- What is ovarian aging?
- How much we can expect from a fertility treatment after 38? What are the limitations?
- What is the prognosis factors for IVF success at advanced maternal age?
- What is the probability of live birth?
- How can I actively participate in planning my treatment?
- How can I find out what type of ovarian responder I am?
What are the IVF options for women over the age of 38?
What age is considered advanced maternal age? What are the risks connected with advanced maternal age? Can I undergo IVF with my own oocytes if I’m over 38? What are my chances? Is it recommended to try with donor eggs from the start?
IVF for patients of advanced maternal age 38+ – summary of the presentation
What age is considered advanced maternal age? What are the risks connected with advanced maternal age? Can I undergo IVF with my own oocytes if I am over 38? What are my chances? Is it recommended to try with donor eggs from the start? In this webinar, Dr Juan Jose Sanchez Rosas and Dr Carolina Alonso Muriel from URE Centro Gutenberg (Malaga, Spain) discuss this important topic in great detail.
Dr Juan Jose Sanchez Rosas starts with reminding us that it is a common trend for women in Western societies to delay their motherhood. Today in Spain women usually have their first baby at the age of 33 years. The development of medicine and increased life expectancy makes them believe they can get pregnant whenever they can and without any problems. However, the rising number of fertility patients proves that age is a very important factor in conceiving. According to URE Centro Gutenberg, in 2018 over 38-year old women constituted, 45% of all IVF with own eggs patients and 84% of all IVF with donor egg patients.
In 2018 over 38-year old women constituted, 45% of all IVF with own eggs patients and 84% of all IVF with donor egg patients
Quantity and quality of eggs vs ovarian ageing
Ovarian ageing comes with progressive (and unfortunately irreversible) deterioration in quantity and quality of eggs. Additionally, it is accompanied by an increase in aneuploidy – an abnormal number of chromosomes. The latter results in reduced fecundability (probability to achieve pregnancy in one menstrual cycle) and an increased risk of miscarriages. When a woman tries to get pregnant for 6 consecutive months unsuccessfully, she becomes an IVF patient. Even if she gets pregnant as a result of an advanced IVF treatment, her pregnancy is at risk of pregnancy complications, such as e.g. congenital malformations, chromosomal abnormalities (Down syndrome), pre-eclampsia, gestational debates or preterm birth.
Dr Sanchez Rosas says that according to Spanish legislation on Assisted Reproduction, ART treatment should be used only when there is a reasonable possibility of success and there are no risks to either woman’s or her baby’s health. Taking this into account, one should separately evaluate both main treatments: IVF with own eggs and IVF with egg donation. In each case, the prognosis is completely different.
Egg donation and advanced maternal age
When it comes to egg donation, the pregnancy rates are high and do not depend on the woman’s age and her ovarian status. That is why this treatment is limited only by advanced age-related pregnancy complications. It is generally agreed that the upper age limit for egg donation is 50 years old. IVF with own eggs, on the other hand, is very much age-dependent and its chances of success drop dramatically as a woman ages. According to the Spanish National Health System, the upper limit for IVF treatment in terms of age is 42 years old. Dr Sanchez Rosas admits that the medical team of a fertility clinic has to conduct an individual study of every patient’s case to provide complete information on the prognosis. There are two main decisive factors such an assessment is based on woman’s age and her ovarian reserve. The female patient’s age is the crucial factor affecting IVF success. Its negative impact on IVF performance is related entirely to ovarian ageing and aneuploidy in eggs. Another factor, ovarian reserve (OR), reflects the potential of female fertility and declines gradually with age (speeding up when a woman reaches the age of 40).
Ovarian reserve testing
Dr Sanchez Rosas says that there are two different tests to determine ovarian reserve: astral follicle count (AFC) performed using a transvaginal ultrasound and anti-müllerian hormone (AMH) in the blood. Normal parameters of ovarian reserve are: AFC=5 and AMH 1.2 ng/ml. The best option for doctors is to consider both predicative factors when deciding on IVF treatment type. They also have to keep in mind that a woman’s age is a crucial factor in excluding a patient from IVF treatment. Generally, it is common to recommend egg donation in case of over 40-year old patients (regardless of their ovarian reserves). Women that are younger than 44 years old will have their personalised recommendation prepared on the basis of OR conditions.
