This is a great interview with Dr. Havelock, from the Pacific Centre for Reproductive Medicine in Burnaby BC Canada. We dive deep into fertility and aging, IVF, the role of PGS (preimplantation genetic screening), and ovarian reserve testing.
Dr. Jon Havelock
MD, FRCSC, FACOG
Board Certified, Reproductive Endocrinology and Infertility
11 years as co-director, Pacific Centre for Reproductive Medicine
Spence: Hello, everyone! Welcome to the Conception Channel podcast brought to you by the Being Fertile Program and Yinstill Reproductive Wellness. I’m your host, Spence Pentland, and today, I’m very excited to speak with our special guest, Dr. John Havelock. He’s here to help us better understand fertility and aging as a whole. We were just talking before we hit record here tonight that we’ll get into the role of PGS and IVF and Ovarian Reserve Testing, and some of the common questions that come with aging infertility. Jon is a board-certified reproductive endocrinologist and specialist in infertility that in late terms is an IVF physician, and he’s spent the last 11 years as a Co-director and Founder of the Pacific Center of Reproductive Medicine in Vancouver, more accurately Burnaby, British Columbia. Jon, I wish I knew what all the letters were behind your name, and I’m going to get you to maybe introduce a bit more of your story, because I know you are a lot more involved in things than this. Welcome to the show.
Jon: Thank you very much. I’ll give you a little bit of background about myself, Spence, a lot of it you already know, but for your audience. Both of us fortunately have the pleasure of being from friendly Manitoba, I grew up just outside of Winnipeg. I did my med school and undergrad training at University of Manitoba, then moved to Edmonton, Alberta at the University of Alberta for five years, did my specialty training in Obstetrics and Gynecology, and then finally did my subspecialty training down the United States in Dallas, Texas at the University of Texas Southwestern. And after finishing there in 2006, decided to come back to Canada, somewhere, a little bit warmer, like yourself in Winnipeg, and moved to the west coast, and I’ve been in Vancouver for almost 12 years now practicing at PCRM.
Spence: Awesome. Jon and I have become friends over the years, and it’s been a great relationship. To have someone like Jon as a resource, thanks for coming on the show, I just think there’s so much that we sit and chat about, and partly, why maybe I started this podcast is to get some of the conversations that I am fortunate enough to have with world
leaders in the reproductive health field and discover the stories and the psychology and everything that has led to your success and as a physician and PCRM. And just to be able to pull some of the pearls and wisdom and knowledge that you have that so many women out, they are just even considering IVF or it just floating past their radar or having even been through a few cycles, will really benefit from. I’m excited. Let’s dive in. When I asked Jon what he wanted to speak about, he said it was fertility and aging, and that’s primarily what I would see at my clinic as well. So, I would love for you to just give an overview of why that was something that you wanted to talk about today.
Jon: Yeah, and with respect to fertility and aging, I’ll talk about essentially the fertility aspect of the reproductive effects of aging or less so than the obstetrical effects. One of the reason I think it’s worthwhile to speak about is over the past 40 years or so, we see in most developed countries, and definitely in Canada, a trend towards women having their first child at a younger age, so that the average age of mother for the first child was in the early twenties in the 1970s. And now we’re up to close to around 29 years of age for a first mother. And then if you look at British Columbia, it tends to be the province where women delay having children the longest compared to the rest of Canada. And there’s a number of theories why that may be, a lot of it probably has to do with cost of living, delaying for education, being in the workplace, a lot of these things obviously result in delayed or deferred childbearing, and is resulted in increase age for first-time mothers and all mothers in Canada. It is more difficult to get pregnant as you get older, and that’s why we’re seeing more and more couples presenting for infertility when there doesn’t seem to be any other cause other than we assume there’s probably an age-related component.
Spence: I had no idea about British Columbia or that statistic from 40 years ago to today. And that socio-economic, it’s got to be primarily just due to the pressures of life, the financial aspect.
Jon: Absolutely. Really, the big reproductive demographic changes that have occurred even since probably the baby boomer era, if you go back 150 years ago, people would
have an average six or seven children, there was high childhood mortality, neonatal mortality. But there were very large families, there was no contraception, and our countries were really developing countries. Now, as countries become developed and they get access to contraception, typically, that brings the birth rate down, but we had a replacement birth rate in Canada probably until the early 1970s, and it was really around then where, again, you see the demographic shift where people are having their children later and we’re also having fewer children. The fertility rate is around 1.6, where you need a little over 2 to really balance out your population. You don’t see a declining population in Canada at this point in time because that group from the forties, they are still, you know, like you and me. I’m not going to say middle aged but in our forties, and if you haven’t seen that demographic age, most of us are still alive, and you won’t see really declining fertility or declining population in Canada probably until later this century. Again, the other balancing act for Canada, which makes it a wonderful country is a very liberal immigration policy, and so these are some of the things that have really allowed us to maintain our population. But it is definitely very interesting with respect to the changing demographics, where people are having their families later, and are just having fewer children.
Spence: Well, and women may be stepping into or focusing on career more so today than in the past, and just delaying prioritizing finding a partner.
Spence: Or a husband or whoever.
