In this session, Vladimiro Silva, PharmD, Embryologist, Founder & IVF Lab Director at Ferticentro, Coimbra, Portugal, has discussed undertaken steps that resulted in successful pregnancy in patients diagnosed with diminished ovarian reserve.
Dr Silva started by explaining what AMH level is and how is it measured. All women at birth are born with around 2 million eggs which are not mature, they are primordial follicles, and they peak in number during fetal life, and then they undergo atresia thereafter and do not regenerate. It means that the ovaries get to the maximum number of eggs at birth, and then it goes only down from there at puberty when women start to ovulate to release an egg every month. They only have 400 000, but by the age of 30, they have 100 000 eggs, and in menopause, they have no eggs. We know that fertility declines with age, however, it is difficult to predict the pace of a reproductive decline in an individual woman. Therefore, when we talk about the ovarian reserve, we are talking about the reproductive potential as a function of the number and the quality of remaining oocytes that are still inside the woman’s ovaries, this is the definition by the American Society of Reproductive Medicine (ASRM). When we say that the woman has a decreased or diminished ovarian reserve, we are comparing her with women of the same age having regular menses, and so when we say that a woman has a diminished or a low ovarian reserve, it means that her ovaries are working worse than the average women of her age. This is not the same as being in menopause, it is different. Menopause or premature ovarian failure (POF), or primary ovarian insufficiency (POI) is about the moment when the ovaries stop working. Low ovarian reserve means we have low numbers and probably also low-quality eggs.
How can we measure it? There are 2 ways to measure the ovarian reserve:
FSH declines with age, as shown on the graph, for all age groups the number of women with normal FSH declines in every age group and the more elevated the FSH, the lower the delivery rate, it is only getting worse when we are approaching menopause. With the low value of FSH, the pregnancy rate is higher, while with higher numbers of the efficacy of FSH, the pregnancy rate is lower. For example, an older woman with a low FSH has a worse probability of pregnancy than a younger woman with a high FSH, so age is more important than FSH, however, these parameters are very important. How does it work? There is a part of the women’s brain called the pituitary gland or the hypothesis, which releases the FSH, which stimulates the ovaries to mature the follicles with which all women are born. Those follicles develop into ovulatory follicles while growing inside the ovary, they release oestrogens, and then the level of oestrogens is detected by the brain, and it lowers the amount of FSH that is produced. When a woman has a very high level of FSH, it just means that her brain is not detecting the response from the ovaries, so it produces more and more and tries to get a reaction from the ovaries. This is why having a high value of FSH is a bad sign.
There is also Anti-Müllerian hormone (AMH), which is considered the best parameter to define ovarian reserve. This single parameter correlates with the probability of pregnancy. We go from primordial follicles, the ones that women are born with, to the antral follicles, which takes about 300 days, and then, when the antral follicles are there, we can also detect them by an ultrasound scan at the beginning of the cycle, they are available to be recruited by the FSH and develop into ovulatory follicles. When they are available to be recruited, they are producing AMH, so the more follicles we have, the higher the AMH will be. While it is better to have a low FSH, in the case of AMH, the higher, the better the prognosis.
The AMH is very high on average until the age of 35, more or less. Then, it starts to go down, and so this is why the pregnancy rates are better below the age of 35 and tend to decline after the age of 35. To establish a normal prognosis, we need to have:
When we are outside these values, so when the AMH is lower than 0.5 ng/mL and FSH is higher than 15, and we have less than 5 antral follicles, the prognosis is bad, but it doesn’t necessarily mean that it is impossible, but the prognosis is low.
If we look at a natural conception and the graph shown, you can see that a man and a woman without any fertility problems have a 25% chance of getting pregnant. Humans are not a very fertile species, and at the same time, it only declines, it’s relatively steady until the age of 34-35 and then it starts going down, and the risk of having a miscarriage increases very steeply. At the age of 46, it goes even above 50%, it’s never zero for any age group.
