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IVF & fertility treatment with own eggs for women over 40 – what are your chances?

Dr Nisa Félix
Fertility Specialist, Ferticentro
Harry Karpouzis, MD
Fertility Specialist; Founder & Scientific Director, IVF Pelargos Fertility Group
Natalia Szlarb, MD
Gynaecologist & Fertility Specialist, UR Vistahermosa

Category:
Advanced Maternal Age

ask-your-doctor_3
From this video you will find out:
  • Can egg quality and quantity be improved for women over 40?
  • How does age impact ovarian stimulation response, particularly in women in their late 30s and over 40s?
  • Should PGT-A be considered for women over 40 undergoing IVF, given the age-related decline in viable embryos?
  • What protocol adjustments or strategies could be considered for a woman over 40 who has experienced failed IVF cycles?
  • What are PRP treatments, and how do they aim to improve the outcomes of IVF cycles?
  • How do AMH levels and antral follicle counts inform medication dosage and treatment strategies?

IVF & fertility treatment with own eggs for women over 40 – what are your chances?

It’s a fact that it’s harder to achieve and sustain pregnancy as women get older, and in many countries, more and more women, for a variety of reasons, are beginning or continuing their fertility journey in their late 30s and into their 40s.

While egg donation is an option for some, many women prefer to use their own eggs if possible and may want to consider all opportunities and explore all options before taking a different route.

- Questions and Answers

Is it possible to improve egg quality and quantity after the age of 40 for a woman?

Dr Harry Karpouzis, Pelargos IVF: Generally, we need to look at 2 different things. The first thing is the quantity, and the second thing is the quality. There is no magic way of miraculously improving the quality. The quality depends usually on 1 factor, and this factor is age. There is some data behind things that might help, and there are some things that women can do before they proceed with IVF or even before they try spontaneously to get pregnant. Folic acid is something that we all know about. Vitamin D and the levels of vitamin D to be proper is something again that we need to know about. Coenzyme Q10 has some good data behind it and it is important. Many multivitamins include different aspects like melatonin, like Coenzyme Q10. Together, all these things might help before an IVF without really miraculously causing a very big improvement in the quality of the eggs. Generally, a healthy lifestyle, diet, all these things, sleep, yoga, and acupuncture, are things that you can try to improve a bit your chances.

Regarding the quantity, it depends on the number of follicles and the AMH. So in 1 IVF, we cannot get more eggs than the amount of follicles that we have. Some data behind the DHEA, it’s not completely proven. In some of the cases, we might use it in relevant doses. PRP which we might talk about later is an option, according to some data, that might help in improving the follicular recruitment and get you a bit more eggs. These are things that you can try before the IVF and to choose a personalized and the right protocol for you. As a general rule, the number of eggs that you get depends on how many follicles you have, and you cannot stimulate follicles that do not exist in one go.

Dr. Natalia Szlarb, UR Vistahermosa: I think that Harry already mentioned almost all miraculous medications available. The thing that we could add probably, there are some studies published regarding the low dose of growth hormone subcutaneous injections and testosterone gels before an IVF cycle. In the US, we are focused on DHEA, and CoQ10, and the dose, according to FDA, is standardized. So, you cannot double the dose because it could be toxic for you. So basically, the quantity of eggs depends on antral follicle count and AMH. So all the patients before they are getting treated here at Vistahermosa are assessed with their ultrasound, and as Harry said, there are no miracle follicles that could appear there that are not there. So basically, the antral follicle count and the AMH will tell us how many eggs we are going to get, and we have to adjust the dose of medication to this ovarian reserve of this patient that we have. But before we perform an IVF cycle, basically, the CoQ10, high dose vitamins, folic acid, testosterone gel, subcutaneous super low dose of growth hormones injection, there’s no more magic, as far as I know. I wish there was.

Dr Nisa Felix, Ferticentro: Unfortunately, I can’t add anything else. I would like it to be possible to do that magic to improve quality and quantity only using some miracle medicine, but unfortunately, from what we know at this point, I think my colleagues just summarized all the best options that we have. So at this point, I think we have to use them carefully and from case to case and always explain that at this point, none of these strategies shown really that they will work, but it’s what we have. So we should always discuss them with our patients and use them case to case.

   

If you were to prioritize what you should do first before seeking treatment? Do we prioritize AMH or number of follicles seen or antral follicle count? 

