It is common knowledge that at the age of 40 and above, women have reduced fertility potential – which means that the chance of having a baby with their own eggs declines rapidly. But does it mean it’s completely impossible? Dr Raul Olivares, Medical Director at Barcelona IVF, discusses IVF options for women over 40 years of age.
It is the fact that motherhood is being delayed across the world. To support this observation, Dr Raul Olivares admits that the majority of his patients are in their late 30s and as much as half of them are over 40 years old. Although all of them look great and live a healthy and active life, the problem is their biological clock. The fertility window which is between 20 and 35 years of age is still undisputable – and it is not going to change in one generation, despite social changes. That is why the route to fertility for many women becomes more and more difficult. Achieving a healthy pregnancy completed with a live birth becomes a real challenge.
The aim of this webinar is to present the ways of treating patients who are over 40. According to Dr Olivares it includes identifying good prognosis patients and deciding what the laboratory can offer them to take care of their valuable embryos.
Ovarian reserve vs. egg quality
Dr Olivares starts with differentiation between ovarian reserve and egg quality. Ovarian reserve means the capacity of the ovaries to produce follicles and eggs. According to the studies, women between 18 and 34 years of age only need two eggs to achieve 15% of live birth rate while those over 40 may need up to 15 eggs to have the same chances. While ovarian reserve means the amount of eggs that ovaries can produce, the quality of the eggs is directly related to the age. Sometimes patients who are 40-43 years old may produce up to ten, twelve or fourteen eggs – but of poor quality. And then, the quality of the embryos is also going to be poor and, as a result, the chances of a pregnancy are not going to be good either. Dr Olivares admits that the most difficult are patients who are not only over 40 but who also have low ovarian reserve – and the latter cannot be changed. So if doctors cannot increase the number of eggs, it is going to be very difficult to help these kind of patients.
Problems 40-year old patients face
Age is highly important in terms of problems with getting pregnant – studies show that 50% of over 40-year old patients are going to be infertile, with no other problem causing infertility. However, getting pregnant over 40 is hard for many different reasons. It refers not only to natural ways of conception but also to assisted reproduction techniques. First of all, there is a reduced number of follicles or no ovarian reserve which is going to make it very difficult to get a good number of eggs. There is also reduced sensibility of follicles to follicle stimulating hormone (FSH) – meaning
low response to the hormonal stimulation. It means that even if there is a high number of small follicles, these follicles do not grow after the stimulation – but they remain small.
Apart form that, there is a higher risk of anatomic abnormalities. Of course, it is not directly related to ovaries but, as women age, the possibility of having fibroids, polyps or other issues such as endometriosis (which is the disease that can reduce the ovarian reserve) increases. Another problem is an increased risk of genetic issues in the oocytes – it well known that older women have a higher risk of miscarriage or Down syndrome. It all comes down to the quality of eggs: the older the eggs are, the more genetic abnormalities there are. Besides, older patients are also endangered with cytoplasmic issues in the oocytes. The cytoplasm is the liquid that surrounds the nucleus of the egg. Among others, it is important to produce the energy through the mitochondria that the embryo needs to develop in the early stages where it lives on what it gets from the egg. So if mitochondria are not ok, the cell division becomes difficult and it leads to the self-blockage of the embryo.
Last but not least, there is a higher risk of epigenetic problems in the oocytes due to DNA methylation errors. This is age-related and it may affect other aspects of the oocyte that can also entail problems in the evolution of the embryos.
Identifying patients for the treatment
According to Dr Olivares, the first step in treating patients over 40 is identifying those who are able to produce a good number of eggs. The reasoning is simple: if there are a lot eggs, there are a lot of embryos and when there are a lot of embryos, there is a higher chance of finding the one that can become a baby. There are two different tests for achieving this goal. One of them is checking anti-müllerian hormone (AMH). AMH is inversely related to the age: the older the patient is, the lower her AMH is. Another way is doing the scan to count the number of small follicles called antral follicles – these are the follicles that can be recruited during the patient’s stimulation. Dr Olivares says that AMH and AFC (antral follicle count) – together with a woman’s age – are the most useful tools for identifying good prognosis patients. This is the fact that has confirmed by a lot of studies.
