The main goal of individualisation of stimulation protocols in IVF is to offer every patient the best chances of pregnancy, based on her own unique characteristics and medical history. In this webinar, Prof. Luciano Nardo, MD MRCOG, Consultant Gynaecologist & Specialist in Reproductive Medicine is talking about personalising IVF treatment and predicting ovarian response for every individual.
Indeed, IVF does not work for everyone – at least not for the first time. At the start of his presentation, prof. Luciano Nardo highlights that all fertility patients fall into two categories in terms of IVF success: negative predictors and positive ones. The negative predictors include female age, ovarian reserve, past reproductive history as well as causes of subfertility and its duration. In the case of positive predictors, there are: ovarian response, the number of mature eggs collected, the number of eggs successfully fertilised in the lab, the number of good quality embryos created and the number of available blastocysts.
The importance of individualised care
According to prof. Nardo, the doctors, aim to individualise medical care and personalise treatment protocols. They should tailor their work to enhance the chance of success, maximise patient satisfaction and achieve a live birth. Prof. Nardo admits that optimising ovarian response to stimulation should be based on knowledge of ovarian reserve and the outcome of previous cycles. His opinion has been supported by a significant amount of scientific evidence and debates about controlling the stimulation protocols and tailoring them to several factors that are specific to the individual patient.
There is surely no one-size-fits-all approach in reproductive medicine. According to prof. Luciano Nardo, the individualisation of care should be divided into three main areas: the first one is the clinician experience and practice, the second is the published best evidence and interpretation of evidence and the third is the patient’s characteristics and their expectations. All of them have to keep in mind when designing a tailored approach in IVF treatment.
Ways of assessing ovarian reserve
Prof. Luciano Nardo states that there are three groups of patients that constitute the biggest challenge in terms of IVF success: women older than 37 years old, women with extremes of ovarian reserve and recurrent poor responders. It is well-known that with advancing chronological age, the number of follicles declines and the proportion of poor quality eggs rises. Thus, as a woman’s age increases, there is a significant decline in her fertility potential.
What is more, within the same age group, there are individual differences in terms of ovarian reserve. That’s why the best thing for doctors to do is to use ovarian reserve tests to further predict ovarian performance and determine the best ovarian stimulation protocol in the first cycle. However, prof. Nardo admits that true ovarian reserve is something that cannot be measured. The solution here is assessing the functional ovarian reserve, which is referred to as the ovarian function. Several tests have been suggested as certain measures of the primordial follicle pool and they include age, antra follicle count (AFC) and anti-Müllerian hormone (AMH). AMH is regarded as a screening test – once you know what AMH levels are like, there is no point to repeat it (at least not within a short window of time). AMH, itself being a good marker of ovarian reserve, is in a good correlation with the AFC. The measurement of AFC, on the other hand, is very important to change the treatment protocol in the same patient – sometimes from month to month.
When it comes to age, it is clear that advancing chronological age is related to a higher rate of IVF cycle cancellation and a higher proportion of healthy women having less than four oocytes collected.
It has been proved that suboptimal ovarian response to stimulation can reoccur in just over 60% of cases. The cohort of recruitable follicles may vary from cycle to cycle. It refers to the cyclic effect on both follicular decay and follicular growth rate.
Defining normal ovarian response
Prof. Nardo says that there is a lot of debate about normal ovarian response to stimulation. What is generally perceived to be normal is, in fact, optimal. However, many women who have suboptimal ovarian reserve may have an adequate available response to stimulation at the same time. The purpose of ovarian stimulation with exogenous gonadotropins (being predominantly FSH and LH) is to rescue follicles from atresia. That’s why the response to stimulation is determined not by the number of follicles and eggs, but by the correlation between this number at the beginning of the stimulation cycle and what was achieved in terms of follicular development and the number of eggs at the cycle end.