Dr Nisa Felix, Ferticentro: When we study a couple, one of our main goals is the ovarian reserve because, in IVF, we depend basically on two things: quantity and quality. The quality we already talked about, is based on the main factor that is age, and the quantity we need to assess that based on two factors: what we see on ultrasound and the antral follicle count, how many follicles we can see in an early phase of the cycle in each ovary, and then the quantity accessed by a blood test, that is AMH, that gives us a number, and that number reflects the ovarian reserve of a woman. We have to take into account the two factors because in my experience, and that’s a very personal opinion, I prefer to base my opinion on the antral follicle count. I always take into account the AMH, but what I see on ultrasound usually reflects during the cycle. As I already told you, we take into account the two factors, and that will help us to advise that couple about the expected success rate of that IVF treatment and also guide us into what type of protocol and what type of dosage of medication we will use. So, I would say both of them are important, and both of them will guide us through the treatment to decide what’s best for that couple.

Dr Natalia Szlarb, UR Vistahermosa: Some people expect a different outcome when they are after egg retrieval (ER), and this outcome does not fit in any way to the ovarian reserve at the beginning of the treatment. So ovarian reserve are three A’s, and there’s no more magic here: age, AMH, and antral follicle count. And I agree with Nisa that we have to take into consideration all 3 factors. Sometimes we see one follicle more, and the AMH is low, from my experience, some colleagues measure antral follicles differently. So some colleagues count the antral follicle, and they have sometimes amazing ultrasound machines, they see even follicles that are 3 mm, and they say they are antral follicles, and some colleagues measure follicles that are 6 mm. These are antral follicles, so some colleagues over-measure the follicles.

We should count the follicles which are 6 millimeters, and everything less than 6 probably will not respond. The factor that brings us really down to earth is AMH. AMH, in a very cold scientific way, will tell us how many eggs we expect from you. So instead of giving a patient this kind of over-expectations and being very optimistic, measuring their antral follicle count, let’s maybe keep it to ourselves, especially when we have young colleagues that are starting the journey in Reproductive Medicine. And let’s focus more on the AMH because this value will never disappoint us. On the other hand, working already 12 years here in Spain and coming from the US, in the US, before any IVF cycle, we were putting patients on birth control pills, and these birth control pills were kind of shrinking the number and the measurement, the diameter of antral follicles. And then these people with low AMH, pre-treated with birth control pills, usually had a worse outcome. So when you have these patients of advanced maternal age, and you have to be very careful how you treat them when you decide which dose of hormones you’re going to give them, probably it’s wiser, and in my experience, and this is something that I learned in Spain, it’s better probably not to pre-treat them with birth control pills, not to downsize the follicles, not to diminish the number of antral follicles. With advanced maternal age, AMH, and antral follicle count, we have to be very careful what we say to a patient, which dose of medication we give them, and how we pre-treat them

Dr Harry Karpouzis, Pelargos IVF: I couldn’t agree more with my colleagues. All 3 of the factors – age, AMH, and antral follicular count – are important. If you ask me, though personally and out of my experience, what I would consider the most important is antral follicular count. We work a lot with that. I think it strongly depends. I mean, we work with very personalized protocols. The important thing in every case is to personalize it to its case. Natalia is very right. I mean, the pill can reduce the number of follicles, can make it more difficult to stimulate follicles, and might cause some follicles to disappear, so you need to know when to use the pill. Sometimes, in medical tourism and people coming from abroad, it might be difficult to schedule without the pill, but despite that, there are options. And if someone has a very low AMH or a low antral follicular count, it is better not to give the pill. Of course, 3D machines and all this equipment measure follicles that are in the middle of the ovary. I don’t agree that these are not follicles. These might be primordial follicles or anything else. Follicles are follicles that you can see. We use many cases of luteal start follicles as well, and the reason that we do that in poor responders is because in the second half of the cycle, sometimes you have better follicular recruitment rather than the first, and it works very nicely many times. The dose depends on the number that you can see, and as Natalia has said as well, it depends on the size, because if you have follicles that are less than 5 millimeters, it is very difficult to stimulate them. If you want to stimulate them, the only possibility is to threshold them with a high dose of gonadotropins. If you have follicles between 5 and 10 mm, though, they can be stimulated with lower doses as well, and these are the follicles that you usually get.

The whole point is to explain to the patient that you cannot get more eggs than the follicles that you can see, that the size plays a role and that it is better to start on the timing of the cycle that you have the more follicles, and of course, you get some information from AMH, etc.

How does age impact the response to ovarian stimulation, you can restrict it to late 30s and over 40s. What are you going to do differently about stimulation in those older age groups? 

