Why High-Quality Embryos Aren't Implanting

This episode explores the complex factors behind recurrent implantation failure. 

I take an evidence-based approach to the role of endometrial health, different types of testing, and the impact of conditions like endometriosis and chronic endometritis.

We will discuss: 

• Recurrent implantation failure

• What makes the uterine lining receptive to an embryo

• Various tests, including the ERA (Endometrial Receptivity Analysis)

• Strategies for addressing silent endometriosis and adenomyosis before an embryo transfer

• The unique challenges faced by female physicians and stress

This is an excerpt from my webinar about the endometrium.

As always, please keep in mind that this is my perspective and nothing in this podcast is medical advice.

If you found this conversation valuable, book a consult call with me using this link:

https://calendly.com/loveandsciencefertility/discovery-call

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Please don’t let infertility have the final word. We are here to take the burden from you so that you can achieve your goal of building your family with confidence and compassion. I’m rooting for you always.

In Gratitude,

Dr. Erica Bove

Transcript:

All right, so what we're going to talk about today is why are high quality embryos not taking and when to do endometrial testing?

I have been practicing over a decade. I have been a coach for a long time now and doing fertility coaching specifically for about almost two years, actually.

And this seems to be the question that comes up over and over and over again.

And people will say to me, you know, why am I in the 5% of people for whom this should be working but it's not working?

And, you know, I really wanted to put together to get the data so we could make some progress on that question.

So again, you know, just by way of introduction, who am I?

I am Dr. Erica Bove. I'm a double board certified OB/GYN and a reproductive endocrinologist.

I do practice at the University of Vermont where, like I said, I did procedures this morning.

I'm also the founder of Love and Science, Driving Through Infertility, which we'll talk about as well.

But that is a fertility coaching practice just for female physicians to help people navigate their journeys in a way where they have success and get to the other side as parents are building their family.

I also recently became the program director of the RAI Fellowship didactics.

Actually, actually, this should actually be different. I am the RAI Fellowship program director.

And not just didactics, but the whole thing. And so that is another hat I just took on a few months ago.

And I think, you know, it was like one more thing, but I think it's really, really good because if anything, I need to make sure the fellows are as up to date on everything as possible so they can pass their boards and other things.

And that means that then I am, right, because I make it happen for them.

So I'm really happy to be able to provide that perspective as well.

And they let me loose in the world after training in 2016. So I think that's relevant as well.

I did my OPGA residency at New York Presbyterian Hospital, Columbia, New York City.

I did my RAI fellowship at the University of Michigan. And I adored that fellowship.

I stayed for three years as faculty, then went into private practice for a few years and then found my way back to academics.

So that's just a little bit about me. And in 2022, I did, I was certified as a certified coach through the Life Coach School, which if you're into the physician coaching world at all, you'll find out that many of us did go to that school.

And it's a wonderful, wonderful program.

All right. So and why did I become a fertility coach? Right.

Like there's I was like happy in my job and all the things.

But, you know, this is really important to understand is that I was seeing patients in my clinic and truly making no progress.

And I was thinking like my physician patients are not getting pregnant at the same rates as other people.

When we talk in the office, there's a lack of connection. There's analysis paralysis.

Like we are not making progress at all. And I'm not helping them.

And it was so disheartening to me that I said, I need I need to figure this out.

I need to figure out a way to help people make empowered choices, have success rates and not just be doing transfer after transfer with the same thing.

And truly, you know, my own friends and colleagues were suffering in silence.

I you know, lots of my close people were on this journey.

I was their doctor for many of them. And there was truly no community.

And especially as I was a new attending myself, you know, you kind of understand what a burden that is and how much responsibility there is.

And then add on to that, you know, being a fertility patient and having at least a part time job in terms of appointments and such.

I saw many people drop out as well. And so I was doing coaching myself at that time for my personal reasons.

And I kind of made the connection. I was like, this is what my patients need to have better treatment outcomes, to have a better experience.

And that's really when I created Love and Science. And so the point is that you're getting a physician coach at the same time today.

So, yes, you will absolutely discuss the science. There's lots of data in this presentation.

But we're also going to do this, do so from a very empathetic, safe space and a supportive community so that we can actually make progress instead of just, you know, one of my mentors says, information is not transformation. We need to take the information and then figure out what to do so that can actually help us and transform us.

Okay. So what are we going to do today in terms of this talk? We are going to discuss the concept of endometrial receptivity.

We're going to talk about why high quality embryos might not take. We are going to talk about sort of what kinds of endometrial testing are there, the data for and against them.

And also the S3 recommendations and a proposed approach. So S3 is the European Society for Human Reproduction.

They do a lot of very good work and they have like a more global perspective. And so in 2023, they just came out with a guideline and we'll talk about that because I think that's actually very useful.

And then we'll also talk about stress infertility and physician outcomes because, like I said, I was noticing in my clinics that my physician friends, my physician patients weren't getting pregnant at the same rate, same rates.

And there's actually tons and tons of data now that female physicians have worse fertility outcomes and worse pregnancy outcomes. And I'm on a mission to reverse that and to change that script.

Also, I just want to say, in this presentation, you know, this is not technically medical advice. And so I will definitely provide my perspective. I poured over the literature for hours.

But just as you sort of, if you have a question about something, please do talk with your REI in the context of that relationship.

Okay. Let's talk about the menstrual cycle. Every single thing we do in REI comes back to the menstrual cycle. And, you know, I don't want your eyes to glaze over if you're not used to looking at this.

