IVF and Fertility Preservation

Podcast Transcript

Erica Newlin, MD:

Welcome to Ob/Gyn Time, a Cleveland Clinic podcast covering all things obstetrics and gynecology. These podcast episodes are intended to help you better understand your health, leaving you feeling empowered to live your best. We hope you enjoy today's episode.

Hi, everyone. I'm your host, Dr. Erica Newlin. Welcome to our fifth episode of Ob/Gyn Time. During this season, we are focusing on topics related to infertility. On this episode, I'd like to welcome Dr. Elliot Richards, who will be talking to us about IVF and fertility preservation. Dr. Richards, thanks so much for joining me on the podcast. Can you tell us a little about your role in the Cleveland Clinic and about your background?

Elliot Richards, MD:

Thank you, Dr. Newlin. It's a pleasure to be here. So, I serve as the director of research in the reproductive, endocrinology, and fertility section. I'm also the associate program director for our fellowship.

Erica Newlin, MD:

Great. And since in this episode we'll be talking about IVF, can you explain what we mean by the term in-vitro fertilization, or IVF?

Elliot Richards, MD:

Sure. So, we use the term pretty loosely to mean the entire process of stimulating ovaries, extracting eggs, performing fertilization in a laboratory, and then putting the embryos back into the uterus to achieve pregnancy. But, strictly speaking, IVF just refers to one part of that process, and that's actually creating the embryos in the lab. So, fertilize eggs with sperm.

Erica Newlin, MD:

And in previous episodes, we've discussed possible causes of infertility, possible treatments. What reasons outside of failure of other treatments might someone decide to turn to IVF to conceive?

Elliot Richards, MD:

That's a fantastic question. There are certainly a lot of different reasons that a couple or an individual might pursue IVF. And I certainly can't summarize all of them, but I would say some big reasons, one would be, so unexplained infertility affects 30 percent or so of heterosexual couples trying to conceive, and oftentimes, other treatments don't work, and so IVF is a great option. Particularly when you have a couple where they are, or an individual who is getting older in age. And so, we know that there's a fertility decline in egg quality with increasing age of a woman. And so, IVF is really able to fast-track couples through fertility. And so, it has a lot of advantages and may even skip some of those intermediate treatments that we think about, particularly if there's an older patient.

There's a lot of other scenarios. For example, if the couple has known inherited genetic condition in their family and they're wanting to screen for that condition and select embryos that don't have that potentially catastrophic recessive condition. Going back to the age issue, there's also, of course, an increased risk of Down Syndrome, of miscarriage, of chromosome problems in the egg which then translates to the embryo, and so IVF is a way to screen for those issues. So, these aren't abnormal genes, these are just chromosome errors that occur in an older egg and so we're able to test for that.

And then, of course, there's other scenarios. Same sex couples, use of gestational carriers, and really, I would say, if you're not sure if IVF makes sense, that's where meeting with a reproductive endocrinologist and talking through the pros and cons. Because it's certainly not a treatment that's for everyone and every situation, of course, is different.

Erica Newlin, MD:

For sure. And I've had patients come to me asking about sex selection, as well. And as far as that, with IVF.

Elliot Richards, MD:

Okay.

Erica Newlin, MD:

But often, then, when we talk about the road of IVF, they often defer.

Elliot Richards, MD:

Yeah.

Erica Newlin, MD:

But it's possible.

Elliot Richards, MD:

Coming out at the beginning with controversial topics. Yeah. Yeah. So, so sex selection or, or family balancing, gender balancing is definitely very controversial, and I would not say that it's universally done. It gets into a lot of complex ethical issues, and I would say not every reproductive endocrinology clinic or provider would feel comfortable with sex selection. But, absolutely, in terms of technically possible, yes. Because when we do genetic testing of embryos, we're screening for chromosome number, and of course we pick up, is there a Y chromosome present. So, we're able to tell if an embryo is male or female.

Erica Newlin, MD:

Sure.