Dr Natalia Szlarb, UR Vistahermosa: In the clinic where I work, we adjust the dose not only to the patient’s antral follicle count but to AMH. I know that with patients with AMH under 2, and these are the patients at the age of 38-42, which is AMH between 0.3 to 1.5 nanogram per milliliter, it’s very hard to hyperstimulate them. The other thing is, with low AMH and high dose medication, my answer is no because this kind of ovaries quite often get blocked through high doses of medication. Spain is famous for this type of cycle called embryo banking where we, in patients with low ovarian reserve, perform 1 cycle with a middle dose protocol. The middle dose in Europe is 250 units. And we see how many eggs and embryos we get, and we test them genetically. We perform PGT-A (Preimplantation Genetic Testing for aneuploidy). Two to three months later, we performed another cycle with a low-dose protocol. The low dose in Europe is between 75 and 150. Don’t go 75 units with patients 38-40 because it’s going to be a kind of insemination, not a low-dose protocol, so you have to give at least 150 units and see how many eggs and which quality of embryos you’re going to get and PGT-A them. I came to this country to learn what PGT-A is all about, and I’ve seen a lot of patients in advanced maternal age generating even beautiful embryos, you know, AB quality. Even in embryo banking, we can go up to 6 embryos and only 1 or 2 are genetically normal. So when we talk about which protocol, it has to be adjusted to the patient’s age and AMH. And then the strategy to develop, to grow embryos to day 5, and to select the genetically normal ones, this will be an approach that we would use in Alicante.

Dr Nisa Felix, Ferticentro: We have been talking about how we depend on quantity and quality, and age, unfortunately, decreases them both. Quantity decreases because we are born with a certain pool of antral follicle counts, and when we reach 40 years old, unfortunately, the pool will only have around 3% remaining. That’s why our ovarian reserve decreases that much with time. Then there’s the quality, which is more about biochemical processes. I won’t get into molecular things, but just to understand that the quality, the competence of the oocyte, and then the embryo generated from that oocyte also decreases with age because we know that quality will depend on the nucleus and the chromosomes of that oocyte. That’s why, with age, women experience more difficulty in getting pregnant, more chances of miscarriages, and more risk of having a baby with chromosomal anomalies. That’s why we tell them that age interferes with quality and quantity.

And that is to say that age will interfere with the response to ovarian stimulation, as my colleague already told me. We have to adapt the protocols to each lady, to each couple. We can have more experience with one gonadotropin or with another, with a certain dose or another dosage. That will depend on our goal. But as Natalia told us, we need to adjust the protocol, and our main goal is to get the highest quantity of eggs possible and the more eggs that have as much quality as possible because our main goal is to generate embryos. As we know, when age increases, the quality of those embryos will be again worse, and most of those embryos will not be chromosomally normal. So that’s why, especially over 40, we advise couples to do PGT-A, just so we can differentiate the embryos that are genetically not normal from those that are normal, so we can only transfer those embryos that are normal.

I think we have to explain to couples why, after 40, suddenly our expectations, our success rates decrease that much. And that’s because age impacts the quantity and the quality of those oocytes and then the success of the stimulation.

Dr Harry Karpouzis, Pelargos IVF: I mean, age affects the quality; this is something that we know for sure. If you’re asking me about how age affects ovarian stimulation, I mean, it does affect because, for example, if we compare a woman who is 41 and a woman who is 35 and they have the same number of follicles and an equal number of AMH, most probably the woman who is 41 will do worse in the ovarian stimulation compared to the woman who is 35 because older women do have resistance in the FSH that stimulates the follicles. The FSH is an important factor that needs to be taken into consideration when we choose the protocol and the dose that we need to adjust for each woman.

If you are asking me what is the best protocol, as a general rule, if someone has more than 3 follicles, it might be a benefit to get more eggs with a high dose of medication. But if someone has less than 3 follicles, even if we give more medications, she will just pay for more medication, but she will not get more eggs. So women that have a small number of follicles, less than 3, the best thing that they have to do is to go on smaller doses because they can get this number of eggs without really paying more money and getting themselves into more injections. And in cases like that, we know now we vitrify, we have the weapon of vitrification, so we are not interested in the implantation window, we are not interested in things like hyperstimulation and things like that. So they can bank.

They should know that if they have only 2 or 3 follicles, they just get 2 or 3 eggs and that’s their target in one go. And statistically, the more eggs you get, and there is clear evidence of that, the more you increase statistically your chances. You might be very lucky and you get 1 egg, and you are 41 years old, and you get pregnant. But statistically, if you have more eggs, you have more chances of one of these eggs being chromosomally normal. So if you cannot achieve this in one go, you need to try more and more and more so that you can get more numbers and hope one of them is chromosomally normal. If you will PGT-A them or not, I’m a very big fan of PGT-A generally. If you can afford it, you do it, of course. And if you find the chromosomally normal embryo, then you don’t need to bank more embryos because your chances will be about 70%.

