By fertility experts from Spain.
The main goal of individualisation of stimulation protocols in IVF is to offer every patient the best chances of pregnancy, basing on her own unique characteristics and medical history. In this webinar, prof. Luciano Nardo, a Consultant Gynaecologist & Subspecialist in Reproductive Medicine & Surgery and Clinical Director at Reproductive Health Group (UK) is talking about personalising IVF treatment and predicting ovarian response for every individual.
It is true that 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 the positive ones. The negative predictors include female age, ovarian reserve, past reproductive history as well as causes of subfertility and its duration. In 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.
According to prof. Nardo, the doctors’ aim is to individualise medical care and personalise treatment protocols. They should tailor their work in order to enhance the chance of success, maximise patient’s 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 a number of 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 patient’s characteristics and their expectations. All of them have to borne in mind when designing a tailored approach in IVF treatment.
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 simulation protocol in the first cycle. However, prof. Nardo admits that true ovarian reserve is something that cannot be really measured. The solution here is assessing the functional ovarian reserve, which is referred to as the ovarian function. There is a number of tests that 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. In fact, 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.
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 outcome. Depending on the relationship between the total number of follicles at the time of trigger in relation to 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 to the number of eggs and 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 about the negative impact of an 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.
Once follicles become antral follicles, they become sensitive to follicle stimulating hormone (FSH) and luteinizing hormone (LH). Basing 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 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 expected hyper response. The benefits of the antagonist are associated with no initial flare-up, shorter treatment, less 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 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 trigger.
In the most challenging group, namely patients with known poor response and low ovarian reserve, the micro-flare protocol seems to be he 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 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.
Surely one of the most important solutions that prof. Luciano Nardo and his team have come up with in their long-term practice is 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 in 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 past experience of suboptimal response to stimulation.
The answer in theory is: yes – but I would not recommend having a fresh transfer for different reasons. First, with regard to your AMH, you will be on the antagonist protocol and probably even lower than 100 international unit dose of recombinant FSH. You’re unlikely to produce a large cart of follicles.
Unfortunately, we know that not all follicles in a woman like you will have mature eggs. So there is a higher risk of having some immature eggs that fail to fertilise if you’re having IVF. If you were to have ICSI, of course some of the eggs will not be injected because they will be seen as being immature. But the concern is the effect of hyper response on your endometrial performance. So my recommendation would be to start on a low dose of stimulation, collect eggs and fertilise them in vitro with conventional IVF or ICSI, depending on the sperm parameters, allow the fertilised eggs to be cultured to day 5 which is a blastocyst (occasionally, it’s day 6). And then freeze them. Give yourself a short break and allow the endometrium environment to refresh itself from the high dose of oestrogens and then come back for a frozen embryo cycle.
In our clinic, the chance of a cryopreserved blastocyst to survive the freezing and thawing process is about 98% – and there is the same chance in most IVF clinics with a good freezing program. So you don’t have to be concerned about the impact of freezing on the quality of the blastocyst and the chance of success. There is also growing evidence, which supports what I have just said, that doing the frozen embryo transfer cycle leads to a better clinical pregnancy outcome when compared to a fresh cycle – especially in women with polycystic ovary syndrome and hyper response.
Generally, we know that smoking and drinking may impact negatively on the IVF outcome. It is not just during the procedure. There is very little benefit in stopping smoking and drinking whilst the IVF treatment because the effect of smoking and drinking which may cause oxidative stress in the ovarian cycle is probably three to four months before you start the medications. We know that the ovarian cycle leading to the presence of antral follicles in the ovaries is about 120 days.
So if you were to be concerned about habits, then I would recommend that you stop drinking and smoking three to four months before you start the ovarian stimulation protocol. The advice I give to my patients in Manchester is to quit smoking and drink very little in the month proceeding the treatment cycle. I don’t think that having one glass of wine a week is detrimental, living a normal life is not a problem either. But the combination of smoking and drinking may impact negatively on the chance of success.
This doesn’t mean that everyone who is smoking and drinking even more than two times a week is not going to be successful. It’s just down to the balanced probabilities and also to the underlined factors. If a woman is 29, has low ovarian reserve and smokes and drinks weekly, she has to accept that perhaps she is going to have a more negative effect as compared to someone who’s 29, with good ovarian reserve and regular cycles. I don’t know your age and I don’t know whether you have had treatment before but if you are known to have reduced ovarian reserve or if you are older than 37, I would recommend that you quit smoking and reduce your drinking habits to no more than one glass of wine per week.