Elliot Richards, MD:

But, yes, it's not as trivial if someone's just saying, "okay, I've got, you know, two boys, I want a girl." Yes, it's a very involved, expensive process for a lot of couples, it will give them some pause when they actually look at what it entails.

Erica Newlin, MD:

And then, we've spoken a little about IVF and creating embryos. Can you describe what we mean when we talk about fertility preservation or egg freezing and the difference between egg freezing versus embryo freezing.

Elliot Richards, MD:

Sure. So, fertility preservation is a big blanket term that encompasses a lot of different things also including sperm preservation and semen preservation. But in my area, we tend to really focus on egg or embryo or ovarian tissue preservation. And it really depends on the scenario which one is most appropriate. The most common consult that I have are young women who are wanting to preserve their potential for future fertility and so it generally is going to be egg freezer. Because there often isn't a partner, and egg freezing has a lot of advantages over embryo freezing. But it isn't always as straight forward, and that's where each individual circumstances are important to keep in mind.

Egg freezing is a pretty involved process. It's very similar to the bigger picture of in-vitro fertilization in terms of medications to stimulate the ovaries, monitoring to see how the ovaries are responding to the medications, an egg retrieval procedure which is done under anesthesia to extract the eggs from the ovaries, and then, with in-vitro fertilization at that point, we fertilize the eggs and make embryos, but for those who are just doing egg freezing, at that point, the mature eggs are able to be frozen.

And so, start to finish, it takes about two weeks from what we call baseline scan to an egg retrieval, although oftentimes there is a month or more of just preparation, getting education and lab work, and oftentimes there's a waiting list to get going. Egg freezing is something that really should be discussed with reproductive endocrinologist because it's not necessarily for everyone. And what I mean by that is that there's actually been studies, just even in the last two years, that have shown, okay, what is the benefit in freezing your eggs at age 20 versus age 30? And there really doesn't seem to be a difference.

And so, I think oftentimes women will feel the biological clock is ticking, there's a lot of social media talking about, "okay, you need to freeze your eggs. Time is running out." But the reality is, for most women, there really doesn't seem to be a difference, freezing it in your late 20s versus your early to mid-30s. And so, is egg freezing something that every young woman should be aware of and educated on? Absolutely. But it's definitely not for everyone.

And interestingly, most women who freeze their eggs don't end up using them later. So, it's something that I'm glad is getting more attention on social media and it's getting women thinking. Because I've certainly seen the other end in my practice, women who are in their late 30s to early 40s and realizing that the reality of biology is, is that we're really limited in what we're able to do with fertility treatments with older eggs. But the 20s are not necessarily an urgent situation as sometimes is portrayed in social media.

Erica Newlin, MD:

Yeah. It's great you bring that up. I think, especially when a lot of the big tech companies started to cover it and more mention of egg freezing on social media, there was a push of women in their 20s. But then, I think I've seen a lot in the New York Times and, interestingly, Slate over the weekend ran an article about freezing in your 20s versus 30s. So it might be that the pendulum is moving in the other direction.

Elliot Richards, MD:

Absolutely. I think that definitely that middle ground makes a lot of sense. People don't always think about it, when you freeze your eggs in your 20s, there's also storage fees every year. And so, there's the upfront cost of freezing the eggs, but then maintaining those eggs until you're ready to use them. And as I said, a lot of women don't end up using their frozen eggs. I think there's also a perception of, okay, this is an insurance policy. There are many articles ... I think New York Times had an article just a couple of months ago highlighting stories of women who had what they thought was this promise of future fertility. They went to then thaw their eggs and make embryos and they were not successful.

And I don't think there's anything wrong with how their eggs were frozen, it's just the fact that when we talk about freezing eggs, we're talking about probabilities, and we're talking about hedging our bets. It's not really an insurance policy in the sense that there's going to be a guaranteed payout at the end. It really is, what is your threshold for comfort in terms of those probabilities of success and having a 90 percent probability, which if you're in your early 30s and you freeze 30 eggs, you have over a 90 percent chance of having at least one live born child. But that also means a 10 percent chance it doesn't work. And so, I think setting expectations is also important for people who are undergoing the egg freezing process.

