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Interview with Professor Zion Ben-Rafael by Dr Jacques Cohen at COGI Amsterdam 2016
Q. Hello. I am here with Professor Zion Ben Rafael from Israel, who is the founder of COGI and the main organiser. He always puts a fantastic programme together. This is the 24th.
A. It is.
Q. This includes the Asian meetings, the American meetings, so it is two a year, right? About two a year?
A. No. It is one a year but, from time-to-time, we do an extra one in Asia, Australia, so basically we do it every year in Europe, but there is another one that runs sometimes every year, sometimes skips a year in Asa – in China, in other parts.
Q. It is the largest meeting organised outside the professional societies, ASHA, etc., that is what I think.
A. You are right.
Q. I am only calling out the infertility ones because those are the meetings I go to; no doubt it is usually thousands of people and very dedicated. There are a few parallel sessions, but you can find your way.
A. Exactly; easily.
Q. What always strikes me is you have the latest speakers on the latest subjects; it is always ground-breaking. I don’t know what I am doing here, but I guess I am here for the interviews.
A. It is reminiscent of times that you are a great researcher!
Q. When is your next meeting and where is it?
A. It is in Vienna next year at the end of November, November 30.
Q. You are also a speaker here?
A. I do; I speak from time-to-time. This time I speak on the treatment of poor responders or poor ovarian reserve, whatever you want to call it, which remains a big problem for now, 20 years, without any solution really.
Q. Yes, it’s 30 years.
A. 30 years.
Q. Any progress, because it is so frustrating?
A. In poor ovarian reserve?
A. I think the real progress is our understanding that, first of all, there is a range of responses in women. There are women who are 25, have a great number of follicles, so they will have a great number of follicles at 35 and maybe even after 40, but there is a group of women that are not small, the range gets 20 times less, so there are women at 25 who have barely the number of follicles that the women who have a good number of follicles have at 45. The range is likely to go between 10,000 and 500,000, but this is a huge range. These women at 25 are probably going to lose the possibility to get pregnant before 35. All women are treated equally. If you go in all the major cities, women do not get married before 30. Some of them it is already too late. For some of them it is going to be too late for the second and third baby. We need to be very aware of that and my conclusion, my take home message from all this, is not the treatment itself, it is that you have to consult them, to tell a woman like that who doesn’t have a good response “Listen, if you want more than one child you should come back very quickly. You should just return to treatment, do not wait three/four” – you know, sometimes they wait until the child is three years old/four years old and so this is for one. Second, recently there was a good study from the US that looked at women treated with two cycles on clomiphene citrate, on induction of ovulation and IVF and it found very clearly that the cumulative pregnancy rate is higher in two successive IVF. The conclusion for women at 39 and on, or even 38 and on, go directly to IVF, don’t mess around with other treatment. Don’t go to the usual old special protocol –clomid, IUI, I don’t know. Some countries, not in US, it is private, but in some countries the HMO would not let you until you exhausted all these avenues, but then you lose time. Your only resource at that age, for all women, is time. In order not to lose time, you have to go to the fasted track. The fastest track is IVF. Its cycles give you more than anything if it is IUI, clomid, any other tricks.
Q. That is important.
A. Yes. At 39, just jump direct to IVF. If you don’t want to cause a delay, 39, 40, 38, 41, just go directly to IVF, don’t do anything else.
Q. Is that approach applicable in your practice in Israel, in the Middle East? Is the philosophy the same in Europe? Is the philosophy the same in the States?
A. I think that people did not get to this message – all doctors did not get still to that message, because we have this old style, old fashioned medical view that you have to exhaust other things.
Q. Simple options.
A. Not only that, there are doctors who do not do IVF, so they start to treat the patient, they exhaust all avenues, then they send them to IVF, so they lose time for the patient. The patient has to know that, if she is 39 or over, direct IVF would serve her best.
Q. You need to get that message out there; it is not just the patient that comes across in your practice and the practice of your colleagues. That message is not well-known.
A. I do agree, but most of the people that you meet here in our congress are opinion leaders in their own countries, so when they hear something they just take it over and the next thing they propagate the message in their own talks to their own doctors, to their own countries, but I think it will take years. As you know, many things were introduced and then it took years to make them common knowledge or common sense. This is the main message: send them direct to IVF as early as possible and if they want more children just come back immediately. You deliver, you breast feed for two/three months, that’s it – finish, come back. Otherwise you will not have the chance; you are losing your chances, and we do not have any good test – forget about to buy a reserve test, forget about this; the only test is how you perform with your eggs in a specific centre and so on. You cannot tell a patient “You have a good reserve” yet, they are good today; they might not be good in a year/two years from now.
