Personalization of (IVF) ART treatments

Considering that we should not expect any problem related to to the sperm, at this point, we have to suspect that the problem is related to the quality of the oocytes. If you are telling me that in 30, 35 oocytes that have been inseminated plus or minus, it was not fertilized, and if as I suppose was, not always the same sperm used. I suspect that you should directly go to gamete donation, I don’t think that anybody can help you, apart of making a more refined diagnosis. Your oocytes, once they are collected before ICSI is done, an analysis should be done with that, and you will have most probably the confirmation that the majority of your oocytes are not treatable to begin a pregnancy. This can also be confirmed if you are looking for babies for a long time and your tubes are open, so you have already done insemination, so most probably you don’t have idiopathic infertility. You probably have infertility due to the quality of your eggs.

Yes, but it is limited. I don’t think that when you balance the risk of hyperstimulation, and the disadvantage of the percentage of results, you should aim to have a fresh embryo transfer.

It would be good to know what is your BMI. Considering that the recommendation to lose weight is not the right one. My suggestion is to start very slowly, so with a very low dosage of gonadotropins, it would be around 100-150, and then keep going with the aim of deselecting follicles. Maybe it would be good to add a bit of an LH during the stimulation.

They are completely different exams. Colposcopy gives you all the information regarding the cervix, so the neck of the uterus, while a hysteroscopy gets a small optic fibre inside the cavity and can check the normality of the cavity. You can do a very elegant and sophisticated 3D ultrasound, and if it’s well done mainly by an expert gynaecologist, we can read a lot of information, but if you really want to know if you have more adhesions if you had a miscarriage before if you had a termination of pregnancy before if you had regular cycles with some bleeding. I mean if you really want to be sure that your uterus is completely normal, you have to do this exam, it is not very painful, it has to be done only once, and it gives the gynaecologist also the idea what is the right time for the embryo transfer. Those are 2 completely different tests with 2 different aims.

There is some data in the literature showing that you can have success but in a reduced percentage of times compared to when the trigger is done with HCG. So the recommendation once again is not to transfer when Decapeptyl is used. It took ages for the clinicians to understand, and now I think it’s extremely important that also patients follow the same concept. Stop thinking about success rate per embryo transfer. Once you define success rate as delivery, or as a clinical rate, it doesn’t matter, it is up to you. You have to think about the concept not for the embryo transfer but for several attempts that you want to do. If you are 30 with normal cycles, normal sperm, only some fallopian tube problem, in our centre if you want to have a chance to delivery 80%, so 10 patients come in and 8 deliveries you have to enter it into the concept that we need to expose you 4 times to an embryo transfer, so it doesn’t matter if you get pregnant at the beginning or at the end. But if you want 80% of chance with that age, with that partner sperm, you need to be exposed 4 times to our procedure. If you want to have your 80%, but you are 40 years old, and you have a poor sperm quality, you need to be exposed to 20-25 embryo transfers, are you able to do so? Do you have the capability to do so?

Probably you must take into consideration that you can try to get your 50%, at the age of 40, to get 50% of chances at delivery, we need to do with you 10 embryo transfers. First of all, design with your clinician what you want, in terms of per cent of delivery, and then you need to have personalized medicine and personalized ART.

First of all, from the clinical point of view, I think that if you are prepared, the best thing is to have an embryo donation. In Italy, it is not allowed, the only restriction of the Italian law at the moment is surrogacy and the treatment of individuals that are not in a stable relationship, so they are not a couple, or they are not married. In this case, this treatment cannot be done in our country.

