What are the causes of IVF Failures?
Egg donation isn’t the magic bullet we’d like it to be. Like it or not, like every medical treatment, it carries a risk of failure. Despite its many advantages, it can’t provide a 100% guarantee of success.
But what can cause an egg donation cycle to fail? To help us understand all the different factors that can impact a donation treatment’s outcome, we asked Dr Natalia Szlarb, the medical director at IVF Spain to sit down with us.
First of all, why is egg donation so effective? Well, as a results of a sociocultural shift in the 1960s, it is now common for women to delay pregnancy and childbirth in favour of getting an education or establishing a career. As such, it’s now more common for women to become mothers in their late thirties or even forties. The problem, however, is that our bodies weren’t designed with that in mind. Women have a limited reproductive capability that decreases with age. As we get older, the eggs we produce have a higher chance of containing genetic defects. If fertilised, the resulting embryo carries on these defects, which significantly increases the risk of implantation failure, miscarriage, or congenital disorders such as Down syndrome.
Oftentimes we start thinking about creating our family when it’s already past the ideal moment; although the precise cut-off point is different for every woman, research suggests that fertility starts dropping significantly past the age of 35. Implantation, pregnancy and live birth rates all drop significantly with the age of the patient. Unless you had the forethought to freeze your own eggs when you were younger, you may find yourself in a situation in which achieving pregnancy using your own eggs may be difficult, if not impossible.
This is where egg donation comes in. By providing oocytes from healthy, young donors, all of the issues stemming from advanced maternal age are bypassed. Unlike own egg treatments, IVF using donor eggs remains effective no matter how old the patient is. So where’s the catch?
Well, there aren’t any perfect donors. Like it or not, no matter how young or healthy you are, once you undergo hormonal stimulation, only about half of the eggs retrieved from you will be euploid – that is, contain a normal number of chromosomes. This ratio will drop with age – from around 50% before the age of 35 to around 11% past the age of 42. Egg donors usually manage a 61% euploidy rate in embryos created from their eggs – which means out of every ten eggs collected, around six of them will result in genetically correct embryos.
How do we know which embryos are genetically correct? We test them through a biopsy – embryologists develop an embryo until day five, when they reach the blastocyst stage. During this stage, an embryo consists of over 200 cells. A small sample – about five cells – is collected from the trophectoderm, the part of the embryo which will later develop into the placenta. This sample will then be used to determine whether or not the embryo is euploid or not.
This type of testing is called PGT-A, although until recently it was also known under the name PGS. Although widely used, it is still not yet widely available as a standard treatment in IVF. There are, however, experts stating that in the coming years, this may change, as the advantages of PGT-A are numerous. By selecting the correct embryo, the chances of achieving a successful pregnancy skyrocket, while the risk of miscarriage or implantation failure drops significantly.
The donor matching process also has an impact on embryo creation. Patients from certain genetic groups – for instance, some African-American populations – can have a higher risk of carrying genetic disorders such as sickle-cell disease. Through genetic testing during the donor matching process, the possibility of creating an embryo which could carry or suffer from such a disorder can be eliminated almost entirely.
Don’t let all this talk about eggs fool you – after all, you can’t make an embryo without sperm, and sperm too has an impact on the viability of the embryos. Certain tests can be performed to determine if there are any issues with sperm, be they DNA fragmentation or poor morphological parameters. Basic sperm analysis is a standard treatment at many IVF clinics, in fact.
Embryos are just one piece of the larger puzzle, however. The endometrium is the other major part of reproductive medicine, and in Dr Szlarb’s view, it has been unjustly ignored in favour of focusing on the embryos. Even if embryos undergo genetic testing, it’s not always possible to achieve pregnancy.
To address this issue, each patient at IVF Spain undergoes a test cycle before the actual embryo transfer. During this cycle, the patient takes oral or transdermal oestrogen; on day 10 of this cycle, they undergo an ultrasound scan in order to measure the thickness of the endometrial lining. In complicated cases, especially in recurrent implantation failure, a uterus lining biopsy is performed on 21st day of the test cycle, in addition to another scan. The sample from this biopsy is then sent for receptivity testing, which tells us about the timing of the patient’s “implantation window”, or the best possible time to transfer the embryo.
It’s not enough to transfer the embryo at the right moment – the uterus must also be free of any physical defects. A hysteroscopy can reveal polyps, myomas and fibroids, all of which can make achieving pregnancy much harder – fortunately, most cases can be fixed with a simple surgical procedure.