It's actually kind of pretty and color coded. But what you can notice is that there's different lines for different things here. So on the bottom is the endometrium, which is obviously the focus of our talk today.

Then you can see the ovarian hormones kind of on the next lineup. And, you know, I will say in IVF, we really do sort of control these hormones. And so you may not see the same kind of rises and falls.

But the point is, everything in IVF is trying to mimic a normal natural menstrual cycle. So, you know, looking at this, this is kind of the point behind the hormonal changes for the endometrium.

And then, you know, if you're thinking about an ovulatory, you have a cycle, you have the anterior pituitary hormones, and then also what's happening at the level of the ovary if there's an ovulation or an IVF cycle involved in that process.

So you can see that day zero is basically the first day of menstruation when the endometrium starts to break down, as it does. And that's when we have the bleeding that happens for peer fermentees.

And then, you know, my mentor always taught me to divide the menstrual cycle into fourths. So the first quarter of the menstrual cycle is the selection of the dominant follicle.

And then from the selection of the dominant follicle, that follicle continues to grow and make estuabial so that the endometrial lining gets thicker.

Okay. Then around ovulation, which in some women is 14 days, but not every person, but the point is when it's time for ovulation, the uterine lining is then thick enough that if an embryo were to come down and implant, it would find a fertile soil to implant and to start a pregnancy.

And so really, you know, this diagram is a little bit misleading because it looks like the endometrium is getting a little thicker with time. We typically actually see the peak uterine lining at the time of ovulation.

And then sometimes we even see the endometrium compact a little bit because the sort of the glands and the arteries are doing what they need to do for, you know, pregnancy.

So what I wanted to say is that if you think about what happens in a natural cycle, ideally the egg is ovulated and that egg is fertilized by sperm, but it actually takes about seven days for that embryo to make its way down the fallopian tube and implant inside the uterus.

Does anybody else find that wild to me?

And it actually takes a full week for that to happen. I mean, it's just amazing. And so if you think about the fact that we will often do like a day five, day six transfer, and I'll do the transfer and I'll say, okay, implantation should happen in about 24 to 48 hours.

We're really talking about that midluteal phase here where the endometrium is at the point that midluteal endometrium, where hopefully the embryo will implant, the body will get the memo that embryo will start making beta-HCG.

And then, you know, that rescues the corpus luteum and then then mentes does not occur because the endometrium is maintained. I know it's complicated, you know, I think about this all day, every day.

But does anybody have any questions about like what a normal menstrual cycle is and what it should look like? Because I think that kind of sets the stage for everything else.

If we're talking about receptivity, we're really talking about what does the endometrial profile look like at that moment of implantation.

Okay.

So let's talk about expectations for success rates after uplight transfers.

It's interesting because there was a talk that came out just a few years ago that said after three uplight transfers, there's a 92% chance of implantation, of live birth, excuse me, of implantation rate of 95% and 92% chance of live birth.

So basically the way that the study goes, and it's right here, is basically looking at it like the rate of true implantation, recurrent implantation failure is low, results of three successive frozen uploid single embryo transfers.

And so they were looking at people who had had, you know, three uploid transfers and their success rates. But what I will say is the interesting thing is that data is not necessarily, we can't always extrapolate that to us.

That's the thing that I learned the most in reviewing this data.

So I read that study, you know, kind of in full. We'll talk about it more detail. That same group then kind of built upon that previous data and did a larger study.

And they said that after five uploid transfers, that the live birth rate should be 98.1%. So that's where I get that question. Why am I in the 2%? Why am I in the 5%?

So what I will say is there were so many exclusion criteria, you know, in those studies that most people were actually excluded. So I just want to make that very clear because I actually do not think that we can extrapolate this data to us for most of us actually.

And they were trying to make the point in their studies that like recurrent implantation failure is actually quite rare.

But I actually think that they weren't looking at real humans with real fertility problems. And so the data are really flawed from my perspective.

So let's look at the first study. Like I said, it was going to be evidence based.

So looking at the study that looked at the three successive uploid transfers and what the rates were. So this was a retrospective study. So we all know that retrospective studies have some limitations.

It was from 2020. Most of these studies, interestingly, are in the last five years, which kind of makes sense because if you think about like, I don't want to say we fixed the embryo problem, but we made significant advances in terms of being able to test for uploid embryos and such.

I think the pendulum is coming a little bit back on that. But you know, sort of that sort of, okay, we've done this. We've gotten to be able to test embryos and their chromosomes.

Now we need to look at the uterine lining to figure out why embryos are not taking. I mean, I think we all know that one of the most frustrating things that we can experience and from my perspective too as a fertility physician is when we put in a beautiful embryo, the transfer goes beautifully.

And then, you know, nine days later, it's a negative pregnancy test. It's truly just crushing. It really is. And so, you know, that's what they were trying to look at here.

So they looked at over 4000 patients. The protocol is important because, right, as you know, we have different FET protocols.

And they actually looked at intramuscular progesterone, so like an estrogen program cycle where people took estrogen pills or patches and then did, you know, injectable progesterone to, you know, sort of trick the body into thinking it had ovulated as we talked about that on that previous cycle.

And then they did the transfer. The inclusion criteria were people who had had at least one unsuccessful FET, which makes sense, and their criteria for the lining and the study was seven millimeters.

And again, this is not about endometrial thickness necessarily. There is some controversy there, but this at least for this study, that's what they looked at.

Interestingly, they excluded biochemical pregnancies. And so, like, I'm sure people even in this room, and I know because I know some of your stories is that, you know, if you have, I hate that term biochemical but in early pregnancy loss where the embryo briefly implants and then the betas go down, like, what does that mean?

