Implantation issues and possible solutions when IVF cycle fails
Infertility is not only a clinical problem. It’s an overwhelming and demanding process for couples who desire to have children. Starting IVF treatment isn’t the end of the hurdle as many times there are more obstacles to overcome before a successful pregnancy.
In this webinar dr. Natalia Szlarb from IVF Spain tries to explain what to do if IVF failures happen to us and, at the same time, gives some hints on how we can increase the chance of embryo implantation.
Nowadays it is common that women plan to have their children much later than they used to. The problem is that women’s biological clock is not aware of these changes. With age, both the number of eggs and their quality is decreasing.
There are three factors of a woman’s ovarian reserve: her age, Anti-Müllerian hormone (AMH) and antral follicle count (AFC). At IVF Spain with every patient they have to calculate how many good eggs she is generating. And this number depends solely on a woman’s age. AMH says how many eggs a woman is able to produce – but it doesn’t say anything about their quality. AFC is a transvaginal ultrasound that tells how many astral follicles (so – in other words – potential eggs) there are in the ovaries. According to the criteria of the American College of Obstetricians and Gynecologists, ideal patients to work with own eggs are women under 40 years old with AMH 1-2 ng/ml and with at least 6 antral follicles in both ovaries. With woman’s age, not only AMH is going down but also the number of genetically healthy embryos that she is able to generate. This number is only stable until the age of 35 years old. About 10 years later, there are almost no good embryos left. That’s why the women at the age of 45 are usually recommended to go for egg donation.
Dr Natalia Szlarb admits that up to recently, medicine has associated bad embryos that women generate only with Down syndrome. Nowadays, when next generation sequencing (NGS) is available, we know that from 35 years old onwards, there is a higher rate of other chromosomal abnormalities, too.
Pregnancy rates in women between 35 – 40 years old (without genetical testing of embryos) are under 20%. When technology is applied to the way embryos are developed and selected, the rate increases up to 70% per transfer and is age-independent. If a woman is young (around 35 y.o.) 50% of her embryos are healthy. With good quality partner’s sperm, out of 20 egg cells dr Szlarb expects 8-10 blastocysts (embryos on day 5 of development) – only 5 of them are genetically healthy euploid embryos.
At the certain age, the key to achieve certain success rates is blastocyst culture. In order to select the best embryos and assure implantation success, an IVF cycle with PGS (pre-implantation genetic screening) has to be performed. First, the biopsy is administered. An embryo biopsy removes about 3-8 cells from each day 5 embryo (a blastocyst). After biopsy, the embryo is typically frozen while PGS testing is performed. For a biopsy to be successful, a skilled and well-trained senior embryologist is required. Screening for both genetic diseases and chromosomal defects with a single biopsy improves pregnancy rates. In fact, with an euploid, genetically normal blastocyst (after the biopsy), pregnancy rates are as high as 70% per transfer.
Here dr Szlarb makes a point that majority of embryos do not implant as they’re just good looking. Doctors have no idea if these amazing embryos are genetically healthy or not unless they perform genetic testing.
According to dr Szlarb, the duty of every doctor is to explain to a patient her success rates. The latter are not only AMH and the number of eggs that a woman generates but also the effort her body puts into achieving pregnancy. sometimes, even if AMH is low (and in this case diminished ovarian reserve), a woman still generates a couple of blastocysts. When working with genetic testing of embryos, the desired number is 6 blastocysts. Then, according to a patient’s age, doctors may predict the number of healthy blastocysts they’re going to generate. Statistically, from the age of 44-45 years old onwards, every patient is a candidate for egg donation. However, dr Szlarb admits she always listen to patients, allows them to have one IVF cycle with own eggs to help them understand that all eggs they produce are genetically abnormal. Then they may psychologically prepare themselves to either adopt a child or allow themselves for egg donation.
Dr Szlarb says that egg donation is the final step in infertility treatment that doctors can offer to a patient. However, sometimes even with best, healthy donors and their detailed qualification process, things may not go according to the plan. After the first unsuccessful transfer with donor eggs, dr Szlarb suggests patients to do receptivity testing. It may turn out that the problem lies in a patient’s body and it is her endometrium that does not accept even good embryos.