Immunology also plays a large factor in implantation. The uterine lining is filled with cells called the NK cells. Their sole purpose is to destroy anything that could endanger the endometrium – sometimes, they may attack embryos trying to implant themselves. Fortunately, immunosuppresants can prevent that response.
Questions from the event
What is the success rate percentage for a 5 day blastocyst?
Ok, If I have the day 5 embryo without genetic testing, the clinical pregnancy rate means: the gestational sac and the heartbeat, in 60% of cases is positive, while when I have embryos with genetic testing, it depends, but at IVF Spain in 2016-2017, the clinical pregnancy rate is about 75-77% per transfer.
We had 2 failed donor transfers and 1 ERA. What difference does a 2nd ERA make?
So, you have to see that there are different endometrial timing tests available – the one that we use tells us exactly if you are pre-receptive, receptive or post-receptive, and indicates how many hours or days more of progesterone you need until you are receptive. The first test which we perform is with five and a half days of progesterone – if the result shows that you are pre-receptive, then a confirmatory test is done with six and a half days of progesterone. If the result comes back and you are pre-receptive again, then we recommend either seven or eight days of progesterone – seven days is quite common, whereas I’ve only seen eight days around three times in my entire career. So, in selected cases, especially when you belong to the group with recurrent implantation failure with egg donation (which means there have been three transfers of good quality embryos and you didn’t get pregnant), then the timing of the uterine lining has to be verified.
What is the price for fresh egg donation?
At IVF Spain, we have prices depending on the quality of the embryo, the day development of the embryo and how many embryos we guarantee. The best programmes that we have, the first of which is called “Exclusive Egg Donation”, where we give you a guarantee of three day-5 donor blastocysts, then the price is €9,700. When we talk about the “Exclusive Plus Egg Donation”, where we guarantee five blastocysts, this programme gives you bigger security, as if we see that the cycle with a donor embryo doesn’t go as we expected and you’re not pregnant, and you only have three day-5 blastocysts, then another donor has to be stimulated for you to fulfil the five blastocyst guarantee. So, in this package you can have two donors, and this costs €10,700. We also have a “Diamond Programme” with a pregnancy guarantee, where we offer patients three different donors, nine transfers and the last cycle with a sperm donor, and this costs €25,000.
Do thyroid results matter? Mine was 2.44.
Thyroid results do matter. In internal medicine, we want TSH to be between 0.4 and 4. In reproductive medicine, we want TSH to be under 2. So, if you are between 2 and 4, internal medicine doctors will say it’s okay. In reproductive medicine, we would treat it. Why? It’s super easy to understand. The baby, in the first three months of development, needs folic acid and thyroid hormones for proper brain development, so that’s why we need to give more thyroid hormones, so TSH needs to be lower.
My first fresh donor egg transfer ended in a miscarriage and since then I’ve had two failed frozen transfers. In the last cycle I had prednisone, progesterone, progynova, baby aspirin, clexane and intralipids and it still failed – I only have one frozen embryo left. What tests would you recommend?
I see that immunology has been covered, as has clotting. The first question is, how old are you? Are the embryos that have been transferred genetically normal or abnormal? How high are the euploidy rates of this egg donation centre? Are the embryos healthy or not healthy? Some embryos have the correct morphology, but are genetically abnormal. What is your lining doing? What is the timing of your endometrium? I would consider a uterus lining biopsy before the last transfer, to see how many days of progesterone you need to open your implantation window. Last week, it was a very busy week for me – I had many doctors visiting me from other countries, and they were very interested in receptivity testing – we give doctors that collaborate with us a kit for receptivity testing, and if you would like, we can collaborate with your doctor to check this before your next transfer, so drop us an email at email@example.com and we would be more than happy to help you.
Would you recommend a 1 or 2 blastocyst transfer to improve success? I am 41.
When we talk about blastocyst culture, we recommend single embryo transfers, as the twin rate with blastocysts is over 30%. We have to be aware that twin pregnancies are higher risk pregnancies – you have to go to the doctor more often, your cervix length has to be monitored and if it is too short then we forbid you to work, we admit you to hospital, and for you it would mean a c-section. In Europe and in the US, nobody delivers twins normally anymore, so definitely I’d recommend single embryo transfer.
I have adenomyosis and the MTHFR gene mutation. Would I have a chance of implantation with adenomyosis? I’ve had two miscarriages, a stillbirth and two failed IVFs.