Jon: And just further to that, we can probably expand this a little bit later going a little bit off-topic, with career and education sometimes resulting in people delaying having children. A question I often get asked by people who don’t have children and want to delay is, how long can I wait. And that’s a question I can never really answer. I can give you a little bit in the way of probabilities, but I can never tell anyone, oh, you’re going to be fertile today, and I know three years from now you won’t. You don’t know anybody’s
fertility until they try to conceive. There are some things now that you can do to potentially preserve your fertility, so things like egg freezing is something, at least for women who experience an age-related declining fertility, unlike men who don’t experience nearly the decline. People can look at things like egg freezing, but even egg freezing, I tell people, it’s not the Holy Grail, it’s an insurance policy that doesn’t always pay off, and there’s a cost associated with it. But again, with the technology of egg freezing, it does provide individuals with some options, but when people are asking, can I get pregnant now, I say really there’s nothing better than the true gold standard test that is, you just got to try.
Spence: Right. Can you explain a little bit of why the egg freezing isn’t a Holy Grail?
Jon: There’s a couple issues, and again, with respect to aging, which we always talk about with female-related aging, there’s an age-related decline in both a quantity and quality. Quality probably being the most important factor, and that’s purely related to age. There’s a number of factors, the big issue is the eggs don’t sort their genetic material as well, so they may be missing chromosomes or have extra chromosomes. And that happens with a lot greater frequency as women get into the late thirties, early forties. And also quantity, when you try to stimulate their ovaries for an IVF cycle or an egg freezing cycle, they tend not to make as many as they get older. So, the chance of having an offspring from eggs that have been frozen really depends on the age of when you froze them and how many, at least from some date out of span. If you get 15 or more eggs in your 35 years of age or under, you got about an 85% chance of having a child from those eggs in the future. If you’re 36 and above, you’re looking late thirties to maybe 40 at most, and you have 11 or more, you might be looking more like half, a little over 40%. So, it’s really a quality and quantity issue. The quality – age by far being the base factor.
Spence: So, age is, just bottom line, the biggest factor when a woman or a couple is trying to conceive. What happens physiologically, can you kind of give a rundown of what occurs in the body to cause that?
Jon: Well, quantity-wise is pretty simple. Unlike men, where sperm can be reproduced from basically the spermatogonium, essentially, a renewable population that never really gets exhausted. Eggs are a little bit different, woman, how many eggs she’s born with, that’s all she’s going to have, and each month one of those grows into a mature follicle and ovulates, and if conception doesn’t occur, it dies off. But really, there’s a cohort or group of eggs that die every month. You only see the dominant follicle, but there’s a group that dies. At birth, you’re looking at maybe having one million, at puberty maybe 500,000 and then, by the time you get to menopause maybe you’re looking the order of a thousand or so. That quantity, it’s just a function of declining numbers. And having a non-renewable pool with respect to quality, the issue becomes, for some reasons, and there are some theories why this occurs that the eggs as they get older instead of producing an egg with 23 chromosomes and the sperm having 23 to result in the normal conception with 46 chromosomes, there’ll be 22 or 25 chromosomes. It’s thought that some of the molecules that help keep the chromatid pairs together, chromosomes are in pairs, chromatid pairs, and typically, they should split off, and one goes into the oocyte and the other one goes into the polar body. It’s essentially the genetic garbage. There are these molecules called ‘cohesions’ that hold these chromatids together, and it seems with aging, both the quantity and the function of cohesin molecules diminishes. Because of that, they may separate early and not sort themselves properly, and so you either have an extra one in the oocyte or you’re missing one because of that. That’s what the theory is. What we do know definitely from the PGS or the chromosome screening data is that there definitely is a higher prevalence of chromosomal abnormalities in the egg with age. And by age of 44, you’re looking above 90% of the embryos are going to be chromosomally abnormal.
Spence: You slip PGS in there, I want to get you to clarify what that is. From my understanding, that’s testing on the embryos that is done primarily during an IVF after some embryos that have developed are frozen, and it helps with understanding more about the embryos – can you tell everybody what the different acronyms are? We were talking about that the other night I remember, but just a little bit about it.
Jon: There’s been a number of acronyms, people have called it a Pre-implantation
Genetic Diagnosis, it’s not really diagnosis, more commonly it’s being pre-implantation genetic screening. Another commonly used acronym is being comprehensive chromosomal screening. And then the International Committee on the nomenclature for ART, the acronym is ICMART. They have come up with sort of new acronyms to use this, so I think now what they’re wanting is, if I remember correctly, it’s a PGTA, Pre-implantation Genetic Testing For Aneuploidy. Really, the various acronyms aren’t as important as sort of understanding what they’re trying to do, and what they’re trying to do is test the embryo to make sure that it’s got the normal number of chromosomes and there’s not an extra one or missing one. Because these embryos for the most part aren’t going to result in a normal pregnancy. So, these are embryos typically we would not use for embryo transfer. It’s a molecular genetic technology to try to determine if the embryo is chromosomally normal because we know those ones are more likely to result in an ongoing pregnancy.
Spence: Right. Just take us through an IVF cycle, just an aerial view of it, and how and when that testing fits in.
