By fertility experts from Spain.
Alpesh Doshi, Consultant Embryologist & Founder of IVF London, is talking about the role of the embryologist in egg freezing and the outcome of the whole IVF treatment.
Global data has suggested that the best time to consider egg freezing is anytime from 32 to 37. This is a very prime age to consider egg freezing because after 38 the decline in fertility is very sharp and very rapid.
The process is very fast nowadays, so there have been so many developments in the IVF sector or at least even in the stimulation regimes that has enabled us to use very short stimulation protocols. We do appreciate that when women are working or when they’re busy with education, the whole process needs to be very well thought through and most importantly it needs to be non-invasive in their day-to-day life. So the whole process of egg freezing can be finished in around two weeks so hypothetically a patient can come and see us for a consultation, and as soon as they have their period, they can start on the stimulation and from two weeks from then, they would have their eggs frozen. It can take anything from two to three weeks depending on where you are in your cycle, but the short protocol gives us amazing amounts of flexibility now, and the whole process can be very fast.
There is no set answer for this. The way we assess and advise on this concept is by getting women to check their fertility potential. If you remember in my first couple of slides, I mentioned that we would recommend women to test ovarian hormone called AMH and also look at their antral follicle count. We know that a lot of women nowadays have got a declining ovarian reserve so for example if a woman has polycystic ovaries, she may only need one cycle of egg freezing because she’s likely to produce a lot of eggs, but if you have a woman who has got a very low AMH and a very low ovarian reserve such as an AMH of 1 or 2, then they may not produce that many eggs as a result of stimulation and such patients may need multiple cycles of egg freezing. Typically, as a lower average, we get women who would consider at least two cycles of egg freezing to give themselves a good chance in preserving their fertility, and because the whole gross plus is quite fast now it just takes two weeks as I said, it can fit in quite nicely in the whole scheme of things.
In essence, this is what women are asking that how many eggs do I need to have a baby, and again I think there’s no kind of magical answer to this because the factors that govern the answer to this question are age, ovarian reserve. If patients have got a very good ovarian reserve and if they have quite a lot of eggs produced and they’re young then all the eggs that they have from one cycle will be enough to potentially have a baby but if we keep this figure of 6% in our mind, so 6% clinical pregnancy rate, so typically I would say that in order to get a 60% chance of being pregnant you are looking for at least 10 to 15 eggs in storage. As a ballpark figure, if you are a woman in your 40s or early 40s, you may want to consider freezing more eggs because we know that after 40 it’s not necessarily about the number of eggs, it’s more about the quality of the eggs that give you a better chance of getting pregnant.
The pregnancy rate with frozen eggs is around 6% for egg thawed-out, so if a patient has got 10 eggs, then she’s got about 60% chance of getting pregnant, and usually, most women do have around 10 to 15 eggs per cycle. I would say that the pregnancy rates between fresh and frozen eggs are the same. Whether you are 34 right now and were considering fresh egg collection via IVF and wanting to get pregnant versus freezing your eggs and using them later, your chances of pregnancy are the same whether you use frozen eggs or whether you use them fresh.
The survival rate of frozen eggs depends on age. We know that in women who are in their thirties, early thirties the survival rate of the eggs can be very good, this is because the quality of the eggs is a lot more robust and the eggs can take a certain level of trauma during the freezing. Whereas women who are in their 40s have got very fragile eggs and they may not be able to take the pressure of egg freezing per se. Typically what we expect in women in the thirties is a survival rate in excess of 90 to 95% whereas in the 40s we expect a survival rate of around 80 to 85%, still very good but there is definitely a decline in survival rate with age.
18 to 20 eggs is plenty from a donor, one also needs to be very cautious that we do not over stimulate donors because donors also can risk ovarian hyperstimulation. There are two things here about the number of eggs. In my opinion, 18 to 20 eggs are quite a lot. What we’re aiming to get in a cycle of egg donation is between 10 and 15 eggs at the most. Whenever it goes from 18 to 20 or even more than potentially these two aspects that can be compromised and I’m not saying it is compromised but can be compromised. Firstly, the risk of ovarian hyperstimulation. Apart from that, many studies have shown that the higher number of eggs you retrieve, the quality of those eggs starts going down. We know that there are some clinics out there that will stimulate a donor quite heavily, maybe to get quite a lot of eggs sometimes even 30 eggs and what they will do is then they will divide those 30 eggs between 3 recipients and give them ten eggs each. In my opinion, this is not the right thing to do because the quality of those eggs is then going to be compromised.