The first case presented a 28-year-old woman with a low AMH level, married, her husband had no male factor, she took the contraceptive pill for a lot of years and then decided to have a baby, she did have a pregnancy 2 years before, but she had a miscarriage. She had regular cycles, after evaluating her ovarian reserve, we saw that she only had 5 antral follicles, which are borderline with the values that we were talking about, her AMH was 0.5 ng/mL, which is also very borderline, and the FSH was 6. At her age, we would expect her to have more than 10 antral follicles.
We did an ovarian stimulation to do ICSI because she had a very low ovarian reserve, we didn’t get many eggs, we had only 3 eggs, and from these 3 eggs, only 1 was mature, so we decided to freeze this egg. We did a second ovarian stimulation on a consecutive cycle, it is already proven that when you stimulate the patients in 2 consecutive cycles, the effectiveness of the ovarian stimulation is better. We got another 3 eggs this time, all were mature, we were already stimulating her with the highest dosage that we could give her, we warmed the frozen eggs, we’ve injected all 4 eggs, and we got 4 embryos that reached the blastocysts stage which was an amazing result. We performed a single embryo transfer, and she got pregnant, the pregnancy is now ongoing, and everything is fine.
This case is an example of how important age is. If we have a low ovarian reserve in a younger patient, the prognosis can still be good. With these parameters, the prognosis was not very good, but the age effect was significant, and we ended up having brilliant results.
The second case presented a single woman at 41, who wanted to get pregnant with a sperm donor, she had one pregnancy at the age of 22, but she did an abortion because it was an accident, and then she never got pregnant again. She had regular cycles, her AFC was very low, she had 5 follicles, and her AMH was 0.7, which was compatible with her age. FSH was 8 UI/mL, which was a bit borderline, we don’t like it when the FSH is above 8, but it’s certainly below 15, which is our cut-off for a bad prognosis case.
The plan was to do ICSI with sperm donation. We started an ovarian stimulation, we got 4 eggs, but only 1 was mature, we’ve frozen that egg, and we vitrified it and did a second ovarian stimulation. We got 4 embryos, and 2 of them were blastocysts, we did the PGT-A because this patient was 42 and normally above the age of 39 we consider that the risk of having an abnormal embryo is very high and so we always advise all patients to do that. One out of the 2 embryos was euploid and since we only had 1 very precious embryo, we did an endometrial assessment test called the ERA test to find the implantation window. We wanted to control all that we could because we knew that we had only 1 euploid embryo, so we tried to control as many factors as we could. We transferred the only embryo we had, luckily, the patient got pregnant, and she had a beautiful baby girl.
What’s the alternative that we also need to take into account? For the majority of patients with low AMH, the prognosis is not that good and in some situations, there is the possibility of doing an egg donation. It’s kind of the last resource, it’s also the most reliable one. On the graphic shown, the probability of success with egg donation is around 60% in all age groups, while for women using their own eggs, it starts at 50%, and it only goes down as long as the age increases. Egg donation is kind of the last resource, if we try to do a simulation and we don’t get a pregnancy, this doesn’t necessarily mean that you will never become a mother, it will just mean that you will probably need to use another strategy. It is something that we should always inform patients about because sometimes trying to get pregnant with a low AMH can be a very long process. Sometimes we need to do multiple simulations with multiple protocols, freeze eggs, start over, freeze the other 2 eggs, and start over, and this is not for everyone in terms of financial but also emotional terms. Egg donation is kind of the backup plan that’s also available, and for some patients, it can also be the only solution.
Starting from the beginning, normally, I would prefer day-5 embryos because it’s preferable. I always tell patients is that this extended culture will not improve the embryo quality, but it will give us more information about that embryo. If we are not doing invasive procedures like PGT-A, we can at least observe the embryos with video time-lapse and understand if they have normal development. Multiple algorithms can help us understand whether the embryo is a good prognosis or not. The more information we have about the embryo, the better. I would say that day-5 is preferable over day-3. If you tell me that you want to maximize the odds of every single embryo, the less we manipulate the embryo, the better, and so in that sense day-3 is also a respectable option. At our clinic, at Ferticentro, we usually go to day-5 because we prefer to be sure that the embryo is capable of forming a blastocyst. In some cases, when patients say they just want to give their embryo the best possible chance and the best incubator in the world is the human uterus. Therefore, it’s a personal decision if you want to maximize the odds, you should transfer them as soon as possible to lower the manipulation in the lab. If you want to be as informed and certain as possible, then definitely day-5.
