This webinar session was focused on Advanced Maternal Age (+38). Our guest speaker was Rita Matias, ESHRE Certified – Medically Assisted Reproduction Nurse at Ferticentro, Coimbra, Portugal. Rita explained the main causes of postponing motherhood, typical problems that may occur, and treatment options available. Rita also shared 3 cases of patients struggling to conceive due to advanced maternal age.
Pregnancy after 30 years old is a tendency worldwide nowadays, women are starting to have children later in their lives. For instance, some articles shown on the slide from The New York Times say that more than 100,000 Americans give birth in their 40s each year. Women are postponing their pregnancies and conceiving, and this is a concern in western societies, and there are a few reasons related to that. For example, the education level nowadays, people have a higher level of education, and sometimes it’s difficult for women to find a balance between their studies, their jobs, and maternity. Another reason is economic uncertainty, the couples, or women have unstable or temporary jobs. Another thing is the values regarding parenthood which are changing, sometimes, people want to wait a bit more to try to have more stability, and they want to give their children better conditions than they had themselves.
Why is this a problem? This is a concern because studies show that with age, the rate of aneuploidy of oocytes increases. Therefore, the quality of the embryos is also affected. There are increased risks of Trisomies, miscarriages, and the obstetric risk increases as well. On the other hand, the pregnancy and live birth rate decreases.
The obstetric risks include:
The obstetric issues happen more often in women of advanced maternal age than in younger women, but this is the reality nowadays. This is happening hastily all over the world, and we all must deal with the reality, and all the professionals that work in human reproduction and the clinics all over the world must adapt and try to give the patients the best advice given this reality.
What can be done about it? Every patient needs to be evaluated individually. We have to discuss the risks given the situation, so they can make informed decisions with our help and avoid multiple pregnancies since multiple pregnancies are also associated with higher risks for the mother and the baby. It should be avoided and done only when it is safe for both. In some challenging cases, such as patients with viral infections, rare diseases and transplantation, we can work together with the other medical teams from various specialities and their agreement, proceed with the treatment, so it’s done safely and in the best way for the patients. In the case of international patients, it is very important to prepare everything before travelling, and have a close dialogue with local medical teams.
The first thing that has to be done is the pregnancy risk assessment, where it is established if it’s possible to have a safe pregnancy, then there is an ovarian reserve assessment where we check if it is viable to do the treatment with the patient’s own eggs or if we should go for an egg donation instead. We can also conclude if PGT-A is the solution for this particular case, and what are the implantation conditions if we have uterine integrity and uterine receptivity. One of the most significant things to check is the ovarian reserve. The ovarian reserve diminishes as a woman’s age advances, and from 35 years old onwards, it decreases more significantly. Two hormones are crucial in assessing ovarian reserve, it is FSH and AMH. A higher FSH level and a low AMH level are signs of a bad prognosis. For a normal prognosis, we want to have an FSH under 15 UI/l, although the ideal is less than 8, and an AMH should be over 0.50 ng/ml. After assessing both hormones, we will see if it is viable to do the treatment with the patient’s own eggs or not.
There is an option to perform Pre-Genetic Testing for aneuploidies (PGT-A), and it is also possible to do an ovarian stimulation followed by the fertilization and creation of the embryos and then do the genetic testing of each embryo to check for genetically abnormal embryos. Another option is egg banking, also called fertility preservation.
On the graphics shown, there are 3 groups presented: implantation rates, delivery rates and miscarriage rates, in all the groups, the graphic shows results of IVF with PGT-A and IVF without PGT-A. The implantation rates are higher if the embryos were genetically tested, and even if with age, the rates decrease a bit, they decrease in a steady way, not the same way as with the ones that were not tested. Therefore, the delivery rates per transfer are higher when the embryos are genetically tested, while the miscarriage rates are lower when PGT-A testing is performed. Thanks to PGT-A testing, it’s possible to select the embryos, it doesn’t increase the results, but the selection of euploid embryos before the transfer allows us to get better results after the transfer.
The last resource and the most reliable one is egg donation. It’s a treatment that gives great results, and the differences in the rates between transfer from embryos that have been made with the donor and non-donors are much higher, it’s at around 60-50% as age increases. The success rates are much higher with the embryos that have been made through egg donation than the other ones with the non-donor eggs. In Portugal, egg donation is non-anonymous, which means that the child will have access to their origins after they turn 18. It’s transparent, well-controlled and properly counselled, it’s affordable, and there is no waiting list.
The first case presented a single woman at 41- years old with a normal BMI of 20.7, she had no previous pregnancies, and she did fertility preservation in 2021, after that, she had an IVF with donor sperm, but the result was negative. Between 2020 and 2021, she had 3 IUI attempts with donor sperm, but all gave a negative results.
She had a good AMH level of 1.8 ng/ml and FSH slightly above the ideal, but it was still 8.95Ui/l, and the karyotype was normal. We proposed to do an IVF with a sperm donor, but with PGT-A. We did stimulation with Menopur of 300 units and Orgalutran, we used double trigger with Decapeptyl and Ovitrelle. We obtained 12 mature eggs that we fertilized with the sperm donor, and we got 7 blastocysts, we performed a biopsy on all of them, and the PGT-A result showed 2 euploid blastocysts, 2 genetically normal blastocysts. We transferred 1 of the blastocysts, it was type B that have been frozen on day-5 day, and the transfer and hCG came positive, the patient is now pregnant at 23 weeks.
The second case presented a couple, the female was 42 years old with a normal BMI and no previous pregnancies. She had surgery on her right ovary, which was partially removed, her male partner was 43 years old, and they didn’t have any medical or family history. They already had done an ovarian stimulation at a different clinic, but only 1 egg has been retrieved that didn’t have good quality.
