Ep 144 IVF, Part 2: Invention

mid thirties, I wanted to get on with it. So I consulted with my GP and started the process of IBF. There were a lot of hormone injections and other things, pelvic scans, ultrasounds, oral medications, and everything went pretty well for the first little while, but then it started to become a little bit more of a roller coaster. So my first egg collection day, I had a scan. I said I had thirteen really nice follicles. That was what

the obgian said. I went into surgery. When I woke up, they told me all of the follicles had been empty. Now I didn't know that this was a thing, but there is a syndrome called empty follicle syndrome, where you have a lot of fodicles, but they don't actually have any eggs in them. I was really devastated. I had to go another round with different medications, different dosages, and I went in for my next surgery, egg collection surgery, with eleven follicles ready to go, and they were able

to obtain three eggs from those. One of those is a dud. Two of them successfully fertilized. Out of those two, the first transfer didn't stick, and by this point I was actually getting pretty broke. I sold stuffed my motorcycle and things to cover these expenses, and I had the final transfer about a month later. And now I have a four year old. People ask me if I'm going to have another one. I don't have any more embryos.

Follicles are probably not actually making many eggs, and this is actually probably the biggest reason why I wasn't able to get pregnant beforehand, and I just didn't even know. I also found out I had a retroverted uterus throughout the process, which was another surprise. So there's a lot of things that can come up during IVF that you don't necessarily expect, and it can happen just about any stage.

I didn't fully realize that process. I just wanted to help, mainly a member of the LGBTQ become a family because I knew that that's a struggle for a lot of gay men to have children, and so I wanted to do that. That was my choice I made, and so when I went into that process, I guess I didn't think about, like the full what all has to happen?

which I am one percent understand why. But I didn't have to do that to have my own child, right, And then I had to be made They had to make sure I was like compatible with the family that I worked with, and so it was such a different experience. But then when you get into having to have your uterus, your ovaries, your fallopian trips, everything examined very thoroughly to make sure they're all functional. I didn't know mine were

functional prior to that. I mean, I remember the doctor giving me the compliment that I had like very nice eggs and I could have donated them that kind of comment, and I had no clue about that kind of thing

prior to this experience. And like talking to people who I now know who have struggled with IVF, because I think my gestational carrier experience has caused people in my life to come and talk to me about their own struggles with it has really made me empathetic and really made me realize how hard it is, because like I went through this for somebody else, but it's I can't

imagine just like going through that. I had to go through two cycles because I had one miscarriage and then I was pregnant and I carried that baby to term. But to go through that month after month after month, like the psychological toll it must take on a person, and I just like, like I was on hormone suppressants and then I was on estrogen and progesterone and I had to do shots, which I hate, needles. I can't

imagine having to do. I think if it had been me in a situation at my own child, I might have gone down a different path because it's a lot to put on a person, and it's so like they're so brave for doing it.

be looking for? How can we categorize infertility in the broadest and most non broadway possibles, Like non broadway that's a very confusing thing to say, and like broad and narrow definitions. How about that? Really just like the full gamut of things. And then in today's episode we are going to be talking about IVF, and so of course infertility is just one of the things that IVF is used for often as a treatment, but it's not the

only thing. And so really we're just going to approach this from like, hey, how did it get developed, how does it work? What does a typical cycle of IVF entail? And so on.

me and my husband. We found out at that time that not only are my ovarian reserves low, but that my husband's sperm count and sperm motility are really low as well. Essentially, doctors gave us a one percent chance of conceiving naturally. The first IVF.

to produce enough mature eggs for retrieval, fertilization, and implantation. Unfortunately, even with all that medication, my ovaries produced only three eggs for retrieval, and only two of them were mature enough to be fertilized, and only one of those embryos made it to day three after fertilization, So they scheduled my embryo implantation that day to give the fertilized egg the best shot at growing and attaching in my uterus, since we had no backup eggs or embryos that could

be frozen. That embryo resulted in a chemical pregnancy where it had attached. I got a positive early pregnancy test, and then it was lost. We tried another round of IVF a couple months later, this time with far less medication, since the doctors figured I'd only produce three eggs regardless, and this time my ovaries produced only one egg, resulting in a canceled retrieval and a failed IVF cycle. My husband and I decided to stop IVF at that time and are now determining if we want to go any

other routes to grow our family. The whole time, I knew our chances were maybe slim, but going through the process ourselves and seeing the actual stats, percentages, and chances to get pregnant, keep a pregnancy, and then deliver a baby were wild. In a world that told me how easy it was to get pregnant, turns out it is actually pretty difficult for some people.

