In this live event, Dr Clara Colomé, Medical Deputy Director at Eugin International, Barcelona, Spain, has talked about advanced maternal age and shared 4 various IVF cases that ended up with a successful outcome.
The mean age of women having their first child is increasing in Europe and all over the world. For example, in Ireland, Spain, Italy or Greece, the mean age for the first child is over 30 years old, in Spain it’s 32 after Italy. These trends can be observed all over the world. That’s why today, giving birth after 40 is twice more frequent than 20 years ago. When we take a look at all different countries all over the world, we can see e.g, in the US, in the 80s, the birth rate at 40 was around 5%, now it’s almost 15%. This is also a trend in Sweden, Russia, etc. This is due to social changes because women want to have a career, they are working more regularly than 50 years ago, and they want to establish personal and professional life before deciding to have a child. That would be okay if it wasn’t for nature because it hasn’t prepared us for that. Women have a determined number of eggs since birth, no more oocytes are produced during life. They are used until they’re over. Ovarian reserve usually starts decreasing faster after 35 years old, and this is related to the chances of natural conception.
At 20, the chances of having a child are very high, it’s over 80%, but when a woman reaches 40, it gets more and more difficult to conceive naturally, and on top of that, there is an additional higher risk of miscarriage. The higher risk of miscarriage is linked to oocyte quality and aneuploidy, which means chromosomal abnormalities. The older women get, the fewer oocytes she has, and those remaining in the ovaries have accumulated alterations because they’ve been there for over 40 years. That means the chances of having chromosomal abnormalities when the embryo starts multiplying increase.
When we analyze the miscarriage material in abortions following an IVF or an ICSI procedure, we see that the chances of the cause being an aneuploid embryo increases, especially after 40 years old. The chances of aneuploidies and chromosomal abnormality increase with age. This is something that we have to face more and more every day, and we have to find solutions for this kind of problem because currently, almost half of our patients are already 40 years old.
Dr Colomé presented a graphics with statistics from Eugin clinic, where 47% of patients currently undergoing treatment are 40 years old and older, usually between 40 and 44-45. There have been different population studies about the awareness of fertility and age and all these studies analyse the possession of patients of women who try to conceive after 40 showing there’s a lack of knowledge about fertility and age. The studies have shown that while many patients are aware that when they reach 40 years old, it might be harder to conceive, they think they will go to a fertility centre and have a baby. There’s an excess of confidence in ART (Assisted Reproductive Treatment), and although the technological advances in ART that have happened in the last 20 years have had little impact on the prognosis of patients 40 years old and older and yet pregnancy rates are not very high in this range of age, and there’s a high risk of pregnancy loss. The first mean age for the first IVF in Spain is already 38 years old, which is already advanced maternal age. 20% of the treatments in Europe are performed on women over 40.
The patient had a slight thyroid problem which was correctly treated, she had removed the polyp through hysteroscopy, she had regular cycles, and she had never tried to conceive, she was slightly overweight, and her baseline hormonal test that we usually performed around the day 2 to 5 of natural cycles showed an elevated FSH, which is usually linked to a low ovarian reserve. This was also confirmed with a vaginal ultrasound, where the Antral Follicle Count (AFC) was around 5. She had also performed hysterosalpingography to check if her tubes were okay and if they were permeable. The couple decided to go for an IVF with their eggs and donor sperm to maximize pregnancy rates compared to artificial insemination. We went for a stimulation protocol with a high dosage of hormones and in an antagonist protocol which is what we typically use, and we obtained 4 oocytes which were fertilized after ICSI with donor sperm, and we managed to obtain 2 embryos that were transferred on day-3 of embryo development. The result was negative, but since this couple had never tried before, we went for a second round of IVF. We slightly changed the protocol, and we found during the second checkup that there was only 1 follicle developing this time, so we discussed with the patients and decided to balance the risk and the benefits. They decided to try an artificial insemination donor sperm, and as there was only 1 follicle developing, they wanted to avoid the anaesthesia and pick-up procedure, and that’s what we did. We triggered the ovulation, and then we injected sperm from a donor since her tubes were okay, we achieved the pregnancy, and they had a healthy baby boy 9 months later.