You’re better of keeping to only one or two recipients but at the same time giving a couple of the recipients a very good chance of establishing a pregnancy. When it comes to waiting between each donation, I would say definitely a couple of clear periods before you go on to your next cycle. I would not advise a back-to-back cycle, you need to wash those hormones out of the body before you consider another cycle of egg donation, so at least 2 to 3 months is my suggestion.
I think what your doctor advised was correct. It all depends on what stage was that accidental trigger injection taken. If the donor has just started injecting herself and was only at about day 6 or day 7 of simulation and then in the accidental trigger injection was taken, in that case, it’s the correct thing to do, is to cancel the cycle because the eggs will have not been mature enough with such little stimulation. If it was about 10 days or 11 days of stimulation trigger, if the follicles were over 16 millimetres in diameter, then it would it could have been performed. Sometimes, it’s not only just about the day of stimulation, sometimes even on day 12 of stimulation, but the follicles also could not be very big. Because some women stimulate for a bit longer even up to 14 days. I think it’s more about the size of the follicles. If your follicles were all above 14 millimetres and you accidentally took the trigger injection, and egg collection could have been attempted.
From what you’re telling me, the donor is young, she’s had proven fertility 18 to 20 eggs which is great. I would expect at least 8 to 10 blastocysts from this donor. This is obviously bearing in mind that we’re just talking about the eggs, of course, there’s an impact of sperm as well, but you’re saying that the DNA fragmentation test was normal, so I would expect around 10 blastocysts from those eggs. The donor is young, proven fertility, a good number of eggs hopefully good fertilization should be expected about 80%, and I will definitely say 8 to 10 plus.
We often get asked that should I freeze eggs or should I freeze embryos and our responsible answer should always be that embryo freezing gives you better outcomes than egg freezing. But it’s comparing chalk and cheese. It’s got to be understood that when you’re freezing eggs these are eggs, and when you’re freezing embryos they have undergone quite a lot of barriers of development. An egg so hypothetically if you have fine eggs, you may get to 2 or 3 embryos, so one has to take that into account that there is a funnel, egg start off at the top end of the funnel and embryos are the bottom end of the funnel, so comparing eggs and embryos could be comparing apples and oranges. But a frozen embryo gives you a much higher success rate than a frozen egg if that makes sense.
I believe that it is important to more than the timing of sperm production. It is more important than abstinence is there. We generally recommend 2 to 3 days abstinence period in the men, and usually at IVF London, the sperm sample is always taken in the morning. Once the patient has had the egg collection, the male partner will be asked to produce a sperm sample, and the sperm sample will be processed in the laboratory. But there is nothing to say that if the egg collection is in the afternoon, the sperm sample cannot be produced in the afternoon, so there is no evidence to suggest that a sperm sample produced in the morning is better than a sperm sample produced in the afternoon. What is more important is making sure that we have the abstinence period that is required which is at least 2 days.
DHEA is mainly recommended to be taken in women with a very low ovarian reserve. It also must be said that the evidence around DHEA is quite average. The Americans used DHEA a lot because again DHA is available over-the-counter in the US and the UK it’s not. But with all the papers that I have seen or read, DHEA benefit is only if it is taken for a period of at least 3 months, so it’s a slow-acting benefiting drug or an androgen drug. I would suggest that if you have a low ovarian reserve, then one has to take a very calculated approach then, do we want to wait for three months and risk that ovarian reserve goes down further just because we’re trying to see if DHEA improves the outcome. Usually, women with low ovarian reserve or poor ovarian reserve would not want to wait those three months. At the same time I have seen women who will say that well I’m gonna have my IVF next month, is there any harm if I started in the DHEA now, I’ll say no it may not benefit, but it will certainly not do any harm, try it but again it’s got to understand that you’ve got to take it 3 times a day as well, so it’s pretty much a protocol when one has to really follow. In the UK clinics are not so pro DHEA, I find the American clinics very pro DHEA, especially with poor ovarian reserve.