Generally, there are 3 main ways in which doctors can improve success rates in women who undergo IVF treatment at advanced maternal age – 38+. These include ovarian stimulation with gonadotropins, improving egg quality before starting treatment and working with laboratory procedures. Ovarian stimulation is crucial for the optimisation of the IVF process. As most eggs obtained in one cycle are not valid for reproduction, a patient needs to undergo several cycles to get at least one embryo for the implantation. It is estimated that there are around 8-15 oocytes needed to increase live birth rate in IVF.
Dr Sanchez Rosas says that depending on the ovarian response, patients can be classified into 4 groups:
- poor responders (if the number of eggs collected is 3 or less),
- suboptimal responders (4-9 eggs),
- normoresponders (10-15 eggs)
- and high responders (more than 15 eggs).
Most of over 40-year old women will be included into the first two groups. This naturally results in a reduced effectivity of the IVF process. In order to choose the best stimulation treatment, it is essential to predict ovarian response and include the patient in the correct group. In fact, the estimation of the results obtained in the previous IVF cycles is the best predictor of ovarian response. Biomarkers such as AFC and AMH, age and BMI (body mass index) are of great use as well.
When it comes to ovarian stimulation, achieving the optimal egg number is as important as patient’s safety and comfort. However, the stimulation with gonadotropins may cause some problems, such as lowering endometrial receptivity, increasing the levels of estradiol and the risk of premature progesterone rise, OHSS (ovarian hyperstimulation syndrome) and a bigger number of aneuploidy embryos. This all led to a new trend in IVF in the first decade of this century – mild stimulation that advocates the use of lower doses of gonadotropins, leading to achieve not more than 8 eggs.
Currently, the trend has changed again, and the most important progress is the vitrification of eggs and embryos. It led to a new strategy of frozen and deferred embryo transfer that is a great improvement to advanced age group, making PGS (preimplantation genetic screening) possible. Today, the trend among women of advanced maternal age is to get as many oocytes as possible. It significantly increases the cumulative live birth rate, reduces the number of stimulation cycles and time to achieve pregnancy. Dr Sanchez Rosas also discusses a new system to classify infertility patients – the POSEIDON (Patient Oriented Strategies Encompassing Individualized Oocyte Number) classification. It helps to achieve greater homogeneity and individualisation of treatment. According to the POSEIDON criteria, the patients are classified as groups 1 and 3 if they are younger than 35 years old, and as groups 2 and 4 if they are older than 35 years of age. Apart from age, ovarian reserve factors (AMH and AFC) and the patient’s sensitivity to gonadotropins are also considered. It also involves a new group of patients – sub-optimal responders.
When it comes to the patients with the worst prognosis, there are several strategies to achieve the best possible ovarian response. These include waiting for the right cycle (and higher AFC), adjuvant treatment (androgens and growth hormone) and special stimulation protocols. To increase the treatment efficiency, some alterations to conventional stimulation protocols have been proposed, such as mild stimulation with gonadotropins or the use of Letrozol and Clomifen. As follicular recruitment is possible at any phase of the menstrual cycle, stimulation can be started at any time (random stimulation) or it can take place during follicular and luteal phase of the same cycle (double stimulation).
Improving egg quality
Many patients ask if it is possible to improve egg quality even before treatment. Dr Sanchez Rosas admits that ovarian ageing can be influenced by lifestyle. For example, oxidative stress is well-known to cause severe damage to ovarian reserve. In order to limit its negative impact, a patient should, among others, prevent obesity, quit drinking and smoking and increase one’s own antioxidant intake – meaning both healthy food high in antioxidants and some antioxidant supplements (especially coenzyme Q10). Of course, there are also new experimental treatments and therapies, such as e.g., autologus/heterologous mitochondrial transfers or autologous stem cell ovarian transplantation (ASCOT). However, they are not only controversial but also poorly effective at the moment.