It took medicine quite a while to define what is exactly going on in the implantation process. Implantation may be described as a dialogue between the embryo and the endometrium. Endometrium is known to accept only healthy and genetically normal embryos. Through progesterone, endometrium undergoes immunological changes and the creation of immune cells that allow for immune modulation and better blood flow to the lining. The lining accepts blastocysts only at a certain time. Endometrium is made the best to accept the embryos after 5-5,5 days of progesterone intake. There are some women that have their implantation window moved. It needs another average 6-7 days of progesterone to open the implantation window . Before transferring for the second time, doctors double cheek the receptivity. In IVF Spain, they use endometrial receptivity map to check how many hours they need for the lining to have the best receptivity.
In some cases, on the day when the receptivity testing is performed, there is also immunological testing conducted. There might be cases with too many Natural Killer Cells (NKs) in the lining. Then, Intralipid treatment is prescribed. Immunological testing is also used for detecting e.g. antiphospholipid syndrome, KIR polymorphism or placenta antibodies. The solution for immunological issues is the uterus lining biopsy.
Of course, infertility is not only a woman’s problem. According to the new data, 40% of infertility cases are due to a male factor. There is a genetic testing of sperm available, too. It is the so-called FISH test. If a man is over 50 years old and his FISH test results are pathological, he may not generate as many healthy embryos as a younger man. However, there is still a chance of generating at least 1-2 euploid blastocysts per cycle.
Dr Szlarb says that in IVF Spain, on the day of the first appointment with a new patient, they always perform a sperm analysis. It helps to establish sperm quality according to the World Health Organisation criteria, such as volume, concentration, motility and morphology. Dr Szlarb advises to perform additional DNA fragmentation and apoptosis testing as well. If there are some issues indicated, in IVF Spain they also perform IMSI and a testicular aspiration biopsy.
According to dr Szlarb, there are two key elements for successful IVF. It is the new technology that helps to find the cause of your implantation issue and best fertility experts who believe in personalised treatments and are at your side throughout your patient journey.
Questions from the event
Is it worthwhile to do PGS for the blaster 5BC (hatching) on day 6 with donor egg (age 24) & donor sperm (age 32) and blasters 3BC, 4BB & 2BB? The patient’s age is 47-48.
It’ a very good question. You are 47-48. You have to understand that in Spain the recommendation is to treat you until you are 50-51. One blastocyst is BC which is very poor quality. I have seen pregnancies with this kind of embryos. I was sometimes coming to the lab and saying: ‘What quality of the embryo is this?’ At that time we had an amazing embryologist and she was always saying to me: ‘Doctor Szlarb, never underestimate one embryo.’ So without genetic testing listen nobody can tell you if the embryo is healthy or not. Statistically, poor looking embryos have a lower euploidy rate. But from my experience, until you don’t test it, you don’t know it. But if the embryo is frozen and you want to thaw it, biopsy it, wait for the result, freeze it again and thaw it again before the transfer, then I’d say: ‘No’. Embryos need to be fresh to be genetically tested. It is the best for embryos to freeze them just once. So when the embryo is frozen, I wouldn’t touch it. But you deserve a better cycle, madame. Usually, eggs from a healthy young-aged egg donor and sperm donor should be AA or AB quality. So if it doesn’t work, we will be happy to help you with better quality embryos.
I have had 2 cycles. The 1st double donor cycle failed due to no implantation. I have elevated NK cells levels. The 2nd cycle was frozen, with ER map and endometrium classified as receptive. It resulted in miscarriage at 6 weeks. Would you recommend any changes or tests prior to the 3rd cycle? I had immunological protocol in both cycles.
Ok, so we know that the problem is not the receptivity because receptivity testing has been done. The question is what kind of embryos we are putting back. AB quality and genetically tested or not? Do not be disappointed if you are 35 and 40 years old and you have that low pregnancy rates. As long as you do not know if embryos are euploid or not, the pregnancy rates are going to be the way you described them. The real problem starts when we transfer euploid healthy embryos at the right time and you keep miscarrying or have negative results. I would recommend you to put the embryo that you have. For elevated NK cells, there is always an immunological protocol with Intralipid and Prednisolone. Then let’s see what happens. Double donation cycles are usually very successful. If we see that it’s not the case and after double donation, you have negative results or you miscarry, then the second donor has to be matched to you immunologically.
Does the Spanish law allow PGS testing for donor eggs?
When we started doing this, we were afraid that the Spanish law does not allow it. But we found out that in the Spanish law PGS is allowed for recurrent implantation failures. The majority of our patients with the history of unsuccessful IVF cycles, after failing the first egg donation cycle, belong to this group. That is why we perform PGS testing in egg donation.
Do you do NGS testing that tests 300 carrier diseases ?
