Successful IVF treatment after failed attempts. Advanced maternal age – options

Adriàn Moreno, MD
Gynecologist, Specialist in Human Reproduction at Clínica Eugin, Eugin Clinic

Category:
Advanced Maternal Age, Failed IVF Cycles

From this video you will find out:

How does the oocyte quality deteriorate with a woman’s age?
What is the data for permanent involuntary childlessness (PIC) in the UK?
Ovarian Reserve Testing (ORT) – how does it work?
Is IUI an option for women over 40?
How many cycles should I try?
Should I have my embryo PGT-A tested?

Successful IVF treatment after failed attempts. Advanced maternal age – options

What are the fertility options for women 40+ with previous IVF failures?

In this session, Dr Adriàn Moreno, Gynaecologist, Specialist in Human Reproduction at Clínica Eugin, located in Barcelona, Spain has been discussing various IVF options for women of advanced maternal age, also, he had provided lots of useful advice on how to get a successful IVF after failed IVF attempts. When we look at the analysis of the causes of the socio-demographic situation, which could have a strong impact on female fertility. As shown on the graph, there has been a postponement of childbirth during the last decades. In many countries, from the Czech Republic to Spain, and the United States, the age of motherhood has been postponed from, on average, 24 years old to 29 nowadays. This has a strong impact on fertility rates. For example, in Spain, giving birth at 40 is 2 times more frequent than 20 years ago. In 2018 at Eugin, almost 50% of IVF treatments were performed, and patients were over 40 years old, if we take into account, for example, when it comes to 36-year-olds and above, it was almost 75% of the treatments performed. The current tests that can give you an idea of your ovarian reserve testing (ORT) and predict your prognosis are AMH Anti-Mullerian Hormone and Antral Follicle Count (AFC). They are only going to estimate the capacity of the ovary to produce eggs during ovarian stimulation, it’s not a marker of fertility. These markers are not going to tell you the capacity of this woman to get pregnant naturally, it’s about giving the idea of how many eggs we can expect to get after stimulation.

IVF over 40

In women over 40, IVF is more advised than IUI. It’s important to mention that in patients up to 42 years of age, it should not be encouraged to do more than 4 cycles. In one of the studies presented, patients younger than 35 years old had live birth close to 25%, when we look at the group of patients between 42-43, the success rates drop significantly, and after the age of 44, the chances diminish. Data from the Eugin group showed that from 200 patients who went ahead with IVF treatment and were over 43, only 11% had Beta HCG positive tests after the embryo transfer. This wasn’t a live birth rate or ongoing pregnancy, so there is also a risk of miscarriage during the first trimester. IVF may largely overcome infertility in younger women, but it doesn’t reverse the age-dependent decline in fertility. For patients younger than 35 years old, doing up to 5 cycles increase the chances of success, the cumulative rate will still be reasonable, it will be around 63%, according to a study from 2009. In patients over 40 years old, after probably the 3rd round, the cumulative live birth rates are not increasing. To conclude, in the group of patients from 40 to 43 years old, it’s not advisable to perform more than 3 rounds of IVF because probably after the 4th, the result is going to be the same. Patients over 43, do not have a realistic chance of achieving a delivery with their own oocytes.

PGT-A in advanced maternal age

PGT-A is a tool that is used more and more often. It can be useful in the advanced maternal age group of patients to optimize or at least increase the chances for a successful IVF round. PGT-A helps to screen and then identify the euploid embryos. The aneuploid embryos will be discarded, and only genetically normal embryos will be transferred. The idea behind this is to reduce the time to pregnancy, avoid unnecessary transfers, and theoretically reduce the rates of miscarriage. To perform this technique, we need to culture the embryos until day 5 (blastocyst stage), and then a biopsy will be performed. A few cells from the embryo will be taken (from zona pellucida), and this embryo will be identified as normal or abnormal. PGT-A should be applied to some specific patients that could have a higher benefit from it. It is recommended for patients who are older or over 38 years old, it was possible to retrieve a good number of eggs, probably more than 10, and in the end, it was possible to obtain at least 3 or more embryos on day 5.