mine that I feel I should just shut up. But at the same time, I can't talk to anyone who conceived naturally because they do not understand the stress and darkness that comes with IVF, the pain of watching everyone around you get pregnant, the oppressive anxiety of will it work this time, the constant needles doctors, meds, and having

to juggle work at the same time. I'm a wildly successful example of IVF, and it was still one of the most difficult times in my life, not to mention the special hell it is trying to get pregnant by committee. I had a transfer canceled and postponed indefinitely because of a hurricane, and I had to go to a different clinic. This meant months went by, more paperwork, and I had to do all the medical tests again. That's not something people who conceive naturally have to give a second thought about.

In short, IVF sucks, and it's a miracle that I'm thankful for every day.

explanations did people come up with? And I ended up just like summarizing the entire twentieth century by saying, like, as our scientific and medical understanding of infertility and fertility grew, infertility began to be increasingly seen as a thing for science to overcome first with surgeries, hormonal regulation, especially as our understanding of undercnology grew in the early twentieth century, artificial insemination, and ultimately leading to IVF and the first

IVF babies born in nineteen seventy eight. Today, I want to get into that journey to IVF by talking about how this technology was developed, the foundational research that made it possible, and what happened when this pie in the sky idea became reality. Framing it that way makes it kind of sound like developing IVF to treat infertility was the goal all along, all roads lead to IVF, but

that really wasn't the case, huh. Much of this research came out of a desire to understand how human reproduction worked, including IVF and the applications, including using IVF for reasons other than infertility, which is a big part of IVF. These applications kind of arose later on. It's just something I want to put out there because I feel like we tend to think of IVF as like and this has been the end goal and this is the thing that IVF is used for, and that is really an oversimplification.

four basic steps. Number one, retrieving an egg or multiple eggs. Number two fertilizing that egg with sperm. Number three culturing the fertilized egg for a while until it turns into a cluster of cells called a blasticist. And number four transferring the blasticist or blastocysts into a uterus where it will hopefully implant and develop into an embryo, a fetus, and then ultimately a baby.

the egg with sperm? That took a lot culturing, you know, like all of these things took a long time to figure out. And it was really decades, decades of work, of trial and error, of collaboration between scientists and physicians, and of really courageous participation by so many volunteers and patients to get all of these kinks worked out in this process, which like also they're not fully worked out.

But even still, even in nineteen seventy eight, or especially in nineteen seventy eight, there was no certainty that this would become a standard treatment and an industry, or this

industry that it has grown into. And it also took a detailed and thorough under standing of human reproduction, not just the role of major organs like the uterus or ovaries, but also at the cellular level, at the hormonal level, at the genetic level, and how these things work together to lead to the development of embryos into fetuses into infants.

It's incredible, it's really cool. By the middle of the nineteenth century, studies in anatomy and physiology started to shed light on how the reproductive system worked, but this was mostly at the organ level, with things visible to the naked eye. Scientists had known about eggs and sperm since the sixteen seventies, but it took another one hundred and fifty years for people to understand how the two work together. Was the sperm just food for the egg? Was the egg passive?

and Albert Broshet didn't let that stop them though. In eighteen ninety one, Heap transferred rabbit embryos from one rabbit to another, and that rabbit became pregnant and delivered baby rabbits or kids. As I learned that they're called. How cute. It's very cute, very cute. Cool, but not in vitro fertilization. A few decades later, in nineteen thirteen, Albert Broschet was the first to successfully culture mammalian blasticists before implantation. Also cool,

still not in vitro fertilization. Things were moving steadily but slowly. In the first few decades of the twentieth century, the field of reproductive biology seemed to attract more interest from science fiction enthusiasts than it did from biologists. The public seemed particularly interested in the idea of ectogenesis, so fertilization and gestation, completely outside the box.

