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Kristyn Hodgdon:
Hi, I'm Kristyn Hodgdon, an IVF mom, proud fertility and women's health advocate, and co-founder of Rescripted. Welcome to Dear Infertility, the first-ever podcast that doubles as an advice column for all things fertility and women's health. This season, join me along with Dr. Nicole Yoder, a fertility specialist at Spring Fertility in New York City, as we explore what to do when you're trying to conceive and feel like nothing is working. From when to seek the help of a fertility specialist to what questions to ask when IVF fails, we'll address all things fertility troubleshooting so you can become your own best reproductive health advocate. Now, let's dive in.

Kristyn Hodgdon:
Hi, everyone, and welcome back to Dear Infertility. I'm your host, Kristen, and I'm here with Dr. Nicole Yoder, a fertility specialist at Spring Fertility in New York City. Hi, Dr. Yoder.

Nicole Yoder:
Hi, Kristyn. How are you?

Kristyn Hodgdon:
Good. Welcome back. I'm particularly excited about today's topic, which is implantation failure during IVF. And because, as many of our listeners know, I've had five either failed implantations or early miscarriages with genetically normal embryos in the past two years. Done a lot of healing since then, so I'm more than good to talk about it. But I am really excited to hear your take, and I think it'll be really helpful for anyone who is in the same boat and doesn't know where to turn next.

Nicole Yoder:
Yeah, and I'll say, just from the get-go, this is a tough one. This is if you have recurrent implantation failure; by definition, that means you've been at this for a while. And it can be medically challenging, but also really emotionally challenging to have this be in part of your story.

Kristyn Hodgdon:
Yeah, absolutely. I always say I would take the injections every day over, like the mental load of just all of the appointments, and we talked a little bit about embryo transfer protocols last episode. There's not even like a ton of appointments involved with medicated frozen embryo transfers, but at the same time just gearing up for it. That hope, balancing that hope against the grief of like previous failed cycles. It's just a lot mentally and emotionally. So I'm excited to dive in and really just wanted to start with what defines implantation failure because is it you've had one failed transfer, or is it you've had three failed transfers?

Nicole Yoder:
So I'll start by saying to get this diagnosis, you already have to be doing IVF. So, for people who are trying on their own, who haven't gotten the IVF and the embryo transfer part yet, not really part of that picture. But if you are doing IVF and you have done embryo transfers, it's a little bit of a controversial definition. But generally, the thought is if you have had 2 to 3 transfers, that in our minds are a good prognosis, and they have not resulted in pregnancy, then that kind of groups you into this category of recurrent implantation failure. Now, whether we drawing the line in the sand at two versus three or more, it's a little bit up to the overall picture. So, we're taking into account maternal age embryo quality. Is that embryo tested? Is it not tested? What type of morphology did that embryo have? So all of those things are going into that picture of, did we expect that this embryo was going to take what were our expectations? And after putting the whole picture together, then we decide, okay, does this meet that category of recurrent implantation failure?

Kristyn Hodgdon:
Okay. And I'm sure there's a difference between, like, genetically tested euploid normal embryos versus untested, right?

Nicole Yoder:
Yeah, absolutely. So if we know that those embryos were tested and are testing said that they were chromosomally normal, that's going to increase our prognosis for you. So, we expect that normal embryos are going to implant more often than untested. With the untested ones, depending on your age, there may be a good chance that they're not normal. And that explains everything. So that's why we really have to think of this differently when we have tested versus untested embryos. So, for example, if I have a 44-year-old who has done three untested transfers, I'm not surprised. I'm not going to put you in this category. But if I have a 25-year-old who has done three tested transfers, and none of those worked, that's not normal. So, different pictures.

Kristyn Hodgdon:
Yeah, no, I'm always in the back of my head. It's like a chicken and the egg situation. Sometimes you're like. I'm like, is it the embryos, or is it my body? Is it the embryos or my body? And that can happen too, where you don't know with a good embryo when that doesn't implant, is it actually just something with your uterus or. Yeah, autoimmune-related, or it's just so there's not really one definitive test. But I know we'll get into some of the diagnostic tests that you can do if you're dealing with recurrent implantation failure. But first, what are some of the common causes of implantation failure during IVF?

