Dr. Geoffrey Sher is back, and we are going to be covering a very important topic: why do you need to do PGT testing if you’re doing IVF or do you? Dr. Sher is the co-founder of Sher Fertility Solutions (SFS) and internationally renowned expert in the field of ART (Assisted Reproductive Technology) and has been influential in the births of over 17,000 IVF babies. Over the last 30 years, he has helped fashion the entire field of ART, and trained under the fathers of IVF, Dr. Patrick Steptoe and Robert Edwards. Dr. Sher established the first private IVF program in the US in 1982.
Dr. Aimee: Dr. Sher, welcome back to the show. Dr. Sher, isn’t there something important that you’ve done related to PGT as well?
Dr. Geoffrey Sher: It’s a pleasure to be with you, Aimee. Until the end of the last century, and even at the first few years of the Century, people were still using a method for testing human embryos known as fluorescence in situ hybridization, or FISH, where you could only isolate certain chromosomes, not all of them. So, we couldn’t use FISH to tell if an embryo had all 46 chromosomes. We could look at the most important ones, but largely those ones which when they were abnormal resulted in miscarriages, losses in that area.
But it wasn’t good enough. So it was that I became very interested in a new technology that evolved for evaluating the presence of all the chromosomes and was a new technology known as Comparative Genomic Hybridization (CGH). What we did is we started to look at embryos, removing a few cells (blastomeres) from the outer layer (trophectoderm) of the blastocyst, and then looking at the chromosomes to see if they were all present.
Around 2005, we published the very first paper that showed beyond a shadow of a doubt that if you were able to fully karyotype the embryo cells, in other words, know that all 46 chromosomes were present, that embryo would have an excellent chance of propagating a viable pregnancy (“competent”). With that, we published the first paper on fully karyotyping of embryos to assess their “competency”.
The preimplantation genetic screening/testing for aneuploidy (PGS/PGT-A) we introduced, rapidly gained traction, and I got a phone call from a geneticist friend of mine in New York who had heard of our work and wanted to come to our clinic and see what we were up to. He came to visit and was impressed enough to ask me if we could share the technology with his team. We did so, and they dispersed it all over the world. Today there is hardly an IVF program in the world that is not doing PGS/PGT-A to assess embryo “competency”.
Recognizing that it is the egg (rather than the sperm) that is the main determinant of embryo “competency” we, in 2005 expanded the initiative to include testing of the egg to see whether determination of “egg competency” (prior to fertilization) would enable us identify the most “competent” eggs for selective banking . We later published our findings in the prestigious journal, RBM-online.
That’s how Clinical PGS/PGT-A came into being and now is viewed as something that should be used in all IVF. But that is probably going too far…I would say!
Dr. Aimee: Why?
Dr. Geoffrey Sher: As a woman gets older the eggs in her ovaries decrease in number as she uses them up. At a certain point when the number of eggs fall below a certain theoretical threshold, she develops diminished ovarian reserve (DOR) which we can assess by doing certain tests on her blood, the most important of which is the measurement of her blood anti-Mullerian hormone (AMH). But separate from DOR, there is another consideration that impacts the woman’s age. As a woman gets older, regardless of her ovarian reserve (how many eggs she has available in her ovaries), the quality of eggs declines with advancing age.
While for women under 35y about 2 out of 3 eggs are likely to be “competent”, thereafter, there is a progressive decline such that by age 40, only about 1 in 5 is likely to be “competent” and by the age of 42, maybe one in 8 or 10 will be normal. By the age of 45, maybe one in 20 is likely to be “competent”. So, over time there is an inevitable decline in both the number of available eggs as well as their “competency”. In other words, the “biological clock” is on the move. Simply stated, nothing known to man can enhance or improve the chromosomal integrity of eggs that have been in the woman’s body all her age. There is however one caveat and that is that if she goes through ovarian stimulation and you don’t establish an optimal hormonal environment in the ovary, this can further compromise the eggs. The protocol for ovarian stimulation therefore needs to be individualized to fit the needs of each patient. In my opinion, there is no place for a “recipe approach” or a “one size fits all” when it comes to selecting and implanting a protocol for ovarian stimulation.
So it is that I believe that women who are young (clinically defined as under 35 years old), who have normal ovarian reserve, has a normal uterus and a fertile partner do not require routine PGs/PGT-A. I reserve that for women that are older, for those where there is an increased likelihood that egg quality could be an issue, where there is DOR and for those with recurrent unexplained IVF failures or Recurrent pregnancy loss (RPL).