this growing sense of disillusionment with technology. People no longer believed as they had at the turn of the century that technology would solve all of life's woes. War and economic downturn had tipped the scales from assisted reproductive technologies being perceived as part of a utopian future to these technologies being a sign of our ultimate downfall. And maybe that's dramatic, but maybe not, because consider what happened to

Gregory pinkis so. Pincus was appointed assistant professor of biology at Harvard in nineteen thirty one, where he did research on in vitro fertilization in rabbits and studied the hormonal changes that lead to one mature egg being released each month. In nineteen thirty six, his work and his claim that he and colleague ev Nsman were the first to successfully demonstrate IVF and rabbits. That claim was later challenged by people who couldn't replicate it. I'm not sure it's yeah.

There's a lot of claims and a lot of skepticism throughout this whole history, but this his work. Pinkus's work drew the attention of the popular press, mostly falling somewhere between speculative and negative reaction Wise, some journalists imagined a world where human children would be brought into the world by a host mother not related by blood to the child, eventually leading down the slippery slope of eugenics, where quote advocates of race betterment might urge such procedures for men

and women of special aptitudes, physical, mental, or spiritual end quote. Others warned, what would happen to the men if this science were applied to humans? Quote? In the resulting world, man's value would shrink. It is conceivable that the process would not even produce males. The mythical land of the Amazons would then come to life, a world where women would be self sufficient. Man's value precisely zero. End quote. That is so telling, Aaron, Wow, isn't it?

But that didn't matter. The negative press was enough to get him denied tenure at Harvard and let go Wow, and that wasn't the end for IVF or for Gregory Pinkus, who would go on to help create the birth control pill, along with the next name in our IVF story, John Rock, a gynecologist at the Free Hospital for Women Boston and Harvard Medical School. Rock had come across the rabbit IVF paper by Pinkus and became fascinated so much so that

he decided to work on IVF. He teamed up with Miriam Menken, who had been a research assistant working on hormones with Pinkus at Harvard before he was kicked out, And I just I kind of love that, and also her story is really interesting and like, definitely at least go to her Wikipedia page and check it out. But the third member of their team was pathologist Arthur Hertig, and together these three performed groundbreaking research in reproductive biology

in three big areas. The first area was capturing the timing of ovulation, which would prove to be super helpful in IVF later on for egg retrieval, but also for artificial insemination, which began to be more popular around this time. And the second area was in describing the early stages of human embryonic development, which they did at a time when really no one knew how anything worked before even

the development of the ultrasound wow, which is wild. And the third was in the fertilization of human eggs outside of the body, and so to do this they enlisted the help of women who were set to undergo hysterectomies, and they performed the surgeries just before the volunteers ovulated so that they could extract as many eggs as possible, And after getting the donated tissue, Menken would run like literally run up and down flights of stairs over to

the lab where she would begin trying to fertilize these eggs outside of the body in vitro. But after years and over one hundred and thirty eggs exposed to sperm out of the eight hundred they collected, nothing seemed to work.

And then one day in nineteen forty four, exhausted from staying up late with her baby, Menkin only washed the sperm once as opposed to the usual three times, and later she returned to see that the egg had divided into two cells, and they repeated this a couple more times with the revised protocol with fewer washes, and took pictures, and I feel obligated to include this, like this is a well actually that I'm going to throw in here.

There does seem to be some debate on whether that actually represented fertilization, since people later realized that freshly ejaculated sperm actually needs to spend a period of time in the genital tract before they're ready for fertilization, in a process called capacitation. I don't know, I'm not really clear on this, but some people have been like, Okay, maybe the egg just divided without being fertilized, which also has been known to happen or seen to happen. But yeah, okay,

I don't know. That's like my little pedantic well, actually.