And so, I think it's wild that this study excluded people with biochemical pregnancies because that's so many of the people who say, well, I haven't had a live birth but you know maybe I had an implantation, but it was brief, like, what do we do with that large group of people?

It's really interesting that that was excluded. Just want to say that. And also donor egg cycles too, which is also interesting.

So even though they found what they found, I think that there were so many people excluded that that calls into question how generalizable the study actually is.

Just to show, you know, one of the graphics from that study, they looked at the number of embryo transfers and then, you know, the fetal heartbeat rate, you know, was basically pretty high here.

And so what about that next study that looked at up to five consecutive Uploid transfers? And I mean, again, that assumes that people can make five Uploids because some people can't, but in this group they did look at that and they actually looked at pregnancy rates per transfer.

Interestingly, they found that the fourth Uploid transfer, the same pregnancy rates as the first transfer, very interesting data, but their inclusion study, and this is a larger study, right, they looked at over 120,000 patients, included were 461 cycles.

They looked at people who had had no positive pregnancy test after three Uploids and then based on the fourth and the fifth, like, how many, how, what can you expect to gain in those, in those extra transfers.

And of note, look at this, over 99.9% of the patients did not meet the inclusion criteria. Isn't that wild? Isn't that wild?

I just find that, I just have, we actually have pause to appreciate that for a second. They did include program and modified natural cycles.

But they did exclude people with an endometrium under six millimeters. So they did, you know, go, it had a little bit less stringent criteria for the endometrial thickness.

They also excluded people with adenomyosis, which I thought was also wild because I do a ton of G-one ultrasound. I see adenomyosis on so many people's scans, so many people's scans.

So, again, maybe that's why so many people were excluded, but I think we're going to talk about that, how significant that is, or can be.

They also excluded people with severe male factor and they also excluded donor egg cycles. And this is what they found. They found that the cumulative live birth rates are quite high, but after, especially after, you know, transfer number four and five.

But again, you really have to call into question the validity of this data and how much we can extrapolate it.

So I hope that's clear because I think, you know, I had been putting more stock in those studies up until now in this talk, truly.

But I think now that I really read the inner workings of the studies, I'm a lot less enthusiastic about the data.

I think there's a lot more people who meet criteria for recurrent implantation failure. And I think we really need to think hard about it.

So, but one of the tricky things is, is who meets the criteria, right? It's kind of like recurrent pregnancy loss.

Like, how do you define it? Some people have said four high quality embryos and people have said two, you know, and what are the possible mechanisms?

Obviously, if there's a big uterine structural issue, like a big septum or a big fibroid or a large polyp, like that can certainly affect the structure of the uterus.

But I will also say, you know, what if structurally everything looks normal? And that's the people I see, right?

In my coaching practice, in my fertility office, it's like we did the hysteroscopy, everything looks normal. What else is going on?

So people have proposed and we do know that there's an interaction between the immune system and the fertility system, right?

Especially as it involves an embryo, which is technically foreign, implanting into somebody's uterus, right?

There has to be kind of a temporary decrease of the immune system in some ways to allow for that to happen.

But in other ways, there's actually an increase of the immune system.

If you haven't listened to my podcast on the microbiome, recently I did with Dr. Katrina Coulter, kind of it goes over all those different mechanisms.

But yes, I mean, people have talked about, okay, well, maybe NK cells are involved, maybe T lymphocytes are involved.

You know, what about thrombophilia testing, including anti-phosphatid antibodies? What about endometriosis?

What about window of implantation differences? What if, you know, for some, for one person, they need 48 hours more progesterone before they're in that like kind of line that we talked about on that graph for their embryo to implant.

And what about chronic endometritis?

I think that's definitely in the last five to 10 years gotten a lot more attention in terms of a possible uterine factor issue, endometrial factor, as we're putting in good embryos and either people are not getting pregnant or they're miscarrying.

So I think it's, you know, important to think about what are some biologically plausible explanations for what's happening here.

Chronic endometritis, you know, I have a typo. I just wanted to say that, you know, even though it's somewhat controversial, I think I've read every single paper on it. I did want to highlight one systematic review and meta analysis, basically from 2022, that showed that women with chronic endometritis have a lot lower ongoing pregnancy rates and lower live birth rates and clinical pregnancy rates actually compared to those without chronic endometritis.

So the hard part is that 8% of women are thought to walk around with this like kind of on the street.

But if you look at a patient population of people with infertility and or recurrent pregnancy loss, when you treat the endometritis, the outcomes are better.

And so, you know, in this meta analysis, when they looked at it, when they cured the chronic endometritis, the odds ratio was 5.3, right, in terms of increasing the rate of live births, which I think is really important.

And I see this clinically, you know, I've treated a lot of CE in my time.

And I really do believe that it's an important factor. There's so many things that are out of our control.

It is one thing that ideally we can control. Sometimes it's hard to clear admittedly, but it is one thing that we can address to try to improve the environment that makes sense.

I wanted to talk about the area as well. And this is also rooted in a lot of the questions that came in prior to this talk.

I have done a lot of ERA in my career, just because when when that first study came out that was actually funded by the company that makes the test, it showed an improvement in live birth rates after ERA. And there was actually a paper that came out about the personalized embryo transfer.

I don't know, but I mean, I'm all about individualized care and personalized medicine.

But when I hear that title, it actually makes me kind of nauseous because I just there's something like shouldn't every embryo transfer be personalized, you know?