Don’t transfer 3 embryos, not at all. Convince your husband, if there are extra frozen embryos, and if it’s possible to keep the extra embryo for the last attempt. Don’t transfer 3 embryos. Second thing, ERA test can be a good concept for you, don’t forget that only 3 to 5% of the patients that do an ERA test, is finding something, but I think that is worthwhile to do. PGD for aneuploidy makes sense. Even if we are expecting a limited number of aneuploidies as you’re using donor gametes. What I would recommend to you is to check your uterus carefully, so hysteroscopy if it has not been done. Don’t get tempted to transfer 3 embryos, also because if those embryos are diable, but for any reason, you are transferring in the wrong uterus, that means in the wrong month, you’re wasting the 3 of all them, while you could have on the other round, another chance. On the other hand, if the 3 embryos are good and your uterus is perfectly synchronized, you take a terrible risk of having triplets with all the disaster that could follow a triple pregnant.

If you go for as we’ve discussed before, more days of stimulation. It means, you are injecting fewer units of gonadotropins, so there will be a lower risk of hyperstimulation and probably fewer follicles will be selected. So in principle, I am not against it, I also like to remind you that not many clinicians use it, but data show that the original protocol, the protocol for IVF that was published almost 40 years ago in Science by the Australian group, where I was working, was recommending a little bit of clomiphene, 2 capsules per day for 5 days, to which you can add a few gonadotropins, so 150 units every 2 days, so not every day, and this works very well, for PCOS patients. It has to be done under strict control, and as you know better than me, PCOS patients can react differently, depending on the patient. But it is a protocol that for some reason very few clinicians remember to use. It could be a possibility to discuss it with your doctor.

These are protocols that we have generated, it has been published, and the concept is quite simple. We are talking about poor responders patients now. According to the so-called Bolonia criteria, that is a paper that has been published in 2011 and now is followed around the world. It has more than 1500 citation, so Bolonia criteria is the criteria that everybody used in the UK, Spain, the United States, so we define poor responders according to this, maximum 3 eggs, very low AMH etc. There is a category of poor responder patients, they do not respond despite the amount of gonadotropins that we give because the FSH receptor is not prepared, so what we do is we give to the patients long analogue, so GnRH analogue before starting the stimulation. We give to these patients pure LH, recombinant LH for 1 week or 10 days to activate the FSH receptor, and then we start the stimulation protocol, so we stop LH today that has been for 10 days, and then we start with FSH with the routine protocol. What we have found that this system, of course not in all poor responders, but in most poor responders they actually have not cancelled cycles, had a decent number of oocytes, sites that mean not only 1but 3,4 embryos looked good. If you are able to transfer them, the pregnancy rate is acceptable, it’s not like in a normal responder, but it is acceptable. You can find this data in the literature if you wish, otherwise, you just let me know, I can send you this randomized study that has been done by our group. The concept is, you are a poor responder because your ovaries have resistance towards the FSH, that we inject to you.

We start with mild stimulation first with using clomiphene, which I’ve mentioned before. Clomiphene is a very old, a very rough instrument that we as clinicians have in our hands, but sometimes, it’s better than pushing with an enormous amount of gonadotropins since the beginning of the cycle for the poor responders. So we start with the protocol I’ve mentioned to you before, and if we fail, I don’t mean by failing in pregnancy, but if we fail in not getting enough oocytes to produce enough embryos, enough at least to get to the embryo transfer. So if we fail to get the embryo transfer then we move to the protocol I’ve mentioned to you, we call priming protocol. First, Clomiphene, plus gonadotropins, and then we go for the priming protocol.

Assuming that the lab is working perfectly, to reach the same results you need more frozen oocytes than fresh oocytes, so if in a donation program of your centre, they’re giving you 12 eggs that are frozen or opposite to this, 12 fresh oocytes – you should go for 12 fresh oocytes. What I would like to get are 3 blastocysts to have 3 attempts. Then it is up to the centre to provide 3 blastocysts, doesn’t matter if this needs 5,6 or 8 fresh oocytes or 12,15,20 frozen oocytes, actually that is not your problem. What you want as a patient that is waiting to receive an embryo, to have the possibility to get a full-time pregnancy is a blastocyst. Since you need egg donation, you should not be worried about the number of oocytes, it is up to the centre to find the great donor whereas the best vitrification program of oocytes, they want to save oocytes to reach to 1,2,3 blastocysts.

