It is widely known that women encounter fertility challenges if they delay pregnancy until their 40s. This is not only limited to natural conception but it is also attributed to lower success rates with assisted reproduction techniques, including in vitro fertilization (IVF). In this webinar, Andreas Abraham, MD, MBA from the Eugin Clinic in Barcelona, Spain, talks about fertility treatments after the age of 40.
For the last forty years there has been a global trend for women to delay motherhood. Today, giving birth at 40 is 20 times more frequent than it was 20 years ago. It may give a somewhat false impression that advances in technology and medicine are able to balance out the age problem. However, according to Dr Andreas Abraham, it is not that simple. In fact, a lot of chromosomal disorders are linked to maternal age and the probability to have an increased risk of aneuploidy (the presence of an abnormal number of chromosomes in a cell) starts at 35. Aneuploides, the most common of which is Down syndrome, may also cause miscarriage and this is one reason why pregnancy success rates are generally low in women aged 40 and above.
Dr Abraham states that women who are 40 and older make up almost 50% of IVF clinics’ patients nowadays. Unfortunately, in this age group, up to 40% of the patients who start an IVF cycle and get stimulated, will have a transfer cancellation. It means that they undergo a complicated, invasive, and expensive procedure without the benefit of having the embryo transfer and the possibility of an ongoing pregnancy. Based on those observations, the UK scientific community coined an expression called ‘permanent involuntary childlessness (PIC)’. It means the risk of being left without a child even though every measure was taken to reach a pregnancy. If a woman starts looking for pregnancy at the age of 40, the risk of PIC is 35% – while at 30, it is as low as 6%. This undoubtedly proves that woman’s age has an enormous impact on reproductive outcome.
To offer an effective type of assisted reproductive treatment, it is crucial to undertake thorough assessment of patients of advanced maternal age. Dr Andreas Abraham says that the basis for good assessment is always ovarian reserve testing. Although there are a lot of different assessments available (including expensive genetic tests), a gold standard test is still the measurement of AMH (Anti-Müllerian Hormone) and AFC (antral follicle count). The combination of both has the best sensitivity and specificity to predict woman’s ovarian reserve and her ovarian response to the stimulation.
With AMH and AFC determined, doctors can start to consider different assisted reproduction techniques as well as the number of cycles needed for each technique. According to dr Abraham, it generally comes down to deciding whether to use intrauterine insemination (IUI) or ICSI (Intracytoplasmic Sperm Injection) – a refinement of the IVF technique.
Although opinions may vary, the clinical evidence leaves no doubts: as time is a key factor in older patients, it is highly advised to start ICSI immediately. However, if a patient insists on trying IUI, she should know that at the age of 41, she should switch to IVF latest with her sixth failed IUI cycle – and, if she’s 42, she should not do more than three IUI cycles. Another important decline in female fertility comes at the age of 43. Then, as studies show, clinical pregnancy rates after IVF become very poor and it is generally a clear indication for choosing the egg donation route.
In discussing treatment options for 40+ patients, Dr Abraham poses the question whether it is necessary to impose limits on patients instead of letting them decide themselves about their preferred type of assisted reproduction technique. The answer becomes easier when one considers IVF pregnancy outcome based on the age of the patient per retrieval. It clearly proves that from 45 years old onwards, live birth rate in IVF is close to zero. So, although IVF may help to overcome infertility in young women, it does not reverse the age-dependant decline in infertility. That is why setting an age limit for IVF treatment with own eggs makes sense – simply because the likelihood of success declines as a woman gets older. In such cases, even advanced IVF techniques do not do the trick and turn back the biological clock.
For IVF to be effective, one must obey not only patients’ age but also the recommended number of cycles. Dr Abraham provides an example of a study which demonstrated that patients who are 40-43 years old generally reach a plateau after three attempts. It means thereafter, there is no visible increase in success rates. If a woman is over 43, she has no realistic chance of achieving a delivery with her own oocytes.
It is widely believed that preimplantation genetic screening (PGS/PGT-A) increases the pregnancy chances and gives higher success rates in women over 40. Perceived as a way to top-up IVF cycles, it has to be handled with a lot of thought and care.
It is scientifically accepted that PGS must be done at day 5 of the embryo development – meaning the blastocyst stage. The criteria for a day 5 biopsy are strictly determined and they include minimum of 15 mature eggs or 8 (or more) top quality day 3 embryos. All the studies that indicate the usefulness of this technique have been performed in good prognosis patients under 35 who produce a lot of eggs. Taking the latter into consideration, one must realise that lot of 40+ patients will have 15 or more eggs retrieved and will not have 8 or more embryos of excellent quality. Besides, it is very likely that a lot of their embryos will simply not reach the blastocyst stage and this is the imperative to do the embryo biopsy if you want to benefit from this technique.
Another option that is often considered by advanced age patients is the vitrification of oocytes. However, according to Dr Abraham, it is not an option when you are over 40. It is important to know that the studies showing the efficacy of vitrification were performed in women under 37. The minimum number of mature eggs necessary to make an ongoing pregnancy probable is nine and, unfortunately, a lot of women who are 40 or older, will not have this number in one session. Dr Abraham shows a study from 2017 which proved that the likelihood of live birth for elective oocyte cryopreservation is directly proportional to the number of mature eggs and as we already know, the egg quantity and women’s age do not go together.
Having realised that a lot of assisted reproduction techniques do not meet the needs of women over 40, one must consider egg donation as the most effective treatment. It gives the highest success rates because it literally eliminates the age factor. Dr. Abraham admits that regardless of the recipient’s age, the success of the treatment is defined by the donor’s age and the latter is 25 years old on average. So no matter if you are 30, 40 or 51 (which is the legal age limit for egg donation in Spain), you still have the same success rates and equally high probability of an ongoing pregnancy and a live birth.
However, it is true that egg donation is not the first option that comes to a woman’s mind when she faces fertility challenges. In fact, it is probably one of the hardest decisions for fertility patients to make – often due to cultural and social reasons. It is not even mitigated by impressive success rates: 59% on first transfer and – in case of cumulative pregnancy rate after 3 cycles – even up to 93%.
Apart from advanced maternal age (43 years old and onwards), the indications for egg donation include previous IVF failures, premature ovarian failure, premature menopause, and genetic history. The limitations that patients may encounter most often refer to legal aspects (in some countries egg donation is not allowed) and the lack of appropriate donors.
It is obvious that social changes have significantly influenced reproductive behaviour and countries’ demography. Dr Abraham concludes that in the face of these modern challenges, health professionals should fight with ignorance concerning the reduced age-related fertility options and encourage women to have children sooner. When they deal with patients 40+, they should offer good counselling on available treatment methods, paying special attention to their effectiveness in this particular age group. Finally, they should not forget about informing the patients on the correlation between advanced maternal age and higher obstetrical risks. In fact, it should always be a part of a thorough counselling in the first visit.
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