By fertility experts from Spain.
This #IVFWEBINARS with Dr Elena Santiago explains solutions for Advanced Maternal Age focusing on:
Late motherhood is on the rise, but it has its downsides. Can ART (assisted reproductive technology) be helpful in this case?
During this event, Dr. Elena Santiago [Fertility Specialist at Clinica Tambre] tells us more about IVF & women over 38 – what limitations there are and what treatment options and prospects patients can make use of.
Although ovarian reserve is one of the most frequent subjects discussed in relation to IVF treatment, not many patients know what it really means – or how to calculate it correctly. Dr Elena Santiago says that it is very important for us to understand the concept that women are born with a finite number of eggs in their ovaries. This number is reduced as women age – which means that it is impossible to produce new eggs over time. This is in contrast to men who produce new sperm every 3 months.
Of course, ovarian reserve is not the same in every woman. Dr Elena mentions a few important factors that influence it the most. Apart from a woman’s age, these are toxics, lifestyle, the environment we live in, gynaecological pathologies (e.g. endometriosis), ovarian surgeries or oncological therapies. Additionally, we have to take the family background into account. Dr Elena admits that sometimes premature menopause (resulting in ovarian failure) may run in the family.
When it comes to calculating ovarian reserve there are two basic tests that each fertility patient should undergo: an ultrasound (or a scan) with AFC (antral follicle count) and AMH (anti-Müllerian hormone) test. The former is conducted vaginally and it allows us to see the follicles – small liquid sacks that should contain one egg each. The normal ovarian reserve is when we have 10-20 follicles in both ovaries (less than 10 follicles is a low ovarian reserve and over 20 – a high ovarian reserve). Only one of these follicles is going to grow in a cycle to produce ovulation – the rest will disappear. It means that each cycle, women are losing many eggs – that’s why the minimum of 10 eggs is necessary to ensure good pregnancy chances.
The anti-Müllerian hormone test on the other hand, is very specific. AMH is produced in the follicles and it can be measured by a simple blood test (done at any time of women’s cycle – with no need to be fasting). The results are being compared with the scan to see whether there is a normal (1-3.5 ng/ml), high (>3.5-4 ng/ml) or low (< 1ng/ml) ovarian reserve.
Dr Elena Santiago highlights that ovarian reserve is always dependant on the woman’s age. What is more, ovarian quality is also related to one’s age. However, the problem is that the latter cannot be tested – it can only be predicted on the basis of how old a particular patient is. Unfortunately, ovarian quality has very little to do with ovarian reserve itself. Even if a 40- year old patient has a high ovarian reserve, it is likely that its quality is not going to be as equally good.
Ovarian reserve, ovarian quality, AFC and AMH all decrease as a woman ages. Dr Santiago mentions another hormone that is often used in testing ovarian reserve – FSH (follicle-stimulating hormone). It can be used to indicate the ovarian capacity to produce eggs. However, its results are read differently than in the case of AMH – namely, elevated levels of FSH are understood as the confirmation of menopause.
Dr Santiago confirms that the percentage rates of fertility depend on age and ovarian reserve. The maximum percentage is observed in women at the age of 20-24 and it remains at a quite good level until 30 years old. However, from that moment on, the fertility rates decrease rapidly and they achieve a very low level from 40 years of age onwards.
As life passes, not only fertility rates but also egg quality becomes lower. But what does bad egg quality really mean? In the process of fertilisation, an egg and sperm come together to produce an embryo. Dr Elena explains that, with age, the probability of having chromosomal abnormal (aneuploid) embryo is much higher. From 35 years old onwards, the aneuploidy rate is increasing a lot. In parallel with it, the miscarriage rate is going up as well.
Age is the most important factor in female fertility. No wonder that the success rates depending on it change a lot even with the standard (meaning own eggs) IVF treatment. When women are under 35 years old, they have a nearly 60% chance of getting pregnant with own eggs IVF. Between 35 and 40 years old, these chances go down to 56% and – above the age of 40 – women won’t achieve more than 34% of success rates. However, Dr Elena stresses that each patient’s case should always be personalised and treated individually.
The prospects, on the other hand, change significantly when we take egg donation into account. While the standard IVF success rates lower with age, egg donation results do not change at all – independently of the fact how old the female patient is.
Dr Elena Santiago admits that in case of late motherhood, doctors always have to do something else – apart from only insemination or the standard IVF – to achieve satisfying results. This additional procedure is called PGS (pre-implantation genetic screening). However, if – for different reasons – it does not work either, the best solution is egg donation. As mentioned before, in the case of the latter the recipient’s age does not play any role – the success rates are still high for patients over 45 years old.
PGS is an extra procedure in IVF. When blastocysts (meaning day 5 or day 6 embryos) are in the lab, they are biopsied in order to select the chromosomally normal ones for the embryo transfer. PGS rises the success rates and the chances of a healthy baby by reducing the risk of miscarriages and increasing the chances of pregnancy per transfer. What is more, PGS will shorten the duration of treatments. Dr Santiago admits that with good-prognosis embryos, it is possible to reduce the number of cycles it takes to achieve pregnancy. From this perspective, PGS is of the highest importance as it significantly minimises the negative effect of maternal age in implantation rates.