What are the fertility options for women 40+ with previous IVF failures? - Questions and Answers

What’s the percentage of women who got pregnant with their own eggs at 40 or 41 at your clinic?

These percentages could change from one clinic to the other. We should specify for the group of patients that PGT-A could change this percentage significantly, as I explained in my presentation. Through PGT-A, we are only going to transfer normal embryos. Let’s say that the current percentage for this group is around 39 to 42% of positive pregnancy tests after the transfer. If we perform transfer after PGT-A, this percentage could be increased until possibly 50%, or even a bit more, depending on the quality. Apart from the normality of this embryo, apart from the morphological quality of the embryo.

Is there new data about fertility and age for women? I have read that the data that we have today is old. Women have evolved.

Yes, it’s true that all of the data that we have available today belong to some older studies, but what we found in the current studies or the current population that we treat is that this percentage is quite stable. The IVF treatments have indeed evolved mostly technically, but it’s difficult to cope with these treatments. It could overcome the difficulties of age-related infertility in women.

Why is the percentage of aneuploidy higher with ICSI?

This study that I showed you were comparing a common IVF or classical IVF with ICSI. It has been shown that in these two different groups, the percentage of aneuploid embryos was higher with ICSI, but this difference was not significant in this study. Sometimes we can obtain different results or a result that could be anything that we expect. We should always analyze if this difference could be related to chance. In that case, in this study, they said that this difference was not significant. Analyzing the current evidence between classical IVF or ICSI, there are no significant differences in the outcome.

So, what would be the best option to have a healthy baby for a woman over 40?

Each patient should be advised to attend different parameters, but as we said, from 40 to 42 years old, if we have never tried an IVF, I would encourage a patient at least to try 1 round of IVF. Then, depending on the result of this IVF, regarding the number of eggs retrieved, the number of embryos obtained after the end of the culture may be, we can encourage them to try again. After 43 years old, as I’ve mentioned probably, my first recommendation would be to undergo an egg donation treatment.

I had a natural pregnancy and birth at 42 years. Since then, I have had miscarriages. Is my only option at 46 years old donor eggs? (Using ICSI)?

Natural conception is possible, and it happens in our societies. We should differentiate assisted reproductive technology where we are treating patients where probably there is a fertility problem from patients that don’t have a fertility problem, and they can conceive and have pregnancies at 42, 43, or even more. If you’re 46-year-old and you cannot conceive naturally – undergoing IVF is not going to give you a realistic chance of pregnancy. Many studies performed in this group of patients have shown close to zero percent chances for achieving a pregnancy after IVF. To answer your question, for me, egg donation should be your choice or your real chances in this case.

What do you mean by cumulative live birth rates?

Normally, we can analyze the results from different points of view. Live birth rates or pregnancy rates per transfer meaning, each time we perform a transfer. Cumulative live birth rates refer to the percentage of success per cycle, so after transferring probably more than one embryo. We would transfer all the embryos available after an IVF stimulation. That will include fresh transfer and frozen embryo transfer, so that’s the cumulative rate. This could be applied to different treatments, so cumulative live birth rates after 2, 3, or 4 attempts.

Is there a specific time that those 3 cycles should be done? Or is it just 3 cycles in total regardless of whether this was over consecutive months or there is a break in between?

Some years ago, we were advising patients to leave some gaps in between the stimulations. Current evidence published in recent years have shown that performing consecutive IVF cycles is not going to decrease, it’s not going to be detrimental to IVF success. It could be even better because if we are in a group of patients where age matters, maybe in six months, the prognosis could change. Performing these cycles more consecutively could increase the chances a bit. Maybe not significantly, but a little bit. Nowadays, the evidence shows that when it comes to the medical prognosis, there is no need to leave gaps between cycles.

How long is it advised to wait between simulation?

That depends on the result of the stimulation or some setback or side effect that appears, we should wait. For example, if after an embryo transfer, a miscarriage had taken place, it’s not recommended to start again. If we simply have had a negative result, we could start one stimulation after another, it is important. It’s not related to the question, but it’s important to bring that up. IVF treatment should be performed carefully, we cannot perform 15 or 20 IVF cycles, it is not recommended because we know that exposure to high levels of estrogen for a long period could bring some side effects in a long term. Normally, it’s said that less than 6 cycles could be performed without any risk or harm.