Jon: When I talk to patients about IVF, IVF is magical, it’s been around for 40 years now. Louise Brown is now 40 years old.
Spence: First IVF baby.
Jon: First IVF baby. People will look at the technology magic and IVF is medical, but it’s really simple what we’re trying to do. Essentially, each month, a woman ovulates one egg, and so they’ve got one chance for conception to occur, and number of things can go wrong where that doesn’t happen. IVF is really trying to combine a year to a year-and-a-half of trying in about a three-week block. An IVF cycle first involves ovarian stimulation, so we’re trying to convert a woman’s ovaries that only make one mature egg per month to making 10, 15, or even if you’re looking at a PGS cycle, Pre-implantation Genetic Screening cycle, you’re trying to make maybe 20 eggs, sometimes even more,
balancing up the risks of ovarian hyperstimulation. Essentially, it involves 10 to 12 days of taking daily injections under the skin using needles similar to how diabetics would give themselves a medication. There’s subcutaneous injections that occur for a week and after to two weeks. And during that period of time, the fertility clinic has to do a number of ultrasounds every two or three days to see how the ovaries are responding, hopefully getting your target ovarian response of 10 to 20 eggs. That’s a stimulation phase. And then what you go onto is the egg retrieval lab phase. Now we need to get those eggs out, and we give a medication that will mature the eggs, cause genetic maturation, and we do an ultrasound where a needle goes into the ovary to essentially suck out the fluid from the follicle. The fluid itself is not important for us, but the egg is in that fluid. So the embryo, I’ll just need to isolate the egg. We take the partner or sperm search, whether it’s donor sperm or partner sperm and the sperm and the egg are combined, and over the next five days, those embryos develop in the lab. Now, what I tell patients is, you don’t get an egg from every follicle, they are not all mature, they don’t all fertilize, and only about 40% of them will develop to embryos.
Jon: 40%. Typically, somebody who is under 35, we may get five, six embryos, somebody’s in their early forties, it might only be one or two. But there’s, again, a wide variability.
Spence: It depends.
Jon: Yeah. That’s an IVF cycle. Now, you’ve really got two options: you can do a fresh embryo transfer and select the embryo based on what it looks like under microscope. And there’s certain appearances of the embryo that will tell us, this one is more likely to implant and result in pregnancy than this one. But it is a technology that has a lot of observer variability, it’s obviously, again, semi-quantitative but still subjective, it may not be the best tool for selecting the embryo. Now that’s where things like PGS come in. And PGS is a tool that with the newer technologies is now being validated to be able to pick
embryos better. It’s not great at picking an embryo that we know is going to result in a viable ongoing pregnancy, but it is very good, not perfect but very good at picking embryos that we know that won’t result in pregnancy. It allows us to get rid of those embryos from that big group that we really probably don’t have a lot of business putting back into the uterus. Maybe saving time and maybe a miscarriage and those types of things. So, it’s really an embryo selection tool to select the bad ones out, you’ve gotten rid of the other ones that you don’t need.
Spence: Or more likely to.
Jon: More likely to. I say it’s very good at picking embryos that won’t result in babies, but not perfect. We do probably discard embryos, not a large number, but a small percent of embryos with this technology that probably would result in a normal healthy baby.
Spence: Right. From my understanding, the egg in the embryo, have some wisdom and brilliance built into them where they can correct some things along the way, mosaicism, whatever that might be.
Jon: Yeah. There’s a couple things. There are two phases of genetic division for the egg and the sperm meiosis, so there’s Meiosis I and Meiosis II, and you can get errors in either, Meiosis I or Meiosis II. And there are some studies that suggest that an egg that kind of messes up, it’s a genetic division of Meiosis I, maybe up to 15% of the time, it self-corrects itself to Meiosis II. So, by testing these, we call them polar bodies, so after Meiosis I, you’ll have the first polar body, and after Meiosis II, you have a second polar body. These are the little basically genetic garbage cans that get rid of the genetic material that isn’t going to make part of the embryo. And by testing those, they’ve found that sometimes these eggs will self-correct themselves. They maybe won’t throw out enough into the garbage can in the first division, so they self-correct and throw the extra garbage out in the second garbage can.
Jon: That would not necessarily result in what we call a ‘mosaic embryo’. That would then potentially still result in a completely normal embryo. Now, there’s this discussion of what’s called mosaicism, where you do the genetic testing. It seems to say the embryo isn’t normal, it doesn’t have 46 chromosomes, it’s not abnormal, it doesn’t have an extra 47 chromosomes. It seems that maybe some of the cell population has 46 and some has 47, so it’s right somewhere, maybe not right in other parts of the embryo. And that’s where the technology is a little bit of a gray area as well with these mosaic embryos, because there is a growing body of evidence to suggest if you transfer mosaic embryo, it still has a very reasonable chance of having normal baby.
Spence: When a woman’s gone through an IVF, and she’s grown her embryo to a day five or six to freeze, to send away for testing, what exactly happens in the lab? I know some cells are taken, so it obviously maybe depends where, or can you explain just simply what happens?