However, depending on the situation, PGS may not always be an option. In such a case, the ultimate solution is to proceed with egg donation. Dr Santiago reminds us that in Spain, egg donation is anonymous. Donors undergo lots of psychological, medical and genetic tests to ensure the best match with the recipients. They include the blood type test, immunologic matching (KIR AA/HLAC1C1) and genetic matching (to avoid genetically inherited disorders and diseases). Normally, egg donors are less than 30 years old and are always chosen on the basis of the physical characteristics of the women doing the treatment.
When ready for donation, donors undergo ovarian stimulation and egg retrieval at the clinic. The recipients generally need to do the synchronisation with their donors – it means that their uterus and endometrium are being prepared for the embryo transfer. Once the woman is pregnant, the pregnancy is exactly the same as if it was achieved with her own eggs – she will become her baby’s real mother.
Summing up, Dr Elena Santiago reminds us that ovaries have an optimum time to operate – in other words, the sooner we make the use of their reserve, the better. She claims that women have to be highly aware of the influence their age has on fertility and reproductive outcomes. When going for late motherhood, it is always advisable to add PGS to IVF to increase one’s own pregnancy rates. However, when the ovarian reserve is very low, patients should think of egg donation as a direct solution.
It’s true that normally we do not have a waiting list but when physical characteristics are a little bit more difficult to find within our donors, it may take a little more time. In this case, we’re talking about 2-3 months until the transfer.
With egg donation treatment, success rates won’t change even if you are over 45 years old. But here we have to take into account other risks that could occur during the pregnancy – because of the age. We have to very carefully consider such risks as hypertension, preeclampsia or diabetes. So normally we would have to do a lot of tests to see that there are no further risks for that person in particular.
Right. Obviously, if you do not have menopause and you still have periods, we have to have eggs leftover – and obviously follicles, too. It may happen that although in one cycle you don’t see any follicles, you can see one or two if you do the scan in the next cycle. The idea is always to compare AFC with anti-Müllerian hormone (AMH) to have more information.
Firstly, we have to see the morphology of the embryo to see the chances of pregnancy. It means that if the quality the embryos is not good, they won’t be used for the transfer – because we don’t think they can achieve a pregnancy. Other tests that we can do are PGS and a biopsy to see the chromosomes. Nowadays, there are no more tests that we can do. With embryo quality in the blastocysts stage and PGS, we can have maximum information right now.
I’d say the question is controversial. It depends on the patient obviously. Normally, when we try the first, second or even third cycle, the idea is to achieve as many eggs as we can. So normally we put the maximum dose of gonadotropins. But it is true that when we’ve done several treatments and the response is always the same – meaning 2 eggs each time – we can maybe reduce the dose a little bit so it is more comfortable for the patient, as well as cheaper. Obviously, I prefer to do a mild stimulation to achieve 2 eggs rather than do a natural cycle and nearly always achieve only one egg.
This is a very interesting question. In each country, the law is quite different. In Spain, the law – for the moment – says that donation should always be anonymous. So there is no option for donors at all to have contact with their offspring – or for the offspring to have contact with the donor. There are different opinions but we think that donation works quite well in our country because of this. Normally, donors do not have an interest in getting in touch with the offspring after their donation. They don’t even ask about pregnancies achieved – we give them this information but they don’t ask about it. So we – for the moment – could never help in this connection. I do not know if the law could change within time – this is something we never know. However, most professionals, who work with egg and sperm donation in our country, think that the fact that this procedure is anonymous helps us have more donors. It also refers to patients. I think that the majority of recipients will also prefer not to have contact with the donor in the future.
Obviously, the issue is controversial. We could talk about this topic all night. Some people think it’s fair, others think it’s not. Some people say it’s not right for the offspring not to know where they come from. However, not all the people who undergo this type of treatment will always tell their offspring that they come from egg or sperm donation. For the moment, this is how we do it in Spain and it has been like that since egg and sperm donation started in our country.
It is true that it is not mathematical. Normally, it obviously goes down with age. But we cannot control absolutely everything. We’ve seen that the same patient, doing two treatments with exactly the same medication month after month, could have different results each time. The number of mature eggs depends on quality. We’ll have to see what medication you used there. I normally work with nanograms per millilitre, so I would have to change your result into nanogram to see if it’s good. I think it’s nearly 2 ng/ml – which is still good at the age of 38.
It means that the more IVF attempts there are, the greater the chances you have. It does not mean that, for example, if you do the first attempt, you will have like 50% of chances and with the second attempt – 70% in total. It means that if you did two attempts, you can achieve better pregnancy rates – just because you tried two times to be pregnant with IVF and the embryo transfer. It does not mean that within treatments, chances are greater. Your chances will be more or less the same with each transfer – but as you do more transfers, in the end, you will have more possibilities of getting pregnant.