This is a good question and there is lots of debate about when to transfer embryos. In our practice, we always culture fertilised eggs to blastocysts. We believe that an embryo that reaches the stage of a blastocyst has got the best chance to implant. We also use time-lapse systems to monitor the development of the embryo in the lab which provides additional information on whether the embryo should develop or not. My recommendation is that irrespectively of the total number of collected eggs or the quality of eggs or the number of eggs fertilised, if possible and in agreement with the laboratory where the IVF treatment cycle takes place, develop the fertilised eggs to day 5, to the stage of blastocyst, so that you can acquire more information. And if you have a good embryo that has reached the stage of a blastocyst, that one will have a better chance of a successful implantation.
There is no way to improve egg quality. There is a debate about improving ovarian response. And in some cases, by improving ovarian response to stimulation, so by creating a better environment for eggs to develop and mature in the follicles, we can get better quality eggs. But if the egg quality is very poor because of suboptimal ovarian reserve, there is very little that can be done. I think believing that there are options to improve egg quality – beyond the treatment protocols which I described in my presentation – is probably not realistic. But sometimes little changes in borderline cases may improve egg quality. In our practice, we use the hormone LH because we know that this hormone is very important to induce or improve egg maturity. If you have had previous ovarian stimulation cycles with suboptimal ovarian response or with a large cohort of immature eggs, and you have a satisfactory ovarian reserve, then I would suggest to consider adding LH. But if, instead, you have suboptimal ovarian reserve and you have already tried stimulation protocols with the addition of LH, probably there is nothing else to be done.
It is unlikely that LH is 0 if AMH is 0. Let’s just assume that AMH is 0. AMH of 0 indicates very poor ovarian reserve. Having suboptimal ovarian reserve has to be borne in mind when somebody’s counselled for IVF treatment – and other factors have to be taken to account, such as chronological age, number of antral follicles and also the length of menstrual cycles. If the AMH levels are less than 1, the chances of successful outcome are very slim. It’s important that we know the AMH measurement scaling and measurement unit – I’m referring to one picomole per litre (pmol/l). In some cases, embarking on IVF doesn’t add much to the chances of success. However, we have had successful IVF cycles in women with AMH levels less than 1 and that has happened in repeated or multi cycle stimulation.
In our practice, in majority of cases, we would be using a LH dose of 150 international units. Very occasionally the overall dose of gonadotrophins – that’s the combination of FSH and LH – would be higher than 300. In some cases, we go as high as 375 and that will be 225 international units of FSH and 150 international units of gonadotrophins with LH activities.
You’ve got two factors: one is your chronological age and the other one is the age related to the reduced ovarian reserve, which is expressed by a low AMH level. So unfortunately, you fall into a poor prognosis category. In our clinic, we would have not used any of the two protocols you have referred to in your question. We use HMG preparations. Pergoveris is the combination of FSH and LH as recombinant hormones – we use that as well, although we use it as separate preparation. The protocol used in the first cycle is called the flare protocol which we don’t use. The second one is the antagonist protocol which, again, we will not be using. I mentioned in my presentation that in poor prognosis cases, with expected poor response and in those with reduced ovarian reserve, we use the micro-flare protocol instead of the antagonist protocol. I believe that the antagonist protocol impacts the LH levels which you do need in order to mature the eggs. I cannot give my opinion on the two protocols because there will surely be some reasons why the physicians whose care you’ve been under prescribed those protocols – they might have had to do with their own experience, the clinic protocols, success stories, etc. But certainly, this is not something that I would do with my clinic. I agree that there is no point to do blood tests and we don’t do any blood tests during the simulation cycle either. We just do ultrasound scans. I think that you can try something different for the next simulation – you can try the micro-flare protocol. But I think there is a debate whether perhaps you should go straight for donor eggs as the latter option will give you a much better chance of success.
I think it very much depends on the ovarian simulation protocol. Some women have an intrinsic risk of developing ovarian hyperstimulation syndrome. However, that risk can be decreased significantly by adopting a tailored stimulation protocol which includes the antagonist and the low dose of starting FSH. It means that there is less risk of recruiting large cords of follicles, hence less risk of stimulating or hyper stimulating the ovaries. Also, it depends very much on what was given as a trigger before egg collection because that is another risk factor to develop ovarian hyperstimulation syndrome. From what you’ve described, possibly your patient was at a very high risk of ovarian hyperstimulation and obviously she was not well because of it. Being off work for 18 months because of hyperstimulation seems to be little bit excessive but I don’t know the full history and there might have been some complications and precipitating factors. Going forward, I think she will need a low dose of gonadotrophins, the antagonist protocol and possibly a different trigger before egg collection.