PGS is testing for the number of chromosomes. As medicine describes, we have just 46 chromosomes. And in these chromosomes, you can have point mutations. There are mutations responsible for being a carrier of certain diseases. The most common ones in the European population are cystic fibrosis and muscular dystrophy. There are diseases specific to certain populations. For people from Turkey or African Americans, we have quite often sickle cell disease or thalassemia, so blood diseases. In IVF Spain, we use the so-called screening test for donors. ‘Screening’ means that we test donors for the most common diseases. When patients want to know if they are carriers, there is a test where we check about 300 genetic diseases. Then you can match patients to each other. We do it to African Americans in case they are both carriers of sickle cell disease. Also in the Jewish population, there are some specific diseases. If both a male and a female patient are both carriers of the same disease, the Spanish law allows us to test embryos. If you need a donor, we match you with the one that has to be free of the disease your husband is a carrier of.
I was pregnant two times and had 8 failed transfers with good embryos. Should I make ER Map if I was pregnant?
I believe you should because your receptivity could change. But the question is how old are you? What is your euploidy rate? What is the number of genetically healthy embryos that you generate due to your age? I had in my life a patient who was 38 years old. So theoretically, 20-30% of euploidy rate. But out of 25 eggs, we had 6 blastocysts and only one was healthy. So in certain age groups, we have certain statistical probabilities. But they may not apply to some cycles and some patients. Maybe the transfers that you had failed because of genetically abnormal embryos. Maybe next time, when we do a new cycle, we need to see if the embryos that you generate are healthy or not.
I am 44 years old. I have had 9 own egg ivf cycles over the last few years with 3 different clinics. One of the cycles resulted in a positive pregnancy that concluded in a miscarriage at 10 weeks. Due to my age, we have now moved to donor eggs and got 6 good quality blastocyst embryos (3 x AA, 1 x AB and 2 x BB). We transferred 1 AA hatching blastocyst 11 days ago and I found out today that the cycle was negative. I’ve had hysteroscopy, laparoscopy, 3D Aqua scan, etc. and there are no apparent issues. I have also had ERA test which classified my endometrium as receptive. I also had level 1 immune testing and there were no issues. Do you think I should do any further tests before transferring our next AA donor embryo? Or is it just luck and we should try another embryo transfer?
I’m very sorry to hear about your attempts with your own eggs. You must be very strong psychologically because after so so many negative results, you decided to go for egg donation. We have to separate the chapter of patient’s own eggs when the results are bad because of your age. Egg donation is a different chapter. Definitely, one failed transfer in egg donation is not the end of the world. You have to keep trying. If you know that you are receptive, you could add immunological treatment. You could consider Intralipid and Prednisolone. You belong to the group of recurrent implantation failure so maybe you should go with even Tacrolimus.
I have 3 donor embryos day 5 – XB/CB and 2 embryos day 6 – XB/ iHB. Which one is better to transfer? What are the differences between them?
This is the question for the embryology lab. They have certain grading of embryos depending on the kind of the Embryoscope or the time-lapse that they use. You should ask the embryologist in the lab where the embryo was generated. Usually, the best embryos are transferred upfront. There’s no embryology lab in the world that will transfer worse embryos at first. It gives you a higher chance of getting pregnant as soon as possible.
In Spain, can you choose the criteria for the donor egg?
No. Egg donation is anonymous. You cannot choose the donor, you cannot see the picture of the donor. Your donor has to look like your twin sister. In the first step, you have to fill in all the requirements. In the second step, you receive paperwork from us. It’s a document where you describe yourself and your husband in the following terms: how tall are you? What’s the colour of your hair, skin and eyes? What is your BMI? Also, what’s important to you? What characteristics your donor should have? If you have any personal comments, there is a place to write it down. You can choose these criteria, but we match a donor to you. There’s no way in the world that a girl with blonde hair and blue eyes can have a donor who’s eyes are Chinese. Never. So you cannot choose the criteria. You have to describe yourself honestly, you have to prove it with your photos. Then you have to choose your preferences regarding the donor.
I am 35 y.o. After 5 failed transfers with own eggs (low AHM) I’m moving on to donor eggs soon. Do you recommend any additional tests or should I see how it goes first time? Only one pregnancy achieved with IVF/ICSI, but ended with missed miscarriage in the 11th week.
Before the egg donation cycle, you could maybe do the receptivity assay to confirm that everything is okay. Make sure that you have a young healthy donor and the embryos are put on time to your uterus lining. This is how I would start the first cycle which in IVF Spain gives you the pregnancy rate of more than 70% per transfer in the first attempt.