I am 28 years old, and I have had 3 failed IVF cycles. My AMH is 3.14. None of my embryos make it to day-5. I get 15 eggs retrieved, but up to 8 are usually not mature. Do I need donor eggs? Or, I can keep trying with my eggs?

That’s a specific case where we see a theoretically good prognosis patient, but statistics show a group of patients where the quality of those eggs despite probably being normal, there are other factors involved in the quality of those eggs that could impact or explain these results. In your case, before switching or changing to donor eggs, maybe some other techniques could be applied. I don’t know if you have done that. Finally, sometimes, the only way we can help you is to recommend to switch to the egg donation. With the information you’ve provided, I don’t have enough tools to recommend doing one thing or another. I can tell you that undergoing donor eggs is going to give you a much higher chance in future treatment.

Is there any guarantee that embryos will get to day-5 blastocyst?

It’s difficult to tell because when we retrieve eggs after the retrieval basically on day-0, they don’t display quality, so we can only extrapolate if they are mature or not. After fertilizing them, we have embryos on day-1, that again, they’d only display they have been properly fertilized, or not. After day-2, and day-3, we can observe the quality of these embryos, but the quality on day-3, the score that we can give this embryo day-3, is not a good predictor for these embryos to arrive at day-5. With the evidence that we have in some places or some countries or some clinics, they have extended the culture until day-5 widely and generally for all patients currently, we can tell that not all blastocyst cultures could be suitable for all patients. We cannot know, or there is always that if we take these embryos to day-5 too, in the end, we will not have any because they could not be of good quality. We can never know if this embryo from day-3 and ahead, the development of the embryo could be different inside the uterus. To answer the question, in IVF, it’s very difficult to predict how many embryos will arrive at day-5, the more embryos, or the more eggs you could retrieve from the stimulation, the more chances you have for them to arrive at day-5.

What causes the plateau after 3 attempts between 40-43 years when this is 3 years apart, versus someone trying 3 times at 42 or 43 all in one year?

What we are seeing is that again we’re talking in general groups, but about specific patients. That means that probably the eggs or the embryos produced by a patient in this group, these embryos they haven’t proved to be good enough to the implant, give a pregnancy within these 3 cycles probably afterward this is not going to change. It’s pointless to try because patients with such specific characteristics are not going to be able to conceive after an IVF. A patient at 40-41-year-old has a better prognosis than 42 or 43, so each patient should be treated and analyzed individually.

Why would you not recommend PGT testing if the egg retrieval resulted in a lower number of eggs?

It’s a very good question, it’s quite controversial. Some groups are doing PGT-A in every patient. It is evidence-based on important Cochrane reviews where the studies are very well performed, they include a lot of data, and we’ve seen that PGT-A is not a free error tool or technique. Basically, with PGT-A, we’re taking cells from the surrounding area from the trophectoderm, and these cells that we obtain the result could be extrapolated to the whole embryo. Within the same embryo, there can coexist different lineages of cells, normal and abnormal. They are called mosaic embryos. We know today that probably every embryo is a mosaic, they have a different lineage of cells at some point when they are developing. We’ve seen that in young patients performing PGT-A, some embryos were abnormal when in most of its part, they were normal. If we perform PGT-A, this embryo will be discarded, so we’re going to limit the cumulative success rates for young patients. This is the theory, but when we apply this to clinical studies, we see that when we do PGT-A in patients older than 38, their chances per transfer will increase. In younger patients, if we perform PGT-A, or we transfer embryos just by assessing the morphological quality, we will see that there is no difference in success per transfer. If we analyze the cumulative rate, so after transferring all the embryos created in a fresh cycle and then transferred in the frozen cycle, we will see that in the younger patients group that has done PGT-A the chances are lower than in the group that hasn’t done PGT-A. That’s because we are removing or we are quitting on embryos that could be suitable. This same study has been performed in patients that we call advanced maternal age 38-year-old or over, and we’ve seen that their chances per transfer and cycle don’t change. That’s the reason why we recommend only doing it in this group of patients.

How many MII oocytes are needed for 40 years old to obtain a blastocyst?