have children. Rock personally replied to many of these letters with like cautious optimism and was like, maybe someday we're not quite there yet, But he also took the time to explain the science and I just appreciate that I don't know. And by and large, the public response to this announcement seemed positive. The war had just ended, and this is also like primarily US specific, but like the war had just ended, the economy was booming, pro natalism was in full force, and IVF was going to solve

the problem of involuntary childlessness. Over the next couple of decades, things were kind of quiet on the human side of IVF, but some researchers were exploring the technique and other animals, and in nineteen fifty nine, doctor Min Chua Chang successfully used IVF in a rabbit to produce kits nineteen fifty

nine nineteen fifty nine. The enthusiasm for IVF in humans began to die down by the end of the nineteen sixties, in part due to a lack of progress, in part due to rejection of technology sort of across the board, and in part due to a decline in pro natalism. But that happens to be when significant progress on the technique began to be made in nineteen seventy three and nineteen seventy five, researchers reported the first IVF pregnancies, although they only lasted a few days, and the first IVF

babies were just around the corner. Robert Edwards, Patrick Steptoe, and Jean Purdy formed a powerful IVF team in England that had spent a good deal of the nineteen seventies working on this technique, leading to a chemical pregnancy in nineteen seventy five that turned out to be ek topic. But this heartbreaking result did show them that they were on the right path, and a few years and a few tweaks to the protocol later, and they tried out their new method on a few people at their clinic.

Nine months later, on July twenty fifth, nineteen seventy eight, the second person they tried this out on, Leslie Brown, gave birth to Louise Brown, the world's first IVF baby.

Sunit Mukerjee, and Saraj Kanti Badachara. Whereas Steptoe, Edwards and Purdy relied on natural cycles of ovulation, the team in India used drugs to induce ovulation and then froze the embryo before implanting it.

This reaction might have been because the Indian team allegedly carried out the work somewhat secretively and without formal approval, but it wasn't a fluke or fraudulent. That didn't matter though, to the institutions where Subas Mukerjee, who was the team leader worked. Mukerjee was sent to an ophthalmology institute where he couldn't do He couldn't do any work, but it was just as a way to be like, we're preventing you from doing any of the work that you actually

want to do. He was forbidden to present his IVF research or participate in conferences, and in July of nineteen eighty one, he took his own life.

But even with these births, IVF was by no means a sure thing technologically speaking, financially speaking, and in terms of regulation. The news of these first IVF babies was met with a lot of feelings, some very pro, some very anti, but rarely indifferent. The potential that IVF held good bad other was and is tremendous. And we'll get

into some of these things next week. But I want to wrap up today's history section with a brief look at when IVF came to the US and how that set a precedent for IVF becoming a mostly private pay for services institution, a market driven enterprise for better or worse. After the birth of Louise Brown and the other early IVF babies. The US realized that IVF might be here to stay, so they began to call for congressional hearings to discuss the implications of IVF and policies for how

treatment and research should be regulated. Should IVF research or research involving embryos be allowed to receive federal funds? That question has been debated for years, and there is currently a ban on federal funding for research involving embryos in the US, but for quite a long period of time it was anticipated that it would be allowed. To verify, the research is still allowed to be conducted, it's just that it can't be federally funded. The funding has to

come from other sources, just throwing that out there. In the late nineteen seventies, when it was looking like federal funds would be approved, two researchers, slash clinicians and married couple Georgiana Seeger Jones and Howard Jones, left Johns Hopkins University for Eastern Virginia Medical School where they could pursue IVF research. Their story is actually really cute and it goes back like really far and there are like cute

letters during the war. Anyway, Georgiana was a pioneering, highly accomplished reproductive endocrinologist and her husband, Howard, trained as a general surgeon and then specialized in gynecology so that he could work closely with his wife, and for years they worked together, sharing a lab, an office, even a desk, and Robert Edwards from the England IVF team actually trained

with them for a while. But not being willing to wait for federal funding for IVF to be approved, they would still have been waiting, they decided that this technique was enough in demand that they could seek private funds and charge for services. In nineteen eighty one, the first IVF baby in the US was born from their clinic. Each couple had to meet the following criteria youth under thirty five, good health, bad fallopian tubes, a husband, and the unspoken one was that you had to have money.