Erica Newlin, MD:

Yeah. And on that note, how do you counsel patients about the likelihood of success?

Elliot Richards, MD:

There's really not a straightforward answer there, because there's so many different variables when it comes to IVF and egg freezing. Egg freezing is even more difficult because there's such a time delay, and many women who get egg freezing, we don't even know if they have infertility. There are tests we can do. There's a screen for different kinds of infertility, but there's no blood test that could tell us, what's the quality of your eggs? The biggest indicator is age.

When it comes to IVF, we have a lot of data, and in fact, what I would encourage people to do is, there's actually success calculators online. So, the CDC website actually has a great calculator. It's using data from SART, which is Society of Assistive Reproductive Technology, and they gather data from over 90 percent of IVF clinics in the United States. And so, you can plug in some of your numbers. Your age, your weight, your obstetrical history, and it'll spit out a number as a rough ballpark. And of course, there's going to be variability clinic to clinic.

But to illustrate what I mean by, it's an age dependent lot of variables, you get a patient who's in her early 30s, she may have a predicted success rate of 60 to 70 percent. You take that same woman and fast forward 10 years later, it's five to 10 percent. So, really a dramatic difference between early 30s to early 40s.

Erica Newlin, MD:

And then, other than the age, where do things like AMH or, can you describe what antral follicle count is and how that may success rate, if it does?

Elliot Richards, MD:

Sure. So, what you're describing is what we test of ovarian reserve, or egg count. The most commonly ordered one is AMH, or anti-müllerian hormone. That's a hormone that's secreted by small antral follicles, or small little cysts on the ovaries that hold the eggs. Another test of ovarian reserve is the antral follicle count. So, that's an ultrasound, and we're, in the ultrasound, we're actually measuring those tiny little cysts. And both of those tests have pros and cons to whichever approach. The biggest thing to keep in mind with tests of ovarian reserve is they tell us nothing about egg quality.

And so, for me as a fertility specialist, I would rather have a patient who has low AMH, a low egg reserve but is 30, than a patient who is 40 who has a very high egg reserve. And that's certainly because egg quality trumps quantity. And that's been shown with epidemiologic studies, actually, that in the general population, AMH actually isn't predictive of fertility success because there are plenty of women who have very low egg counts who, those eggs are great. I mean, every month, you know, with natural fertility, you just need one egg to ovulate. And so, if their pool of eggs every month is just three, four eggs but those are good quality eggs, they're going to potentially be very, very fertile.

Whereas a woman who has 30, 40 eggs a month, but there's an egg quality issue, they may have significant reduced fertility. So, when we bring up tests of ovarian reserve, always want to caution patients and providers that even though it's a pretty remarkable test, that through a blood test we're able to tell roughly how many eggs a woman has every month, it really has some serious limitations in terms of predicting treatment success. Where it's most useful when we're looking at doing an IVF or an egg freezing cycle and we're trying to predict how many eggs we're going to get.

Erica Newlin, MD:

And I recognize that there are tons of different protocols and treatments, but when we speak to an IVF cycle, what does that cycle entail?

Elliot Richards, MD:

Sure. So, a lot of the questions that my patients will have been, how long will this take? How soon can I start? And as I mentioned before, the process of stimulating the eggs with medications were really all those eggs that month, I mentioned there's a pool of eggs. It may be five, it may be 50. With an IVF cycle or an egg freezing cycle, what we're trying to do is stimulate those eggs with hormones. And that process takes roughly two weeks. Some patients will just take eight or nine days of stimulation, some may take 15 or more days. It's unpredictable. And so, it can be a little bit hard for patients who have a busy lifestyle, who are working.