In conclusion, Dr Carolina Alonso Muriel talks about different treatment techniques that URE Centro Gutenberg offers to patients of advanced maternal age, such as extended embryo culture up to the blastocyst stage (improving in vitro embryo selection and reducing the number of multiple pregnancies) and Time Lapse imaging (that allows for uninterrupted embryo culture environment). However, the most important technique is surely preimplantation genetic testing (PGT-A) of .embryos As advanced maternal age involves an increased chromosomal aneuploidy of embryos, PGT-A is crucial to assure higher pregnancy rates per transfer, lower miscarriages rates and a greater chance of having a healthy child.
Questions and Answers from the event
I am 39 years old. My AMH is 15.5, FSH 8.9. My AFC was 7/8 on each ovary. I had three rounds of IUI and one round of IVF ICSI (7 mature eggs collected, only one fertilised and it was abnormal by day 2). I am concerned my next round will have the same result.
It seems that you belong to the group 2 of Poseidon. The parameters of ovarian reserve are not excellent but not too poor either. In such a case, we consider that an improved response is possible in a new cycle. Maybe with higher doses of gonadotropins and a longer stimulation and LH effect, the greater number of eggs is possible. So it is worth to repeat a cycle and we may see the improvement.
Are there any benefits in mild stimulation to get better quality eggs in older women?
To be honest, I have never heard that mild stimulation increases eggs’ quality. In my opinion, the general use of mild stimulation has no sense. The vitrification process is an excellent strategy to achieve the benefit of a higher response to get more embryos to be selected or make PGS. Mild stimulation doesn’t increase the quality of the eggs.
When you are discussing group 2 vs. group 4, does it mean only antral follicle count or also how many mature eggs there are? I had one cycle with 8 oocytes retrieved with 150 Menopur/300 Gonal-F, but 4 months later I did a cycle with 150/150 (Menopur/Gonal-F) and got only 3 oocytes. However, in both cycles only 3 oocytes were mature and able to have ICSI.
It is a difficult question because the rate of mature eggs can be influenced by several factors like e.g. the timing or the size of follicles at the moment of recruitment. When we talked about suboptimal and poor responders, we said that we can increase follicle recruitment. But it is still not clear how to get more mature eggs. Maybe by using the LH effect and increasing the number of days of the stimulation and delaying it a little bit, we can help to get more mature eggs.
What dose of coenzyme Q10 is recommended?
Usually, the normal supplements for daily use are about 30-60 milligrams. But as the scientific papers say, the doses should be higher: between 100 and 300 mg. It is said that when we want to improve the quality of eggs, the doses should be higher. For some neurological problems like Parkinson, the doses are even up to 1200 mg. But for normal daily supplements, 30-60 mg is a normal dose.
What’s the risk of not using a mosaic embryo after PGT-A which otherwise could be viable?
It is a very controversial question. Some genetic laboratories decide to transfer such embryos while others would never transfer them. So finally, it is always the decision of the genetic laboratory. I can ask my colleague who’s in charge of PGT-A and we can email you about any problems with mosaic embryos. He can answer this question without any problems.
I am 40 years old. I had AFC of 7 last year but this year there was no egg in one ovary and they couldn’t really see the second ovary because of fibroids. What can I do? Because I really want to use my own eggs. Can ovarian rejuvenation help? Or can I do egg banking monthly?
Freezing eggs may be a good option for you. 40 years is not obviously an optimal age but low ovarian reserve at this age does not mean that pregnancy is not possible. It is true that you have enough time to try to get pregnant with frozen eggs. Ovarian rejuvenation is actually an experimental treatment. The effectivity of this treatment is still very poor at this moment.
I’m a 40-year old woman and I have just experienced my 5th miscarriage. I suffer from unexplained subfertility and unexplained recurrent miscarriage. Each pregnancy ends around 7th week. NK cell testing – done! Various autoimmune issues tests – done! There are no concerning results in my hysteroscopy. Can you suggest any further issues I could be tested for, which may be causing the miscarriages?