Each couple had to shell out around four thousand dollars in nineteen eighty dollars or fifteen thousand dollars in today's dollars, but the cost didn't keep people from flocking to the clinic. Other IVF programs in the US followed shortly, first primarily at medical schools, then in community hospitals, in partnership with private infertility practices, and finally in independent centers. Despite urging from the American Fertility Society to come up with federal

guidelines and oversight for these clinics, progress was slow. The most they could do, like the Society was establish a subgroup, the Society for Assisted Reproductive Technology, and required clinics to follow particular standards if they wanted to be SAAR Team members. But there was no way to enforce these guidelines, and the number of clinics grew steadily, in part because of the appeal of no strict regulation, or really no regulation.

The introduction of the vaginal ultrasound probe made things easier for IVF, which required only local anesthesia and meant a surgeon and operating room were no longer required, and this marked the end of many relationships between private IVF clinics and academic medical centers in the US, and it enabled even more growth, which led to, among other things, improvements in technique and application for IVF, so people not just

with tubal factor infertility, but also endometriosis, unexplained infertility, male factor infertility, genetic conditions, same sex couples, single parents, and so much more. Age restrictions began to be raised. Intracytoplasmic sperm injection was introduced at ICSI, as was egg and embryo freezing, and many clinics began to incorporate donor eggs

and embryos and gestational and traditional surrogacy. IVF was bringing more and more people the children they had always wanted, and as the number of clinics grew globally, as technological advancements were made, more questions were being asked about the financials of IVF, about access, about ethics, about transparency from clinics, about what the future could hold. That's what we'll be getting into next week. But for now, Aarin, I'll hand it over to you to tell us all about how IVF works.

of getting the sperms inside of my uterus. So we wound up going with intrauterine insemination, which is really just inserting the sperm through the cervix with a long needle directly into the uterus. The chances of pregnancy are slightly higher than with just intercourse, but not super high, so that's usually the first step, and then if that doesn't work after a few cycles, the next step would be using medication to boost fertility, and then after that is

IVF and mutual fertilization. So we did all of the prep stuff. We did genetic testing, we bought sperm off a sperm bank, and we also did genetic counseling, which is required because they just want to kind of gauge how you would deal with having a donor conceived child, how you would talk about that with friends and family, and of course, most importantly, how you would talk about that with your child. So, after all of that prep

work was done. I'd been charting my cycles and tracking my ovulation, and then once it was regular, I alerted the fertility clinic when I was ovulating, and we got the sperm transported from the storage facility to the fertility clinic, and I went in for my first insemination. The first one didn't take, so we did a second one the next cycle, and that one did take and I became pregnant. So the first few weeks they monitored my pregnancy at

the fertility clinic. They did a couple of tests to confirm, they did the first ultrasound there, and then I was released into regular prenatal care with my regular obgyn, and I wound up having a great pregnancy and giving birth to an amazing baby. Our daughter is fifteen months now,

and she is absolutely the best. And I am so glad and so grateful for all of the support that we had and for the fact that we have that option and that that was something that we were able to do to have our baby, and to live in a state where most people are supportive and understanding and where we didn't have to fight very hard to make

this a reality for us. It's been a really amazing experience and I'm really proud to be part of the of the IUI community of having used as system reproductive technology and having had the chance to have that in my life to help bring our child.

twenty twenty three. We've experienced a total of seven pregnancy losses through unassisted spontaneous conceptions and frozen embryo transfers, including the seventeen week fetal demise of our daughter conceived through IVF tank in March twenty twenty, and have had no live births throughout the years of IVF treatments and multiple surgeries.

I was diagnosed with endometriosis suspected adnomiosis, gestational trophiblastic disease, autoimmune disease that attacks my reproductive organs and pregnancies, and

