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Interview with Prof Dr Fady Sharara by Dr Jacques Cohen at COGI Amsterdam 2016

Dr Fady Sharara -HD 1080p

Q. Hello. We are here at the COGI meeting in Amsterdam. We are here with Dr Fady Sharara from Western Virginia, which is near Washington DC. Dr Sharara is of course a well-known IVF specialist, runs probably one of the best clinics in the country. Looking at SART data, it has always been my opinion it is the top-five clinics, maybe the top three; hard to tell at some point when you look at the data, but really up there, a very meticulous clinician and scientist. He just presented at the COGI meeting about a topic that is important for all of us, about how to avoid multiple pregnancies. What are the insights from a fertility specialist? Fady, tell us, what are your conclusions?
A. Thank you, Jacques, for your introduction. We definitely create more multiples than we should. The basic message is we have to push much more towards single embryo transfer for the vast majority of patients. It is the right thing to do; we are not meant to carry litters – one at a time. Anyone who has had children will tell you that one is a lot of work, two at a time is pretty hard, beyond that it is insane.

Q. Personal experience, yes?
A. Exactly. I have rarely had a patient who had twins come back to ask for twins, they all want to say “Please, make sure that it is not a twin”. They don’t listen the first time when they listen. They don’t; they think twins are fun, they think “Two for the price of one”, they are paying out of pocket, they don’t want to deal with it, it is like instant families be done. The price to pay, obviously they don’t think about, other than the financial and the physical, the emotional tolls that a multiple pregnancy takes and many marriages just don’t survive this. This is a lot of work and, unlike other countries where there are extended families that can help, in the US or in Europe you are basically the husband and wife or the two partners and it is a lot of work.

The other thing they just don’t think about the financial implications down the road –going to school at the same time and then to university at the same time, so it is a major hurdle and that is assuming they get children that are normal. Obviously multiple pregnancies are associated with significant morbidities and eventually mortalities, but morbidities for the mothers and for the babies, like hypertension, diabetes, early delivery – very early delivery, and those kids can be born with cerebral palsy or eye issues or multiple other organ damage. We want to try to eliminate this and just go, shoot for the one. Any sane person will tell you the outcome should be a single pregnancy at a time, even IVF pregnancies by themselves, even singletons, have a higher problems compared to spontaneous pregnancies, so we don’t want to add insult to injury by having this.

Clearly the message, and most of the higher order multiples are because of us and that has to do with putting multiple embryos when you are trying to do this. In my opinion, there is no reason at this point why you should not transfer a single embryo for the vast majority.

Q. What do you tell your patients now? I know you are in the North East of America and there the statements you have made, observations, are right, the patients come and ask for twins. How do you respond now?
A. I did this as a prospective study, tried to convince people to go with one by removing the financial issues, so giving them free medications and free storage and free freezing for the embryos, to convince them to go with a single embryo, and 30% refused. They want their twins. – They refuse, not because the pregnancy rate was –the pregnancy rate was identical; what differs is the incidence of twin pregnancies. 30% on the people that refused and 1.5% we had one baby.

Q. This must be unheard of in Europe?
A. Of course; this is the Transatlantic divide; in Europe it is socialite medicine; the mean age is about four years younger in Europe than it is in the US and they come in and, if their IVF cycle fails, they don’t throw themselves off the roof of the building; they come back and say “When can I start again?” versus in the US, other than the 15 States out of 50 that have mandates, they have to get the money to pay for this, and IVF is very expensive as you know, in the US, the cost of IVF, the cost of drugs, so this is what complicates the issue. Now, with the introduction of PGS that has really allowed us to test embryos, get a single euploid embryo and transfer one at a time. Over the past three years I have seen the uptake in PGS increase from about 15% to over 50%. Patients are now coming in to ask for PGS to say “I don’t want to get pregnant and miscarry”; other than the traumatic event that a miscarriage is, they lose about three to six months in the process before they come back to do another cycle. I know there is a big Transatlantic divide between the US and Europe in attitudes towards PGS, but in the US, it has already taken off and I think that is going to reverse.

Q. You think our European colleagues are going to follow that, or are they going to maintain their criticism of PGS in particular?
A. I think ultimately they will. I think maybe potentially it is a healthy debate to have until in the US we have enough evidence to show that this method really works. Until we make sure that we are not throwing away embryos that potentially are normal; this is the biggest issue that Europeans have a hard time with.

Q. We over-call in PGS, because we have to.
A. Absolutely.

Q. If you don’t you are in more trouble. You would want to find a basis that you are exactly right, that doesn’t happen in any test, so yes.
A. It is how you define mosaicism; that is your call rate.