The second question is: how many embryos should I accumulate to have a pregnancy chance at my age? It depends on a lot of factors, your AMH is very low, so probably, in theory, we will be talking about 5 to 10 per cent of pregnancy, so in theory, it should be around 10 to 15 embryos, but this is statistics. It depends on luck, we are working with a low number of eggs. Statistics are an indication, but when we are discussing an individual patient’s case, statistics are not that important. My advice would be to do 3 maybe 4 ovarian stimulations, that’s already a lot to protect your health. Then, if you want to be as sure as possible, possibly refreeze all the embryos, take them out to day-5. Do an embryo biopsy to do a PGT-A to see if the embryos are viable or not, and just transfer the viable euploid embryos. If you don’t want to test her embryos in terms of genetics, we can just take them to day-5, see which embryos form a blastocyst, and transfer those. If you don’t want to do that as well and you just want to maximize the accumulated pregnancy odds, then you should transfer 1 or 2 embryos at the same time. In our clinic, our policy is always the same, just one embryo. Why is that? Over the age of 40, having twins can represent a lot of risks. However, in this particular case, since the AMH is low and the probability of pregnancy is also low, it’s not shocking to transfer 2 embryos at once to maximize the odds of getting pregnant. In that particular embryo transfer, 2 embryos seem like a sensible approach.
If we’re working with day-3 embryos, I would probably say, transfer 2 embryos. If we’re working with blastocysts, maybe just one, if we were working with PGT-A, tested blastocysts just one.
It will depend on the clinic system of embryo classification. In principle, day 3 embryos should have 8 cells, so in the theory, the potential is not the same, but this is another reason for taking them to day-5. If the embryos are not perfect, if they have some fragmentation and not the right number of cells, it would be preferable to know a little more about them. I would take them to the blastocyst stage.
I would say that I don’t think this could be an effect of the subcutaneous implant. To explain to the other patients, this patient had been a subcutaneous implant working as a contraceptive. Sometimes we have that effect in the first couple of cycles, but then six months later, things should be back to normal, so, unfortunately, I don’t think there is any reliable way to make AMH rise. Your AMH is very low, and having an FSH of 29 is also of concern.
My advice is to do IVF as soon as possible with a very strong ovarian stimulation protocol and see if your ovaries respond. I wouldn’t lose a single extra month because it’s becoming urgent, and your FSH is going up and down, this is very characteristic of the transition to menopause. You’re not in menopause, but your ovarian reserve is certainly, very low, and you’re getting there. We need to understand why it is happening, but the bottom line here is you can’t lose any more time. Try to do treatment next cycle if possible or as soon as you can, because this will not get any better, you are still 32, which is a good prognosis factor.
Starting from the beginning, in Portugal, an IVF treatment costs at least at our clinics (Ferticentro) at around 4 000 – 4 550 EUR. We have to add the cost of medication and blood tests to this. Medication can only be bought in pharmacies, it will cost you more or less another 800 EUR or 1000 EUR depending on the treatment protocol. Regarding your case, you are 40 years old, you had two day-3 embryos. It’s one of those decisions that we always have to balance between optimizing the chances of implantation for those embryos or trying to see if they make it to the blastocyst stage. The option was to optimize the perfectly respectable chances. We sometimes do it, but in an eventual new attempt, I would take them to the blastocyst stage.