Dr. Aimee: There are some people who might have a chromosomal disorder, something that they basically inherited at birth. How do you rule that out before they do IVF?
Dr. Geoffrey Sher: That’s really an important point, which I should have mentioned. There are certain situations where there are chromosomal /genetic abnormalities that we know can be transferred to the offspring. In such cases, we would also do testing. But those aren’t that common.
Clearly, if there’s something genetic that you want to test in an embryo, you would need to look at the gene sequence on the chromosomes of that embryo. But at the same time as doing that, you would also have access to the embryo to do PGS/PGT-A for chromosomal integrity.
Dr. Aimee: If a patient says to you, “Dr. Sher, I don’t want to do PGT, because I don’t want my embryos to be harmed,” how would you reply to that, or how would you address her concerns?
Dr. Geoffrey Sher: I know there are people that will disagree, but based on our extensive experience, if done correctly, PGT will not compromise the embryo.
However, re-biopsying embryos that were frozen in order to belatedly assess their “competency” is another thing altogether. In my opinion, to take an embryo that has been frozen, thaw it for biopsy, refreeze it to have it ready for transfer at a later stage, and then again re-thaw it for transfer to the uterus, is not a wise thing to do. Pregnancies are indeed reported following such practice but, in my mind, this can be traumatic on the embryo and is not a prudent strategy.
Dr. Aimee: Right. Then the biopsy, if not done expertly, could harm an embryo. I’ve seen patients come to me where they had morulae biopsied or early blastocysts biopsied, and my eyes just jump out of my head. You can probably tell I’m a little passionate about this topic. I get so furious. In that type of situation, they could destroy an embryo for somebody. I always say if a doctor is telling you not to do PGT because it might destroy your embryo, you really want to question doing PGT there. I have the same response as you. Here, embryo biopsy is done so expertly that I feel very confident that we are not compromising an embryo, because we really choose our embryos wisely before we even do the biopsy.
Dr. Geoffrey Sher: I agree 100% with you on this. You shouldn’t be biopsying morula, and I don’t believe you should biopsy embryos earlier than that. An embryo deserves the opportunity to get to the expanded blastocyst stage with lots of fluid inside by no later than day six. Trying to do this, seven days after you’ve fertilized the egg, in my opinion, is also a travesty because the pregnancy rate is virtually zero in such cases. You may see an isolated pregnancy, but the truth is that day 7 blastocysts are highly unlikely to propagate live, healthy babies. I recommend discarding such embryos.
Dr. Aimee: I’ve been lucky and fortunate. I think sometimes when your retrieval is after 12:30, for example, and your ICSI is much later, in those types of circumstances, I think.
Dr. Geoffrey Sher: I am sure there are exceptions to the rule, but as a rule, you want to biopsy by day five or six. I agree with you, you need the expertise. Our people have been doing these biopsies for 20 years. Your people are also experts. Our program in New York is still manned by some of the people that did the original research with us that launched PGS/PGT-A, almost 20 years ago.
From my perspective, everything is expertise. It’s not something that you can teach someone from a book, just like you can’t teach someone to be a good IVF doctor by following a recipe in a textbook. You must have done it over and over, made lots of mistakes, learned from them, and been better for them.
Dr. Aimee: Why do you think there is so much criticism about it? Do you think it has to do with how expensive it is? What do you think the issues are related to why it’s so controversial?
Dr. Geoffrey Sher: First of all, I believe that there is a large group of women that don’t need PGS/PGT-A and that by subjecting them to the process, is exploitatory.
But why is it controversial? I think it’s because many doctors go to their patients and say, “We did PGS/PGT-A, it was a beautiful blastocyst, it was normal, but you didn’t get pregnant” so it could not have been my fault.”There has to have been something wrong with the PGT process in the laboratory”. This ignores the reality, namely that there are many other factors that are unrelated to the embryo that can also impact outcome, profoundly.
Take the embryo transfer (ET) process as an example. ET is a very precise and delicate procedure. You can’t teach proficient embryo transfer from a book or a lecture. It takes experience, seasoning and acceptance that you will learn through mistakes. do. A way to learn is through doing many intrauterine insemination procedures, where precision is far less important. I have trained many doctors to do ET’s proficiently by schooling them through performance of intrauterine inseminations. In this way, they get familiar with passing a catheter and tracking its passage through the cervical canal, into the uterus, using ultrasound.