But that's what they called it. And so even at the time we were doing it, we did not know what it was.

We just knew that there was a paper that showed that it improved live birth rates.

And basically, now we know that they were looking at 238 genes.

There's an algorithm. But when patients would say to me, Dr. Bove, like, what is it? I'm like, I don't know.

It's really crazy. Like, let's test your endometrium. It's going to give me your report at the end.

But I don't even know what it's measuring, which was like a little disconcerting.

And so I think, you know, what I would get is I'd get like a report that would, you know, we basically go through a mock embryo transfer cycle in every other way.

But the embryo transfer on the day we would normally transfer an embryo instead of doing that, we do an endometrial biopsy.

And then we'd send that tissue off for analysis. It was very finicky. If you sent too much, they'd reject the sample, whatever, whatever.

You know, we got it. And then about two or three weeks later, they'd send back a report saying either this patient is receptive, which is about 60 percent of patients, or about 40 percent of patients would get, OK, this result is non-receptive.

You need to do this progesterone correction of, you know, it would either be pre-receptive.

So, you know, you could sort of say, OK, well, this person needs 24 hours more progesterone or 12 more hours of progesterone or post receptive, meaning we need to decrease the duration of progesterone from the time of it starts to get that person in the correct window of implantation.

Now, I will say since that time, this has been debunked, you know, there may be a very small subset of patients who might still benefit from this.

I think it's to be determined. But this was very much in favor in the past.

And now there's actually data to say that it might actually show some harm and that outcomes might be worse if you employ this testing.

And so I wanted to go through that because I think all of us, our eyes are kind of catching up to speed on all of this, especially if they're in my mid-career generation, where this was like really people really had a lot of stock in it.

I think now with newer data that's not being funded by the company that makes the test, I think that we're learning more and more.

So there is a study that came out in 2022 by Cozolino. It was retrospective.

Again, we talked about limitations of those. The inclusion criteria were at least one unsuccessful embryo transfer.

They included over 3000 autologous cycles, meaning it's from somebody's own biological eggs, and over 2000 donor egg cycles.

So pretty good numbers. And what they found, and I want to sort of color, I'm a color person.

This green line is the personal embryo transfer, and on the y-axis here is the sort of the delivery rates, right?

And you can see you have fresh embryo transfer and frozen embryo transfer, and this is the number of transfers on the x-axis here.

And the personalized embryo transfer, which is based on the ERA data, is actually much lower than either of the two combined for not doing the ERA, which is really interesting.

And this is in somebody's own oocyte autologous transfers. And then if you look at the data for the same thing, basically for PGTA-tested embryos, so that's where you actually know the chromosomes, you can see those differences persist as well.

So you have your frozen embryos transfer data, which continues to go up after you keep doing more transfers.

But if you keep the ERA data and use that, there's a ceiling on your likelihood of delivery.

So I think, like we said, outcomes actually may be worse if people hang their hats on the ERA data.

It's really important to think about. And like I said, about 40 percent of ERAs will come back non-receptive, even in people who have no sort of recurrent implantation failure, et cetera.

So it really does call into question the sort of whether it's a helpful test or not.

Then we have an RCT, right? We know that's the gold standard in medicine for data, right?

And so this wonderful human, Nicole Doyle, did a study looking at if you just do this before you do an embryo transfer, is it actually going to help?

They looked at 767 females. The first group was sort of randomized to getting an ERA and then correcting the progesterone timing prior to a transfer.

And then the other group was randomized to a standard FET at the standard timing, regardless of receptivity test results.

And their primary outcome was actually live birth at 23 weeks of gestation or beyond.

And they found that the rate of live birth was not different between the groups, which is really, really interesting, suggesting that you go through this rigmarole of like practice embryo transfer cycle, you wait for the data, you might even do another mock depending on that data to prove the concept, but that might even not come back appropriate.

And so I really think we have to be thinking about whether we need to be doing this because there is more and more data that it doesn't make a difference.

Okay. Everybody doing okay?

Need a bathroom break? Need a water break? You guys are good. I'm going to take a sip of water.

All right. What about silent endometriosis?

Because even though endometriosis is by definition outside of the uterine cavity, like it certainly can affect the uterine environment because of the connections in the body between the two.

And so there are good data that endometriosis does negatively affect fertility, both in terms of egg quality and embryo transfer data.

I usually quote that if somebody has endometriosis that their success rates for transfer are going to be about 10% lower than somebody who does not have endometriosis, which is substantial, especially if you're thinking about the ceiling being, you know, 50, 60, 65%.

You know, that could be a 20% difference in pregnancy outcomes.

So they looked at actually treating endometriosis, which is the sort of the endometrial glands and stroma outside of the uterine cavity, before people underwent a fresh cycle.

And both of these studies showed a benefit in terms of IVF outcomes.

And then also, if you look at data for endometriosis and adenomyosis, there's data that if you actually suppress the endometriosis and the adenomyosis prior to an embryo transfer, that the success rates are actually higher as well.

And some of the endometriosis data is controversial, but we have pretty good data.

They've looked at Lupron alone.

They've looked at Lupron post-letrasol.

There is a study that shows that Lupron plus letrasol combined has better outcomes compared to Lupron alone.

So I really do think that, you know, we need to be thinking critically about endometriosis when present, as well as adenomyosis.

And really, it's all about optimizing the environment.

There are some physicians who do what's called BCL6 testing.

And I wanted to mention that because it is technically a form of endometrial testing.

It's the same thing.