After checking the AMH, we saw that it was quite low, 0.1 ng/ml, and the FSH was at 4.29. We explained and presented 2 options. We’ve explained the success rates of both IVF with PGT-A and the egg donation. The couple decided to go ahead with the egg donation. We had the time to do a mock cycle, which means we did a test cycle in a natural cycle, we tested the endometrium response, we used ovulation tests and ultrasound control and also a blood test to check the progesterone levels and check how the cycle of the patient was, and if we had a good endometrium to transfer the embryos afterwards.
We used the eggs of an egg donor who was 24 years old, and from 10 mature oocytes, we have done the fertilization with the male sperm, and we obtained 3 blastocysts and transferred 1 blastocyst of type A. The patient is now pregnant at 4 weeks at the moment. Everything seems to go just fine with the pregnancy.
The last case showed a couple where the female was 39 years old with a regular normal BMI, she had no previous pregnancies, and her partner was 43 years old with no kids. The partner’s sperm analysis revealed isolated teratozoospermia, but it wasn’t problematic for the treatment, they were trying to conceive for a long time since 2009. They had done 8 embryo transfers, and all of them were negative.
After assessing the ovarian reserve with AMH, which was good at 2.47 ng/ml and the FSH level was 5.3 UI/l, their karyotypes were normal. The couple preferred to do an IVF, we started the ovarian stimulation with Menopur of 150 UI and Cetrotide. We got 8 mature eggs that were fertilized with the male sperm, obtained 3 blastocysts, and performed PGT-A. Unfortunately, all 3 embryos were aneuploid, so none of them had conditions to be transferred. We proposed to do the egg donation treatment, and they agreed. We got 11 mature eggs from a 31-year-old egg donor, and we had 5 blastocysts, which is a very good result. We transferred 2 blastocysts on that same cycle, and we got a positive pregnancy test, and in November 2017, a baby girl was born. They had the remaining frozen embryos, and so the couple decided to do a new transfer in 2019, and they had another healthy child.
We usually ask for lots of other hormones, I’ve mentioned FSH and AMH as the most important to assess the ovarian reserve, but yes, we also ask for the estradiol levels, prolactin, thyroid hormones, there are others that I didn’t mention, Estradiol is included in that list, and we do ask for Estradiol levels at the beginning of the cycle usually on day 2 or day 3 of the cycle.
We do that type of test, such as DNA fragmentation. All of our donors, sperm or egg donors are tested, and the karyotype is checked as well. When we use a sperm or egg donor, we always ask the other member of the couple whose gametes we’re using to also test for the karyotype.
DNA fragmentation is not always performed, there are lots of cases where it’s not indicated. However, in most cases with a significant male factor, it is proposed quite often.
Single embryo transfer is recommended most of the time. We always tend to propose transferring a single embryo at once, and that’s what the guidelines tell us to do as well. Nowadays, most clinics tend to do that, and most professionals prefer it. That doesn’t mean that we can’t do a double embryo transfer in some cases. It depends on each case and each patient, there are some situations where it’s contraindicated. We don’t advise the patients to do a double embryo transfer when, for example, the uterus doesn’t have the conditions. We don’t transfer more than 2 embryos in particular. If there aren’t any contraindications or any clinical situations that tell us to do otherwise, of course, we can perform a double donation.
The rates between single and double embryo transfer in patients over 40 depend on the kind of treatment. If it has been done with their own eggs or not, or with sperm donation or not. The rates don’t double because you transfer two embryos.
Let’s say that you’ve done treatment with your own eggs, you only had 2 embryos, so that means you can do 1 transfer or 2 tops. If you choose to transfer them both at the same time, it won’t double your chances. If you have a negative outcome, you’ve lost both of your embryos at once. Possibly, you could have done 2 embryo transfers, and you could have had a second chance to get pregnant. This is something that you need to look at individually.
Most of the time, if we have the conditions to do so. We tend to culture the embryos until the stage of the blastocyst. However, we also have lots of patients who got pregnant with day-3 embryo transfer.
It’s been a while already, and we usually try to do the culture until the blastocyst stage.
Yes, because let’s say that we do an ovarian stimulation, and we have 8 eggs, we do the fertilization of those 8 eggs, and we have 5 embryos, and we do the PGT-A on those 5 embryos, we get the result, and 2 of those 5 embryos are genetically healthy, and there are 3 of them that are aneuploid, they have abnormalities.
We are only going to transfer those 2, and the other 3 will be discarded. If PGT-A hasn’t been done, we would be transferring at least 3 embryos that weren’t healthy and genetically normal. We wouldn’t have a good outcome, or we would have negative results or maybe a miscarriage, and possibly the patients would give up and wouldn’t want to continue. With PGT-A, we are already transferring healthy embryos that are going to give us the best success rates and the best chances. The pregnancy rates will increase because we are already selecting these healthy embryos.
The trigger is always something that depends on each case. Some studies show us that it has good results with the maturity of the eggs, but the trigger depends on the goal of the treatment, whether we are going to do the transfer on the same cycle of the stimulation or not. Sometimes we only use Ovitrelle, other times, we only use Decapeptyl when we aren’t going to do the transfer on the same cycle, so it depends.
There aren’t two equal cases. Sometimes it helps us to relate to other cases, but it’s never black or white when it comes to that, it’s not maths. The correct protocol has to be implemented and needs to be tailored for the patient or the couple.
As I presented in the previous slides, the fact that your cycle is regular doesn’t mean that the ovarian reserve is good, so we would have to check your FSH, AMH levels and other hormones, as I’ve mentioned before. We have to assess the ovarian reserve to be able to decide if it’s viable to use your own eggs.