Jon: By day five or day six of the embryo development, the embryo under the microscope is sorted itself out into specific types of embryonic structures. And at this point in time, you can look at the embryo and you can identify something called the Inner Cell Mass, which is what is destined to become the embryo and the fetus eventually, the baby, and the trophectoderm, which is destined to become the placenta. And again, if these all originate from one single cell to zygote that creates the sperm in the egg, and that cell just divides under what’s called mitosis, and divides, divides and divides, well then, every cell in that embryo theoretically should be the same and reflect what the initial fertilized egg was. We don’t biopsy the embryo itself, so we look at taking some cells off the trophectoderm. Around the trophectoderm, there’s something called the ‘zona pellucida’. If you want to think of egg analogies, it’s like the eggshell. And what happens is on day five or day six, typically using a laser, there’s other ways to breach the shell or the zona pellucida, but laser is used to make a hole in the embryo and a few cells from the trophectoderm are then taken off. And by taking more than one cell, again, few cells, you’re more likely to be able to get DNA that you can amplify and identify. So, those
cells are then frozen and transported to a reference genetics diagnostic lab. Meanwhile, the embryo that you just biopsied is frozen and awaiting the results of genetic testing.
Spence: Okay. Now, the question I think most people would have is when you explain that they could do this, because it’s not something that you tell people they have to do, it’s an option within their IVF cycle, and so the obvious question would be should I — there’s a lot of ‘should Is’, I’m sure.
Jon: Yes. That’s a hard question to answer. And the philosophies, with respect to the Pre-implantation Genetic Screening varies from country to country, practitioner to practitioner. I would say that in North American, especially United States, there’s been a lot more uptake in the technology and in liberal use of it compared to say in Europe, and so it depends on who you ask. I am a little bit less of an interventionalist, so I really explain the pros and the cons, and let the patients decide. What I do let them know, in one IVF cycle, however many embryos that woman creates, if it’s one embryo, two embryos, ten embryos, if there is a healthy child in that batch members, there’s a healthy child. This technology will not in any way increase the chance of having a baby from one IVF cycle. What it does do potentially is reduces the number of embryo transfers you may have to undergo, especially if you have a large number of embryos, or may reduce the number of potential failed transfers. Because if you have ten embryos, and let’s say we take someone who’s in their late thirties, and we know an average half of those embryos are going to be abnormal, allows us to get rid of one half, 5-10 embryos. It’s hypothetically very good respond patient here. I always tell patients, you’re not paying for an increased chance of having a successful treatment, you’re really paying for information. So, the pros are, you may have fewer transfers, you get information, and you potentially then are able to identify embryos that you know have extremely low chance of implanting. I find the people who may be affected by a miscarriage, where it’s been a chromosome abnormality, or pregnancy that’s been affected by chromosome abnormality, and that for them has been an adverse or outcome that they did not want to experience. They use this technology. I find other times when patients have done multiple IVF cycles and it hasn’t worked, they want answers from you and you don’t have them. Now what are the
downsides? Well, it adds significant cost to treatment. When you biopsy an embryo, there’s a chance that you might damage the embryo, it’s probably about 1-2% chance of an embryo being damaged when we take a few cells. Now, if you think about these CSI shows, where they’re doing DNA testing from a drop of blood. A drop of blood is a ton of DNA compared to what we’re working with. Sometimes it’s one, two, five cells, so you may not get enough DNA to amplify, and then you may have to decide whether you biopsy the embryo again. Those are some of the downsides. Some other things, even if you identify a completely normal embryo, there’s no 100% chance that that’s going to work. It’s maybe about 60% chance that embryo’s going to work. One of the final things is, unfortunately, there haven’t been a lot of well-designed studies in this technology for some of the things, such as the technology validation, but there is one lab in the United States, they’ve done a real good job of validating technology. And one of the big steps was trying to figure out if the embryo is normal, how likely is it going to result in the baby, and what about if the embryo is abnormal. If you put an abnormal embryo in, identify it as being chromosomal abnormal, what happens? So, this one lab in the U.S, did this. They transferred embryos into a woman’s uterus. They did the biopsy, and this is before the technology had really been proven to work, and so they did the biopsy, they did the genetic testing but they didn’t know what the results were when they put the embryos in. They said, okay, well, we’ll just see what the pregnancy outcome is and then we’ll look at the results. Essentially, what happens, when you transfer the chromosomally normal embryo, I think in that study it was in the high 50s, now success rates have gotten higher, so it was normal pretty good implantation rate. But I think the more interesting part was if you put a chromosomally abnormal embryo back into woman’s uterus with this technology, 4% of the time, it resulted in a normal, healthy, chromosomally normal baby. If you make the assumption to larger numbers that this 4% number holds true in a much larger data set, then one out of every 25 embryos that we biopsy and we say are abnormal, we’re throwing out, and they could have resulted in a live birth. It’s a small number, but we are occasionally probably almost certainly discarding embryos that could result in the pregnancy. So, there are some limitations to technology, it’s not perfect.
