2, it is necessary to focus on your uterus lining and prepare your endometrium. Having 5-6 blastocysts up to the age of 35 gives you a 90% of probability that you’re going to have 2 children. Therefore, it’s worth thinking about your fertility when you are young because, in 1 cycle, we can plan your entire family. The problem starts when women are getting older and do not generate as many eggs at once, then embryo banking is an option. In advanced maternal age, if you do not genetically test your embryos, the pregnancy rates are about 18%. If you go for IVF with PGT-A, after 1 transfer, 60% of all patients get pregnant, after 2 transfers, it’s 80%, and after 3, it’s 91.3%. The more embryos you have, the higher the cumulative pregnancy rate. Embryo banking cycles are for patients whose AMH is under 2 ng/mL according to European units, in the UK, the threshold is more than 14 pmol/L The issue that we have is that if we generate 10 eggs in a cycle, out of those 10 eggs, we will get 5 blastocysts and out of 5 blastocysts, at the age of 35-37, 44% of embryos are going to be healthy, but at the age of 41-42, only 17% of embryos will be healthy. We have to be aware that out of 5 embryos, we can only have 1 healthy embryo. PGT-A with embryo banking is recommended for patients with a diminished or low ovarian reserve who still potentially due to their age can generate genetically normal embryos. Normally, the cut-off age for using own eggs in reproductive medicine is 42-43. We know that patients older than 43 have less than a 10% probability of finding genetically normal embryos. Sometimes, the patients are doing an IVF cycle or embryo banking cycle at the age of 46, and we know that they will generate eggs and we will get embryos, but statistically, less than 10% of them will be healthy. If after 1 IVF cycle with PGT-A at the age of 46, we are not getting a genetically normal embryo, you will receive a document, which will tell you about genetic abnormalities your embryos have due to your age. In such cases, the best chance of achieving a pregnancy is going for egg donation.

Egg donation

In Spain, egg donation is allowed for more than 30 years, it’s the country with the longest experience in egg donation in Europe. It’s important to remember that egg donation is a last and very unique step in infertility treatment. According to Spanish law, egg donation is anonymous, so you will know details like age and type of donor you will have, nothing else. The donor and recipient must be matched, sometimes it’s like looking for a twin sister, somebody who looks like you, and have the same colour of hair, skin, etc. According to Spanish law, it is possible to treat women until they are 50 years old and 11 months. The donor has to be under 35 years old, and all donors are screened for infectious diseases, genetic diseases and mental health, such as schizophrenia, depression, personality issues or no drugs. The second step of a donor selection process is to find out about your characteristics, for example, how tall you are, your haircut, skin colour, blood type and whether you want to match a blood type to a donor or not, etc. It’s also important to discuss if you should tell your child or not about his origin, and of course, you will be supported throughout the whole process. Before the transfer, a mock cycle is performed, then with artificial hormones, your natural cycle is mimicked to see which dose of hormones you need to grow a good thickness of a lining, and it is always between 7 and 12 millimetres. This dose of hormones is adjusted, you will be on estrogen for 15 days and 5 days on progesterone, then you will be synchronized with the donor, and you stop a birth control pill together with your donor. You are prepared for the transfer while the donor has her egg retrieval. For egg donation treatment, you have to stay in Spain for a week so the team can work with the fresh eggs and fresh sperm. If frozen sperm will be used, you can stay for a long weekend and just for the transfer. It all depends on the partner’s sperm. If your first egg donation cycle fails, we need to evaluate it because it is different from your own eggs. Why? Because with egg donation after the first transfer, 70% of patients should have a positive pregnancy test. Usually, patients after the first unsuccessful transfer get something called uterus lining biopsy, where their immunology is checked as well as their Natural Killer cells (NK cells), cytokines, chronic endometritis, but also chlamydia infection. It is also important to check your uterus lining receptivity window, 70% of all a patient needs 5.5 days of progesterone to open the implantation window, some others need 6 or 7 days of progesterone to open the implantation window.

Case studies

42-year-old woman with low ovarian reserve (AMH: 0.3 ng/mL and AFC:2) with 2 previous failed IUI cycles and 3 previous IVF cycles

As we know, at 43, less than 15-17% of embryos are healthy, so we know we will have few eggs and few chances of having genetically normal embryos. We suggested IVF with PGT-A, where we received 2 blastocysts, 1 of them was with Trisomy 21 and the other one with Trisomy 13, so we had no embryos to transfer. Therefore, we suggested going ahead with egg donation treatment. We performed a single fresh embryo transfer, and the patient got pregnant and delivered a healthy child.