Asherman syndrome following multiple miscarriages. We've completed IVF with three different clinics, two conventional clinics and one specialty clinic that uses mini IVF, both in and out of state, worked with a reproductive immunologist out of state, and consulted with almost a dozen reproductive endocrinologists specializing in recurrent pregnancy loss

and endometriosis across the country. However, despite pursuing every evidence based treatment and if you not so evidence based, my body is unable to sustain a pregnancy to term and live birth, even with the perceived quote guarantee of IVF resulting in a live baby. A critical factor in our pursuit of IVF was having insurance coverage, which made a huge difference in our treatment options because we weren't limited

to what we could afford at the time. Since most of our IVF was covered by insurance, we didn't deplete our savings then, which allows us to now pursue gestational surrogacy. Following the suggestions of our physicians and the limits my husband and I agreed we'd reached, which we called our heartbreak tolerance. We are grateful for the opportunity to try to have a biological child through IVF with gestational surrogacy,

and we grieve everything we've been through. There aren't many stories from long haulers who've suffered multiple miscarriages like myself, for whom IVF doesn't end with the live baby, because our stories are sad, but we do exist.

IVF with ICSI or that interra cytoplasmic experm injection. It also even includes things like egg and embryo freezing, even without the in vitro fertilization part of it, and again those other less common procedures that people don't do as much anymore today. So how do the steps of this work? Because the steps for all of these different procedures start out in many cases the same, and I caveat this as of course, each cycle of IVF is going to

be very individualized. So these are just like broad overview steps. But step one, and this is the step erin that didn't happen in your cycle, I guess in your description. And that's because it doesn't didn't always happen, though it pretty much always happens today. But step one is to overstimulate your ovaries to produce a whole ton of eggs. Right, So typically we produce and ovulate only one egg per

menstrual cycle. Sometimes two and multiple eggs do start to develop during each menstrual cycle, but typically only one kind of comes all the way to the point of being ovulated. But for IVF to have a real chance at being successful, you have to boost this number in large part because there is attrition at every step in this cycle. So that process of overstimulation involves often a lot of needles,

but definitely a lot of hormones. This is one of the first places where there's going to be a huge variety of variation in what the specifics of each algorithm are going to be, Like the specific drugs that are going to be used is going to be very person

and patient and doctor specific. So I'm not going to get into all of that, but all of these are doing the same basic thing, all of these various hormones, and there's a number of different options that you can use trick your body into readying for ovulation a whole bunch of eggs at once, and this process often starts the month before in order to get your body ready to next month start this process of inducing a whole

bunch of eggs to be ready for ovulation. That whole process often takes about two weeks, but again it starts before, like the month before, so we're talking already like a multiple week process. And then we get to step two and that is taking the eggs out. Yeah, so egg removal usually starts with yet another hormone injection the day or so before the egg removal process, and that's to help the eggs mature at the correct rate to be

ready for aspiration. And the aspiration process takes place in usually a doctor's office or at a hospital under ultrasound guidance, which you mentioned aaron, where they take an ultrasound and a very long needle, hopefully under mild ivy sedation, though not always, and they use that to not always, it is standard practice to do ivy sedation, but I think in some cases, either for patient preference or for a number of reasons, they might not, and they might use

like a regional anesthesia or something like that. Okay, yeah, but they use this really long needle to through the back of the vaginal wall aspirate out as many of those ripe and ready eggs as possible. While this is happening Step three, potentially your sperm donor or your partner is leaving their sperm sample or it is being defrosted from the freezer. These sperm have to then be washed and checked to pick the healthiest sperm. To pick the ones most likely to be able to fertilize the egg,

and then comes the in vitro part step four. The eggs and the sperm unite, and this process can go one of two ways. So traditional IVF throws all of the sperm in with all of the eggs, and the sperm are going to fertilize the eggs in a similar way that they would in the reproductive tract. Or there's ICSI interra cydoplasmic sperm injection, which is fascinating and exactly what it sounds like. It's injecting using a very very very tiny needle, one single sperm directly into the egg.

And then that fertilized egg is grown in culture for between three and five days until it reaches either the cleavage stage or the blasticist stage. And the final step, step five, is that this blasticist is transferred back into the uterus via a long catheter tube that goes up through the cerfax towards the top of the uterus and is deposited there either one or a number of blasticists.