Spence: Right. Well, I remember, Jon, it was even earlier in the days, it must have been a couple years ago, you and I were out for a dinner and we were talking about PGS, and it
was really interesting to me. Because I think it maybe was partly due to age, but just more so just coincidentally, that when a woman responds and produces X amount of eggs and resulting in X amount of embryos, which is a fairly low number, two, four, six, I forget what we’re talking about – where is the point where it’s worthwhile doing the PGS, or maybe just transfer because it’s going to tell you the tale that way anyway?
Jon: Exactly. Another hard question to answer. It’s hard to see the right number. You can talk to some infertility specialists who think you should never put an embryo if it hasn’t been biopsied and tested. I think that that’s really getting a bit carried away personally. I mean, I’m more pragmatic, if you’ve got one or two embryos, why not transfer the one or two embryos, because the gold standard of ‘is this a good embryo or not’ is, are you pregnant, do you have a healthy baby from it. And really this technology, again, tells you pretty good about embryos that won’t work, not as well as saying you have this embryo well, but gets rid of the ones that won’t. But, again, the gold standard still is, do you have a healthy baby from technology. So, it’s really hard to say when you should be biopsying and when you shouldn’t. I think as you get older, the chromosome abnormality rates go up significantly. Also as you get older, you tend to make fewer embryos, so if you’re 42 and you’ve got one or two embryos, well, you’ll be pretty sure that there’s probably a 70-80% of chance that those embryos are going to be chromosomally abnormal. So, do you spend several thousand dollars to biopsy those embryos to determine that, and then find out they’re both abnormal and not do an embryo transfer, or do you just transfer them back into the uterus and see what happens. When you think, well, that’s kind of crazy, if there’s 70-80% chance, but these embryos are chromosomally abnormal, you’re going to put a chromosomally abnormal embryo into a uterus and that’s going to result in an ongoing pregnancy that’s maybe chromosomally abnormal. In fact, the matter is, most chromosomally abnormal embryos don’t implant. If they do implant, they may miscarry. But most commonly, they don’t comply. When we think about things like Down syndrome, which is probably most well-known chromosomal abnormality, look at a 42- year old, it’s the chance of you having a Down syndrome, which is an extra chromosome 21, is somewhere between 1 to 2%. It’s still pretty, pretty low. You have to ask yourself, what is it you’re trying to do, and at the end of the day, if you have one or two embryos,
often think that maybe just transferring them and seeing what happens rather than going through the issues with testing.
Spence: And prenatal screening is so vast now. In 10 to 12 weeks now, you can find out a lot about your baby.
Jon: Yeah, and one of the questions patients will ask me, they’ve done IVF, they’ve done the genetic screening of the embryos, well, do I need to do any prenatal screening. I’m not aware of Canada having a specific guideline, the U.S. a couple years ago issued a guideline. They said, if you’re doing a prenatal screening test and it’s normal, don’t do another test except for Pre-implantation Genetic Screening. They still recommend that you do PGS, and it’s normal. You should still either do non-invasive prenatal testing or nuchal translucency or an integrated pregnancy screen, depending on what’s being offered in your jurisdiction. But they do still recommend it. And there is some data out of the United States, suggesting, if you put a chromosomally normal embryo in the uterus, in the chromosomally normal embryo implants and becomes a clinical pregnancy, so you see something on the ultrasound, the chance that that pregnancy, which you were told is chromosomally normal, it’s 1 in 500 chance that it’s not, it’s chromosomally abnormal. So, that is really the rationale, still at least consider or offer some sort of prenatal, not pre-implantation, but prenatal testing on top of what’s already been wanted.
Spence: Right. There’s a lot of factors say it, because where you take this, the cells come off, and so you might have got just a bad little bunch of cells, and that embryo was still okay.
Jon: Especially if you’re talking about, again, the theory behind mosaicism, and let’s say there’s an early mitotic error, and so you’ve got a cell population, some are normal, some are abnormal and biopsy and B5. And you’ve gotten a little batch of normal cells, well, what ends up happening is the abnormal cells basically take over and you’ve gotten abnormal pregnancy. That’s one of the theories. Or, the other possibility is to see, again, the technology is not perfect, and what was thought by DNA amplification and the
mathematical calculations to determine whether it’s anepluoid or not, it just didn’t reach that threshold for whatever reason, and it misidentified an embryo as normal.
Spence: Or the opposite of maybe there still being some sort of corrective technology inside the embryo where it might…
Jon: Go the wrong way.
Spence: Yeah. That’s great. I think that gives everyone a good sense, because it’s crazy, you think you are going into IVF, and you’re going to be told exactly what you need to do. But there are some options still and some decisions you’re going to have to sit with. But that’s great, I thank you for that information, it’s such a new technology for people. And I think like you said, it may be more the Holy Grail in their opinion in their clinic practice than others. So, collecting information, doing your due diligence yourself as well, are there good places for people to do some research, because there’s probably stuff all over the internet?
Jon: Yeah, it is really difficult. I mean, I think part of the concern is if you go to certain websites, especially websites where the companies have a financial commercial interest in the technology, they’re going to maybe call the rationale to do it in a certain way. There’s a bit of a vested interest in doing it. So, you just have to be careful with the commercial websites, there are essentially the best places if you can get access to the medical literature, the American Society for Reproductive Medicine, I’m not sure, their patient information with respect to PGS, but they do often have a lot of patient resources on there. You just definitely want to make sure that the information you’re getting, the people giving it to you, don’t have a self-interest, and there’s some scientific basis behind it.