Now regarding the protocol, there are many different protocols. What I like to say to people is that the best protocol is a personalized protocol. And second, keep it simple. The best protocol is always an antagonist protocol, but you need to perfect this protocol. You need to personalize it and measure the blood test, the LH, and the estradiol so that you can make sure that all the follicles will reach the same size at the same stage. The more you can sometimes it is impossible, and in the end, if it doesn’t work, then yes, there are innovative protocols. We use double stimulation protocols, we use Letrozole and agonist protocols, and many weapons in our hands. But first, keep it simple, and second, personalize.

 

I had a PGTA-tested embryo that was normal, but I still didn’t get pregnant. What might have some impact and improvement on quality or quantity, particularly some of the newer treatments like PRP treatment? 

Dr Harry Karpouzis, Pelargos IVF: First of all, PRP (Platelet-rich plasma) means drawing blood from the forearm, centrifuging it in a machine, and in the end, separating the plasma from the red cells. With all this process, what we try to achieve is getting a sample that has an increased rate of growth factors og cytokines. All these factors have a role in the follicular recruitment in the follicular development. The of revitalizing tissues is seen in reproductive medicine; Orthopaedics and Plastic Surgery. The only difference is that here we take this sample that we have created, and we inject it inside the ovary in a procedure that is very similar to egg collection. We give it time, and we measure the AMH and the FSH before and after the whole process of follicular recruitment of follicular development. It takes about 3 months to know if PRP has worked or not, it might sometimes take 3 to 6 months. If it hasn’t worked in 3, or 4 months, my personal experience is that it will not work.

PRP is the last resort before you go to egg donation. If it is not working at all well with you, and you want to try it, you can do it. We have kind of pioneered at IVF of Live Centre where we usually cooperate in Athens, and we have many different PRPs as well.

There are numerous variations to consider, but based on my experience, despite our prolonged exploration of these methods, I cannot confidently state that they are associated with an increase in pregnancy rates. However, I can attest that significant changes have been observed, particularly in women under 40. While not all women exhibit these changes, many younger individuals with low ovarian reserve have experienced improvements in follicular recruitment and egg production. Essentially, as previously mentioned, a higher egg yield typically corresponds to increased chances of success. Although there are studies examining potential quality enhancements, I cannot definitively link these methods to improved pregnancy rates. Women with very poor ovarian reserve, particularly in their 40s or 42, may find these options helpful before undergoing IVF. If a cycle has not resulted in a positive outcome, and you are hesitant to pursue egg donation or similar alternatives, exploring these methods carries low risk and could potentially enhance egg retrieval.

Dr Nisa Felix, Ferticentro: First of all, we would need to study that couple, to conduct a more detailed clinical history, to gather more information. We are currently focusing on eggs, but we also need to address the male aspect, so we need to cover that as well. However, let’s concentrate specifically on the quality and quantity of the egg. Of course, we also need to assess the ovarian reserve, and based on that, along with age and the woman’s weight, we will then determine which protocol to use. When a couple has done other cycles before, we study them and figure out ways to get better results. If the cycles had uneven follicle growth, we may use pre-treatments. Then, we make a special protocol for the woman.

Of course, if we are discussing individuals over 40, we typically do not expect a significant ovarian reserve or response. Therefore, more often than not, I advise these couples to consider egg accumulation. This is a process we usually undertake with women facing low ovarian reserve. We initiate one cycle into the follicle phase and then, based on the results, attempt another cycle five to six days later to accumulate more oocytes. Once we achieve a satisfactory number of oocytes, we proceed with fertilization. We await the blastocyst stage and then perform PGT-A.

I think this is our first step. As such, based on the results, we as Dr. Harry mentioned earlier, will start with a simple method and then adjust our method for each couple accordingly. While alternative technologies such as PRP may be recommended in some cases, they are generally considered a last resort.

As Dr. Harry also mentioned, there is limited information and research available on these technologies. Therefore, much groundwork needs to be done before we can confidently recommend them to everyone. However, I believe these are the main procedures we would undertake. Furthermore, we need to find out how many positive blastocysts we obtained, how many of them were genetically normal, and based on these results determine the appropriate embryo transfer method, the appropriate system that they are followed up, and what tests we have to do before they are transferred.