You could have maybe 10-15 eggs, but if we have bad fertilization, so maybe only 50%, you will have 7-8 embryos on day-1. I believe it’s enough for a 40 years old patient, but if we retrieve, for example, just 7 but all 7 will fertilize, and the development of the embryos is good, maybe we could have the same result, in the end, having a different number of mature eggs. In regards to the number of eggs retrieved, you will have a different chance, but the minimum that I believe could be considered in a patient who is around 40 is maybe 8-9 mature eggs, and it will be fine.

I have heard that mild IVF( up to 225 UI FSH) is better for older women than high dose(300 – 450 UI FSH) stimulation IVF. What is your experience with that? Will it help to get more mature eggs?

First of all, the current evidence says that doses should not be higher than 300. Most of the studies published say that there is no difference between 450 and 300, so 450 I believe that should not be offered to the patients because it’s not cost-effective. Mild IVF is normally recommended to be done with doses of 150, not 225, which will be closer to the classical or more common stimulation than the mild stimulation. I believe that doses of stimulation are not going to increase your ovarian reserve, so it’s not going to make the ovary offer more than it’s able to offer. If you have a lower ovarian reserve, maybe you have 3-4 antral follicles so 300 units or 150 units is not going to change the prognosis. We’re going to have the same response or the same result afterward. It could be a little bit more cost-effective, but this depends on each patient, on each clinic, on the ovarian reserve, for example, only based on the age, we could have a patient at the same age, but with different ovarian reserve, if I have the chance to retrieve more eggs, I will try to use higher doses because clearly, the number of eggs retrieved is a key factor to success in this kind of treatments.

What’s the average number of eggs retrieved in women of 42 years old per cycle? My AFC on day 3 was 11 and AMH of 3.1 pmoL. FSH 9.5. How many eggs could I expect on my 1st retrieval?

Normally, I rely on antral follicle count more than AMH. In your case, I would use high doses of gonadotropins because the number of eggs is one of the main points for a successful treatment. If I would have only your AFC at 11, I would probably expect to retrieve 7-8 mature eggs, maybe a little bit less, this is a prediction, of course. The best marker for a result of egg retrieval is to do a simulation because the estimation or the parameters not always work well in all patients.

Is it possible to predict chances for a successful treatment both for IUI and IVF based on the AMH value? What would the value be?

There are always two factors, which involve female fertility in regards to assisted reproductive techniques. It’s an ovarian reserve, so the quality and the quantity of the eggs. Ovarian reserve, we can check it through AFC or AMH, the quality could be extrapolated from the age. We could have young patients with low AMH where they are going to have a good prognosis most of the time. For example, a patient who is younger than 35 years old with a low ovarian reserve is probably going to have a better prognosis than a patient who is 40 years old with a good AMH. Based only on AMH, we’re not going to do a treatment to a patient. For example, if the patient is young and is going through inseminations or IVF despite retrieving an unlimited number of eggs, we still have good chances to achieve a good result

I am 40, AMH 8.2, AFC 11, and 5x failed ICSI rounds, no pregnancies. Would you recommend egg donation now? We also had no blastocysts last round out of 9 eggs.

We shouldn’t lose the focus of other factors involved in the success of the treatment. From the information you’ve provided, I believe that maybe it was not always possible to perform an embryo transfer. I assume that there is an embryo factor, maybe the embryos are not of good enough quality. Probably, in your case, after five attempts of trying IVF despite trying different techniques or maybe different protocols, probably egg donation will be recommended. We should also assess the male factor, sometimes the sperm can also cause problems to the evolution of the result, so I would recommend assessing the male factor. If in your previous cycles you were able to transfer embryos with failed results, you could probably also check your endometrial receptivity. I’m not referring to a specific test, I would also advise doing hysteroscopy or an endometrial biopsy, I believe I would offer that in your case.

How do you assign the donor with the mother in Spain? Can we choose any features for resemblance?

In Spain, the donation should always be anonymous, which means that the patient cannot choose the donor from a catalog. Current legislation says that the clinic should guarantee a donor that should share the same physical traits, so the same phenotypical appearance with the recipient.