Age counts the most
The main problem encountered in the group of patients over 40 is that almost half of them (40%-45%) do not even reach the egg collection. That’s why when talking about the chances doctors can offer to these patients, the only statistic that is really useful is life birth per started IVF cycle. It is, among others, due to the fact that even after transferring the embryo successfully, up to 70-75% of over 40-year old patients who get pregnant have miscarriages.
The situation in which there is no success in the first attempt is quite common. Dr Olivares says that it is generally worth trying again. To support his argument, he recalls the study showing that with each treatment, a 40-year old patient slightly increases the so-called cumulative live birth rate. It translates into the probability of having a child either in the second, third or even fourth attempt. However, this is also limited by age – according to the study, these chances diminish completely once a women reaches the age of 45. That’s why, according to Dr Olivares, you can consider more than one treatment if you are 40-42 years old – but once you are 44-45, you can try once (if you think it’s worth trying ) but if it does not work, further attempts are not really recommended. The reason is that the chances of success are simply going to be very low. In other words, using own eggs over the age 44 makes very little sense. Dr Olivares stresses that it relates to the patients with a long infertility background – meaning those who have been trying to conceive for a long time and have problems resulting from the quality of their eggs. Nonetheless, there are still some exceptions (lesbian couples, singles, male factors like azoospermia, etc.). In these cases, since the starting point is different, the limit of 44 years of age can sometimes be flexible and doctors can conduct at least one attempt to see if it is possible to succeed.
How stimulation protocols work
When considering possible IVF stimulation protocols, doctors have to take into account ways of increasing oocytes’ quality and quantity. Dr Olivares says that the former is simply impossible – regardless of protocols, medicines or vitamins used. According to him, the only solution is to try to get as many eggs as possible, hoping that among those eggs, there is a viable one that is going to produce the healthy embryo. When it comes to improving oocyte quantity, there are different methods available which can include increasing the dose of drugs, using new generation of drugs (like e.g. Elonva) or adding androgens.
Dr Olivares explains that in the past it was thought that getting too many eggs might have resulted in their quality worsening. However, four years ago there was a study carried out proving that the more eggs you produce, the higher the cumulative life birth rate is. Cumulative live birth rate means the chances of getting pregnant with any of the embryos a patient creates in a single cycle. It is true that doctors are not so focused on being successful in the first attempt but rather on being successful with one of the embryos – and cumulative birth live birth is directly related to the number of eggs that a patient produces. For example, if a patient produces more than 15 eggs, her chances of having a baby are going to be 5.6 times higher than someone’s who produces 0-3 eggs. Apart from that, if doctors gain a lot of embryos, they may be able to freeze them – and this is especially important if a patient (or a couple) wants to have a sibling in the future.
At this point of his presentation, Dr Olivares refers to the traditional method of increasing the doses of the stimulation drugs in order to produce a higher number of eggs. He claims that there is a lot of evidence that the higher the doses are, the poorer the quality of eggs. This was confirmed by a large study that included more than 650,000 cycles. It revealed that increasing gonadotropin doses is negatively correlated with live birth rate. That is why it is not recommended to go beyond 300 units – otherwise it’s going to be a waste of drugs and money and on top of that, the quality of eggs can be seriously impaired.
What Dr Raul Olivares strongly recommends for
stimulation protocols is the drug called Elonva. One of the reasons for that is the concept of follicular output rate. It can predict clinical pregnancy in women with unexplained infertility undergoing IVF or ICSI and it means the capability of the drug to make small follicles grow. As it has been proven, over 40-year old patients have reduced sensibility to FSH which causes small follicles not to grow. Elonva is claimed to have the best follicular output rate. Its another benefit is that it has a very similar profile to the one that FSH has in the natural cycle – which is good for follicles. Finally, it stimulates a patient not only in a more physiological but also in a more comfortable way. The stimulation lasts for up to 7 days so there is no need to take injections on a daily basis.