Dr Natalia Szlarb, UR Vistahermosa: When someone’s coming here for their final treatment, we need to review your medical history, and the previous cycles you’ve had, and consider what we can do differently. If we look back and find that you responded well to a particular medication because, as some people do, they respond better to one brand over another, we’ll stick with what worked for you. I come from a line of gynaecologists spanning three generations. My approach is influenced by the conservative German School of Gynaecology, which advocates for transferring everything fresh rather than freezing. Consequently, we aim to avoid high doses of medication to prevent hyperstimulation or adversely affecting endometrial receptivity. Instead, we might prescribe a lower dose, like 150 units of recombinant FSH/LH.

Coming from a medical background rooted in the late ’90s to the early 2000s, following the teachings of Professor Bruce Shapiro, who advocates for a freeze-all, transfer-all, test-all genetically approach. Sometimes, we encounter cases like Harry mentioned, where women with polycystic ovary syndrome, even at 42, produce a remarkable number of eggs. However, to achieve this, we must carefully consider a patient’s inclusion criteria for an IVF cycle and their AMH levels before deciding on a medication dosage whether it’s a moderate or higher dose.

Nissa and Harry focus more on the antral follicle count in their treatments, while American medicine often emphasizes AMH levels, partly because insurance coverage for medication is often tied to AMH levels. Thus, we tailor the medication dosage based on a patient’s AMH levels. Ultimately, it’s crucial to align our treatment approach with our goals. For instance, if the aim is to transfer three embryos, we must ensure that your estrogen levels at the time of triggering don’t exceed 2,000 units. Overmedicating could jeopardize this goal.

When deciding whether to transfer embryos fresh or after testing for genetic abnormalities, such as with PGD, we also consider AMH levels. However, it’s important to note that different regions use different units to measure AMH levels. In the European Union, AMH is typically expressed in nanograms per millilitre, whereas in the UK, different units are used. To convert between the two, you’d multiply the nanograms by 7.4 to get the UK unit. Doctors must be mindful of these differences, especially when treating patients from abroad. For example, an AMH level of 6.8 would typically indicate a UK patient, as such levels are uncommon in the European Union.

In conclusion, it’s essential not to overdose on medication, as there comes a point in a person’s life where no amount of medication will significantly impact an AMH level of 7, for instance. Therefore, it’s best not to invest time and energy in such cycles that are unlikely to yield favourable results.

How many eggs are you expecting to get if a woman is 40 years old, and has an AMH of 4 or 5 and 12 antral follicles? Can you also explain the difference between follicles and an egg? What sort of success rate you might expect? Pregnancy rate and live birth rate, with and without PGT-A.

Dr Natalia Szlarb, UR Vistahermosa: I had not long ago a patient like this, and when you give them antagonist middle dose protocol, let’s say 250 recombinant FSH LH, an AMH over 2, we expect 15 to 20 eggs. We fertilize all of them, and develop them to day 5, day 6; we usually expect out of 20 eggs to fertilize 16, have 6-8 day 5 embryos, and if we do not test them genetically, we have to freeze them because with these numbers, we are afraid of hyperstimulation, and we don’t know really what we have.

A 35-year-old woman with 8 embryos, statistically, will have 4 that are genetically normal. Someone between 38 and 40 might have a 20-30% chance of having genetically normal embryos. Out of 8 embryos, she might have 3 normal embryos. Women over 40 are sometimes expected to only have 1 or none. In Spain, where I’ve worked for 12 years, we often see these patterns, especially with PGT-A cycles.

Genetically normal embryos are valuable. For older women, like those aged 40-42, it’s common to have only 1 or 2 genetically normal embryos out of 20 eggs retrieved. Because of this, I take extra care in the process. Before transferring the last 1 or 2 embryos, we conduct receptivity testing to ensure the timing is right, there are no infections, and everything looks good. With this approach, the chance of pregnancy per transfer is over 70%.

PGT-A testing is very important, statistically, only 1 or 2 out of 7–8 embryos are genetically normal. Wasting time, money, and emotions on transferring embryos that are likely to be genetically abnormal can be heartbreaking. For women with good AMH and response, freezing all embryos and testing them with PGT-A can be a beneficial strategy, even at 40 years old.

 An AMH under 1 nanogram per milliliter suggests a low ovarian reserve, while an AMH over 2 nanograms per milliliter indicates a good ovarian reserve. AMH between 1 and 2 suggests diminished ovarian reserve.