At our clinic, we do monitor scans early in the morning and lab draws, and so we have answers by the afternoon. And what we're doing with those monitoring scans, and those are occurring every, every one to four or five days. It really depends. Sometimes they're spaced out, especially at the beginning, but as we get closer to that, after week one and into the second week, we're now having patients come back potentially every day. And so, it can feel a little bit like a part time job. They're going in the morning and they're getting this lab work and this monitoring, and then they're getting instructions later that afternoon.

And that's simply because everyone responds to these hormones differently and we need to monitor carefully as we change dosages and prepare to give what's called a trigger shot. And the trigger shot just starts the process of ovulation. But before we lose those eggs and they ovulate out of the ovaries, that's when we capture them with this egg retrieval procedure. So, as I mentioned, from start, baseline ultrasound, get going on the stimulation, to the egg retrieval, that's roughly two weeks, give or take several days.

But it often does take us a month or two to prep work. There's testing for the individual and if there's a partner, for the partner, as well. And education, and there's a lot that goes into this. And there's also a waiting list at most clinics. And they just simply, the volume, the capacity to be able to see all the people who want. So, what I would say to those listening today is that if you're contemplating IVF, you know, it's typically not realistic to say, "okay, and I want to start next week."

And then there's also just timing of your cycle, and oftentimes we'll put people on birth control for a week or two before we baseline. Because really when we start our medications, we really want the system to be synchronized. Okay, so then you have one to two months of sort of prep time. One to two weeks of the actual stimulation, then the egg retrieval. And then, the hard work is sort of done, at that point, for the patient.

And it's now, the eggs are in the lab and if they're proceeding with IVF, then the lab takes over. And that process takes about a week from fertilization to monitoring the growth of the embryo. And then at about five to six days in the lab, at that point, the embryos are what's called the blastocyst stage. They can be biopsied, they can be frozen, or they can be transferred or put into the uterus to create pregnancy in what we call a fresh transfer.

So, for a patient who has cancer, who we're having to fast-track and get those eggs out as soon as possible because they're about to start chemotherapy, we can potentially get eggs out a week or two from like, seeing them to that. But I would say for most patients where we don't have those time pressures, we're often looking at a couple of months.

Erica Newlin, MD:

What kinds of side effects might people expect from the medications?

Elliot Richards, MD:

So, allergies are extremely, extremely rare to these medications. And these medications are called gonadotropins. They’re follicle-stimulating hormone, HCG, which is the pregnancy hormone that we use as one of the treatments. And the side effects are more what they are doing to the body, not direct effects of the medication. What I mean by that is, is that follicle stimulating hormone is causing the follicles or those cysts in the ovaries to grow. And so, the ovaries will become quite enlarged, and so a lot of women will feel bloating.

They're at risk for something called ovarian hyperstimulation syndrome. They're at risk for something called ovarian torsion, because the ovaries are so enlarged that they can twist. Thankfully, those two more serious, scary things are actually quite rare with newer protocols and with precautions. But, yeah, I'd say most women will feel bloated, especially by week two. There are less common side effects like headaches and nausea. If a woman is particularly sensitive to estrogen, because these hormones are going to cause the estrogen levels to rise quite high, then there's a potential for that, too. But generally speaking, these are pretty well tolerated medications.

Erica Newlin, MD:

And then, you mentioned the trigger shot, but all of these medications are pretty much injectable medications, correct?

Elliot Richards, MD:

Yeah. It's a great point. There have been, in the last five years, oral GNRH antagonists. So, you may have on the news about elagolix and some of these others. And these are really treatments for endometriosis, for heavy bleeding normally associated with fibroids. But these are actually the same type of hormones that we use in IVF. And I would not be surprised in the next five years if there's a shift towards using these newer oral medications in lieu of the injectables. It hasn't hit prime time yet, but I do think that that's in the future. So, there are protocols and options to be pretty close to needle-free. But generally speaking, yes, most of the injections are subcutaneous injections.

Erica Newlin, MD:

And then, when someone is starting a cycle or coming to you expecting to start a cycle, are there any lifestyle modifications or things in that interim that you recommend increasing success rate?