Most people then still need to keep taking some form of hormone, either injections or oral medications for the first few days or weeks of that potential pregnancy to try and get it to stick. This is especially true in US using frozen embryo cycles because you haven't just ovulated, and so you have no corpus lutium of which to speak,

which is the hormone producing part of your ovary. That's IVF in like a very small nutshell, And shout out to pen Medicine's Patient facing website because I thought that was the most comprehensive but detailed breakdown of IVF that I found on a patient facing website.

really are. How many blasticists, how many blastoicists at what stage?

get you know, X number of eggs. Some percent of those eggs won't be fertilized for one reason or another, and then some percentage of those fertilized eggs won't make it all the way to the blasticis stage, especially, and some of those blasticists won't manage to implant or therefore won't cause a pregnancy, so to kind of help counteract that, especially historically kind of actually before we got to blasticis stage culture, because it used to be more common that

IVF happened at day three, which is when you're still in what's called the cleavage stage, then multiple blasticism would be transferred during that IVF process. Today, what's called single embryo transfer is actually a lot more common, and in some places it's like the recommended, if not required, thing to do. And that's because the risk of multiple pregnancies is significantly higher than the risk of a singleton pregnancy, that is, twin or triplet pregnancies are significantly higher risk

than a singleton pregnancy. So in some cases, single embryo transfer has become the kind of norm in most places, But it all just depends on the situation. Because you can also imagine, especially in maybe an older couple who only has either a certain amount of money left to be able to do more transfers because each transfer costs money, or who only has a certain amount of time or a certain number of embryos that are left, then they might opt for a multiple embryo transfer. So there's kind

of a lot. There's a lot that goes into that decision of how many embryos to transfer. The lowest risk in terms of like birth risk and risk of the pregnancy is going to be a single embryo transfer, but with multiple embryos you might have a greater chance at a live birth. Okay, I also just want to this is a little bit pedantic, but.

that has been growing for five to six days. In culture media, this particular stage of development is it's fast. It's one cell layer thick that forms about a ball that has a fluid filled portion, and then one section of it that's about three to four cell layers thick. So in total we're talking about two hundred or so cells, and this little part of the blastocyst that's three to four cell layers thick. That is what will become an embryo upon implantation in the uterus. There's number of steps

that have to happen. Usually around days nine to ten is when it is then becoming an embryo, which will then eventually develop into a fetus and then eventually a baby. And so I do think that these terms are kind of important because they help us conceptualize what we're really talking aboutte So I just want to point that out, but I'll probably say embryo transfer because that's what literally all the literature says.

things like bleeding or infection or injury. These risks exist, they tend to be very small. The other major risk of IVF as a process is something called ovarian hyperstimulation syndrome or OHSS. This the risk I see cited usually as between one and five percent, but it really can vary. But this is a life threatening complication of that. In process of stimulating the ovaries to make a whole bunch of eggs all at once.

severe and life threatening. We don't fully understand the exact causes and mechanisms of this, but it's thought that it's a result of the ovary responding to this like supra physiologic doses of hormones signaling ovulation, that what it results in is really large scale vasodilation, so all of your blood vessels dilating, and that causes this increased capillary permeability.

So basically all your vessels like get really wide and then permeable, so that fluid can shift from inside of your blood vessels to the outside of your blood vessels. And these fluid shifts are things that happen during pregnancy, but in a much different and slower fashion, And so this is something that's happening at a very fast and like super physiologic rate.

that you're at. But almost always what it does mean is that if you were planning on a fresh embryo transfer, So we talked about that whole process of IVF, kind of assuming that at the end of it you take those embryos and put them directly into the uterus. But

the other option is to freeze them. And so if someone develops ovarian hyperstimulation, then almost certainly they're going to have to have those embryos frozen because they have to have that condition managed before you can go on to then complete the steps of IVF.

significant morbidity and mortality. It is not a riskless condition. But what's interesting is that it seems that IVF pregnancies are also a bit riskier than spontaneous conception pregnancies as well. Specifically, we see in some studies an up to fifty percent increased risk of hypertensive disorders including pre eclampsia, and an up to fifty percent increase risk of gestational diabetes, and these risks seem to differ between frozen embryo transfers compared

to fresh embryo transfers. Again, we don't fully understand the mechanisms behind this, and it might have something to do with whether or not there is like a corpus lutium like I mentioned that's in the ovary, but we don't really know. There also seems to be an increased risk of abnormal placentation, and that's especially true in fresh embryo cycles.