I do not think it is something mandatory. It depends on your obstetrician, the risks, your health situation or the size of the baby. But if the delivery starts and everything goes smoothly, then why not? We can have a vagina delivery. However, it’s true that caesarean rates increase with age as well. It results from the fact that it is simply more difficult to have a vagina delivery and there are more risks related to going through all the procedures and stages of delivery.
Yes, it’s true. Normally, when we do PGD, we can get 3 types of results: an aneuploid embryo (which won’t be transferred as the possibility of having a healthy child is 0%), a euploid embryo (when the chromosomes are correct and the embryo could always be transferred) and a mosaic embryo. Let’s say that mosaicism is like the ‘middle’ result. Geneticists see that some of the cells are chromosomally normal and some others are not. Within mosaicism, there are lots of types. So we have to see what type of mosaicism we have – meaning if lots of cells are affected or not. Is it a simple or more complicated mosaicism? Additionally, it’s important what type of a problem a chromosome has. Sometimes, mosaicism affects only one chromosome – other times, it could affect two or more. Depending on this, there is a very complicated classification. Normally, a gynaecologist will be helped by geneticists to know a little bit more about the options of that mosaic embryo. And normally, they would give you the probability of getting pregnant, the probability of having a miscarriage and finally, the probability of having a normal, healthy pregnancy and baby. All this information will be given to a patient and a patient will finally decide whether they want to transfer the embryo or not. This is, of course, an option only when we don’t have healthy (euploid) embryos. If there are only mosaic embryos, then we would have to decide together if the patient wants the transfer or not.
This is a very difficult question to answer precisely. There are so many types of mosaic embryos. Genetic experts should give you percentages depending on the type of mosaicism. Normally, the best ones to transfer would be those that have only one chromosome affected. There are chromosomes that could have a worse prognosis than others, such as, for example, chromosome 21 – which is the one that produces Down syndrome. It has worse – let’s say – the percentage of a healthy baby than others. But it is very difficult for me right now to give you exact details in each chromosome. Normally, we have to look at the type of mosaicism and the chromosome affected so that we can give you more information. But if you do get mosaic embryos, don’t worry about that. The specialists will give you as much information as they can so that you can finally decide whether to do the transfer or not.
Unfortunately, I’m not the person to explain prices here. But do not worry, we will get in touch with you regarding this question. I assume you know there are different costs, depending on packages and we can explain the meaning of those to you later. My colleagues can contact you and give you all the information.
Yes, we do. We’ve done lots of treatments with black people until now. It’s true that it’s sometimes more difficult to find donors with black skin but we have them. We even have a bank of frozen eggs from black donors that you could use in the future if it is impossible for you to find a fresh donor. So normally we have no problems with that.
What we normally do right now is to give you treatment with analogs during 3 months before the transfer. In this way, we try to diminish the situation of adenomyosis before doing the endometrial preparation. So it’s like a 3-month hormonal pause with this treatment. We’ve done it with several patients and it worked good with them. Of course, we cannot say that this treatment works for 100% of the time but it does work some of the time with patients who have adenomyosis.
Obviously, sperm is also important. It’s true that men’s age is not going to affect the chances of pregnancy as much as women’s age but sometimes we also have to take these factors into account. So what can we do if – let’s say – a man is older than 45-50 years old? We can do other tests regarding the sperm, such as DNA fragmentation – this is something that could be more affected within time. We could see if we could increase the chances of pregnancy when DNA fragmentation is not good. We could use other techniques at the lab for sperm selection to improve our results. But generally, the sperm quality or age shouldn’t affect egg donation treatment so much.
I understand this question completely but it’s difficult to answer. It’s true that nowadays we don’t have yet the key to that. We’re looking at different treatments to try to improve egg quality and ovarian reserve as these are the problems we have with so many patients every day. So we’re trying different options but it’s still only investigation. I cannot tell you about any treatment that is really used clinically nowadays. But I hope that we will have more options for this in the future.
Firstly, we should see more information on sperm count. We should check DNA fragmentation – is it only single-stranded DNA fragmentation or are we talking about double-stranded fragmentation? If we have enough sperm quantity – even if the morphology is poor – we could use techniques to improve the outcome by choosing less fragmented or not fragmented spermatozoa for ICSI (sperm microinjection).
I heard about studies done with the speed of the sperm and the outcomes. I can’t say if this is true because I don’t know if it is really scientifically proven. But I think that in IVF there shouldn’t be any differences because we’re selecting the sperm that moves and has good morphology. We’re not looking at the sperm speed normally. So here the results should be 50-50 when talking about sex outcomes.
Yes, we have donors of either African or Caribbean descent. We always look at your physical characteristics and we ask where you come from. It does not mean that the donor has to be from exactly the same place as you but obviously, we try to match you both as best as we can – taking the origins into account.