Elliot Richards, MD:

Yeah. And you can certainly get down a really deep rabbit hole on the internet.

Erica Newlin, MD:

For sure.

Elliot Richards, MD:

When it comes to supplements and adjunctive therapies that are there. And I really caution patients that, when we think about the different variables that affect success, most of them are completely out of their control. And I think it's important to emphasize that, because when things don't work out, sometimes our first inclination is to blame ourselves. Like, what did I do wrong? Oh, you know, did I not do this, did I miss out on this supplement? Is there one other thing. There is, when it comes to egg quality, which really trumps, it's the most important thing, it's down to age. And so, until we can invent a time machine or some way to refresh or create new ovocytes, that is always going to be one of our biggest limiting factors.

Now, there are supplements that have been looked at for their antioxidant properties and maybe they might reduce inflammatory damage to eggs in an older woman. This has not been proven. I don't think it's unreasonable to try some of these, but again, deep rabbit hole and not supportive data for the vast majority of these type of supplements. We do see a benefit in lowering the BMI. And so, for high BMI patients and who we have some months to years to optimize weight, there's certainly a benefit.

And again, those success calculators that I mentioned online, take that into account. And oftentimes you can play around with some sliders and see, "okay, if I lose this many pounds, how does that affect my success rate?" So, the general things that we often talk about, a good diet, exercise, weight loss, those things definitely help. Do they make a major contribution? That's certainly debatable. And again, unfortunately, most of the factors are out of the control of the woman undergoing IVF.

Erica Newlin, MD:

What about things like caffeine intake or even just light to moderate alcohol intake? Does that show any difference?

Elliot Richards, MD:

The data's mixed. There are some studies showing a slight benefit. The other thing is that for many of these patients, if they're undergoing like, a fresh embryo transfer, we're talking pregnancy. And so, when it comes to caffeine, you don't want to make major shifts in your intake in early and late pregnancy, just risk of rebound headaches. And then, of course, obviously alcohol use, no amount of alcohol is really safe in pregnancy per the current national guidelines. But in terms of, does this play a large role and effect on oocyte quality, that has not been definitively proven.

Erica Newlin, MD:

And then, we've talked a lot about egg quality, and you mention that there's that week from egg retrieval to that final blastocyst stage at like, day five, day six. Can you describe the kind of attrition rate in that week or what embryologists are looking at during that week and what a patient might expect?

Elliot Richards, MD:

Absolutely. I'm really glad you brought that up. IVF is very much a numbers game. And one of the reasons that we look at AMH and egg count, is because really, a couple may say, "well, I just want, you know, one kid or maybe two kids. So, why is it better if I have 20, 30 eggs versus, you know, just extracting a couple?" And I like your term, "attrition rate," because when we extract the eggs, not all of them will mature, and not all of them will fertilize. And those that fertilize, not all will continue to develop. And so, all throughout the process, we will lose embryos.

And so, it's not uncommon to extract 20 eggs and then only get two or three embryos. And as long as we get a pregnancy out of those two or three embryos, this is a successful cycle. But it can feel a little bit like a rollercoaster ride, because we can say like, "oh, we got this amazing stimulation, things look really great with all these follicles," and then we don't extract as many eggs as we want just because there's not always a one-to-one ratio with an egg in each follicle that we see on the scans beforehand. And then, we do expect to lose some of these eggs, and fertilized eggs through the process. So, the attrition rate varies per patient. There's a wide range of sorts of what's normal and expected.

Erica Newlin, MD:

As far as switching gears a little bit, embryo transfer. I know there's fresh embryo transfer and frozen. What's done more commonly and when would you suggest a patient go one way versus the other?

Elliot Richards, MD:

Yeah, there are definitely advantages to both. A lot of practices, including ours, really moved to more frozen embryo transfers with the pandemic. The pendulum is starting to swing a little bit the other way. I mean, historically, fresh embryo transfer was preferred because embryo culture simply wasn't advanced enough, and embryo freezing technology and protocols so that there was a concern that, okay, let's, we've got these embryos developing, let's transfer them. Sort of this, as soon as we can, because we don't want to risk them not surviving in culture.