I mean certainly, the DHEA should not be given without consultant prescription, in my opinion. Some women who have a high androgen level can have quite bad side effects with DHEA. So DHEA is nothing but an androgen as well so what we want to make sure that in women where it’s contraindicated, we should not be giving them DHEA. Again, I say that you need to take DHEA under supervision of your consultant and you shouldn’t just take it because your friend from the US has given you a bottle of it.
The answer is yes because most importantly, what you want to know is what your ovarian reserve is. I have seen quite a few women who are in their thirties with a very very low ovarian reserve. Sometimes they’re 33-34, but when they come for an ovarian reserve test or fertility assessment, we find out that their ovarian reserve is very low and they are at high risk of premature menopause and again you’d rather know this information early than later because if you do know it in good time, then you can at least freeze the eggs or even consider starting your family earlier because you have a real-time check on your fertility potential. I think it’s very important to get a fertility assessment done. Every woman as she turns 30 should have fertility checked to see what the ovarian reserve is so that they can plan their future. They can plan when to have kids, they know exactly how much time potentially they have to be juggling a family career, education etc.
Generally, women who are considering egg freezing for social reasons are usually working women, so for them to take 2 to 3 weeks out of their work just to go and freeze eggs abroad can be quite an inconvenience. I think the biggest inconvenience is being away from your setting whereas if you had egg freezing at a clinic in London or in the UK, then you can continue your lifestyle as usual for example in IVF London we have all of our scan appointments from 7:30 a.m. in the morning, so women come and have their scans, and by 9 o’clock, they’re potentially at work. This is not possible obviously during the pandemic, but if everything was normal, then we get a lot of women coming here for 7:30 scans, they leave the clinic by 8:15 and start work by 9:00 o’clock. They can fit the whole egg freezing or IVF treatment as part of their normal day-to-day routine whereas travelling abroad has its own inconvenience, it may be cheaper, but I think when you try and put everything into perspective including the cost of travel, the loss of income potential in the holiday, then you take the accommodation that you may have to spend on it probably comes to the same thing. I mean in a foreign country the language barriers etc. are all challenges one has to consider.
There is emerging evidence on ERA test. In my opinion, if you had 2 or 3 failed IVF cycles despite having good quality embryos transferred at the blastocyst stage, then I feel it’s worth having an ERA test. Let’s not forget an ERA test is invasive. You have to prepare yourself by taking all the drugs that you would have ideally taken in an embryo replacement cycle, so you have to do a dummy cycle by taking all those injections and drugs, and then you have to perform an ERA test. An ERA test is not cheap, it’s expensive, but also patients have to mimic their body as if they are performing a real transfer which is taking them to a more dummy embryo transfer cycle. It has its value, I believe but not as a first-line approach.
I think if a patient has such a low AMH at such a young age, as long as the patient is 18, of course, they can be legally treated, one really needs to take an expert opinion from a gynaecologist, it may be a case of premature ovarian failure and if at all there is any ovarian reserve still there which indicates there is some there although, the units of measurement of AMH in the UK is picomoles and not nanograms that we can convert that. She really needs to take expert opinion and consider egg freezing or fertility preservation because this definitely a very low AMH.
IMSI is a technique whereby you just magnify the sperm and look at it under very high magnification typically 6000 times magnification. What are you trying to identify by magnifying the sperm to that level is to see if you can spot any abnormalities in this firm head which are called vacuoles. This is what IMSI typically looks at, but the data has been very mixed about the benefits of IMSI, and I must say that in the clinical setting we used to use a lot of IMSI about 6-8 years ago and now it’s kind of died its natural death. That is because there are better tests that can now look at the health of sperm, so IMSI used to be done in men with high DNA fragmentation, but now you have better in robust tests in the laboratory that can select sperm with much, much lower DNA fragmentation. IMSI used to be a thing of the past, and nowadays, very few clinics are using IMSI because the real-time benefit can be really questioned.