I had one IVF cycle with only 2 blastocysts class BB and CB and another one with 7 blastocysts class AA. Why is there so much difference between two cycles? I am 37 now.
Sometimes you see one patient with amazing eggs quality at the age of 35 with 7AA embryos and at the age of 41, the same girl has just 2BB or CB blastocysts. This is age-dependent. Also, cycles are sometimes very uneven. For example, you have one person and her AMH is changing in 6 months. In January, her AMH is 2 and in June it’s 0.7. I’ve seen this kind of cases in my life. With age and time, the number and quality of eggs can change.
What if you are 33, no immune issues, have normal embryos in PGS, lining looks good on scans on hysteroscopy and have done ERA – what next? Do you believe in the hidden infections test?
I do not believe. I have sometimes seen patients that had old endometritis and this was the reason why they were not getting pregnant. So if you exclude an old infection, just keep trying. Maybe some immunological protocol added to your case will improve your results.
According to the Spanish law, how do you choose a sperm donor?
In the same way, as we choose the egg donor. You describe yourself, you describe husband, how tall he is, what his skin colour is. We need his pictures and we send them to the sperm bank, European or Spanish sperm bank. According to the characteristics that you’re providing, we choose the sperm donor for you.
I’m 39 years old. At the age of 26 I was told by 2 hospitals in UK that my FSH and AMH showed early menopause and they advised egg donation. I have had 6 IVF attempts with donor eggs since. I had positive pregnancy tests but all resulted in failed attempt through ectopic pregnancy, early miscarriage and chemical pregnancy. We had my husband’s sperm tested in Spain and FISH test showed chromosome 21 abnormalities of 0.1% compared to general population. Could this be the cause of failure. Do we need a donor sperm, too?
I’m very sorry to hear about your case. It’s doesn’t happen often that somebody that young is diagnosed with premature ovarian failure. Egg donation is a very good decision. But you have to be given the opportunity to develop blastocysts (day 5 embryos). You said that you had six attempts with donor eggs and I need to ask you what quality embryos you were given. Were they blastocysts? Blastocyst culture has to be offered to you. If I see sperm abnormalities in FISH test in your husband, I’d recommend you to test embryos of the donor eggs and your husband’s sperm. I’d perform the genetic testing of them and see how many genetically normal embryos can be generated – if any. The upside of the treatment in IVF Spain is that we give you a guarantee of 5 embryos on day 5 of development in exclusive Egg Donation PLUS. If we are reaching the point that we are afraid that your husband might develop genetically abnormal embryos, in exclusive Egg Donation PLUS we can fertilise 8 embryos with your husband’s sperm and we can fertilise 8 eggs with the donor sperm, like 50-50. Then we develop embryos to day 5 and test them genetically. With this FISH test, we are not moving the situation any further, even though it’s egg donation. Genetical testing of embryos has to be performed with this kind of FISH results. And then we see where the problem is. Maybe your husband is not generating any good embryos at all. But then we have embryos with a double donation as the backup.
Do you use IVIG in IVF Spain and if yes for which immunological problem and in which protocol?
I do not like IVIG. I don’t like medication that is from somebody else’s blood and proteins. This can cause reactions that we don’t like. I prefer Intralipid a lot more and we use it for NK cell issues. There is the same indication for both Intralipid and IVIG, and this is high NK cells. Intralipid and IVIG are used in the same protocol: 3 weeks before the transfer, around the transfer day and 3-6 weeks after the transfer. But I’m not a very big fan of IVIG.
Can you comment on my husband’s semen analysis? We will be using his 42-year old frozen semen: Ejaculate Volume: 5.2 mln; Sample Viscosity: normal; Liquefaction: incomplete, Sperm Clumping: 15%; Aggregate Debris: normal; Round Cells: few; pH: 8.2; Sperm Concentration: 67.3 million/ml; Total Sperm Count: 349.96 million/ ejaculate; Progressive Motility: 69% progressive; Total Motility: 73% progressive; Progression Rating: 3/4; Sperm Vitality: not required; Normal Forms: 4% of normal forms; Isotypes: not done. Other significant findings: Patient Result: SFA freeze for assisted conception.
Do you know how, according to WHO criteria, I define sperm results as normal? Volume: more than 1 ml – here we have 5. Concentration: I’m happy with 15 million – here we have 67 million. Motility: I’m happy with 30% – here 73%. Morphology: 4% – and I have 4 %. So this sperm looks perfect to me – even for fertilisation with frozen sperm.
How will you choose a blastocyst in priority for implantation among 5BC, 4BB & 2BB created on day 6?