Your adenomyosis is just an immunological factor for us. In the first 12 weeks of pregnancy, adenomyosis is endometriosis of the uterine wall, so basically when patients are downregulated, the endometriosis/adenomyosis is not growing anymore. When patients are put on prednisone, which in reproductive medicine is given until the 12th week of pregnancy to calm down the immune system, it can solve simple immunological issues, and we can take care of them pretty well. The problems which you mention, the two miscarriages and the stillbirth – the most common causes are poor genetic quality of the embryos, which is age dependent. If you are still working with your own eggs, then you need a cycle with genetic testing of the embryos – also, patients who have had a stillbirth should be consulted by a hematologist for factor V mutations. In addition, some of them could, even though hematologically everything may be okay, be given clexane until they deliver – this is what I would approach your case from the simple information you have provided.
We have had 3 failed donor IVF transfers and our clinic is now advising a KIR-HLA test. How will this improve our chances?
It depends on whether your HLA matches your KIR properly – this will bring you the same pregnancy rates as everyone else with egg donation. The problem that we have with KIR and HLA is KIR AA is very well published, while KIR B, I can tell you from experience that we struggle with. If you are KIR AA the case is very straight forward, but KIR B still remains a challenge.
Would you recommend PGS testing for all egg donation blastocysts?
Yes. Let me explain why – I started doing PGS testing with egg donation after a case I’ll never forget, when patients came to me from Berlin, as it was a case that changed my life and turned reproductive medicine at IVF Spain upside down. The patient was offered an exclusive egg donation programme, we generated six good (AB) quality blastocysts, and the patient kept having miscarriages. I was trained in Berlin, so it’s a very small world, and doctors know each other, and the patient came back to me with results of her cytogenetic examination from the miscarriage material, and it turned out that she had a miscarriage of an embryo with Trisomy 13, and this was a donor embryo. After this type of case, doctors get a lot more grey hair at once, and I was nervous and suspecting a lawsuit, especially as the couple were both lawyers. However, the patient came back and said that they wanted to continue working with me, but asked that the second egg donation cycle would be done with PGS, and the patient got pregnant with the PGS embryos immediately. The first child born in Europe through egg donation was born in Berlin in a hospital that I know very well, and this is how it started. In 2016, we reserved PGS for second egg donation in patients who failed with the first donor, and we were able to see that with PGS we have better results and a shorter time until pregnancy than without, so I think that PGS is the future. At IVF Spain, we have an 80% euploidy rate, so I don’t think we should do it routinely at the moment, but I think in the future it will be the standard.
We had our last frozen embryo transfer in November. What is the best time to try again?
Timing is one thing, but the second thing is focusing on why the first transfer didn’t work. Is your endometrium growth proper – the anatomy, the thickness? Has the endometrial receptivity testing been performed or not? These questions should be answered before the second transfer is done. I do not like to transfer in the same protocol when the first transfer was unsuccessful – I always want to change something. We can transfer every two or three months, but if we keep repeating the same, it’s like taking a USMLE test and repeating the same mistakes in the test, so you will fail. You need to see what you did wrong, try to improve it and try again.
Is there a good or bad KIR result? How does the KIR test help you in egg donation?
No, there is no good or bad KIR result. There are things in medicine that are examined and better known than others. In transplantology, when we transplant a kidney or a liver to someone, we have to make sure that the blood type matches, and certain HLA are matched in A, B subtypes. We know that that KIR AA accepts C1/C1 embryos, and at IVF Spain I was able to confirm this. There are no papers published about KIR B, and it is very inhomogeneous, meaning some KIR Bs react as ABs, some as BBs, and sometimes it takes 2 donors to find which immunology this KIR B accepts better. There is still place for reproductive immunology to take a look at the KIR B genetic expression subtypes and say, for example, that there is no DS4 or DS5, so this is KIR B which accepts C1 embryos, or that if the other receptors are missing, then this accepts C1/C1. So, medicine needs to look more deeply into KIR B, but KIR A is well known.
Do you match the donor KIR to KIR (woman with the donor) or KIR of the donor to HLA of the male partner? How does the KIR-HLA matching work?