Spence: And know that it also might have some opinion if it is a practitioner. Ultimately, it is something that you probably have to make a decision, take in all the logic you can and all the information you can and then follow your heart. If no one’s given you a clear,
you should do this.
Jon: Absolutely. Again, my personal approach, I give them the pros and cons, I tell patients if the government was picking up the tab for this technology, I would say them, then, go for it. You still are going to be where there is some benefits, it’s not the Holy Grail. Then I often find patients will be interested in doing it more often if they’ve had multiple failed embryo transfers, or if they’ve had a previous pregnancy affected by chromosomal abnormality. I find that there may be an early uptake for using the technology then.
Spence: Right. I don’t know if it’s still really kind of the messaging that goes out there, but for a while maybe a few years, it seemed that, oh, the PGD or the PGS is good for women that have experienced recurrent pregnancy loss.
Jon: Yes. The scientific rationale for that, it makes perfect sense. A lot of miscarriages are due to chromosomal abnormalities, the majority are, at least half, and so, if you could then test these embryos, then you can potentially avoid that. Now, the issue with respect to recurrent miscarriages, sometimes these patients that are not having any difficulty getting pregnant, they’re just having difficulty staying pregnant. Then you’re taking somebody who has no infertility issues and putting them through IVF and PGD and all the cost associated with that. The PGS studies have concentrated specifically on infertility, couples with infertility. So, at least, a very well-designed sentence. Now, there was a study a couple years ago in the West Coast out of Seattle in San Francisco, where they looked at the recurrent miscarriage population. It’s not a randomized trial, which is sort of the gold standard trials, but it was a trial where they looked at women who had recurrent miscarriage. And they looked at one group that decided, we’re going to do IVF chromosome screening, and they looked at the group that decided, no, we’re just going to keep trying on our own. And they looked over a six month period of time, a reasonable length of time but not a real long period of time, and they wanted to look and see what’s a chance that you’d have a conception that then subsequently resulted in a live birth over the next six months, and time to pregnancy as well. And they found that your chance of
having a baby, healthy live birth in the PGS group was the exact same as the group that just said we’re going to keep trying it on our own for the next six months. The group that just kept trying alone for the next six months didn’t have to spend multiple thousands of dollars on treatment, and the time to pregnancy was no different between the two groups. There was a non-significant difference between the two groups, and if anything, the ‘just trying on our own group’ got pregnant a little bit quicker. Again, we don’t have great studies, it’s all we have, but the biologic plausibility of doing the technology for curb miscarriage makes complete sense. So far, the data doesn’t seem to support it though.
Spence: Okay. Obviously, PGS is something that you decide on when you go through an IVF cycle, and you have embryos that can be biopsied, but is there the testing that happens beforehand like the Antral Follicle Count ultrasounds, the FSH and Estradiol testing, the AMH, Anti-Mullerian Hormone – is that picture that’s painted beforehand, seemingly going to correlate? I know it correlates with age, but is it going to correlate with viable embryos as well?
Jon: The Ovarian Reserve Tests, especially when we talk about delayed childbearing, they involve one of these tests, the Anti-Mullerian Hormone being sort of the newer one in the group, that the lord of this test give me the result, and they’ll say, okay, well, I’ve been trying to get pregnant, but can I wait two years. The Antral Follicle Count essentially is an ultrasound to look at the resting follicles and date, and then the day three is FSH. A blood test, it’s done third day of the period, and if it’s high, that means the ovaries aren’t working as well. None of these are very good tests of your chances spontaneously conceiving, if you haven’t been trying to get pregnant. You order one of these tests, it’s not going to tell you whether you’re going to get pregnant in the next year if you haven’t been trying. The day three FSH, when it gets really high, might predict it a little bit, but they are really good tests. They are very good tests of predicting success of the IVF, none of them are really good predictors of IVF. Day three after FSH might be, ,especially, above twenty, you’ve got a real chance that IVF can work. If you’ve got an AMH level that’s undetectable, it’s going to predict the success rate with IVF because you probably won’t make any or you might make one or two. But if you’ve got moderately
low Antral Follicle Count and moderately low Anti-Mullerian hormone, they’re not great predictors of whether IVF is going to work, not great. A little bit, they do predict how many eggs you make when we stimulate you, and to some degree, eggs do correlate with pregnancy rates, but really once you get above eight to ten eggs, the chance of you getting pregnant in that fresh embryo transfer really doesn’t change, eight to ten, verses 15, versus 20. But, when you get more eggs, it does increase your, what we call, your ‘Cumulative IVF Pregnancy Rate’. So, that’s really talking about your chance of having a baby from the IVF cycle, including the fresh embryo transfer and all the frozen embryos. We’re just looking at that one single embryo transfer as long as your AMH is not really low and your FSH is not really, really high. It’s not a great predictor, and these really just predict how many eggs you’re going to make.
Spence: You touched on it quickly, but what role did they play then in spontaneous or natural conception?