It is something that embryologists have to decide about, I do not get involved. 5 is an expansion grade, BC is for the inner cell mass and the body. Eventually, embryologists will decide. I’m not sure if an expansion grade will go first. I’d probably choose 4BB embryos first, even though they’re less expanded than 5BC. We can send your question to our embryology lab and our embryologists will be more than happy to answer you a lot more professionally.
I am 44 years old. I moved to donor eggs (not proven fertility) after 5 failed transfers – all with the same clinic. I have been discouraged from doing any further testing of sperm or myself, just same protocols. I’ve been now trying naturally again for a few months but I am wondering: would you suggest trying again with your clinic? Would my partner get all his sperm testing done, for fragmentation, etc., during only one visit? He is reluctant to come to Spain and I feel it is my best chance for a family.
When I was sick myself, in Europe I was going from one doctor to another and nobody really knew what to do with me at that time. I was stubborn and thought that I had to survive it. And you want to be a mum, so you’re stubborn, too. Please come to IVF Spain for the second opinion. We will be more than happy to assist you. When I see statistics, your euploidy rate is low. In my entire career, I’ve seen just once a pregnant woman in your age. But if you want to do one cycle with your own eggs, do it with genetics. Do it for yourself, to make you understand why it’s working or why it is not working. The number of genetically normal embryos that you generate at the age of 44 is low. But maybe you belong to this fortunate group that is going to win a million dollars in lottery and you’re going to have one genetically normal embryo. Then the chances that you’ll be pregnant are 70%. If I see that you still generate embryos but they’re all genetically abnormal, then you know what I’m going to say. You can take it or leave it. I need one or maximum of two cycles to define if you are generating health embryos or not. Because this is the most common reason why embryos do not implant – they’re good-looking but genetically abnormal. Of course, when we get a new patient, during the first appointment we want to know about your husband’s sperm. The basic sperm analysis, the DNA fragmentation, the apoptosis is routinely done to every new patient in IVF Spain.
Should a surrogate be tested for auto-immune diseases?
Surrogacy cycles are not allowed in Spain. But I will answer this question. There are a lot of women that have antinuclear antibodies (ANA) positive. This is the immunological beauty of these women. You just have to re-test them every 6 months, once a year, to see if these antibodies are there or they are coming and going. Rheumatologists usually test ANAs in different subtypes and then they know in which direction you could potentially develop an auto-immune disease. And this subgroup is being monitored every 6 months. The big problem starts when you have positive ANA and you start developing symptoms. What symptoms? You wake up and you are stiff, you have swollen joints. I remember my first sign was a feeling that ants are going under my skin. You’ve got a feeling that your feet are hot. It’s called paraesthesia. Everybody thinks that you’re crazy but you just feel something that does not exist. It’s a sign of the inflammation of neuronal endings of your nerves. They’re coming to your feet and hands. When a patient has this kind of symptoms and has positive ANAs, should undergo neither IVF treatment nor egg donation nor surrogacy. But when you work in IVF centres and you do a medical history with potential candidates for treatments and there’s a touch of auto-immunology due to potential rheumatology, you contact a rheumatologist and say: ‘I’ve got a patient/donor/surrogate with these symptoms. Your evaluation is kindly asked.’ And the specialist will tell you.
What is the cut-off age for woman at your clinic?
Officially, the Spanish law allows me to treat patients until 50 years old and 11 months. But in IVF Spain we treat every patient individually and we have complicated cases. And we will listen to these cases. And then, especially for Christmas, I go for a meeting and introduce the case to my colleagues. Before that, I collect all the information about you, that, for example, a psychiatrist in your country allows you to be treated, that your GP will support you, that your gynecologist will follow you up in the pregnancy. With this kind of documents, I go to the meeting with my CEO and my colleagues. I introduce your case and say: ‘Nobody is going to leave the room until we all decide positively on this case as this case truly deserves it and I have all the support.’ This is how in selected cases we fight for certain pregnancies to happen.
What about the treatment of Hashimoto patients (prospective mother) with donor eggs? Is it also an autoimmune disease?
As long as your TSH is under 2, I can influence your antibodies with Prednisone. We have quite good results with Prednisone and Hashimoto. Your TSH under 2 is a lot more important than antibodies. It’s doable. Don’t get nervous because of Hashimoto as long as you take your Eltroxin. It depends where you are, either you are hyperactive or underactive thyroid. Your endocrinologist has to see a follow up of TSH and then do the transfer when it’s under 2. The rest can be taken care of very well with Prednisone.