So that means that the placenta is either implanting in a place that's a little bit more risky in the uterus, like overlying the cervix or something like that, or in some cases invading a little bit too far into the uterus than is typical. And those kinds of abnormal placentations can put somebody at higher risk of hemorrhage during delivery

or after delivery. And then there also seems to be an increased risk of severe outcomes like stroke or blood clots or ICU admission kind of in the postpartum period, which seem to be higher in iv F or ART pregnancies compared to spontaneous conception. And that does include after controlling for things like maternal age or comorbidities that might affect those risks.

real risk. I guess if that makes sense, Okay, And we talked already about the risk of multiple pregnancies as a risk because of multiple blastocyst transfer. But what I also learned is that the rate of monozygotic twins, that is, like identical twins, is also significantly higher in IVF pregnancies. And I do have numbers on this, okay. The baseline rate in spontaneous conception pregnancies of identical twins is like zero point four percent. It's super low. It's between two

and three percent in IVF. Wow. And we don't know what the mechanism is. The thought is maybe because in an identical twin pregnancy, what has to happen is that during the development the blasticist. Usually I always thought of it as the zygote. I don't think I even realized it could happen like post blasticis stage. But the blasticist or the zygote prior to that divides into two separate blasticists or two separate zygotes, rather than implanting two genetically

different blasticists. And that's how you end up with identical twins. So we don't know what the mechanism of this is the thought is maybe it's related to the culture media that's used. Maybe it's related to the timing of the transfer. Again, absolute risks still very low, but significantly higher than the population level, which I think is so interesting.

person to person. But there's obviously a huge question of like what's the overall success rate, Like if you go through this whole IVF process, what are the chances that you are going to have a baby at the end of it? Right, we don't have numbers on that either, And it is in part because it's going to vary so much person to person, but it's also in part because it's going to vary so much location to location.

And there's some really interesting papers that I read that are looking at, like how do we even define what a success rate actually is? Are we talking about, like what is the live birth rate per cycle? And usually when we say per cycle, we're meaning like one embryo transfer or do we mean per retrieval where you might have to do multiple embryo transfers after that one retrieval? And also, are we talking about the success rate of like first berths or if people then are going through

IVF to try and have a second child. Are we looking at total births? Are we combining fresh and frozen cycles or are we separating those two out there's so

much nuance it's almost it's almost impossible. And that being said, people cite rates like most websites, most papers say like up to four twenty percent of cycles of IVF will result in a live birth, and that's a huge generalization, and if you look at global numbers, it's actually also a real overestimation because just we'll talk more about global

numbers next episode. But what it has been reported to the institution, this large international institution that tries to monitor IVF globally in twenty twenty one, they reported about three million cycles of IVF and about seven hundred and fifty thousand babies A little bit more, okay, so that Aaron math is about twenty five percent as a success rate

per cycle. The CDC has a very interesting calculator where you can input your individual data and it'll estimate your probability of a live birth, and you can break it down by like one two or more retrievals and one two or more transfers, which I think is really interesting and paints some more realistic picture, though it is still going to vary like place to place.

very badly. And so because of that, I really just want to say thank you again so much to everyone who took the time to write in and share your story and record yourselves and share it with us and with everyone that is listening, because one of the things that I hear over and over again is just how hard this experience is, regardless of what the outcome is, for so many people. And so I just want to say again, thank you so much for sharing your stories.

And we'll get to talk a lot more about what IVF looks like on a larger scale and a less personal scale next episode.

But then there are things where it's like, maybe that's not that way, and so it's like, I think that's That's what I just keep circling back to, is how important it is to understand that there's it's not just one thing, it's not just one feeling, it's not just one experience, and it's many, many, many, many different things.

There was a paper in BMC Pregnancy and Childbirth from twenty twenty one untitled Assistive Reproductive Technology and Hypertensive Disorders of Pregnancy Systematic Review and meta Analysis, and a few other papers as well. We will post the sources from this episode and all of our episodes on our website, this podcast will Kill You dot com under the episodes tap.