27-year-old patient with AMH of 3.5 ng/mL, and AFC:20, she had 2 previous failed IVF cycles with day-3 embryos

We got 25 eggs, and we performed IVF with PGT-A, we got 8 blastocysts, 6 embryos were euploid, and one was transferred, but the result was negative. After 1 unsuccessful transfer with 1 genetically normal embryo, we decided to do further investigation. Statistically, with the genetic testing performed, 70% of all the patients get pregnant after the first transfer. Therefore, we did an endometrial receptivity test (ERMap), and we saw that this patient needed 7 days of progesterone to open the implantation window. We did a second transfer with 2 embryos and the result was healthy twins. We do not recommend double embryo transfer most of the time, and we always make it clear, that patients need to sign a consent to have a double embryo transfer.

Why the embryos keep not implanting? - Questions and Answers

I have had repeated IVF treatments at the age of 46. The reason was that they don’t implant. I know my age can affect pregnancy, but I had 3 embryos the first time and 2 the other time, all were healthy, but they don’t implant. Any advice?

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.

What do you think about HCG booster and intracervical injection HCG before embryo transfer?

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.

Does transferring 2 embryos possibly reduces the implantation of a good embryo? What if 1 of them is not good?

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.

What do you think of adding hydroxychloroquine if TH1 and TH2 are raised?

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.

What do you think of giving steroids and intralipids before embryo transfer?

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

Do you think stimulating the endometrium with Gonal-F is better than with estrogen?

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.

Can you use too much progesterone in the 5 days before embryo transfer?

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.

I am 40 with 2 failed IVF cycles. In the second cycle, PGT-A was done, and all 3 blastocysts were abnormal. Is there anything that can be done to overcome the maternal age factor?

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.

What is the maximum age for IVF in Spain to do IVF using their own eggs and using a donor egg?

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.

What vitamins do you suggest for women for good quality embryos apart from folic acid?

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.

Would you recommend, for instance, CoQ10 as a supplement to increase egg quality?

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.

Could I expect a better result (number of eggs and quality) using Pergoveris (300ui+150ui) instead of Gonal-F (300UI)? My AMH is 1,7, FSH 7, BMI 26, TSH 1,2.

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.

At 40 years, I had 9 (5 good) blastocysts transferred resulting in 2 biochemical pregnancies and one miscarriage. There are no thrombophilia markers positive, immunological endometrial analysis did not give any results. What would be my next steps?

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.

With embryo banking are you only performing the PGT-A after several cycles? Why is this done? Would it not be better to know the results after each cycle?

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.

Does a compromised cervix affect the success of a transfer? I’ve had a cone biopsy in 2003.

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.

Is a genetic test always necessary before treatment?

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.

Do fibroids affect the outcome of cycles?

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.

During stimulation, my follicles grow 2 mm each per day. Is it better to stimulate 10 days or 12 days? Does it make any difference in egg quality? I have read that it was not good to stimulate for too long to avoid over mature eggs.

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.

Does it make a difference in egg quality using Decapeptyl versus Ovitrelle to trigger? Not a transfer cycle, only banking.

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.

What do you think is the optimal TSH value for infertility treatments?

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.

What are the best questions to ask your consultant after a failed 1st donor egg cycle? I am 45 with a good endometrial lining thickness.

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.

I miscarried twice at 6 weeks with my own pregnancies and had three egg donor transfers, and none worked (one was a chemical pregnancy, the second didn’t stick, and the third miscarriage at week 6). Could this be implantation failure? And if so, what do you suggest I do? All my tests come back normal. (no endometritis, ERA – receptive, etc.)

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.

Is 40 not too early to give up to have a baby with my own eggs?

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.

Do you think the Female EcologiX test is worthwhile? For PH levels?

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.

I had 2 failed donor cycles with both times euploid embryos, I also did an ER map – receptive to check implantation window, but it still failed. What can I do differently in my new cycle?

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.

Do polyps affect implantation?

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.

How many mature eggs are to be expected with 2000 estrogen levels on trigger day? My AMH is over 1.

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.

With no history of previous IVF, what tests/hormone levels would you recommend before a fresh 3rd-day transfer to ensure you get the best possible outcome. I am 42,5 .with low AMH, and 5 out of 5 eggs were fertilized.

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.

I have just requested PGT-A testing on my 4 remaining embryos. I am anxious that they don’t make it or aren’t great. They are donor eggs, anything you can advise?

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.

When it comes to the part where the clinic gives several blastocysts, is this based on sperm analysis results?

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.

Do you think outside stress affects implantation?

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.

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Authors

Natalia Szlarb, MD, PhD

Dr Natalia Szlarb a Gynaecologist & Fertility Specialist at UR Vistahermosa, Alicante. She graduated from a medical university in Poland in 2002 and then worked in gynaecology and obstetrics wards at several German hospitals. She also participated in international internships in Egypt, Brazil and Poland during her medical studies. In 2011 Dr Szlarb obtained her PhD in Immunology in the United States of America. She has extensive experience in IVF with donor eggs and is known by patients as a friendly and warm doctor. Dr Szlarb speaks fluent English, Polish, German and Russian.

Event Moderator

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.

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