For AMH levels around 1, such as between 0.2 and 1.2, I still expect around 7–8 eggs, resulting in 2–3 embryos, with statistically at least 1 being of good quality. However, the protocol needs adjustment; we lower the medication dose to avoid overstimulating the ovaries.

With very low AMH levels like 0.3 or 0.2, cycles become challenging. In such cases, if we manage to obtain even one blastocyst, I recommend embryo banking. Since consecutive cycles are not advisable, we space them out every 2–3 months to let your body recover. The goal is to accumulate 4 or 5 embryos, hoping that through this process, we’ll find at least 1 genetically normal embryo.

However, if no embryos during a cycle indicates poor egg quality, making embryo banking risky. If you’re determined, I might allow 1 or 2 more attempts, but if after 1 cycle there are still no embryos, alternative options are necessary.

Dr Harry Karpouzis, Pelargos IVF: To have statistics in your favor and on your side, you need to aim for about 15 to 20 eggs in the age group of 40 to 42. This number is crucial because, upon analysis, it consistently shows that 1 or 2 blastocysts might be viable, or even just one. I’ve witnessed instances where women at 42 get two eggs, which develop into blastocysts, undergo PGT-A, and turn out normal. However, it’s largely a matter of chance” how many chances you have and whether the statistics align with your situation. Therefore, in cases like these, honesty is paramount. Patients need to be informed upfront about the challenges they may face.

For example, women with a history of polycystic ovaries often have excellent AMH levels and antral follicular counts, even at ages 42 to 44. In many cases, they achieve a chromosomally normal embryo. The key takeaway here is that having a chromosomally normal embryo, also known as a euploid embryo, offers nearly equal pregnancy chances, regardless of whether you’re 44, 40, or 35. However, obtaining such an embryo becomes more challenging with fewer eggs available.

If you undergo stimulation and don’t even reach the blastocyst stage, it indicates a quality issue. As we’ve emphasized from the beginning, there’s no miraculous way to improve quality. Therefore, in such cases, it’s crucial to be transparent with the patient and acknowledge the difficulties. Additionally, there’s a notable difference between the 40 to 42 age group and the 42 to 44 age group. The decline in quality is quite steep, and beyond 44, it becomes exceedingly rare. So, many factors come into play, but what’s important is that the patient is informed in advance, as the decision ultimately rests with her.

I’ve had patients with chances that were close to zero, and I’ve suggested egg donation. However, some are not content with that option and wish to try again. It’s a challenging situation, especially when the odds are so low. We must select the right protocol, communicate clearly with the patient, and ensure everything is understood. Despite the challenges, it’s possible to achieve pregnancy even at the age of 45, though they’re very rare.

Dr Nisa Felix, Ferticentro: It’s always very challenging, but it’s the reality we must convey to patients. We must rely on the numbers and what they reveal. Our ultimate goal is to achieve a live birth. Having a good embryo does increase your chances of pregnancy, but we can’t guarantee it.

The best predictor is the live birth rate, supported by studies and the clinic’s success rates. If you’re about 40 years old, your chances of a live birth could be between 10-20%. Once you are 41 or 42, that number drops to 10%. Between 42-43 age, it decreases to around 4%. By the time you reach 45, the likelihood of a live birth is less than 1%.

 The numbers are important, and we need to share that information with our couples. In my career, I’ve had some amazing news and surprises that brought happiness to me and my couples. However, these moments are rare, maybe only about 1% of the time. As Dr. Natalia stated, we are all humans, dealing with couples and their feelings. I always tell couples that this process is a marathon, not a sprint. They should be strategic about where and when they put their energy.

In my opinion, it’s crucial to provide honest advice based on these sometimes harsh realities. It is advisable to make decisions based on success rates rather than relying on luck alone. As Dr. Harry said, we need to assess each case individually, analyze specific parameters, and offer conscientious guidance. The data clearly shows the importance of being well-informed, and I always stress to couples that if they are committed to using their eggs for pregnancy, they should be ready for a challenging process. We know that achieving a viable embryo and, ultimately, a pregnancy and live birth requires a significant number of oocytes. However, we’re here to support couples every step of the way and provide them with opportunities to feel confident in the choices they make.

We know that achieving a viable embryo and, ultimately, a pregnancy and live birth requires a significant number of oocytes. However, we’re here to support couples every step of the way and provide them with opportunities to feel confident in the choices they make.

What about mosaic embryos, meaning some cells within that embryo are normal, and some are abnormal? But when we take a biopsy, we don’t know the extent of that mosaicism. Should I consider transferring it?