How much would be the live birth percentage for a woman over 40 who has 13 frozen eggs retrieved at 37-38?

These changes will be around 55 to 60% of at least having one child. The age when you did the egg freezing is important. The age when you have done the transfer is not. After many studies, we’ve seen that the age of the recipient of the woman that received the embryo from herself after egg freezing is not a factor related to the success. The success will be the same, no matter if you are 40 years old, or 43-45, that doesn’t change.

I have recently been diagnosed with endometriosis after 3 failed cycles show that my egg quality has been impacted due to inflammation. My endometriosis has been removed, and now I am doing donor egg IVF. Will I still have to worry about inflammation/immunes with donor egg?

Endometriosis is still under research because there are many things that we don’t know about endometriosis, but it has been published that the inflammatory environment produced by the endometriomas on the ovary could impair the maturation and the quality of these eggs due to different molecules that they regulate due to this inflammation of the ovary. We’ve seen after clinical trials that the eggs produced by a donor, and then the embryos have been transferred to a woman with endometriosis don’t have a different prognosis than other women who don’t have endometriosis and who are at the same age. It seems that the problem is only with the ovary, and it’s not affecting the endometrium and so on. Some patients who have endometriosis could also have adenomyosis. It is focused on endometriosis in the thickness of the muscle. These patients with adenomyosis, but possibly they could have a little impairment on the results due to that, is quite controversial. If you only have endometriosis, you shouldn’t be worried about this.

Can we conclude the reverse? Someone with adenomyosis would have high chances of endometriosis?

Endometriosis could appear even without endometriomas. Normally, a patient gets diagnosed with endometriosis because they have a cyst on the ovaries where it’s identified. Some other patients will only have implants of endometriosis on the pelvic organs, in the rectus, in the uterus, in the outer part, or the wall, the bowel. Adenomyosis is only diagnosed when we find this focus on the thickness of the muscle of the uterus. It could appear alone without endometriosis or together with endometriosis. The answer to your question regarding IVF is probably yes because the alteration that endometriosis will produce on the ovary could be significant. In adenomyosis only, very advanced clinical cases could impair the receptivity of the uterus.

What causes the variability in the number of follicles/eggs in women where the AMH level is the same?

The AMH is a hormone produced by the antral follicle, so those little follicles that are in the ovary. The higher level of AMH you have means that your population of antral follicles is higher, but other mechanisms are not related to hormonal reactions that are involved in how many follicles could be available in one determined cycle. We know that there is variability between the same patient in different cycles. For example, some patients could do any stimulation in one cycle, and obtain 10 mature eggs, and the same patient in two months could do the same and get only 6. We know that this is related to this capacity of the ovary of putting follicles ready to be recruited on the stimulation, but we don’t know still how this is working, it is a very interesting field. To answer your question, there are many factors involved, maybe environmental, even that could make it more difficult for the follicles to grow. The patients with the same AMH or even the same patient could have different results in different cycles. This variation normally is not very high, it’s not dramatic but could be significant.

At what point of embryo cultivation would you recommend 3rd-day transfer? Is this defined by the number of eggs retrieved?

It could be defined by the number of eggs retrieved, but mostly it will be defined by the number of embryos evolving. Normally, we would check the development of these embryos from day one, and depending on the number and the quality of these embryos, I would recommend extending the culture until day-5, or maybe better perform the transfer on day-3. The age of the patient and the percentage of aneuploidy should be taken into the account as well.

I have tried a short protocol, and the follicles did respond, although at variable rates. What are the chances of a long protocol with suppression help with more steady growth? I have read that estrogen priming can also help?

Short protocol with GnRH agonist I rarely use it because there is always a risk of synchrony. The effect of the discharge with the GnRH agonist will produce that the follicles could start growing in different sizes, so probably I would not recommend a short protocol. The short protocol has been proved to be equally effective as the antagonist protocol. The antagonist protocol is currently probably the golden standard. If you do a long protocol, estrogen priming is not pointless because the idea with this is to keep the FSH down until we start the stimulation. It is a kind of blockage as in the long protocol but with less suppression over the ovary. If you do the long protocol, your pituitary gland, your hypothalamus will be blocked. You don’t need to do the estrogen priming, this only makes sense probably in antagonist protocols.