At this point, prof. Luciano Nardo introduces the concept of the follicular output rate (FORT). It is said that antral follicular responsiveness to follicle-stimulating hormone administration assessed by FORT may predict in vitro fertilisation-embryo transfer outcomes. Depending on the relationship between the total number of follicles at the time of trigger about the follicles at baseline, it is possible to distinguish three groups of patients: low FORT (below 42%), average FORT (42-58%) and high FORT (over 58%). In the group of patients with the high follicular output rate, the number of oocytes collected, the number of metaphase II oocytes as well as the number of achieved embryos followed by the clinical pregnancy rate and ongoing pregnancy rate is significantly higher when compared to the other groups.
Prof. Nardo also mentions the association between the number of eggs and the live birth rate in IVF treatment. According to 400,000 treatment cycles conducted in the UK, the best chance of live birth in a fresh IVF cycle is associated with the number of oocytes around 15 and declines with more than 20 oocytes. The nomogram (number of oocytes to live birth) may be used to inform about the potential outcomes and to reduce the risk of complications. However, it is important to remember here the negative impact of increasing maternal age. Prof. Nardo explains that the same number of eggs in younger women (18-34 years old) have a three-fold increase in the predicted live birth when compared to women over 40.
Optimising stimulation protocols
Once follicles become antral follicles, they become sensitive to follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Based on that knowledge, doctors can individualise stimulation protocols and enhance the chances of a successful IVF outcome for patients (taking into account the fact whether it is first or next cycle, if there is a good ovarian reserve or previous poor response).
Prof. Nardo says that in his clinic, they use the antagonist protocol for patients with PCOS (Polycystic Ovary Syndrome), egg donors and women with an expected hyper response. The benefits of the antagonist are associated with no initial flare-up, shorter treatment, fewer gonadotrophins, more individualised stimulation, less risk of OHSS (Ovarian Hyperstimulation Syndrome) and the choice of ovulation triggers.
The other possible protocol is the so-called long-down regulation, which is used for patients with endometriosis and expected normal responders. This type of protocol is associated with longer treatment, gonadotrophins dose adjustment, less individualised stimulation, low incidence of OHSS and using human chorionic gonadotrophin (hCG) for the trigger.
In the most challenging group, namely patients with known poor response and low ovarian reserve, the micro-flare protocol seems to be the most beneficial. It means shorter treatment, the possibility of introducing anti-oestrogen or aromatase inhibitors, gonadotrophins dose adjustment (FSH and LH), individualised stimulation and hCG for the trigger.
In prof. Nardo’s opinion, it is also important to take into account the fact that LH is beneficial in women with poor (suboptimal) ovarian response. The reason for adding LH to stimulation protocols is its ability to reduce the apoptosis of cumulus cells, increase FSH receptor responsiveness and up-regulate growth factors. Besides, LH enhances the expression of anti-apoptotic proteins.
Observations from the IVF clinic’s practice
Surely one of the most significant solutions that prof. Luciano Nardo and his team have come up with in their long-term practice are consecutive cycles for blastocyst banking. It means multiple cycles of controlled ovarian stimulation (COS) and leads to a larger number of blastocysts available for genetic testing. Pre-implantation genetic testing for aneuploidies (PGT-A) has been shown to increase the live birth rate and reduce the risk of miscarriage – so exactly the result that doctors want to achieve in chronologically older women. What is more, by stimulating the ovaries, it is more likely not only to achieve a better outcome because of the cumulative effect of gonadotrophins but also to limit the impact of age on ovarian function. And finally, thanks to multiple cycles of simulation with blastocyst banking and PGT-A, it is easier to reduce the cost of repeated fresh and frozen cycles.
What prof. Luciano Nardo wants to highlight the most is the fact that two patients are never the same. Thus, the one-size-fits-all approach is not the right direction in the field of reproductive medicine – nor any other field. Patients’ groups can be subdivided into different types of protocols and the dose of gonadotrophins varies depending on AFC, the patient’s chronological age and response to previous stimulation. The positive news is that multiple cycles of simulation with blastocyst banking and PGT-A seem to be a promising solution for patients with suboptimal ovarian reserve or the experience of suboptimal response to stimulation.