Dr Harry Karpouzis, Pelargos IVF: This is a very difficult question, a very tricky question, and this is something that needs to be explained very nicely. As far as it regards my experience, people are coming from all over the world, every unit creates the embryos, and the mosaicism rate varies with different standards. It needs to be very clear. It is recommended by the guidelines, but it is not always used. So, when you get a result, you need to know exactly what it means euploid, what it means aneuploid, and what it means mosaic.

Usually, when we say aneuploid, it means a mosaicism rate of more than 80%, at least with us. And when it is aneuploid, it has close to zero chances to get implanted, so you shouldn’t transfer it. But you need to make sure that this is the case. When we say euploid, even euploid embryos sometimes do have mosaicism, and we usually grade as low embryos that have mosaicism of less than 20%. But the chances of getting implanted are very high. Then we have a middle category, which is between 20 to 80%, and even this category is further divided into low mosaicism, 20 to 50, and high mosaicism, 50 to 80.

Even after that, you need to know that when we take a biopsy, we take it from the trophectoderm, which is the outside part of the embryo, which is the part that creates the placenta. But what later creates the embryo itself is the inner mass, which usually we don’t take with the biopsy. It is not always the case that the biopsy we take from the trophectoderm corresponds with what is happening in the inner mass.

So, when it comes to Mosaic, there is a possibility of the inner mass to be Mosaic, or to be euploid, or to be aneuploid. You need to know that sometimes the decision between the 20 to 80% mosaicism rate, if you transfer it or not, needs to be very well documented. First of all, documentation in the PGT-A, and second, you need to have genetic advice if you drop in this category because it doesn’t depend only on one factor. For example, it depends on if it is a whole chromosome or a segmented one. If it is a segmented one from a very good morphology embryo with a low mosaicism rate, for example, this is an embryo that you can transfer, and it can achieve as high as 40% chances of implantation.

But if it is a whole chromosome or a complex aneuploid like your case, and it is documented as aneuploid, and it is properly documented as aneuploid, this is an embryo with a complex abnormality aneuploid, which means more than 78% mosaicism rate, it has close to zero chances, and I wouldn’t transfer it. So, the answer is that it’s a very complicated issue.

Mosaic embryos can sometimes be transferred, but of course, you first transfer your euploid ones. If you don’t have euploid, and you have mosaics only, and it is your last resort embryo, you get genetic advice, and you transfer it if needed. If you have an aneuploid embryo and a complex aneuploid embryo with a full chromosome abnormality, I mean, this is an embryo that you shouldn’t transfer.

Dr Nisa Felix, Ferticentro: I completely agree with Dr. Harry. Look into it in more detail, get some genetic counselling, and speak to someone else, certainly if you haven’t got an opportunity to make another embryo. In our clinic, when we get the result, we have euploid embryos, and those embryos are transferable. Then, Mosaic, and when we have Mosaic, we have low-grade or high-grade. Low-grade mosaics are embryos that are good to transfer. For high-grade and aneuploid embryos, we will not advise transfer at all.

Dr Natalia Szlarb, UR Vistahermosa: That’s exactly what we do. I still see patients in general gynecology and follow-up for pregnancy. The only thing that I could probably add is that all the patients transferred low mosaic embryos, and we are not sure how they are going to develop at week 10 of pregnancy, are verified with non-invasive prenatal tests to be sure if the fetus is genetically normal or not. Aneuploid embryos in Spain cannot be transferred. It’s completely illegal, and if we transfer any mosaic embryos in this clinic and this country, they undergo, as said, genetic testing and special lawyers’ consents are prepared that patients are transferring this kind of embryos, and this is their responsibility. We recommend non-invasive prenatal testing during the pregnancy, and we do not recommend the screening test with the RK evaluation. We go directly to the non-invasive prenatal cell-free DNA (cfDNA) test of the baby at week 10.

Regarding PGT-A, I am 42 and I found out that 3 blastocysts that were tested were found to be abnormal or complex. Should I go through the whole procedure again at my age?

Dr Natalia Szlarb, UR Vistahermosa: One of the best studies published regarding the euploid rate, meaning the number of genetically normal embryos in different age groups, was from 2015. I believe 60,000 embryos were genetically examined back to reproductive times. We realized that at the age of 35, 50-60% of embryos that women have, are genetically normal. When we talk about a euploid number of chromosomes, between 38 and 40 years old, 30% of embryos are still normal. At the age of 41-42, about 20% of embryos are genetically normal statistically, among the 60,000 embryos examined in different age groups from people all over the world. At an age older than 43, less than 10% of embryos are genetically normal.