Q. There are tests.
A. But they are not good enough. They cannot tell you what is going to happen. They can tell you what is your status now. What is your status now? I would know immediately if I stimulate this patient. If I find the right stimulation –
Q. Then you know.
A. Right. Also for doctors many times some doctors think, this is another message that is hidden in my slides there, but I bring it over. We wrote already in the ‘80s when we knew each other, you know all the field was very young, we already wrote at that time for Philadelphia that high doses of FSH do not serve patients who respond to lower doses, so just use the lowest dose possible. Now what happens is with low responders you need a higher dose, but people just go higher and higher; some people use 600/900; it doesn’t serve. Above 300/375 it is the same. The only thing that happens is there is a variability month-to-month, a variability between the same patient; every month you might have a different number of follicles ready to respond. I compare it to a train with cars and every car has some load of follicles, so whatever your chances on that specific month is the number that you can recruit. In a successive month you might recruit a double number, but that is by chance, unless you want to do ovarian reserve tests for a specific month and what are you going to lose month after month to search for the best month? The idea here is that variability is much more important than the doctor or the amount of FSH and, if you can use the lowest amount of FSH possible, just go and do that. The dose, the lower dose of that patient – I am not saying which is the dose, because for every patient they have a specific dose. If she responds to 375, drop down to 300.
Q. What about the introduction of freezing and vitrification with such high survival rates; would you just go at a very low dose and maybe even clomiphene and just freeze everything and when you are ready – is that an approach at all for patients like this?
Q. One embryo at a time?
A. In an ideal world, where money is not counted, I would tell an older age patient or a patient with low ovarian reserve “Just come month after month, or one of successive cycles and just collect as many eggs as you can, as you know very well, only one out of 20 eggs, or maybe 25 eggs will create a take-home baby. Just freeze as many as you can and then now we can settle and treat you with the eggs frozen away.” But we are not in an ideal world and you cannot just put all these eggs behind because if she gets pregnant you say “What do I do with all these eggs that I have frozen away?” There was a trial to go on freezing successive cycles or just doing one cycle to a patient and seeing if freezing under two cycles compared to a group – this was done by ?Como, but when you look at the results you see that the results were not better; it is like comparing two cycles to one cycle because she had better results in those frozen, but those that are not frozen that went onto one cycle had a lot of cancelation and no embryo transfer and so on. When you really make the comparison with one cycle and two cycles, maybe the variability played around more in those that went to two cycles, that is why they had a little bit higher pregnancy. I don’t think that freezing, per se, is the idea. Maybe if, one day, somebody will prove that freezing all, the idea to freeze all and then transfer afterwards is much better than putting fresh embryos in the first go in the womb because the endometrium is faulty and so on and so forth. That would be something else.
Q. Some trials, small trials, have been done like that. I was involved in a trial in Oregon that was presented at the ASRM this year, which similarly involved PGS in both arms, control, fresh transfer and vitrification and then transfer later in a monitored cycle. It was a slight improvement.
A. Yes, but the problem with more cycles is that, after 30 years in the profession, you tend not to take them seriously. It is nice, okay, it is a good discussion, let’s talk about it, but give me the large numbers. I would like to see the large numbers to believe it.
Q. This was not a small trial, but it was not 1,000 or 800 or 600.
A. The number should be substantial to show difference.
Q. I agree. The difficulty with a lot of small trials is you have to do a special analysis and then you can manipulate that too, that process.
A. Remember that the definition in the past was very heterogeneous. In that congress that you mention in Jerusalem that was in ’89, I spoke about low responders already, then, and I said the degree of the incidence is 9 to 24%, because it depends what kind of definition you take. If you take a very strict definition like this, like they did now with the Bologna criteria of three eggs and two cycles and so on, then your group gets very small so you cannot accumulate enough numbers in one cycle.
Q. No, you couldn’t do it.
A. It is very fishy. I think it will remain in the part of the art of medicine rather than things that are proven, well accepted and so on. Each one will have to find its way and, like I say, luck also goes on your side because if you missed one cycle maybe the next one will be – the variability will make it for you.
Q. To do a large trial is still difficult, because it has to be a major, multicentre trial. People would have to be very patient.
A. When you do multicentre it has its downsides because each one does whatever it thinks is important and then the support is important and then the selection criteria. There are fields in medicine that will not lend themselves easily to randomised controlled large studies and so on and so forth, and there will always be within the realms of selection by the doctor or selection by the patient or discussion between both sides and a decision what to do, but a doctor has to be equipped with the possibilities. You have to have all kinds of possibilities, let’s say, in his working tools and then you can offer to the patient together and decide what is best for her.
Q. Thank, you very much.
A. I thank you.
Q. Great talking to you as always.