We match KIR to HLA. So, your KIR as a recipient is the one which decides which HLA of the donor you need. We do not only match KIR in egg donation cycles, we also look at this in IVF cycles, and if there is a KIR mismatch, then we put patients on immunological protocols. The reason for immunological protocols with Tacrolimus, the medication which is used in kidney transplantation, started at IVF Spain 2 years ago. A friend of mine, a gynaecologist, was my patient and she needed my help – she came with a Tacrolimus protocol from Germany, and I understood that certain KIR demands certain HLA of a donor, but it’s not enough. In order to have success with a certain KIR-HLA mismatch, you need not only prednisone but also a Tacrolimus protocol. At IVF Spain, we have it defined what protocol we recommend for each immunological problem.
How soon after a failed egg donor transfer can you try again?
Basically, you can try in the next cycle, but the question is: does it make sense? I would recommend that you use one cycle to find out why the previous cycle didn’t work. What is your immunology doing? What is your receptivity doing? Give yourself a month to find the diagnosis of what has gone wrong – then transfer.
I’ve had two failed donor egg cycles in the last few months (all have been frozen embyro transfers, no PGS). My clinic doesn’t feel that we need to do an ERA test as I’ve had a previous successful pregnancy (own egg IVF). What tests do you recommend prior to our next transfer?
I have seen in my career patients who have been receptive with 5 days, and they were getting pregnant in the first egg donation cycle, and I have seen them 2-3 years later receptive after 7 days with the second egg donation cycle. If you have failed with two egg donation cycles, then you need to know what is going on – is it a problem with low euploidy rate of the egg donation embryos with this cycle, is there a problem with your immunology, if there is a KIR-HLA mismatch, or is it the receptivity window. These factors have to be examined. If your clinic doesn’t feel they need to do something after you have failed with two egg donors, then I’m not sure if this is the correct approach. I personally would like to know what the issue is. I wouldn’t like to have one more donor, good quality embryos – are the embryos day 3 or day 5? These are the details which need to be looked into deeper. If you feel psychologically strong enough for a third cycle, then I would invite you to be a patient at IVF Spain, to check the reasons for why it hasn’t worked before.
How old are your donors on average? Is it possible to receive their name or some sort of contact in the future?
Donors, according to Spanish legislation, have to be under 35 years old – at IVF Spain, we want them to be under 30 years old. No names, no pictures and no contact is allowed. We can only give you their age and their blood group when you are pregnant, nothing else.
Many doctors say that ERA tells you the implantation window only in the tested cycle. What is your opinion?
No. It tests the implantation window in the test cycle, but to transfer, I perform the transfer in exactly the same type of cycle as the test one. At IVF Spain, we do not do fresh cycle transfers anymore, everything is done in a substitute cycle: patients receive 15 days of estrogens, 5 days of estrogens and progesterone, so I can move the knowledge from the test cycle to the transfer cycle. From my experience, and I have been using receptivity maps for over 5 years, so I have a lot of experience. Usually, the ERA map, the test we are using at IVF Spain, has the same results for a long time. What changes the receptivity? A miscarriage, D&C, birth of a child. Even though somebody has delivered a child and comes for the second one, we usually repeat the same protocol used previously with success. However, there are cases where we repeat the same protocol which previously was successful, but this time it doesn’t work, so we then repeat the ERA test. This occurs in about 20% of cases for the 3 reasons I named previously.
I am 45 and haven’t had a period in 2 months. Can I still get pregnant with IVF? What are my chances of success with my own eggs or with donor eggs?
Amenorrhea, which means you don’t have a period – there can be different reasons for this. If somebody doesn’t have a period for 2 months, this doesn’t necessarily mean you are menopausal. You need to see your ovarian reserve – the three factors this is dependent on are: your age, your AMH and your antral follicle count. When your AMH is less than 1ng/ml, we know that getting pregnant with your own eggs is going to be extremely difficult, because you are not going to generate so many eggs, so then your euploidy rate, which means the number of genetically normal embryos, at your age, is less than 10%. You have to generate 20 eggs, 10 blastocysts, and 1 will be genetically normal. I have never seen this type of cycle in my life. The magic number for euploid embryos is maximum 43 years old, and I have never seen anybody pregnant with their own eggs older than 44. I would say definitely because of your age and euploidy rate, you should go for egg donation. With your eggs, without genetic testing, the chance that you will get pregnant is less than 10%, and if I find genetically normal embryos using your eggs, then the pregnancy rate is 70%. With egg donation, the pregnancy rate is also 70%, but the problem is that at your age, you are not going to produce genetically normal embryos. I’m sorry if this sounds cruel, but it’s better to be aware where you stand, so you can make proper decisions.