When we stimulate patients over 38 or over 40, there’s a chance of low response to an IVF stimulation. In this case, we try to always discuss with the patient the options. It’s always best to discuss the pros and cons:
The next case presented a heterosexual couple, the woman was 43, and they had 4 years history of infertility. The patient had removed a fibroid a few years back, they had no previous pregnancy, she had long cycles, and the partner didn’t have any particular history, they hadn’t done any treatment.
We performed all hormonal tests that revealed an elevated FSH level, low AMH level at 0.1 ng/ml, and the AFC result was 2 follicles, which is very low. On the male side, the sperm was normal, so we discussed the options with the patients, usually, if the woman is 43 years old and older and has a low ovarian reserve, we have a tendency to at least offer the possibility of changing the female gamete and go for an oocyte donation, but this couple had never tried before, so they wanted to try with own eggs. Since we didn’t expect a very high response, we tried a modified natural cycle which is a very mild stimulation protocol, and we obtained 1 mature oocyte, but unfortunately, there was a fertilization failure. This happens when we only have 1 follicle. At that point, the couple decided to go for an egg donation.
In Spain, all donors are less than 35 years old, so they have good quality and quantity of ovarian reserve. We obtained 6 embryos, and we only transferred 1 on day-5, we transferred a very good blastocyst, and the patient is currently pregnant.
The 3rd case presented a woman at 41, they’ve tried to conceive naturally for 6 months without success. The woman had mild endometriosis and she had removed a cyst a few years back and had removed a fibroid from her uterus, no previous pregnancies, regular cycles, normal BMI, and a low ovarian reserve at 0.7 ng/ml. The vaginal ultrasound showed a correct number of follicles.
The male partner had no relevant medical history, no previous children and a normal sperm count. The couple wanted to try with their eggs, we did 1 IVF cycle with a higher dosage stimulation of an antagonist protocol. We obtained 2 oocytes, both fertilized, and the embryos managed to develop up until day-3. We transferred 2 day-3 embryos, but it didn’t work. Since we had managed to get to the end of the procedure, the couple tried again, but unfortunately, there was only 1 follicle developing, and they decided to cancel the cycle. We started a new cycle, we slightly changed the protocol and this time, we obtained 5 oocytes, 4 fertilized with the partner’s sperm through ICSI, and we transferred 2 embryos on day-3. They have a baby girl who is almost 1 year old now, and the couple has 1 frozen embryo from the same cycle.
We usually recommend doing a maximum of 3 or 4 IVF cycles because after that we see that pregnancy rates do not increase, it can work, but cumulative pregnancy rates start to decrease up until 3.
The fourth case presented a heterosexual couple. A 44-year-old woman, this couple already had children together, they had 2 previous children that were aged 7 and 5 after 2 IVFs that had been performed at 37-38 years old. They had a history of IVF that had worked a few years back, but she was 37-38. She had a regular cycle partner and had no relevant medical history. They had already performed an IVF cycle in another centre with a negative result after transferring 2 day-3 embryos.
We did hormonal tests that showed normal FSH, and an AMH that was quite good considering the age, it was 1.7 ng/ml. She had some follicles on her ovaries, and the sperm was normal. Due to age and the previous failed IVF cycle, we advised them to go for egg donation, but they were not ready for that, they had already had children through IVF, so they wanted to try again. We went for an IVF with a higher dosage stimulation protocol, we obtained 5 oocytes, 4 were fertilized which is a very good result, and we transferred 2 embryos on day-3, and they implanted, there was a positive pregnancy test, there was the first ultrasound with a positive heartbeat, but unfortunately it was a miscarriage at 8 weeks of pregnancy. At this point, we didn’t have any embryos left embryos, so the patient accepted that even though she managed to get pregnant with her own eggs, there was also a risk of miscarriage or chromosomal abnormalities. Therefore, they decided to accept egg donation, we inseminated the oocytes from the donor with partner frozen sperm through ICSI, and we obtained 7 embryos, we took them to day-5, blastocyst stage, and we transferred 1 blastocyst but unfortunately, it was negative. We had 6 frozen blastocysts, so we decided to do a natural preparation cycle for the endometrium where we monitored the natural ovulation cycle, and we transferred another blastocyst that was thawed on the same day to this patient’s uterus, and she’s currently pregnant with another baby girl.