My opinion possibly can clash with other opinions of other colleagues. In 2021, next year it will be 40 years that I am doing IVF and related techniques, having started in Australia. I’m saying this because, along this almost 40 years, I went through plenty of frustration, plenty of excitement, every time that the new drug was coming out, every time a new technique was coming out, every time a new instrument was coming out, and I always heard by the deep of my heart and also by my colleagues that it would be the real solution for all the patients. We are now coming back to the concept of personalized medicine. The basket of infertile patients is plenty of completely different individuals, so we cannot expect that one technique, one procedure, and one drug, one instrument would solve the problem for everybody. So when we are talking about PRP or stem cells, we need desperately to look into those small categories of patients that could benefit from it. Furthermore, once we have identified these subcategories we desperately need to prove that they are first safe, secondly efficient. Until we don’t take these two pieces of information, I would recommend anybody not to have an opinion on this. We need science first and to reduce the risk to do treatments that are not necessarily helpful to patients, we need first identify those subcategories of individuals that could benefit from this. For instance, not all the poor responders, not all the patients that have an ovarian insufficiency or not all the patients that are older than 40, for sure would benefit from stem cells. If in that ovary there is no substrate, you can inject any stem cell you want, but you will never get anything out of that. Let’s first select the patient that could benefit from it and do proper work, even if with a small trial and then allocate if this technique works to the right group of patients.

Well, the late 30s give you a higher risk of having chromosomal abnormalities including, for instance, trisomy 21. If you think that you were asking me late 20s or early 30s, that would be most appropriate, also because, in many countries including Italy, oocytes cannot be donated by patients over 35, so we have restricted area. What donor would you prefer, 3 eggs donated from a 34-year-old woman who had twins, or 10 eggs from the 28-year-old woman that has never been proved to be fertile. I’m saying this because age, as we have discussed before, is not the only real marker of fertility, and we should always remember this.

It has to be balanced with expenses. If the cost would not exceed 20%, I would go for the fresh one if the cost would exceed 20% I would go for the frozen oocytes. As far, as from those 12 frozen eggs, you get more than 1 blastocysts, and you should get more than 1 blastocyst, the second or the third blastocyst should also be negotiated in terms of price. Be aware that if you need 12 frozen oocytes from a young woman to get only 1 blastocyst, possibly the donor has not been selected carefully. From a young lady, from 12 frozen oocytes, you should expect to have 2 or 3 blastocysts.

A lot of my colleagues would disagree with me, so once again, it’s possible my opinion does not reflect the concept of all the other clinicians. We have a certain number of patients that varies between 3 to5 %, that seems small, actually, it is 1 out of 20 including the couple, 1 out of 30 that have some chromosomal abnormalities, and that could affect the implantation, could affect the results of IVF. The question I ask myself and I ask the patients is always the same. In Italy, at least in Italy, chromosomal analysis costs around 100 EUR, and it lasts forever, I mean it’s like to have the blood group, it will not change in your life, and it lasts forever. I’m not advocating to do all these things to everybody, but I would like to have one dinner less, one new jumperless, but having done this exam before the beginning of all my infertility treatment and the reason is very simple. If after 3, 4, 5 failed IVF attempts or ICSI, somebody suggests me to do a chromosomal analysis, and it turns out that I am one of those 1 in 30, 1 in 50, it doesn’t matter, that has a problem, that has an explanation why it was not successful, I’m going to strangle my clinician, I am going to strangle myself, as those 100 EUR, one blood sample which will be valid all your life.  When you say PCOS is your only infertility reason, it’s wrong, it could be the only fertility reason. How do you know that your husband has not a chromosomal rearrangement or yourself have not a chromosomal rearrangement, maybe a simple piece of chromosome that doesn’t change at all your life, it makes you perfectly sane, but it reduces the quality of your oocytes.