Are your donors known (so the child can find out the donor when they turn 18) or is it all anonymous?
No. Egg donation in Spain is anonymous, which means we can only tell you the age and blood group of the donor when you are pregnant. The child can never find out who their mother is at any age. But, according to the law of this country, the child has to fit into your family- the donor has to have the same hair colour, skin colour, the same body shape as the patient, so when the child is born, everyone has to think that the patient is the genetic mother. I am aware that there are two worlds of egg donation: the first is anonymous and the other is non-anonymous. In the US and in the UK, the child at the age of 18 can find their mother, but in Spain this is absolutely not the case. When you become a patient of IVF Spain, we teach you how to speak to the child about where it is from. There are beautiful books in english, where at the age of 2-3 years old, we recommend that you read these fairytales to the child as bedtime stories, and in these books, this is the first moment where the child understands that part of them comes from Alicante. At the age of 8-9 years old, we recommend that the parents come back to the clinic to show the clinic to the child, going from department to department. They cannot go to the donors, because they are in a different building in a different part of Alicante, but they go to the nurses, go to the marketing department, and the children even take pictures with us. They make a family book, put pictures with us inside, so they understand that there is a part of them from Spain, so psychologically you have to know when to speak to the child – the best is before 10yrs old, to have the identity process closed. We’d be more than happy to have you on board and explain to you how we can choose the donor for you in an anonymous way, without showing you information of the donor, but how to make your life and the life of your child, through proper counselling, as good as with an open ID donor.
I’m 33 and have premature ovarian failure. I’m having menopausal symptoms and considering starting HRT. Will that affect my chances of donor eggs working?
You have to be aware that the mean age for menopause for women in europe is 45-50 years old, and you at 33 are too young to live without estrogens – they make us feel young and make us look good. When we do egg donation cycles, we put you on a substitute cycle with estrogens and progesterone, and you have the same success rates as everyone else who is having regular periods.
We have had three failed IVF donor transfers. On our last attempt, we had an endometrium biopsy, an endometrium scratch and intralipid infusion. What would you propose going forward?
I may sound like a broken record, but the first thing is – do we know if the embryos that they are transferring are day 3 or day 5? Are they genetically normal? Did the results of the endometrium biopsy come back as receptive? Is the dose of the progesterone being given to you correct? Why have you been given intralipids? Have your NK cells been tested or not? I would consider maybe using prednisone and using clexane or aspirin. If the first egg donation cycle doesn’t work, then we have to see why.
I haven’t had my first implantation yet. I live in the UK and normally send my ultrasound to IVF Spain. How will you know if my endometrium is ready for implantation as you mentioned timing having to be right. Also, after having a diagnostic hysteroscopy, my cycle is delayed. Should I be worried? I am 44 years old.
In egg donation cycles, we erase your age, so the pregnancy rates are age-independent. How would I know if your lining is working or not? The first thing is the patient history. When patients come to you, you have to speak to your patient, and 80% of the success is reached if you are a good listener. If your patient tells you she was pregnant 4 times but had 4 miscarriages, then you know that the lining is working. Then, routinely, we would not perform a receptivity assay before the first transfer. If another patient comes to you and says she has never had a positive pregnancy test in her life, then this is the moment when you should do a uterus lining biopsy or at least an endometrial scratch to improve the implantation chance in the egg donation cycle. So, this is how I know if the patient’s endometrium is or is not working.
Would you always recommend a fresh transfer over a frozen transfer?
At IVF Spain, we have higher success rates with frozen, genetically normal embryos than with fresh ones. So, if I have a young donor, and I know that she has a high euploidy rate, and I know that this lab has a high euploidy rate, then you can go for fresh transfer. But, if I have a donor that is matching the patient phenotypically, but I know that she does not have a high euploidy rate, then definitely I would recommend PGS and embryos which are genetically selected.
I had a chemical pregnancy in my last donor egg fresh embryo transfer. Do you suggest I follow the same protocol in my next transfer? Does me having a chemical pregnancy affect my next frozen embryo transfer?
A biochemical pregnancy is very good news for us – it means that the uterus lining is working. However, you need to go further with one more transfer and then maybe try an immunological protocol – maybe prednisone, maybe clexane and aspirin to improve clotting.
Do you accept HIV patients?