I definitely suggest that before you do another round of IVF, you and your partner should have further investigations because IVF doesn’t help to overcome all the problems. I suggest you undergo a pool of investigations to exclude contributing factors to miscarriage, both for you and your partner. These include genetic tests, the diagnostic hysteroscopy and some blood tests to exclude immune problems, tendency to form blood clots and thyroid problems and for your partner – some genetic tests as well as the sperm DNA fragmentation test. If everything comes back as normal, then, when you embark on IVF and create embryos, I would recommend that you go for pre-implantation genetic testing. It is possible to speculate that some of your embryos will be genetically abnormal, hence ending in a miscarriage.
We use most of the gonadotropins. We use Gonal F and Luveris, we use Meriofert – so we use a combination of all the gonadotropins you referred to. There is probably not much difference amongst those in the general population and in the good prognosis cases. But it is all about how you use the combination of those. In my presentation, I referred to using FSH and LH. LH can be in the form of recombinant LH or it can be in the LH activity that is contained in Meriofert or Menopur. So we use different gonadotropins but it’s a combination of those that sometimes leads to a successful stimulation protocol – and, also, what agonists or antagonists have been used in the same protocol.
We use both of these. We use Ovitrelle and we also use Gonasi. Our preference is general for Ovitrelle. In some cases, especially in women with reduced ovarian reserve and a previous poor response or a previous suboptimal cohort of mature eggs, we will give a double trigger – we will give a double dose.
I would recommend the micro-flare protocol, based on the fact that your AMH levels are low for your age. Of course, we need to know what your antral follicle count is. The fact you’ve got irregular periods per se doesn’t add much to your history – everything depends on how irregular they are. Generally, the micro-flare protocol, using a combination of FSH and LH or LH activity drugs will be good. You can have a fresh transfer, providing that you have good embryos that reach the stage of blastocysts.
I’m afraid we do not offer any money back guarantee programmes within our clinic. This is because we believe that adding the thing such as money back guarantee will give the medical treatment that we’re providing to our patients – and that we are very passionate about – too much of a commercial theme. Instead, we have programmes where we assist our patients with the cost of the treatment by reducing the cost in subsequent cycles. But we do not offer any money back guarantee programmes.
This is the problem that can occur in some cases. It depends on the agonist or the antagonist that was used. Normally, we will be using the contraceptive pill in the month prior to the stimulation and it will be an given in conjunction with the micro-flare protocol, if you have reduced ovarian reserve or low number of antral follicles, or with the antagonist protocol instead.
I think that, unfortunately, IVF is a number game and it comes down to a chance of conception every time you try. It is good news that you have had two good quality embryos. However, I do not have much information about your age, your ovarian reserve, your husband’s sperm analysis or whether he has had the sperm DNA fragmentation test or not. But what we do know clearly is that having morphologically good embryos – so embryos that look good on day 5 or day 6 so at the stage of blastocyst – doesn’t always mean that the embryos are genetically normal. So it may well be that your lack of success with an IVF cycle and your miscarriage at 10 weeks are different faces of the same coin. It means that you may have an underlying problem that has not been overcome by IVF.
There is a combined test called EndomeTRIO – it looks at the time when to perform the embryo transfer as well as adds the bacterial environment within the uterus and excludes the presence of something called chronic endometritis. So it is possible that it will be a good way forward for you.
IVF and ovarian stimulation are the same. My recommendation would be to consider donor eggs. I would not recommend you embarking on an ovarian simulation attempt and IVF using your own eggs.
A blastocyst on day 7 is not really a too firm blastocyst. We’ve spent so long to get to the stage of a blastocyst and that per se indicates a developmental problem with the embryo. So the embryo transferred on day 7 is not really a good quality embryo – and it is not something we would be doing in our clinic. It also raises issues about the synchrony between the embryo (and then the blastocyst) and the endometrium. If you have had reduced ovarian reserve in subsequent cycles and slow development of embryos, then it is, in my opinion, exactly what has happened in the first cycle. There was a slow development of embryos as they reached the blastocyst stage on day 7. So it is important to have an accurate assessment of your ovarian reserve, that is the combination of AMH and antral follicle count (AFC). Perhaps consider multi-cycles stimulation to maximise the chances of the ovaries to respond to stimulation. But there is no guarantee that this approach will lead to a successful cycle.