The third way of trying to increase the number of follicles in the stimulation is adding androgens. The latter are claimed to be very important in the early stages, when going from the so-called preantral follicles to antral follicles – meaning the ones that can be recreated. It has been observed that younger patients have higher intra-ovarian levels of androgens. That is why stimulation protocols include adding testosterone during the first days and then following with FSH (in the form of e.g. Elonva). By doing this, doctors can basically improve ovarian response in low responders.
The role of time-lapse monitoring
When eggs are collected and fertilised, embryo cultivation plays a crucial role in assuring successful further treatment – especially when the number of embryos is low. Growing embryos to the blastocyst stage has been revolutionised with the introduction of new generation incubators called time-lapse. Dr Olivares says they have some indisputable advantages compared to the traditional ones. Most importantly,
time-lapse incubators have a camera inside that takes a picture of the embryos every 15 minutes. With these images, doctors can assess embryo quality without having to take them out from the incubator and, by doing that, disturbing them during their culture. Besides, with the use of time-lapse incubators, doctors can record videos showing when and how embryos divide and this functional information should be always added to embryo morphology – proving that those looks are not everything. According to Dr Olivares, time-lapse incubators allow keeping embryos in an environment as close to the human uterus as possible – and that’s why they are a largely recommended tool in IVF treatments. As a proof, he recollects the data showing that ongoing pregnancy rates at his clinic are significantly better when time-lapse technology is in use.
Choosing the most suitable embryos
It is widely known that as women grow older, the risk of having genetic issues is growing as well. It means that the live birth rate decreases and the miscarriage rate increases. Dr Olivares says that in patient’s IVF over 40, the main reasons for having an implantation failure are genetic abnormalities in the embryo. Even if the embryos look good, it is highly probable that they have genetic issues inside of them. That is why it is crucial to have the embryos tested before the transfer. This is when PGS comes in.
PGS/PGD (preimplantation genetic screening/ preimplantation genetic diagnosis) is the procedure during which a hole is made in the embryo and up to 3-4 cells from the future placenta are taken out to have their chromosomes tested. By doing that, it is possible to transfer those embryos in which the risk of a miscarriage is going to be as low as in any embryo obtained from e.g. a 25-27-year old woman. Of course, the number of chromosomally normal embryos in an over 40-year old patient is going to be low – but if doctors manage to find a healthy one, the chances of success are going to be really good.
For years, morphology has been the most common way of
assessing embryo quality. Dr Olivares does not share this view as he claims that
embryo morphology is not really related to genetics – it means that even perfectly looking embryos may still have genetic issues. Nonetheless, it is true that the prettier the embryos are, the higher the chances of being normal they have. When morphology is good, the number of embryos that are genetically normal is higher (73%) than when morphology is poor (about 40%). On the other hand, once it is known that an embryo is genetically normal, its morphology is no longer relevant. The latter clearly supports the importance of PGS over morphological assessment.
Take-home message
Concluding his presentation, Dr Olivares gives some important pieces of advice. First of all, there’s no way to deal with time and the biological clock. Once you are over 40, the sooner you start your IVF treatment, the better as – literally – every month counts. Secondly, you should try to avoid treatment protocols with high doses of gonadotropins. Instead, it is much better to use drugs like Elonva, which are more physiological, comfortable and effective. Thirdly, look for clinics that use time-lapse technology in their labs. A time-lapse incubator is always a good tool to increase the embryos’ number and quality and to choose the right one for the transfer. Finally, add PGS to your treatment whenever it is possible. It does not only save your time, money and emotions – especially when the number of embryos is very high – but it also allows doctors to gather more information about the real quality of the embryos. Before external factors are started to be considered, it has to be identified which embryos are really good inside. Only when they are transferred and the pregnancy does not occur, it is time to take into account other problems, such as immunology and endometrium receptivity.
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