We don’t offer IMSI, we actually offer high magnification ICSI because with IMSI you have to use what we call oil immersion etc. So we prefer to use what we call high magnification ICSI, and all of our ICSI is done under high magnification. As I said if it is using IMSI purely for high DNA fragmentation, we believe there are more proven methods or better laboratory techniques that can assist in using more viable sperm compared to IMSI, so we don’t use IMSI per se, but we certainly use what we call high magnification ICSI.
Pregnancy rate is around 6% per egg. I would say the live birth rate is around 5% per egg. So again 10 eggs from a woman who’s 35 years old or less you have a 50% chance of live birth.
If you’re thinking about egg freezing, I would say you’re looking at a couple of cycles of egg freezing. If your antral follicle count is 6 and your AMH 0.739 presumably nanograms and I think you’re looking at a couple of cycles of egg freezing.
In some women, we have what we call a discrepancy between an AMH and AFC, and in such cases, the AFC is a better predictor. In fact today, I had a patient who’s AMH was 1.3 nmol/l as but she has got about 15 eggs, we stimulate her at the moment, and she’s got about 12 to 15 follicles that are growing simply because her AFC was good, so she had a good antral follicle count but a very low AMH but when you compare AMH and AFC is a better and a stronger predictor especially in cases where you have that discrepancy. I would say the answer to the question is yes, You can certainly attempt to freeze your eggs because your antral follicle count is around 7. What I would expect is around 4 to 6 eggs being retrieved.
There is very little evidence for that at all. There is very little that has shown in terms of external supplementation to benefit egg quality. The most important thing to do is to time it right and freeze the eggs whilst your egg quality is better.
Usually, we don’t freeze the metaphase 1 egg. We would only freeze metaphase 2 eggs unless you were a cancer patient then they wouldn’t be an added advantage of freezing metaphase 1 or immature eggs. The common practice is to only freeze metaphase 2 eggs, one has to obviously also make sure that we try and get more mature eggs from you so if you have a lot of immature eggs, then one should be questioning if the stimulation regime applied was correct or not.
This is very bizarre because why would the eggs thawed and why were the eggs refrozen because if it is a matter of the sperm not being available, then the eggs should not have been thawed. It’s not easy to give an answer to this because I don’t have enough information here. The answer to your questions is it safe to refreeze the eggs, yes eggs can be refrozen but again as I said in my talk when you freeze eggs you are stressing them out to a certain degree so why would you apply that stress twice unnecessarily. If this was about not finding sperm on the day, then I would have not thawed those eggs, to begin with, and only thawed them once we have sperm.
Firstly, I want to say that nuclear and spindle transfer is still under research and development. There’s a lot of validation and clinical information that we need on its safety, so I would not recommend that you look into any of this technology because it is still not validated, it is still not considered to be safe. It’s important to understand that we are creating a life here, we try to create a baby, so we don’t want to be experimenting too early. Technology is moving very fast in reproductive medicine, and I feel it’s my responsibility to say that all this technology including spindle transfer is very much in its infancy, maybe in 10 years time it will be a reality, but at the moment there is not enough known about it. I know there have been some live births from Mexico from China on spindle transfer but what we fail to understand is how many times has it gone wrong. We only see the number of times that it’s gone right, that’s what we hear about, but we don’t hear about how many times it’s gone wrong, so it’s very important to understand, and as a scientist, I would be very sceptical about using technology which is very raw and not ready.
Your fertility clinic should be able to manage your endometriosis. It’s not always necessary to be addressing the endometriosis before egg freezing because sometimes we use what we call a long protocol for the patients with endometriosis which gives us a much better outcome. It doesn’t necessarily mean that you have to have any surgical intervention to address the endometriosis before egg freezing but again it depends on the grade of endometriosis. There’s not that much information again, here to go by, but I can tell you that, no it’s not mandatory to have surgical intervention before egg freezing for your endometriosis and at the same time fertility clinics should be able to manage this for you, you don’t have to wait to get a GP appointment unless you’re planning to get the whole endometriosis thing addressed at within the NHS. I hope I’ve answered your question because there are certain stimulation regimes where you can still stimulate women with endometriosis and yet get a good outcome.