When we discuss all the options with patients of advanced maternal age, we always have to inform them about the risks associated with pregnancies over 40 years old. Those are mostly miscarriages, and aneuploidies, but also obstetrical pathologies, such as diabetes, preeclampsia or pre-term labour. Some of these risks are minimized with the use of donor oocytes. However, other risks such as diabetes or preeclampsia, which is high blood pressure during pregnancy, are linked to age, especially to the patient’s health status. That’s why we also monitor the weight, we advise the patients to quit smoking, we always need to control the thyroid function, we need to make sure before conceiving that other risk factors are as minimal as possible to achieve a healthy child which is our goal.
There are different schools on PGT, which is the genetic testing of the embryos and in fact, I could do another whole topic about that. It’s a discussion topic with gynaecologists and fertility experts everywhere in the world. We try to individualize each case, so I know there are centres where when you reach 40 years old, they always go for an IVF with PGT. Randomized studies have shown us that PGT, which is analysing the embryo, helps us in certain cases reduce the time to obtain a pregnancy and might slightly reduce the risk of miscarriage during the first trimester. Unfortunately, at this point, PGT doesn’t allow us to say that you will have more chances of having a healthy child in the end, considering the cumulative cycle. We usually discuss PGT in patients over 38 years in our facility, there’s always a discussion.
ESHRE society, The European Society and the most recent studies on PGT tell us that if you’re over 38 years old and you have a good ovarian reserve, that is the case where you will most likely benefit from a PGT. In other cases, it depends.
We typically analyse the number of oocytes that we obtain, we analyse the fertilization rates, and then we analyse the evolution of the embryos, which we put in the time-lapse incubators that allow us to control the development of those embryos much better and then on day-3, we see how many embryos there we have, and their characteristics. Depending on that, we advise the patients to go for a day-3 transfer or leave them in culture until day-5. There will be a loss from day-3 to day-5, we’ve had many pregnancies from transferring day-3 embryos. When we have day-5 embryos, it allows us to select better the best embryo, so we try to go there, that’s what we do automatically, for example, with donor eggs, but there’s also a risk.
If we only have 1 or 2 embryos – what are the advantages of waiting longer? We have a huge risk of losing everything. When we have at least 2 blastocysts, and you’re over 38, I would recommend doing a PGT, assuming the risk of limitations in this last case, this patient was 44, we had 2 embryos on day-3. We had beforehand discussed this possibility with the patients, and I told them that if we had a good result, then maybe it will help us, but if they assumed that we might not have any embryos to transfer, we decided to do the transfer on day-3 because there were only 2 embryos.
Your case is relatively more and more common. Regarding the first part, it’s very difficult to say. The blastulation process, which is the process that takes the embryo from day-3 to a blastocyst stage, is around 60%. In good conditions, 60% of the embryos reach the blastocyst stage. If you’re 40, probably this percentage will be slightly lower, and we obtained these percentages using the time-lapse incubators. The EmbryoScope that’s the one we use here, but there are different brands. This is in an environment where we control all the rest of the elements of the equation.
There’s a kind of trend now to think that the best thing is to transfer a euploid blastocyst, and this is true but in a theoretical world. When we do a stimulation for your ovaries, there are different steps, and we don’t like to give you a general road that you have to follow. Each case is different, each patient is different, we have to see the results as they come.