First of all, when a woman is 40 years old we cannot talk about unexplained subfertility and unexplained recurrent miscarriages. The risk of chromosomal miscarriages is simply too high at that age. To be honest, I don’t believe much in immunological treatment as in most cases it is not effective. We may recommend you to undergo IVF with PGS to obtain more information with respect to the chromosomes of your embryos. Probably, egg donation is an option. Egg donation does not only increase the pregnancy rates but it also decreases the miscarriage rate up to 30-40%. And in this case, it is highly possible that chromosomal problems are the reason for miscarriages.
What about the issue with false positives in PGT-A testing? It is estimated that women have been throwing away embryos for false positives (due to undetected mosaicism) in 20-30% of those that test positive. Maybe not necessarily false positives but e.g. embryos that could have self-corrected after transfer through selective apoptosis.
Again, the issue is very controversial here. And yes, you can transfer some of them because they can self-correct. The laboratory will report what they have found and then the patient can decide. They can transfer the embryo and then do the prenatal test. So it is very optional and it depends on the clinic you’re working with. It also depends on the laboratory you’re working with because some laboratories will report to you about the mosaic embryos while others won’t. They will just tell you if the embryos were chromosomally normal or chromosomally abnormal.
What is your opinion on tests like ERA/ EMMA/ ALIS in older women as well as the use of intralipids/IVIg/ Clexane/Aspirin?
If this question refers to the implantation failure, then yes, the test of endometrial receptivity like ERA can tell us a lot about the failure itself. However, intralipids or immunoglobulins are not of any help in this case. There is a very limited number of cases when their use can be beneficial – so their general use is not a good option. Aspirin and Cleaxane can be used if there are serious indications.
Do you see any benefit in using calcium culture in the lab before fertilisation/ICSI attempts when using donor sperm? Does it increase the fertilisation rates?
We don’t use calcium culture. We have read many studies and there is no conclusive evidence that it is beneficial to patients. Calcium culture is not widely used, at least here in Spain.
What, in your opinion, is the maximum number of times an egg donor should be allowed to donate – from the point of view of the donor’s health and, as a result, her eggs?
Here the law does not say anything about the maximum number of times a donor should be allowed to donate. It says about the number of positive results. The Spanish Fertility Society agreed that 5 times could be ok but it is not the maximum. If an egg donor wants to donate one more time, she can do it. At our clinic, a donor cannot donate more than 5 times – even if she has good results.
Do IVF cycles affect the health of the donor and the health of her eggs if she keeps donating?
The answer is: no. It is not going to affect the donor’s health or the health of her own eggs. Of course, there is always a risk in repeated donating – but it is the same risk when you do it for the first time. Several ovaries stimulations don’t influence the number of follicles. Of course, you cannot do it all the time but 5-6 times have no effect on your health and do not affect your fertility.
What is your opinion (or evidence) on DNA fragmentation impact on the success in IVF? Can ICSI/IMSI help with this?
I’ve done many studies with DNA fragmentation and I think it is important. Here in our clinic, we do DNA fragmentation test, we use techniques with DNA fragmentation depending on the rate the patient has. Then we recommend to do ICSI and, depending on if there are single or double strand DNA breaks, we have to recommend a sperm donor in some cases. ICSI can also help, but not only ICSI. Sometimes we also have to use Annexin-V or – what we are using now – a fertility chip that gives an improvement in pregnancy rates. We haven’t done IMSI but – just like with calcium culture – it is very controversial and there are no conclusive studies showing benefits of this technique.
How does egg retrieval affect thyroid? If there is an elevated thyroid after a retrieval, will it stay that way forever? The doctor said they want to start thyroid meds because of the elevated level.
I imagine you’re talking about TSH (thyroid stimulating hormone). High levels of TSH may mean poor functioning of thyroid. In this case, it is very important to use levothyroxine to increase the chances of pregnancy. There are women who – after the ovarian stimulation with gonadotropins – may produce changes in thyroid hormone levels. The proper functioning of thyroid is very important before the start of any fertility treatment. Make sure it is neither too high or too low. Your doctor was right to use thyroid meds. It is very important to have thyroid under control before stimulation.
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