That is quite a poor outcome especially if your donor is 27 years old. If your donor is 27 years old, she’s got two kids, she’s donated a few times, a good number of eggs, only 4 blastocysts – that’s not good, and only 1 normal after PGS testing, so you’re also saying that your partner has had a normal DNA fragmentation test, it’s really challenging but the outcome should have been much better. I think the DNA fragmentation would have been the first thing I would think about because people always kind of focus on the egg and egg quality but they don’t necessarily sometimes realize that the other half that makes the embryo is a start. The importance has to also be given to the sperm quality, but you’re saying that the DNA fragmentation is normal.
I would recommend using a technique such as choosing sperm with more intact DNA and then there are some procedures now available, or equipment available in the market, one of them is called ZyMot which we use here at IVF London, and it’s microfluidic channels through which sperm swim but sperm only with good or no DNA fragmentation swim through it and then we pick the sperm which has swum through and use them for ICSI or IVF. I would also question stimulation here because if the donor is young with proven fertility, a good number of eggs why did you not get good blastocysts, so something is not adding up here it would be very difficult to troubleshoot based on that little information, but it could be anything from sperm to mismanagement of the cycle.
AMH test can be done at any time in the cycle, there is no set time, but the AFC is best done between day 2 and day 4 of your cycle.
If you have two cycles of egg freezing and considering that I have said that an embryo is potentially better than an egg in terms of outcome what I would suggest is if you are considering another cycle, and it would be very wise to consider another cycle. I would consider embryo freezing now, just to kind of keep your options open in both directions but yes a 37-year-old egg is more potent than a 39-year-old, but if you’re going to be creating eggs at 39, then you potentially should start looking at furthering the process which is trying to create embryos out of it. However, that is if you have a partner right now, or if you don’t have a partner right now then one can potentially look at considering just freezing the eggs or using donor sperm, so I have a very good friend of mine who’s had two cycles of egg freezing which is again 38, and now she’s gonna be coming through for embryo freezing using donor sperm, she’s still single. It just tries to keep all the options, there is the pursuit of having a child, but I wouldn’t worry about the risk of ovarian cancer and stimulation, I wouldn’t worry about premature menopause. The most important thing to do is try and make sure you add more to that freezer because in another year or two the scenario would be very very different.
You may conceive naturally as well, there’s nothing to say that women in their 40s don’t conceive naturally, you may, but again this is an only insurance policy and looking out for something which is unprecedented because you never know this may be the routes that you may need to take in order to conceive.
The evidence is very weak on PRP, it’s very much in its infancy. Most fertility clinics do not advise the use of PRP when it comes to getting better quality eggs. I think we’re quite fortunate in the UK, any kind of new technology needs a lot of validation whereas in some parts of the world these procedures are unregulated. All I can say is that in my opinion, PRP doesn’t have enough evidence to suggest that it improves ovarian reserve or egg quality.
There is never a 100% success. If you are in your 30s, then you should look to freeze about 15 – 18 eggs if possible to give you a very good chance of getting pregnant, but we can never tell you what the magic number is to obtain 100% because there are so many variables. When it comes to the embryos, it depends on the genetic status of the embryos, so you and I both know that having embryos is one thing but having those embryos to be genetically normal is another. I can just tell you that if you reapply genetic screening to those embryos and if you have 3-4 normal embryos out of the genetic screening or after PGS, then you are most likely to get pregnant with live birth, the chances are extremely high.
If you are stable and your condition is managed, then you can potentially go for egg donation. I would seek the opinion of your fertility specialist, you need to seek the opinion of your consultant who’s managing you for your lupus. You can then safely embark on treatment, so I wouldn’t like to give a very clear answer to that because I think it can be a complex one, you’re saying that your condition is managed, but the green light has to be given to you by your consultant.