Usually, when we go for a PGT-A, we like to have 10-15 mature oocytes beforehand that will most likely allow us to have at least 2-3 blastocysts. We just need 1 to reach the blastocyst stage, we typically go for a blastocyst culture when we have at least 3 good quality embryos on day-3 and to have that, we would need to have probably 5 or 6 mature oocytes. This is something that we see one step at a time, and reaching the blastocysts stage allows us to select easier the best embryo, and it allows us to minimize the risk of multiple pregnancies. If 1 embryo will implant, it will implant regardless if we transfer them on day-3 or day-5.
I would encourage you to try once again. At 40, you will have a low AMH. What I can advise is, if you’re smoking, quit smoking, if you’re slightly overweight, lose weight and have a healthy lifestyle before starting. You have to be aware of the limitations, but also be positive, once you start the procedure.
I would say endometrium is a complicated element. The most important element for the success of IVF is the oocyte and its quality. Sperm is significant, so is the uterus, but the most significant thing is the oocyte.
When we are not sure if something is happening in the endometrium, we always do a hysteroscopy and an endometrial biopsy to rule out the infection. Also, to make sure there’s not a polyp, etc. and to see the cavity by itself.
When the endometrium does not thicken correctly or does not have a correct pattern for the transfer, we sometimes freeze the embryo. We try another protocol to prepare the endometrium again. I don’t know the details of your case, but probably that’s what we would do in this case.
AMH is an element that we use a lot, but AMH is a hormone that is produced in the ovary, in the follicle, and it gives us an idea of the amount of ovarian reserve left. Unfortunately, it’s not a direct predictor of the success of IVF. It gives us an idea of the quantity that we will have, it gives us an idea of whether this patient will respond correctly to the stimulation or she will be a low responder or a high responder, and it allows us to adjust the dosage of medication, especially when we talk about IVF treatments.
There is a slight correlation between our AMH levels and pregnancy rates, but it’s not direct. We consider normal AMH, we need 2 nanograms per millilitre or more in general. I might have a 39-year-old patient with a very good AMH of 4.0, and she might respond very well to the simulation. I might have many embryos, but her chances of conceiving will still be lower than that of a 29-year-old with an AMH of 2.0. The age of the oocyte is the most important factor when we discuss success rates for both treatments.
AMH allows us to correlate it with the chances of you responding to the treatment and how to adjust the protocol.
It is an excellent thing that you’re trying to lower your BMI to below 30. This is one of the most important things you can do to help yourself. There are other things, polycystic ovary syndrome has to be taken into account. If you have never tried to conceive, we would also have to analyse the presence or absence of a partner, but usually at 39, if your ovarian reserve is acceptable, I would probably recommend going for an IVF to maximize pregnancy rates because chances are still quite reasonable.
IUI is typically for patients who have, for example, never tried to conceive naturally, and who don’t have a partner, who wants to minimize the intake of hormones or have financial difficulties as it is a more economic treatment, but then I would recommend not to wait. You’re still at a point where your chances are reasonably good, so I would probably decide for an IVF to shorten the time to pregnancy and maximize your chances.
We try to individualize decisions with our patients, I give them a recommendation, but this is something that we always discuss. Usually, in the case of a natural cycle where we only do a natural or a mild stimulation cycle, the goal of the treatment is to try to obtain 1 or 2 good quality oocytes, not more. We typically recommend transferring on day-3, we could eventually wait for day-5 but again, what will be the advantage if we only have 1 embryo to take it to day-5.
There’s a school that says that if it doesn’t reach day-5, it will never work. The problem is that we will never know if it would have reached day-5 inside the uterus. Our incubators are perfect, we have the best technology, but many centres have the same technology, but still, it’s not a real uterus. If you only have 1 embryo, I always recommend transferring that on day-3 if the embryo has good characteristics.