Yes, we do. One of the craziest presents which I have ever received was from my parents – my mum desperately wanted me to go back to the United States and take over her office, but it wasn’t meant to be. I was closed for 3 weeks in a very famous school in New York, where I was preparing myself for the USMLE. Believe it or not, the life expectancy for HIV patients now, through modern medication, is the same as everyone else. What I am very specific about, and it has to be clear for everybody, when we work with a HIV positive male partner, the sperm must be washed, because we have to be aware that even though in your blood the viral load can be undetectable, in the sperm and the white blood cells, there can be HIV particles present. So, our lab does sperm washing and freezing as well as PCR to make sure that there are no HIV viruses in the sperm. So, in HIV patients, fertilisation always takes place with frozen sperm. This is the male part. As for the female part, it is very straight forward. In Europe and in the US we have centres for HIV patients, where you visit your doctor every six months, and the medication has to be adjusted to you so that the viral load is low, so you will have the same life expectancy as everyone else. On the day of the transfer, when we have a female HIV positive patient, we look at when she had the last HIV blood testing, and how high the viral load was. I have unfortunately cancelled transfers because the viral load was too high – on the day of the transfer, you have to be undetectable, so the number of copies has to be under 5 per ml. All the children that we have had born at IVF Spain to HIV positive parents have been HIV negative. So, thanks to our hard work doing sperm washing, freezing, ensuring the mother’s HIV is undetectable on day of transfer, we have all children born healthy.
I have two frozen embryos already 3Bb. Do I need hatching for my first implantation?
It’s usually decided by the doctor and the embryologist – hatched embryos seem to implant better, so if the first transfer didn’t work out then maybe hatching, immunological protocol and blood clotting support can help you.
What is the age limit? Is there a weight limit?
The age limit is 50 years and 11 months. The oldest patient that we had at IVF Spain was 54, so though you have to see the law, you must also take into account individual cases.
As for weight and BMI – there is no weight limit. The first transfer is done and the patient’s weight is not important. If we see that you are more than 90kg, then we would recommend you to lose some weight. One of the nurses working with us was my personal trainer and my nutritionist, and I myself lost over 20kg with her, so we have a protocol and we teach you how to eat, that you should have 5 meals a day – 3 big ones and 2 small ones. Also, weight training – everyone is afraid of weight training, though with weights you can lose a lot more weight than cardio, so we would be very happy to support you through this.
There is a study in the UK stating that intralipid infusions are not effective and as a result, many UK clinics no longer offer it. What is your opinion?
There are no big prospective studies showing that intralipid infusions improve pregnancy rates. I’m aware of this study, but I’m also aware of cases in patients with high levels of NK cells in the endometrium who received intralipid infusions who got pregnant eventually. At IVF Spain, when we see high NK cell levels in the endometrium, we do still perform intralipid infusions.
Are there any exceptions where the child can get information about the genetic parents/donors? For instance some genetic diseases or other cases?
Routinely, the child can never ever find out who their genetic mother is. If we have a life threatening disorder, for example if someone needs a bone marrow transplantation or other very serious cases, then we have to go to the court, and the Judge decides if we can give you the identity of the genetic mother. Then, we have to go very individually, but routinely the identity of the mother is never disclosed.
Spanish features are often dark hair and olive skin. What is the volume of fair skinned, blue/green eyed and blonde egg donors?
There is a lot of international students studying at universities in Spain now. If you see pictures on our instagram and facebook, you can see we are very international – there is a big Ukrainian immigration to Alicante now. In order to work correctly with patients, the 500 donors who we have are divided into 4 groups.
Phenotype 1= blue eyes
Phenotype 2= green eyes
Phenotype 3= brown eyes
Phenotype 4= donors from Asia and Africa
So, our donor department has to make sure that we have balance in all the phenotype groups. So, it’s super easy to find a donor with brown eyes, so we can fill the Phenotype 3 group very quickly. It’s more difficult for the 1st and 2nd group, but in order to run so many cycles, knowing that the donor can have 8 cycles or 6 live births, the donor department has to find donors with blonde hair and blue or green eyes, so we can run the clinic properly. It’s more challenging, but in collaboration with universities and talking to students, as well as word-of-mouth recommendations, the percentage of patients in groups 1,2,3 is even – 150 donors in each group. Group 4 is more difficult but we differentiate the cases very well – we understand that a girl from Nigeria needs a different donor to a girl from Ethiopia. On top of this, one of our colleagues is South African, and I grew up in Detroit, so we can see the differences very well and can tell where somebody is from by looking at them. As for girls from Asia, these are the most difficult group, and the waiting time is around 3-4 months, but it’s still doable.