Besides all the medical possibilities and statistics: how important is the psychological state of the patient? Do you have any insight into spontaneous pregnancies after the treatment or in breaks?

Psychological assessment is critical. In fact, in our clinic, I believe that all clinics should offer such consultations. We work with a psychologist, with a team of psychologists that specialize in this field, offering egg donation treatments for patients is not easy. For us, it’s clear to offer that because only from the medical point of view I’m offering the best chance to that person. The conditions that these patients should assume are not easy to take into account, though. I can tell you that after a successful egg donation treatment, none of the patients have any complaints or have any regrets about what has been done. In regards to spontaneous pregnancy after treatment, they indeed happen. It’s not rare that we see infertile patients that after IVF treatment that they required and then they got a spontaneous pregnancy, so probably an immunological factor is involved in this. Theoretically, the immunity system probably was involved in the infertility of that patient. We shouldn’t forget that 50% of the proteins or the structure of this baby, of this embryo, belongs to another person, so it’s like there is a stranger for the woman, and the woman’s uterus should be immunomodulation to accept that part of the embryo. This could explain why we have pregnancies after IVF treatments. To answer your question, there very few cases of spontaneous pregnancy after egg donation treatments. That means that the egg donation should be recommended when there is any indication, and the chances of spontaneous pregnancy afterward are quite low.

What is the percentage of women who frozen their eggs after 35 and used them later to give live birth?

The age of the woman when we’re doing the transfer is important. However, the age where you use your own eggs to transfer is not a factor of success. Let’s say, for example, a 35-year-old has a quite good prognosis with 10 eggs, it will be 70%, with 20 eggs, it’s close to 90% if we freeze them independently and if you’re going to use them when you’re 40-45. We should pay attention to the risk of pregnancies in advance maternal age. It can be a cause of premature labor, hyper pressure disorders, there is also a relation to the health of your future baby. We can postpone motherhood use these frozen eggs for the future. We should also advise our patients that the later they use those eggs, the more exposed to a risk they are during the pregnancy.

I tend to notice on AFC one month low next month high and so on. Have there been any studies to show any pattern/trend to this variable higher and lower follicle numbers?

When the follicle appears, or we can recognize it through a scan because it has enough measure, maybe two millimeters minimum. This follicle has been evolving for probably many days and many weeks until it reaches that stage. We should understand which mechanisms are involved in this evolution because they are independent of hormones. No FSH or stimulation will make antral follicle appear in a determinate moment, this could change from one cycle to another, but we don’t know why this is happening. We should understand that because with this maybe with just one simulation, we can offer the maximum chance for this patient. If you find, let’s say, 5 follicles on day-1 or day-2 on the ultrasound, that doesn’t necessarily mean that these 5 follicles will grow. Sometimes, some of them don’t have receptors for the hormones for FSH. What we are sure of is that if you do an antral follicle count and you have 3 follicles on day-2, and you start the stimulation, you cannot expect more than 3, so this could be a useful tool for patients with a very low ovarian reserve to decide if we start or not the stimulation for one specific cycle.

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Authors

Adriàn Moreno, MD

Dr. Adriàn Moreno is a Gynecologist, Specialist in Human Reproduction at Clínica Eugin, Barcelona. Dr. Moreno is part of Eugin's medical team since 2017. With more than 10 years' experience, he has a degree in medicine from the University of Barcelona and completed his residency at the Hospital Trias i Pujol in Badalona (Barcelona). He has also worked as a reproduction specialist in Ireland and currently teaches in the Master's Degree in Human Assisted Reproductive Technologies at Universitat Pompeu Fabra.

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Caroline Kulczycka is managing MyIVFAnswers.com and has been hosting IVFWEBINARS dedicated to patients struggling with infertility since 2020. She's highly motivated and believes that educating patients so that they can make informed decisions is essential in their IVF journey. In the past, she has been working as an International Patient Coordinator, where she was helping and directing patients on their right path. She also worked in the tourism industry, and dealt with international customers on a daily basis, including working abroad. In her free time, you’ll find her travelling, biking, learning new things, or spending time outdoors.

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