It's an endometrial biopsy in the luteal phase.

But there's a high false negative rate.

So that means that a lot of people who have endometriosis actually don't get identified as having endometriosis and are not treated.

And so if it were my patient, I wouldn't want to go on that data alone because I don't think the test characteristics weren't enough to trust that data.

Surgery for endometriosis remains the gold standard, although there can be, you know, in terms of -- well, I would say in terms of diagnosis, right?

We always say endometriosis is a pathological diagnosis when you have glans and stroma diagnosed by the pathologist.

But now that our imaging studies are getting better, you can actually do a pretty good job diagnosing endometriosis, you know, presentively on ultrasound, especially if it's stage three, stage four disease when you can see an endometrioma.

Or also MRI can be useful too, especially if there's, you know, disease affecting the rectum or deep, deep infiltrative disease as well.

But so, you know, it's -- the question is, if you can diagnose it, then do you do Lupron plus Lutrazol before a transfer?

Or do you do surgery plus Lupron plus Lutrazol?

I mean, there's all different ways to think about it.

But the thing I would say is I wouldn't trust the BCL-6 alone.

And I would say some sort of suppression, whether it's medication alone or medication plus surgery or surgery alone and then moving forward, something to address the endometriosis before a transfer, I think, will increase success rates based on data.

Okay. So what does this European guideline have to say to us about recurrent implantation failure?

This is a pretty extensive article, actually very interesting if you decide to read it.

And it does go through, okay, well, what are the factors that relate to implantation?

Age, you know, certainly age is important.

Of note, I will say as an aside, one of our maintenance of certification articles this year for OBGYN and REI, you know, boards, we have to do these every year, is on looking at euploid embryos and how women over 35 actually have lower success rates with euploid embryos compared to women under 35, which I think is just really relevant because I think so many of us women, female physicians, defer childbearing until we're further along in our training.

And oftentimes we're trying to put in euploid embryos at kind of older ages.

I've always thought that women over 40 had worse success rates.

There's been some data to refute that. Again, this is one study.

So I don't want to say that it's a literature review, basically a systematic review and meta-analysis.

But there may, what I'm trying to say is that age actually may play a role in implantation in a way that we may not have appreciated prior.

Hormone response, certainly, you know, making sure that if somebody is taking estrogen/progesterone, that they're actually absorbing it.

I'm going to reference the microbiome podcast again.

We talked about how intertwined the microbiome is with progesterone and glycogen and the ability to grow a lining.

And so there is definitely, you know, how we absorb the hormones is very important because we need the hormones to attach the receptor in the target organ to then have its desired response.

So we often will check, like, you know, estradiol levels as we're doing pros and cons transfers or we'll check progesterone levels.

And I think, you know, that doesn't always translate into what's happening at the level of the tissue.

But I think it can be helpful just to kind of understand the endocrinology part of it.

Endometrial and uterine status, certainly understanding the structure is important, certainly understanding if there's any lesions or structural abnormalities.

And also how the endometrium looks.

I'm actually going to give a talk in a couple weeks about the endometrium.

So I'll keep you posted with some pretty pictures on that.

But I think that it's really important to do that evaluation.

I think pretty much everybody agrees on that.

It's not really controversial.

Embryo competence, I wanted to mention because I think that we falsely look at euploid embryos and say, oh, well, this is euploid embryo.

It should take.

Or, you know, I got to my euploid embryo, like, it's going to work.

And I think we have to remember that, you know, even euploid embryos might not be competent.

And that it might not just be a uterine issue.

There may actually be some embryonic issues that are related to implantation failure that may be playing a role.

So that's when I counsel a patient after an unsuccessful euploid transfer, we do talk about, you know, embryo competence factors and uterine or systemic factors that might be playing a role.

The ploidy status, which is the chromosome status of the embryos, whether it's 46XX, 46XY, that certainly, you know, we know that tested embryos have higher pregnancy rates than untested embryos.

But again, now with that conversation about mosaicism and that we're learning more and more that maybe the PGTA data are not as accurate as we thought initially, you know, I think it's important to keep that as part of the conversation.

Always looking at previous implantations, I will tell you as a specialist, I think very differently about people who have had that interaction between the embryo and the endometrium, even if it hasn't worked out in a live birth.

I do think about people in that scenario differently because that's another step in the process has happened. And then we have to figure out, okay, where are things still not moving forward?

Male factors, you know, there's been a lot of research recently into the role of male factor infertility and in it, there may be a role in embryo development, especially the day three to day five progression.

So it depends if you're transferring day three embryos or day five embryos. That's a whole other area. But again, just to sort of big picture, these are the things that the S3 document thinks about.

And then also external factors. I mean, let's be honest, not every IVF lab is the same. And so if you are a patient at a place with an excellent IVF lab, then that may not be as much of a variable.

But truly, you know, I'm grateful to practice a place where I fully trust my lab, but we all know that there are other places that maybe don't have as high success rates.

It's really hard to sort out this data, by the way, because SART is not always, you know, it really depends on who you accept as your patients in terms of how your data looks overall.

But I think that the performance of the lab in the clinic is a very important factor because if you're not at the best lab, then, you know, then those embryos might not have as good of a chance, no matter what you do, right.

And that's important to consider as well. And then also we know that, you know, especially politically, there are different policies in different places and people have various reasons of putting in different numbers of embryos, even if the guidelines are the same across the board.

So we have to also think of like the political and legal climates as well.

So what they say in their guideline is, and to be clear, recurrent implantation failure is a phenomenon specific to IVF, right, because we don't really know what's happening inside the body.