Q. Exactly, that is the middle group becoming more interesting now, because we find out all these small differences that tell you that maybe this embryo should go before another embryo, but what do you do with the clear aneuploidies? Are you suggesting in IVF, when you don’t do PGS, you transfer those?
A. If you don’t do PGS you are putting them in.

Q. Now you have the diagnosis; the diagnosis is not 100%; I think it is around 97/98%. Norbert Gleicher thinks it is more like 50% or less. His data in the Vitaly Kushnir study that was recently published, and it is a nice paper, it is a small dataset, but how do you deal with that? Should we freeze aneuploidy embryos and retest those?
A. Excellent question. Now with NGS this is what we are doing anyway. We are biopsying and we are freezing and we get the result a few days later then we sit with the patient and say “This is what we have”. As long as they have at least one euploid embryo, this discussion doesn’t really materialise as much. It is the aneuploid embryos. If you get one with multiple aneuploidies, no-one asks about this – the ones which the question comes in, if there is mosaicism or we get the segmented aneuploidies, a lot of people don’t even know what that means. We have the patient call the genetic counsellors, they talk to them and they decide at that point. If they have a euploid embryo that goes first. If there is nothing and there is a mosaic embryo, and patients cannot afford to do another cycle, with proper consent, I think it is worth transferring these embryos because they have led to live births. Significantly lower chance – a higher chance of a miscarriage, but these potentially, if that is the only thing you have, you give it a shot.

Q. The segmental aneuploid you push towards the back of your choices.
A. Absolutely.

Q. Whereas the more gentle mosaicism you keep at the front.
A. Correct.

Q. Mosaicism is part of what we know; it is common in the trophoblast.
A. Sure, that is how an embryo corrects.

Q. Right. There is some functionality to it probably. Dead haploid cells by these assays are usually not picked up and GS doesn’t see that dead haploid and we think it is very common. It is just becoming more interesting I think.
A. The technology is improving significantly. Now with NGS we don’t know what four or five years from now we may get a method even better than what we have right now.

Q. Aren’t you afraid with NGS that you know too much?
A. That is an excellent question. What we are doing right now I think is a big experiment. We are collecting all this data and we have this data that we would have to see, as we collect more data, what this means in terms of live births down the road. This is a huge experiment in progress and this is what the Europeans are very uncomfortable about that we are basically throwing away potentially normal embryos or transferring embryos that are called normal and they could be abnormal. However, the miscarriage rate is significantly lower when you do PGS afterwards.

Q. But that doesn’t exclude the possibility that you get risk still as well, discarding embryos you can call non-viable that are viable as normal. That is the issue.
A. That is the problem with the method itself.

Q. Okay, and we need to look for solutions. One question, a final question I have is you have done all this, what is the ratio of number of embryos you transfer across the board now?
A. One for the vast majority. Every now and then we have patients that come in and they insist on getting two. Any patient that asks for more than one I give them a 22-page brochure that deals with the problems of multiple births. I tell them “I will not do your transfer until you have read this, and if you still insist on getting two, then you consented for this and I am not going to babysit”. I tell them this. 85 to 90% go with a single embryo. There are some who still come in and say “I still want my twins”, again, based on the study that I did. Even with PGS, however, that decreased from about 30% to about 10/15%.

Q. Your counselling of these patients must have changed over the years. Are you now pretty confident?
A. Yes. 

Q. You are not worried? Because I see a lot of doctors being worried, nurses being worried talking patients out of transferring three or two embryos. It is a crazy thing to do.
A. The quantum shift we did a few years back, we were introducing embryo transfer back in 2004, so we are very comfortable in transferring single embryos. PGS has made us even more comfortable and it has made the patient more comfortable with it. Before you were putting two blind embryos, you didn’t know how many. Even in younger age groups, up to 40% could be aneuploid, so now when you are putting one they feel much better. Even before I used to ask patients “What is the worst call you can get? ‘Sorry you are not pregnant’, or ‘Congratulations but we may be dealing with twins’.” It is amazing how many now are saying “The twins one would worry me much more”. This never used to happen two/three years ago. There is something that has changed, at least in big, urban cities. Rural cites, they come in much younger, it is a different story, but now they are more comfortable with a single embryo story.

Q. It is progress. It is wonderful to hear how you have developed this in your own clinic. Having brochures ready for the question is just amazing. Thank you very much; I enjoyed talking to you.
A. It’s a pleasure.

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