I think my advice will be to have neither down regulation nor the antagonist – not with your AMH level and your chronological age. I think you have had high doses of gonadotrophins which we would not be using in our clinic. We would use lower dose of gonadotrophins with the micro-flare protocol aiming to get less eggs. Having mature eegs is not the answer to get good blastocysts. I think it’s the combination of the genetic material that you cannot observe just by looking at the mature eggs. Your AMH is low so you will benefit from multi-cycles simulation in our clinic. That’s what we would be recommending – with the combination of FSH and LH. And I would not go for so many eggs but I’d be aiming for less eggs in each cycle. I’d be trying to get three cycles batched together and then have the blastocyst genetically tested.
This is an interesting case. Obviously, your age is a negative prognostic factor. However, your antral follicle count and AMH are good for your age. I understand you’re a poor responder so you have not responded well to previous cycles. I’m not quite sure what protocol you have had. But again, our recommendation would be to have the micro-flare protocol using FSH 225 and LH 150.
No, it is not. The technology used to biopsy blastocysts carries a very small risk of damaging the blastocyst. You will have more chances of having an abnormal embryo than the chances of the embryo being damaged because of the biopsy.
One in four of our patients travels to come to our clinic – either from within the UK or overseas. We can work with clinics overseas – the patient has the scans and monitoring done there and then they travel to our clinic. We’ve done that with patients from Africa, Europe and also from the Middle East so it’s not a problem. We do the egg collection, the patient travels back to her country and we start the stimulation again. Then, after the stimulation is underway and once the doctors – wherever the scans have been performed – deem that she’s ready for egg collection, obviously with our advice and coordination, we’ll ask the patient to return to the UK for the egg collection.
It very much depends on the sperm as well. Frozen eggs from the women over the age of 35 may not lead to the same success rates as in women under the age of 35. The chances of eggs surviving the thawing process, so being defrosted, are quite high – about 70-75% of eggs survive.Then the eggs have to be injected with sperm. So I don’t think that the problem is the age now when you want to use them (meaning 42) but I think it’s more about the age when the eggs were collected and frozen – so 38. The chances of successful IVF depend on many variables, including the quality of the sperm and other factors that you may be investigated for. Provided that everything else is optimal, so everything is normal, and you’ve got a good quality blastocyst, I would say that your chance of having successful IVF leading to a live birth is about one in five.
This is a difficult question because it depends on how many eggs are retrieved at the time and also on the quality of these eggs and whether the eggs are going to form blastocysts or not. I presented one of my slides saying that you need about ten eggs to have the chance of
having at least one genetically normal blastocyst in somebody of your age. However, you know it’s not one-size-fits-all and obviously there are variations within the same age groups. In our clinic recently, we have had a set of patients of your chronological age and unfortunately, we have seen that a great majority of their embryos were abnormal, despite collecting a good number of eggs for each of them. So we don’t have to look at how many egg collections you need – it is more about how many blastocysts – that can be potentially tested – you have in each cycle. If you happened to go through three stimulation cycles with no good quality blastocysts and the blastocysts – if collected in each cycle – have been genetically tested and turned out abnormal, then I would recommend you considering egg donation.
Yes, I would recommend the ERA test in order to assess the time when to do the embryo transfer. It is equally important if you have one or three embryos – it is even more important if you only have one embryo because you’ve got more to loose. So determining the exact time when to do the embryo transfer has showed to be beneficial.
Yes, I think that in some cases low stimulation protocols are better because more is not always better. More doses of medications can lead to the development of a large cohort of abnormal eggs.
It is possible to identify the presence of adenomyosis from the scan which is a very reliable diagnostic test. It depends on how sparse adenomyosis is. Sometimes it is important to organise an MRI scan of the uterus because that will give us indication about the impact adenomyosis has on the junction root zone which is the limit with the endometrium. And in that case yes, it indeed can have impact on the embryo implantation. So if it is obvious that adenomyosis is impacting the junction zone and it is close to the endometrium, then there is no need for any other scans or other investigations – otherwise, I would recommend an MRI scan.