We can talk about recurrent pregnancy loss, right. But recurrent implantation failure means that we are putting in embryos and they're not taking.

Or, you know, I kind of think about biochemical pregnancies along the same spectrum, like there was a brief implantation, but then it didn't continue.

So they look at if somebody's had at least two embryo transfers where a pregnancy has not resulted, then we do this calculation.

And I will be very clear, like I'm not going to do this calculation because I think it's kind of very intricate.

And I'm not sure, like I think there's other ways of getting this just all without doing this whole mathematical equation.

But their whole point, let's like think for us instead of trees, their whole point is that if your cumulative chance of implantation and pregnancy should be over 60 percent at this point and you haven't yet gotten pregnant, then that's when we do the evaluation.

And so, you know, they and that is actually two untested embryos or two tested embryos across the board.

If you've had two, you put embryos no matter your age range, they recommend evaluation.

If you are have untested embryos, then you do the calculation and then based on your age range under 35 is one range, 35 or 39 is another range.

And then, you know, 40 and above is another range. Then, you know, you sort of obviously you've had like four untested embryos at the age of 40.

That's very different than if you've had four untested embryos at the age of 30.

So there are those differences there. But if you think about it, if you sort of should, I hate to use that word, but like if the success rates for somebody in your situation in general are over 60 percent and it hasn't yet happened for you and you've had two transfers, that's really when they suggest the evaluation is started. Does that make sense? Yeah.

I will also add my own caveat because I have to. If it's taking you three or four cycles to get to one, you put embryo.

That's a situation where I would individualize the care and just say, like, we're not going to wait for this not to work.

We're going to start this sooner because if somebody worked that hard for that embryo and we don't know if or when they'll be able to get to another one, that's a situation where I also, you know, think more strongly about it.

Also, you know, donor cycles are extremely expensive, too. I know the data we reviewed excluded those patients. But I also think that if somebody's, you know, has limited embryos and, you know, so much to get to them in many, many ways.

I also think differently, a little bit differently about people in that situation as well.

Yeah. So the big picture here is I think, you know, we should look at the green and the yellow and they don't recommend the things that are on the red.

And so they're recommended testing for people who, you know, sort of have have not gotten pregnant despite a greater than 60 percent expected chance of pregnancy to reassess the lifestyle factors.

I will tell you, my people are doing things the way they should be. Sometimes partners will have some, you know, smoking or vaping or marijuana or something like that.

Most of my female physicians are doing like are like overdoing it right in terms of the things that are lifestyle factors. But yes, you know, alcohol, caffeine, smoking, nicotine and even BMI they talk about in the article just in terms of looking at that.

Looking at the endometrial thickness, I would add also the appearance because I think that the more recent data that's coming out is looking at the qualitative nature of the, you know, endometrium, not just the quantitative nature of it.

In terms of the anti-phosphat antibodies, there's actually good data that people with recurrent implantation failures should be tested and that perhaps giving Lovanox might actually help with implantation and sustained implantation.

So that's important to think about. And that's actually in their highest quality green recommendations.

Can be considered, you know, I'm like a leave-no-stone-unterne kind of a person. So they talk about karyotyping for both partners.

I think that's a little more relevant if people have been transferring untested embryos, although there are some situations where people have, you know, a very small mutation that's not picked up on typical PGA testing.

So, you know, that's something to think about depending on the number of embryos transferred and also the reproductive history of each person in the couple if there is a couple involved.

3D ultrasound/hysteroscopy, I will generally choose hystere--well, I like them both, but I think hystereoscopy allows for a visual of the endometrium.

Sometimes I look at an endometrium and it's like very gray and doesn't look very healthy. Other times I look at an endometrium and it's like very beefy red and looks like there's a lot of endometritis.

And so, you know, just the structure of a 3D is not going to entirely help me. It does provide the external contour of the uterus, which of course we can't see with hystereoscopy alone.

But some sort of, you know, most people in the fertility clinic are getting at least some two-dimensional ultrasound and if something looks strange, we can always follow it up with 3D ultrasound as well.

Endometrial function testing, that's, you know, sort of the ERA. We talked about that. You know, I probably have three patients in my whole career, I think, got pregnant based on an ERA timing and they wouldn't have otherwise.

But again, it's hard to say. They've also--they also had, you know, more and more and more transfers and so would they have gotten pregnant without the ERA? Really hard to say.

I'm a believer in chronic endometritis. We talked about that. Testing and test of cure, right? We want to make sure it clears before people move forward, ideally.

And assessment of thyroid function, there are data that people do have higher rates of miscarriages. But again, you know, what's the line between recurrent implantation failure and recurrent pregnancy loss as well?

I think thyroid is a low-hanging fruit, pretty easy to treat. My thoughts about thyroid testing is that if basically the TSH is less than four and somebody does not have anti-thyroid antibodies, that's the goal.

If somebody does have positive anti-thyroid antibodies, the goal is less than 2.5.

And then pedestrian levels, you know, that's an interesting topic. I think that this sort of goes along with, like, some thought about endometriosis and progesterone resistance and, you know, what's actually happening at the level of the endometrium.

We do check progesterone levels in my practice. You know, generally we like the progesterone level to be between 20 and 40 in an IVF cycle. If it's 19, are we going to lose sleep over it? Probably not.

But I think that seems to be the sweet spot based on a lot of the data that we've read.