Jon: That’s a good question. AMH doesn’t seem to predict spontaneous pregnancy at all. What Danish group did was interesting, they took a bunch of their women to the infertility clinic, they all ordered their AMHs on, and then they also in that hospital that they work out of, they got approved a research study and they recruited a bunch of female workers at the hospital who’ve recently had a baby. And they said, well, we want to test your AMH levels because you are a big group, you guys have higher AMH levels in our infertility population, and it was no different. With the infertility population, some women have low AMH, some women have average AMH and some have high AMH. And in the fertile population some women had low, some had average, some had high, and it distributed itself out essentially the same. There have been some other similar types of studies, and again, the AMH does not seem to predict chances of conceiving spontaneously.
Spence: I think I remember a number of years ago when the WHO finally updated their semen analysis parameters. To my understanding, you could confirm or correct whatever I’m saying, but the parameters of what normal sperm constituted had never included studies of fertile men. Is that right?
Jon: Well, the most recent semen analysis parameters now are based on fertile people. They took a number of individuals who have had a recent pregnancy and got the semen parameters, and they essentially did calculations of the mean and some deviation, and they basically said, anyone under the fifth percentile, so the people with the lowest parameters, volume, concentration, motility, morphology, the lowest 5%, we will use that as a cutoff, and that’s what we will consider abnormal. But you still got to remember, those 5% of people are the 5% of people who still have babies with no problem. Again, just like having abnormal AMH, and abnormal semen parameter doesn’t necessarily predict fertility. Again, it’s really, really low. But you can have some abnormalities in one parameter, and that just means you might be a little bit low.
Spence: Everyone’s always hoping for that, you using the terminology, that Holy Grail test, give us like a feedback that’s just heavenly and helping determine clinical decision making, etcetera. But it always seems to still come down to collecting as much info as you can than making a decision based on your experience and maybe your colleagues.
Jon: Yeah. A lot of medicine has to do with probabilities. You’ve got this percentage chance of it working, whether we’re talking about infertility, cancer treatment, treat your diabetes, heart attack, usually dealing with probabilities. As we get better, we may be able to refine patients into categories a little bit better, but people always want to know, well, why did I end up in the 60%, whether it be your cancer treatment or your infertility treatment, and this other person ended up in the 40% that didn’t. And then unfortunately, a lot of times, we don’t know, which is difficult. But I always tell people at the end of the day, I can give you probabilities. At the end of the day, we can do the therapy, you need that information for you to make an informed decision. You will not be 60% pregnant or 40% pregnant, or 20% pregnant, whatever your pregnancy rate may amount to, based on your individual parameters, age, ovarian reserve. You’ll be 0% pregnant or 100% pregnant. You just need probability to make a decision and then just kind of move forward.
Spence: Yeah. Just rewinding, you mentioned AMH not really being a predictor of spontaneous or natural pregnancy, but when you put together that with Antral Follicle Count ultrasound and FSH and estrogen levels day three, what is it telling people? Is it giving them an idea of whether they’re basically closer to the end of their reproductive years, or what info can they get from that?
Jon: It does. A really high FSH level is going to be a prognostic value for an IVF cycle, it’s likely to end up in a IVF cycle cancellation, and so you won’t get pregnant because we don’t get to the egg retrieval. Same with the undetectable Anti-Mullerian hormone. If it’s below the lower limit of the assay, so if it’s like under one picomolar, well there’s probably about a 50% chance that that IVF cycle will be canceled and you won’t get the egg retrieval. So, it’s going to have a low prognostic value because you don’t have time to get to an egg retrieval. We know individuals who have low AMH levels and people who don’t respond well to IVF inevitable cycle cancellation, they are going to menopause earlier. But trying to predict that date is impossible. I tell people, you will go to menopause earlier, but I don’t know if that’s going to be next month or five years from now on.
Spence: That’s still a crystal ball.
Jon: When I graduated from medical school, they did not give me the crystal ball.
Spence: Yeah, yeah. But to be clear, there’s actually a psychic fair here today. Anyway, just the irony. But to be clear, the word ‘quality’ would come up then, because, are people mistakenly equating these tests with lower parameters to egg quality?
Jon: That becomes more of a quantity issue as opposed to quality. Quality is pretty much dependent on age. The elevated FSH and the low AMH really reflect quantity. You may not even get an embryo because you don’t get to the egg retrieval. You are going to have fewer embryos to test. But it seems to be predominantly a quantity rather than quality,
and age is really the almost sole predictor of quality.
Spence: Where it would be more likely for someone to achieve their goal naturally than with IVF, and you would be honest about that with the patient in front of you?