Dr. Aimee: We could have a whole interview just about this, but quick. What do you tell patients about their mosaic embryos or the possibility that their abnormals could really be normal when they share those concerns with you?
Dr. Geoffrey Sher: Let me tell you how mosaicism was born. We had a procedure we were offering our patients, which I still offer, called “Hindsight PGS/PGT-A”. Patients would come for IVF, they didn’t want to spend the money on PGS/PGT-A, but they wanted to know that if pregnancy did not eventuate or if they conceived but later lost the pregnancy, whether the embryo had been chromosomally defective.
So, with “Hindsight PGS/PGT-A”, we biopsy the embryo, freeze the cells, and hold it in storage. We go ahead and transfer fresh embryos to the uterus in the same cycle. If the woman doesn’t get pregnant or she gets pregnant and loses it, or if for any reason once she’s pregnant she wants reassurance that the transferred embryo was a normal one, could she request that we test the frozen DNA from the transferred embryo(s)? We would then send the specimen to the genetics laboratory for testing, and they will get the answer they seek.
Doing this in many patients, we were able to define a group of patients who had babies that were healthy and normal, but when we looked back at the “Hindsight PGS/PGT-A results we found that in many cases, despite an abnormal result the women gave birth to normal babies.
Aimee: Do you mean the cells were mosaic when you looked back?
Dr. Geoffrey Sher: No. We said to ourselves if it was abnormal before, but the baby was born normal. It was either that or the test was faulty or there had to have been a conversion to a normal embryo, in the uterus. I’ve seen probably close to 20 women who have given birth to healthy babies with abnormal embryos. That’s how the term mosaicism came up, patchwork. It’s a real entity.
The women that I would say should be given the opportunity of using embryos that are chromosomally abnormal are younger women with single or at the most two aneuploid chromosomes.
Dr. Aimee: I find it extremely frustrating. That’s why it’s so important for us to talk about this over and over. Doctors aren’t making those calls to patients about their genetic reports anymore because everyone is just so busy. Patients are just getting a phone call, they’re being told your embryos are abnormal, click, the embryos are getting discarded, and there’s no follow up. Patients aren’t getting their actual reports.
If you’re listening to Geoff and I talking today, you’re obviously interested in PGT, or you’ve already gone through it. It is so important for you to get your official reports. Do a post-IVF consult with your fertility doctor, with the genetic counselor affiliated with the genetic testing company. Your embryos deserve that. They deserve a chance. If there is a chance for them to be a viable embryo, find that out before they’re discarded. You don’t want to find out after the fact that you could have discarded a perfectly healthy embryo that was mosaic and could have turned into a healthy blast for you.
It’s so important. I know what you and I are saying, we’re probably about five years ahead of folks. Other people will finally be catching on, but I know there’s a movement for transparency for fertility clinics to share with their patients upfront what their reporting practices are for mosaicism and what their transfer practices are ahead of time, but it’s still not happening yet. I’m so glad that you talked about this today.
Dr. Geoffrey Sher: You and I are absolutely on the same page. I have a consultation with every one of my patients once the results come in to discuss the meaning of it. When I go through the consultation and recommend PGS/PGT-A, we have this conversation as well. It’s back to the old concept, “you can teach people to give care, you can’t teach people to care”. If you don’t care, you shouldn’t be doing what we do because your patients deserve better than that.
Dr. Aimee: So true. Geoff, thank you again for coming back on. I would love to talk to you more and have you come on again. I want to talk about endometriosis. I’d love to talk to you about OHSS and how you approach that diagnosis. Will you do that another time?
Dr. Geoffrey Sher: I’d be more than happy to. I love talking to you.
Dr. Aimee: Thank you. Can you just share with our listeners where they can find you should they want to do a consult with you?
Dr. Geoffrey Sher: The way to reach me for an online consultation is to contact my assistant Patty Converse, 702-533-2691, or email her at [email protected], and have her set you up with an online consultation with me. We’ll go over all your records and discuss your case. I generate a report which you can do with what you wish. I will do that for you and be more than happy to talk to you.
Dr. Aimee: Wonderful. Thank you, Geoff. Thank you for being so generous with your time. Thank you for just being such a light out there for all of us. I must tell you, my patients who are coming in and they’ve listened to your podcast, the feedback has just been so tremendous. The things that you say really resonate with them and they really feel heard. I know if my patients are saying that you can imagine that listeners all over the world feel the same way. Thank you again.
Dr. Geoffrey Sher: I appreciate that.
Dr. Aimee: Of course. Have a great day. We’ll see you soon. Bye.
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