And then, you know, what has not been shown to be, you know, evidence-based, interestingly, vitamin D testing, microbiome profiling, natural killer cell testing, T lymphocyte testing, blood cytokines, a lot of that, like, sort of reproductive immunology stuff.

That's what's really thought to be not helpful, at least not in 2025, maybe later we'll see.

And DNA fragmentation has also not been shown to be helpful because I think the thought is if you can get to a quality embryo, then it shouldn't really matter about the DNA fragmentation.

And there's data to show that actually.

Okay, so now let's say what about physicians, right? So we know that female physicians do have higher infertility rates.

One in four female physicians has infertility. One in three female surgeons has infertility.

People say, "Oh, it's just because of deferred childbearing." It is not just deferred childbearing. We need to just get that straight.

We have stressful lives. We lose sleep. We take care of very sick patients.

There's now data that female physicians, you know, die earlier than other groups of people.

I mean, I think we really need to be looking at this.

And so if you look at age matched to non-physicians, female physicians still have higher infertility rates. And that's really important to think about.

Also, higher pregnancy complications. I know some programs that are looking at call during the first and third trimesters and, you know, really focusing on trying to reduce the burden.

But like if you're in a division like mine where we're, you know, sort of missing a faculty member due to disability and other things, like, it can be really hard to say, "Well, then who's going to do the work?" And that's a really tricky question that I help people with all the time.

And maybe it's like going to your chair like I did yesterday and I'm like, "We need help. Like, you need to help us." Like, I don't know what the solution is, but I think we have to use our voices because I don't think the answer is like, "We just have to keep sucking it up," like we were told in residency.

I could go through this data, but I won't. There's so much data in the last five or so years about, you know, female physicians, female surgeons, infertility, pregnancy complications.

Even wives of male surgeons have worse outcomes, which I find interesting. You know, there must be something stressful about the lifestyle in general.

Female surgeons, you know, hiring fertility rates, pregnancy complications again, and also, you know, this article down here, and also surgery calls for a culture change, which I absolutely 100% think we need a culture change, and that's largely why I'm here today.

But let's talk about the silent variable, which we have not really talked about as of yet, which is stress and infertility.

There is a PhD scientist, Ali Domar. I adore her as a human. I adore her as a researcher. She has an article, and if you haven't read it, it's a good one, from 2018, that talks about how the difference in success rates is not explained by age alone.

And, and basically, you know, this, this is talking about, well, I should say female physicians, this is my this is my interpretation of her research as we would apply it to our population.

You know, when she looked at people who came in for their first new patient infertility appointment, 40% of the women met criteria for anxiety or depression.

And if you look at the literature, it's 25 to 60%. And if you also look at the cancer literature for people who go to their first, you know, cancer intake appointment, those data are very similar so so people with infertility are having similar anxiety and depression rates to people with cancer, which I think it shows what a threatening diagnosis it really is.

Dr. Domar found a dose dependent relationship with each unsuccessful cycle that anxiety and depression rates went up.

She also quoted a study, looking at IVF patients and looking at hair cortisol levels because hair cortisol looks at the stress levels in the last three to six months, and that correlated with a lack of success in terms of IVF outcomes so that the higher the, the cortisol levels in the hair fall in the hair, the higher the lack of success so the less success they had.

Also, she quoted a study looking at salivary alpha amylase levels, and that the higher the alpha amylase levels in the saliva, the more infertility and the increase time to pregnancy.

And I think that's really important to think about as well.

Then it's like okay well what do we do about it you know we're stressed. Her research actually shows because she does these mind body programs are fantastic.

She actually shows decreased when you decrease the depression anxiety with people with infertility, you actually increase the pregnancy rates. So I get asked all the time well what about stress like this is the variable I think we're not talking about enough and you know it's hard because I think we can't use it against ourselves we can't say oh well you're just stressed and you just need to decrease your stress and then it's going to work.

It's like telling someone to like, build a house without tools, you know, it's one of those things where we have to figure out how to translate the tools give the tools so that this can actually happen, so that things will flow and I'll tell you, I've seen this time and time and time again in my patients and my clients. There are so many women who have had success when they are able to employ these tools. And I mean, we'll talk about it but I personally believe that it affects uterine receptivity.

So how does stress negatively affect fertility. I mean there are limited data and I think when people report their own stress levels sometimes they under report and such, it's a hard thing to measure.

But I think we could all agree that stress, you know, decrease with the quality of life for sure. And it makes relationship issues worse.

I think marriage is split over infertility not infrequently, not infrequently which is so sad.

I think, and again, well, you know the hyper vigilance that that is experienced during the particular journey like is my clinic getting it right are they going to make a mistake, what if I mess it up like what if it doesn't work like that sort of chronically stressed state that leads to chronically high cortisol. We know that chronically high cortisol increases blood pressure and heart rate.

So my theory and again, I don't have specific data to prove this I would love to do some research and figure it out. But my theory is that people who have high stress have lower uterine receptivity.

I think that's why I see so many people positions with recurrent implantation failure because this is a variable it's never the only thing but I think it's a variable that we really need to pay attention to.

So when it happens on the fertility journey with stress. We have what I call analysis paralysis so kind of going over the same fertility treatment options over and over again not knowing what's the best for us, being afraid that we're going to make a wrong decision.

Maybe having less meaningful follow through maybe we don't, you know, talk with the idea coordinator about, you know, the next protocol step maybe we don't schedule the hystereoscopy maybe you know, maybe there's something that's holding us back because it's like a blind spot, it's just a painful thing and we can't address it. I saw somebody in my office today or not today this week, a physician who just said like I think I've been avoiding coming in and now I know I'm older but it is what it is and I hope I hope you can help and that's just the truth we avoid that which is painful for us.