Jon: I think, obviously, the younger somebody is and the shorter duration they’ve been trying to conceive, the higher the chance that they’re going to get pregnant on their own. I tell couples, if you look at these spontaneous pregnancy data from populations in Quebec in the 1800s, higher rates in the 1800s, early 1900s, some other populations prior to contraception, prior to relationship breakdowns and in long-term stable relationships, where large families were valued, you would see that the overall infertility rate or the chance of essentially sterility rate where a married couple don’t have any children, it’s maybe 2 to 3%. By the time they get to age 35 though, one in nine women are unable to have a successful ongoing pregnancy. By age 40, it’s one in three. Age 41, it goes to 1 and 2 and then by age 45, it’s almost at 90%. You can see that they decline. It does to some degree also reflect how long you’ve been trying to get pregnant. So, if you look at somebody who’s under age 35, they’ve only been trying to get pregnant for a year, which after a year of trying, 85% of that population will be pregnant. You look at the 15% left over, I tell them between year 1 and year 2 if your fertility test is normal, you got close to 50% chance of getting pregnant even if you just keep trying on your own. The younger population, definitely in the late twenties, early thirties, we encourage typically if all the testing is normal to really wait two years to try to conceive. Once they start getting to late thirties, early forties, you might want to be thinking about treatment after six to twelve months depending on what age range you’re looking at.
Spence: Is it true, just bottom line, I’m not sure if there’s a bumper or two or a dip in this, but the younger you are the greater the chance that IVF will be successful? I know there’s confounding factors, but the younger you are the greater the chance that IVF will be successful for you?
Jon: Yes. Even at age 32 and above, you start to see subtle declines in IVF success rates,
and at 37, 38, it starts to go down quite a bit. By the time you hit age 45, you’re looking at a 2 to 3% chance that IVF is going to work using your own eggs. It’s really under age 32 where you’re going to see the highest success rates.
Spence: Okay. Sometimes when I see younger patients, late twenties, early thirties, unexplained infertility commonly at that age, if they start even thinking about IVF, I’m like, well, if it’s something you want to do, go have your first child through IVF. I can’t guarantee anything but your next one will come on your own, barring any other major blockages. And that’s kind of my messaging to almost anybody. If something’s come on your radar and you’re feeling a pull toward it, regardless of statistic, or, you know, you’re young and you should continue on trying naturally, do what feels right for you because you’re going to have a whole bunch of people telling you what’s right or wrong. All I know for sure, Jon, is that I’ve never met a woman or a couple that has regretted doing IVF when they’re holding a baby.
Jon: Yes, absolutely yes. And for some people, that’s it. Some people don’t want to wait two, three, four years. There are less sort of financially and medically intensive treatments that you can engage in before IVF for a lot of people, which are very good treatments. They don’t have the same success rates, but are often sort of the intermediate rate before you get to IVF, and we often talk about doing those before IVF. But sometimes people say, you know, I’m just for logistics issues and success rates issues, they just say, we want to go to IVF. Because for most people, especially under age of forty, definitely in the twenties and early thirties, there’s no treatment that’s going to really beat that.
Spence: If there’s no financial barriers, over the years now, I’ve been doing this, not as long as you, but almost 15 years now, with this focus on infertility, I’ve seen such a change because everyone knows somebody that’s been through an IVF basically now, I think. And the stigma of it, it’s not a big mystery as to how it works anymore. I love to encourage people to find their route because I practice Chinese medicine, and people come to me expecting, I don’t know what they are expecting actually, they don’t know
probably half the time, but typically people practicing may not necessarily have a balanced perspective of how and what people should be doing. There may be dogmatic beliefs in this medicine or that. And to me it’s, let’s get you to your goal. If you’re open to IVF, that is fantastic, I would love to work with you for a bit and get you healthy, especially if there’s weight issues or whatever it might be beforehand. And then you can go see Jon, and we’ll just hopefully be optimizing your chances of success. I think it comes as a real comfort to people when they come to someone like me, and I’m the one that’s encouraging them to keep doors open, like IVF, to keep whatever path it is that you’re meant to get to your baby with. Leave that open and be willing to explore it, because I guarantee you’ll be happy no matter which way you get to your goal.
Jon: When couples or patients don’t want to do IVF, I obviously want to try to explore the reason why. Sometimes people have misconceptions, sometimes there’s a moral or ethical issue that they have with the technology, and I’m never going to be one to try to talk an individual out of the set of beliefs. Unfortunately, and this is where I get on my soapbox, unfortunately IVF is very expensive, and unfortunately, outside of Ontario nowhere in Canada insures it. Of course, Quebec had their experiment with insuring it for several years. And that is without a doubt, the number one barrier to doing IVF for a couple, is finances. The experiment in Quebec, where they had funding in late 2010, they had funding for five years. And the IVF utilization rates or the number of people doing IVF per capita overnight went up by 250 to 300%, and then when they took funding away it went back to what the baseline rate for the rest of Canada was. That tells you that funding is the number one barrier to accessing IVF. If you look at the country that has the highest IVF utilization rate in the world, it’s Israel. And the reason is in Israel, they will fund as many IVF cycles as you want to do.
Spence: How do they do that?
Jon: I don’t know. Some people obviously at some point in time stopped doing the treatment, but they have the highest IVF utilization rate per capita. And so, it’s really access, and access predominately has to do with funding. There’s nothing more
depressing when you see somebody who wants to do the treatment, may do well with the treatment and can’t afford it. That’s tough. And I tell my patients, write your MLA, write the Health Minister and really get the information out there that this is really important. Infertility is a disease, it’s recognized as a disease, our government will pay to investigate and diagnose your disease but they will not pay to treat your disease.