Recommending a second IVF with donor eggs or trying again with your eggs? This is a personal decision. Your AMH is 0.83, which is not bad, FSH is 4.7, so I would say that it’s still possible to try with your eggs. Perhaps, we could do a genetic test to see if they are viable. Egg donation is not the first-line option, we only suggest, or we only offer egg donation when we think that’s impossible or a very low prognosis with the patient’s eggs. We like to try at least 3 times with the patient’s eggs before resourcing to egg donation. At your age, these previous results and this ovarian reserve, the decision to go directly with egg donation is perfectly understandable, and we can do it, but it’s part of the discussion that we have with the patients. We always ask patients what’s more important to them, to have a family as soon as possible and forget all of these treatments and so on, or do you value the fact that you can try to have a baby with your own eggs. It’s more about the moment where you are ready to take that step. From a medical point of view, it’s perfectly possible to try with your own eggs, but it’s your life, relationship, money, and your body, we can only give you the information, but the decision has to be made by the patient.
Regarding the sperm, a male factor can also play a role. By doing ICSI, we can overcome a lot of problems, but if sperm is not genetically normal, it’s not the fact that we are doing ICSI that changes it. The issue is that we don’t have that many eggs to try, and so in principle, we also don’t know the cause of the sperm abnormality parameters. ICSI can help us overcome that factor, but that’s not insignificant, we all know that IVF, and in this case, ICSI has a lower prognosis when the sperm has lower values.
Regarding the surrogate, I don’t see any indication for that. I would say no to endometrial biopsy. If the embryo is viable, yes, if we don’t know anything about the embryo, I wouldn’t do it. It’s preferable to know if the embryo is viable or not, and if you have a viable embryo, then we could think about optimizing the endometrium. At the moment, no to the endometrial biopsy and yes to trying again with your own eggs.
Unfortunately, there are no miracles. There are lots of supplements, there is some scientific evidence, not very strong, that in some situations some supplements can help. I would say that it is more important for younger patients to try to conceive naturally without the help of IVF and so on. If you have a low ovarian reserve and need to do IVF, I would say that the effect of the supplements is limited.
At the same time, you can try because they won’t do any harm, they might or might not do some good. Typically, what we say is you can try, we leave that decision to the patients, we don’t oppose it. We like to know what the patients are taking because sometimes certain things can be taken that we don’t advise. However, I would say they won’t do any harm, but I don’t know if they would do any good.
A few years ago, mild IVF for low ovarian reserve patients was kind of the thing in medical congresses. A lot of people in the world were doing that. We were also doing that at Ferticentro, and the results are variable.
Nowadays, the tendency is towards the highest dosage stimulations. You are still young (32 years old), in that case, it’s preferable to try to take the ovaries to the limit and see what we can do. In mild IVF, we will maybe get an egg, no more than that and theoretically speaking, they would be of better quality, but we don’t know whether that’s the case or not. In cases like this, we always start to try the high stimulation approach, it doesn’t necessarily mean that we cannot try mild stimulation, but the first-line approach would be a high stimulation.
We always advise patients to transfer one embryo at a time. That’s because of the risk of multiple pregnancies. The rationality behind this sentence is that sometimes having multiple embryos can trigger a higher immune response from the body, and so you can sort of trigger a cascade of events that will end up in a miscarriage. Sometimes, if that embryo is abnormal, it can cause complications and ultimately harm the other embryo. Normally, embryos have an individual probability of implantation. they won’t harm each other unless we are one of those very rare cases with immune disorders, KIR antigen and incompatibility, or for example if there is implantation and the vanishing twin. Those kinds of factors can cause problems, but those are very rare circumstances.
In the vast majority of patients, a second embryo will not harm the first one. It’s preferable to transfer just one good embryo to understand whether the embryo forms a nice blastocyst, whether that nice blastocyst has the correct genetical constitution. Then transfer just that one to an optimized endometrium, that’s the golden standard of IVF these days. Transferring multiple day-3 embryos and so on is acceptable, but it’s not something that is recommended. When you do a transfer, and you don’t get implantation, you don’t know whether it was the embryo or the endometrium, and you are kind of lost, so it’s preferable to do things in them in a best-informed way. The best-informed way is to know whether the embryos are viable or not.
It was just a question of optimizing the procedure because in Portugal there are two reasons, one is a legal reason, and the other one is a kind of technical reason. In Portugal, the law states that we can only create new embryos once the previous embryos have been transferred unless there is a medical justification for that, the clinical director can justify situations where we can accumulate embryos. Normally we only do that in PGT-A cases.