So, at 43, statistically, the chance that this will happen again, and we do one more cycle is very high, that you will have another unsuccessful cycle. I know that for some patients, psychologically, it’s very hard to give up on their own eggs in these kinds of cases. We review the protocol that you had, and we try to introduce something new into your treatment. But I wouldn’t recommend, at the age of 42, to do another cycle to look for genetically normal embryos. If you were 40, it’s a different ball game because then we know that 20% of embryos still have a chance to be genetically normal euploid. Genetically normal means euploid, if you understand what I’m talking about.

If you decide to do one more cycle, you have to introduce a different protocol. I agree with Harry that the best protocols are antagonist-short protocols, but the dose of medication has to be adjusted to your AMH. So if you had a high-dose protocol with 300 units of recombinant FSH, why don’t we give you a middle dose or a low dose, 150 this time, to maybe prioritize quality over quantity? But, as I said, statistically, 10% of your embryos are good. So if you are not ready to move on and discuss egg donation, which is the final step in infertility treatment, consider another protocol.

We would probably do something called embryo banking, so we do two cycles gather embryos, and send them all through genetic testing to increase your chances. So, this will be my strategy for your case.

Dr. Harry Karpouzis, Pelargos IVF: We need to know the full history to understand what is happening, what protocol she was on if she could get more eggs, etc. Generally, if you want to go with your best chances, try egg donation. If you are not psychologically ready to go to egg donation, it’s completely understandable. Then, yes, you could try another cycle, but you need to be realistic about your chances. Your chances are low because, in this age group, as Natalia said before, the chances of finding a chromosomally normal embryo are low. And this is something that you need to know from the beginning if you decide to go for a new cycle.

Now, regarding adjustments in the protocol or being able to get more eggs, the fact that you’ve managed, first of all, to have three blastocysts is good. I mean, other women do not even have blastocysts. But I mean, the more you get, the more you increase the chances. However, the chances remain low. So yes, most probably, you will be able to do different things. Most probably, if you are not psychologically ready to go to egg donation, you can try something different.

Could you briefly explain what PGT-A is, as simply as possible? Could you discuss how you would use it, if at all, in this age group?

Dr. Nisa Felix, Ferticentro: PGT-A is a Preimplantation Genetic Test that distinguishes between chromosomally normal and abnormal embryos. When we stimulate the ovaries, our main goal is to retrieve as many eggs as possible. After retrieval, mature oocytes are fertilized, and the resulting embryos undergo culture until they reach the blastocyst stage. At that point, a biopsy is performed to remove a few cells for genetic analysis. This analysis tells us if the embryo has normal chromosomes or not. Abnormal embryos are discarded, while normal ones are considered for transfer. PGT-A helps us avoid transferring embryos with little chance of success, reducing negative outcomes such as miscarriages and chromosomal abnormalities. Studies suggest it also improves live birth rates in this age group.
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Authors
Harry Karpouzis, MD

Harry Karpouzis, MD

Dr. Harry Karpouzis is an Obstetrics and Gynecology Consultant, specialized in Reproductive medicine/infertility and minimally invasive surgery, with over 7 years of full-time experience in the field of assisted reproduction. Dr. Karpouzis was fully trained and specialised in the UK. He has worked at some of the busiest hospitals in London (Guy’s & St. Thomas NHS Trust, King’s College Hospital, Newham University Hospital, University College Hospital, Homerton University Hospital. He has been a member of the Royal College of Obstetricians and Gynecologists since 2011 and is a scientific director and founder of IVF Pelargos Fertility Group.
Natalia Szlarb, MD

Natalia Szlarb, MD

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.
Dr Nisa Félix

Dr Nisa Félix

Dr Nisa Félix is an Obstetrician & Gynecologist, Fertility Specialist at Ferticentro.
Event Moderator
Professor Alan Thornhill

Professor Alan Thornhill

Professor Alan Thornhill is a fertility expert with over 25 years of experience and more than 100 scientific publications in IVF. Specifically, he’s a clinical scientist (specialising in embryology and genetics). Uniquely, he’s worked in IVF and diagnostic laboratories, research, clinical and business management, and even with the UK’s fertility regulator. Working in US and UK-based IVF clinics and consulting globally, he’s been involved in the IVF journeys of thousands of couples (both professionally and personally). He’s helped and advised patients, friends and strangers with issues including low sperm count, sperm and egg donation, genetic testing, surrogacy, treatment overseas and more. He currently works in the biotech industry, and his personal mission is to provide his unique brand of fertility coaching to people in need of help.
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