If there are doubts about its viability, then I would say, let’s wait a bit more to see, but I don’t see the advantage of waiting when we only have 1 embryo. We won’t select it any better, so if it has to implant, it will implant regardless if we transfer it on day-3 or day-5 in this case in particular. If one of my patients assumes the risk of having 0 embryos to transfer on day-5 and wants to go for the blastocyst to see how it looks on day-5, we could do that eventually.
The egg retrieval itself doesn’t impact the thyroid. Hormonal stimulations might have an impact on thyroid function, around 20 to 30% of women, in general, will have thyroid problems during their life, so it’s quite common to have thyroid alterations.
In fertility, we’re really cautious with thyroid function because studies show us that if TSH (the hormone that makes the thyroid work) is higher than a certain range, the risk of miscarriage during the first trimester increases. That’s why we try to keep it under a regular range, and hormonal treatments might impact thyroid function.
The fact that after stimulation and a pickup procedure, your TSH levels were high means that you’re at a higher risk of developing thyroid issues later on in life. The levels probably will go back to normal in a few weeks, a month, or two. The important thing about thyroid function is to control it regularly, we have ways of controlling it, we have medication that’s easy to take. The impact of hormonal stimulation or hormonal changes on thyroid function exists, and it usually disappears over time.
When we discuss hypothyroidism, which is the real alteration of the thyroid, and you talk to general doctors, they say it should be lower than 4 or 5. For fertility purposes, we like it to be between 0.5 and 2.5, that’s our ideal because if it’s higher than 2.5, it typically slightly increases the risk of first-trimester miscarriage.
Obesity has been determined as one risk factor for infertility, it alters the quality of the oocyte, it doesn’t affect the embryo per se, but it might affect the quality of the oocyte, and therefore, it might be more difficult for this oocyte to be fertilized and to develop into an embryo. Once we transfer the embryo into the uterus, we’ve seen that obesity has been linked to implantation problems, the vascularization of the uterus might be impacted, the hormonal balance might be altered.
When we transfer one embryo to the uterus, there has to be a kind of biochemical dialogue between them, they have to do a mating ritual, the endometrium, and the embryo, they have to get to know each other and decide if they like each other or not.
If there’s obesity, this dialogue might be altered. Therefore, it’s more difficult for the embryo to attach, and then it has also been directly linked to the risk of first-trimester miscarriage. Obesity increases the risk of first-trimester miscarriage and increases the risk of some genetic abnormalities, so losing weight is not always easy, but it’s something that you can change.
We cannot change the egg, the age, but losing weight is possible. It has a direct impact on your health and your chances of having a child.
We do an ovarian simulation, we do a pickup, and then a few days later, usually 2 to 5 days later, we start stimulating again to accumulate oocytes or embryos. It has been done especially for PGT purposes to accumulate embryos to do a genetic biopsy.
We do not do it very often because typically it’s advised for financial reasons because if you have more embryos, it is cheaper to do the biopsy and analysis, it’s not the case here at the clinic (Eugin). We do not typically do that because, for example, if we have at least 2 good quality blastocysts and you want to do a PGT-A, I would go for a PGT-A. If the good embryo is there, what’s the point of repeating and repeating stimulations and accumulating embryos, and maybe the good one was the first one.
I’ve had patients who were 39-40, and they said they would like to try to have at least two children, but for whatever reason, they cannot do the transfer now, they are moving, and they can’t do the stimulation, and in a couple of months they will be able to, then this is a good strategy to gain time. Regarding results, it doesn’t change much, and for me, it’s not the goal of the treatment because the goal of the treatment is to get you pregnant as soon as possible, not to accumulate embryos, but it is a good strategy in some cases.
With donor eggs – plenty. With your own oocytes, which, I’m guessing, the question is leading to, there have been a few in the literature. Here in the clinic, we’ve been working for over 22 years old, we do thousands of cycles every year. We have had a handful of patients at 45 who have conceived and had a child at the end, the oldest we had was 45. We accept patients for IVF with your own eggs until you’re 46, included in very limited and specifically selected cases, but unfortunately, we haven’t had any successful cases at 46, and that’s why we stopped there.