The other reason was to optimize the process from an economic point of view. It costs the same to fertilize one embryo or 20 -30 embryos, it’s just one ICSI procedure, and so if we can save the patient some money, we do it. To do this, we have to have a very good egg vitrification system in place, we have to trust in our lab. Nowadays, egg vitrification has more or less a 90% of survival rate, which is a great percentage. It allows us to do this kind of technique and maximize chances. if we fertilize an embryo, at the time, we’re doing more procedures, but it’s less manipulation for the initial act, so it also has its advantages, it’s something that we can do in some cases. Most of the time, we freeze eggs.
I think you should start IVF as soon as possible because at the age of 45 the odds of having a pregnancy with your own eggs are below 5%. Your AMH and FSH are still compatible. We have lots of cases where at this age and based on these values, we achieved pregnancies through IVF. The chances are indeed low, but they are certainly a lot higher than trying just naturally or via triggering insemination. If donor eggs is not an option for you, it is either IVF or not having kids, because unfortunately, there’s not much else that we can do.
When we are doing IVF, we are turning the process a lot more effective, we are controlling the number of hormones that are there while the egg is developing, we are controlling the rate of the development of the egg. We are inducing the egg to mature in the right way with the right amount of hormones. We are collecting the egg directly, we are making sure that one selected spermatozoa will enter the egg in the perfect moment. Then, we are developing the embryo in the lab, and we are placing the embryo in the right place at the right time. We are doing a lot of procedures that will turn the process more effective. If the egg or sperm is not good, there’s nothing we can do about it. IVF clinics can’t make eggs or embryos, but by doing this, artificially, we are becoming a lot more effective than what happens in nature. My advice would be doing egg donation, but if egg donation is not an option, I would advise you to try IVF as soon as possible. You’re running against the clock, and every additional cycle you lose is one less chance for you to have a baby.
It’s an indication for donor eggs. I can’t say that it is impossible with your own eggs because you still have eggs even with Letrozole or other stimulation protocols, I think we can try with a more aggressive approach and see if the ovaries respond. There’s no comparison between the probability of getting pregnant with donor eggs, which is between 60- 70%, and the probability of having a baby with your own eggs at the age of 40 and with such a low AMH. It has to be a personal decision, you can try it because your ovaries are still working, there is still something that can be done, however, chances are low. From a medical point of view, the indication is egg donation.
We don’t know the quality of these embryos, this is why it becomes important to test the embryos. I remember a case of a patient who came to our clinic, and after having 8 embryo transfers in another clinic, she was always transferring day-3 and day-5 embryos, it was a mix of those, but she had 8 negative embryo transfers. She was 40 or 41, and we did another ovarian stimulation, we did ICSI and then PGT-A to test the embryos, we had another 4 blastocysts, and all of them were carrying genetic abnormalities. When we got to that point, we told the patient that her body is probably not producing viable eggs, and now she has two kids from egg donation.
Sometimes, it’s a personal option, and we have to respect the patients when they don’t want to have donor eggs, it’s completely acceptable. However, in your case, I would say that it would be important to understand whether these embryos are viable or not. If we do a PGT-A and these embryos are viable, maybe the embryos that you transferred before were also viable, and there was a problem in the endometrium. There are additional tests that we can do, and we can try to find a cause. We wouldn’t be transferring possibly the last viable embryo of that patient’s life without being in control of as many factors as possible. First, check if your embryos are viable, if they are viable let’s focus on trying to optimize the embryo, the endometrium. If the embryos are not viable, the only solution is either to try again or to use donor eggs.
We treat patients until the age of 49, at 49, we can only do donor eggs. We focus more on the patient’s condition and the ovarian reserve, the parameters, than on the age. We have people getting pregnant with their own eggs at 46, but that doesn’t happen every day. We take a look at the situation, we discuss it, we make sure that the patient makes an informed decision, and as long as the patients are aware of the odds and it is medically possible, we give it a try. We don’t give up on patients just because of their age, but we have to be sure that patients are aware of the odds.