And so, it was very common, 10, 20 years ago, to do a lot more even day three transfers. So not even growing them out to the blastocyst stage. At our clinic, we exclusively now grow to the blastocyst stage because we're so confident in our embryo culture system. And then, we're really confident in our egg freezing protocols and survival rate that that's sort of allowed for these freeze all cycles.

The freezing cycle has the advantage of, you know, if you think about all these hormones that were just super stimulating the ovaries, they're also acting on the lining of the uterus. And there's some thought, could it be actually better to extract the eggs, make the embryos, freeze the embryos, kind of wash out the hormones in the system, and start over so you have a fresh lining that hasn't been influenced by all these high levels of hormones.

The other advantage of a freeze all cycle is that with some of our protocols, we're able to determine the exact moment that progesterone has started. Whereas a natural cycle or a fresh transfer cycle, really there's a natural rise of progesterone which may not exactly happen, but we don't know exactly when that moment happens. So, we're certainly able to synchronize things and control things much more tightly with a frozen transfer. And there's interesting data to show, and this has been replicated multiple times, that the birth weight is actually higher in babies born using a frozen versus a fresh transfer. We don't fully understand all the reasons why. There's some epigenetic programming probably involved.

The advantage of the fresh cycle is that there's no delay. You're able to immediately turn around and put in an embryo. Because it's immediate, you're not able to do the genetic testing that we mentioned, because that's another reason why we do it frozen. With the fresh, also if it's a young patient with a lot of eggs, they're really at risk of that ovarian hyperstimulation syndrome I mentioned.

And so, one of the reasons that we do a freeze all cycle is also just to let everything cool down and let the ovaries shrink down a bit and not set them up for severe ovarian hyperstimulation syndrome. So, I would say fresh embryo transfer, while it has some advantages, anyone who is contemplating going that route, they really have to be prepared to convert to a freeze all cycle if we're concerned at any point for ovarian hyperstimulation or if they decide that they want to do genetic testing. It's not a really viable option for every patient.

Erica Newlin, MD:

And then, last question, potentially ending on a controversial note with the recent Supreme Court decisions and the concern about how that might affect IVF, what options are there currently for people who may have embryos left after completing childbearing and how might political decisions affect those options?

Elliot Richards, MD:

So, yeah. Great question, and it's something that is definitely on the minds of my patients. It comes up in my consultations with great frequency, I think it's important for women and couples to know about the new political realities. Let me start by saying I don't have a crystal ball, and if someone had told me, you know, five years ago that Roe v. Wade would be in danger, I wouldn't have believed you. And so, I think anything is possible, honestly, at this point.

Erica Newlin, MD:

And then, outside of that, there are options as far as donating to research or donating to others, correct? Donating to other couples? Or individuals? If someone would like to do that?

Elliot Richards, MD:

Yeah. It's not as straightforward as you would think, because as soon as you get into what's called "third-party reproduction," so you're essentially, would be that person who'd be donating eggs or embryos, it would be akin to like, a gestational surrogacy arrangement.

Erica Newlin, MD:

Sure.

Elliot Richards, MD:

I mean, obviously it's not the same. And so, that's where there's additional regulations that are required prior to the freezing of those eggs or embryos, which are often, those steps are not done ahead of time. And so, I think that's the ideal. It's certainly technically possible, but legally, currently, there are some restrictions unless they planned ahead of time to allow for that.

Erica Newlin, MD:

Well, thanks so much for joining us. This has been a great conversation.

Elliot Richards, MD:

Yeah, it's been my pleasure. Thank you so much for having me.

Erica Newlin, MD:

Thank you for listening to this episode of Ob/Gyn Time. We hope you enjoyed the podcast. To make sure you never miss an episode, subscribe wherever you get your podcasts, or visit clevelandclinic.org/obgyntime.