I think you know when we're in a state we can often make more mistakes again, mindful self confession, now but like we can make mistakes with our medication or forget to give meds or things like that.

And we also, you know, because of sort of the way that things call us we can have some optimal treatment cycles, and many people there's actually good data about this that that many people drop out of treatment on the sooner side because it is just so hard. It's financially expensive. And, you know, actually that one of the one of those earlier days we looked at in terms of numbers of you put embryos, if people didn't have more you put embryos they were just like, we can't go through this again and then a lot of those people got a treatment as well. So I think we have to look at like, yes, there's the journey and there's the science, and there's this whole other emotional component that makes the science work less well, if that makes sense.

So I just want you to close your eyes for a second and just think about if you actually had decreased stress in your life, like what would that look like, you know you are going to the fertility clinic you're still doing the things you need to do.

You're still showing up at your job, but you feel lighter. Right. And so, what if you could be in a place where you were felt calm and grounded. What if you started to trust the process and trust your body.

And believe that at least it was possible that your next transfer might work.

What if you were in the room with your partner and you felt like you were finally seeing each other, like maybe they were seeing you for the first time in a while because they actually got how much this is affecting you and how important it is, you know, and imagine if you didn't feel so isolated anymore because we all know how isolating this is and I think that the isolation worsens the hyper vigilance versus worsens the stress, which again you know starts the whole thing and so what I love helping people with is decreasing their stress, so that this is just a part of their life it's not the whole thing. We talked in our support group, last week about you know experiencing joy along the fertility journey. And I can tell you I have story after story after story of people with years of infertility, and they didn't know why female physicians specifically who have learned some tools to decrease their stress to ask more empowered questions, and it works. I will tell you it works and it's amazing when it does.

So what I would say is, you know, a brief word on, you know, stress reduction and how we can accomplish that. I really do believe that a good fertility coach and I say good because there's a lot of people who hang a single after a day of training.

And why you need both is because this is me on the left hand column in my REI office doing my best day to day with a broken system. And this is me sort of my coaching hat being able to help somebody fully in the full context of their journey.

And so, you know, in my in my clinic visits right like I can offer emotional support during the office visits. But if there's a question or something that happens in between. It's just not that easy right like my team gets my nurses, they can reference the my chart, but it's it's not that same sort of like real time. I can get in touch with somebody who really understands the physician level nuances of all of this.

We all know that treatment plans are often communicated by, you know, nursing teams and although like I have fantastic nurses. Sometimes the questions that especially doctors ask are not able to be answered by the nurse right and then it's like this whole waiting for the answer and all that stress that comes with that.

And I think that, you know, a lot of the limitations of the current healthcare system with delays and scheduling and other things can just create a lot of stress and at some level, the system, it can be very hard to be a patient in the context of a broken system.

And what I will say is, how do I, how do I add to this in terms of what I feel that people actually need emotional support right in between the office visits and so if somebody has a win or a procedure or even bad news in community we navigate these things and then we have a lot of other, you know, ongoing support to say okay well you're going to have your follow up appointment with your REI, how can we prepare you to go to that appointment and ask the most high level questions possible, rather than being like, oh shoot I'm a cardiologist I should have paid more attention to med school, and all these, all these things are out of my comfort zone right so it's more about that empowerment to say okay, how can we make this as high level as possible.

How can we add to what's already being done. And then also like we talked about today the scientific explanations and perspectives that are tailored to your particular situation your evaluations your treatments.

And I think this is one of the biggest things is full belief in you and I'm saying you because there's so many beautiful strong people positions here.

But believe in you and your ability to become a parent, or to grow your family, because I think this process is very soul sucking and I think that a lot of times, it is just the natural process to lose hope, especially bad news after bad news after bad news.

And I think what's missing is this notion of authentic hope which is hope grounded in science. And that's that's what I love doing so like if I ever do like a console call with somebody I'll say okay these are your factors for authentic hope, whether it's, you have this many embryos frozen or you've been pregnant before or, you know, you have robust ovarian reserve and you could generate one bros, whatever it is.

And I always make a list specific to each person because if we don't do that, all the bad news is going to drown it out and it's like, well, why do I, why do I even try.

And then we have all those negative vibration feelings and hyper vigilance and that makes the process left, left accessible. So what I love to do as a coach is I love to help both my patients and my clients fully believe in themselves which sometimes comes through a mirror, so that people can trust their bodies again and and and finally have successful outcomes. And I think that comes with stress reduction and uterine receptivity and all the things in between.

So what I would say is, you many of you know me from the Facebook group. I am super passionate about helping women on their fertility journeys. I absolutely love to connect I have a podcast which goes, the topics range from everything from, you know, this is harder than it would be to birthdays to the uterine microbiome you know we talk about, I will say the science the episodes do get the most downloads and so I'm always open to what topics people want to hear about, I will probably also release this as a, as a podcast just because I know people want this information so badly. But these are my links the link to my website where you can book a discovery call with me if you, you know, heard something that resonated and you'd like my perspective on your situation.

We have support groups we have one on one coaching we have a combination we even have a book club coming up for members which I'm really looking forward to. So, I just wanted to share that's who I am that's what I do I will keep showing up in the Facebook group and empowering but I want to share this talk elucidated kind of what the thought is behind and a mutual receptivity issues and lack of implantation, and, you know, what's evidence based what's not evidence based what's in the middle, and, and maybe what we can do about it.