Nicole Yoder:
Yeah, you really hit the two big categories. So when we see this happening, the first thing that we're thinking of is, okay, is it the uterus, or is it the embryo? Those are two pathways that we're going down. If it's a uterine factor, it may be something about the uterus itself. Structurally, maybe there's something going on with the uterus. Maybe there's a septum, maybe there's a fibroid, maybe there's some fluid in the uterus. Maybe that fluid is coming in from the tubes. Something about the uterus could be impeding that implantation. Or along the same lines as the uterus, some maternal factor. Something about maternal health. Is there a thrombophilia or making blood clots? Is there an uncontrolled medical condition going on in the background that might be impeding implantation? So, something about maternal health as well. So, something on the uterine or maternal side is that first category of causes. Other things are the embryo. Is this embryo good quality? Does this embryo, is there something about the embryo that makes it not likely to implant? Is there something genetically about the embryo? And this is where we get tested or not tested. What are our limitations of testing? Maybe we tested it, and the testing came back said it was normal, but maybe there's some sub chromosomal abnormality we don't have a good test for. And that's what's causing everything. Really, when we think about the causes, it's those two big categories. And then we're parsing it out into the subsets of those two major categories.

Kristyn Hodgdon:
It's so interesting. And then there's sometimes just like no explanation.

Nicole Yoder:
A lot of times, there's no explanation. And that is one of the most frustrating things, is that a lot of times we do the whole workup, and the whole workup is negative. And that's super frustrating, as you said.

Kristyn Hodgdon:
Yeah, I know so many fertility specialists and clinics, and I myself am like a big advocate for PGT-A testing. But when I transferred my untested embryos, that's what gave me my twins. And then, when I transferred five genetically normal embryos that were tested after the fact, none of them implanted. And my uterus looks like base, for all intents and purposes, looks hospitable.

Nicole Yoder:
Yeah.

Kristyn Hodgdon:
So it's okay.

Nicole Yoder:
Yeah.

Kristyn Hodgdon:
It's so hard to move forward. And when you're in that position because you're like.

Nicole Yoder:
Yeah.

Kristyn Hodgdon:
I, you almost want like something to fix, right? Like you almost want there to be.

Nicole Yoder:
Exactly. Sometimes, it's more satisfying to have something come up in your testing because it's aha. At least maybe you can fix it, and you can't fix it. It's an answer. And that can be both frustrating things like mentally is like not knowing which one it is, not knowing which category it is. Because if we get at least narrowed down to one of those two categories, in which direction we need to go?

Kristyn Hodgdon:
Yeah. Absolutely. So, one of your patients has a failed embryo transfer. Do you right away think what tests can we do to prevent this from happening again? Or is that something that you would just say, oh, it might have just been that 40% chance of not implanting, and we will wait to see what happens with the next one?

Nicole Yoder:
Yeah. Typically, after one failed transfer, we're not going down this road of doing all of the tests quite yet. Now, there may be some things that we are on the fence about testing beforehand, and maybe one will tip us over the edge. So we're always looking at the patient as a whole and their specific background, but usually, we're going to wait till at least two transfers have not worked because even with the best-case scenario, best uterus, best embryo, really expect the pregnancy rates to be about 65%. That gives a large proportion, and we just expect won't work. So usually, we're going to start this work up after two.

Kristyn Hodgdon:
Yeah okay. And then what? And what do you typically recommend after two negative pregnancy tests after IVF transfers?

Nicole Yoder:
Yeah. So this is where we're going to start going down those testing processes to evaluate the uterus. And then any other health issues that mom may have. And then also taking a good look at those embryos again. So, in terms of an evaluation for the uterus, oftentimes, we're going to do further imaging, which can include a saline, an HSG, or that tube test. Maybe we didn't think we needed to do at the beginning, but maybe there's some subtle issues with the tubes that we didn't pick up on before that may be affecting the uterus. And sometimes, most often, I would say we're going to do a hysteroscopy and just look inside with our own eyes. Because honestly, even with an ultrasound or an HSG, there's nothing quite as good as seeing that uterus and that uterine cavity with your own eyes in a camera. So a lot of times, we're going to do a hysteroscopy and take a look, maybe get a biopsy sample, see if there's any inflammation, see if there's any structural things that we couldn't detect before. But that's really going to be the first pass evaluation for the uterus itself. Now, the other workup that we're going to do is probably going to involve a set of blood works, and we're going to update all of your sort of routine blood work, including thyroid, hemoglobin A1C. Make sure all your other health conditions are okay. Probably going to add on a thrombophilia workup; see if maybe you have never had a blood clot. Maybe you have no history of it. But sometimes, we do this thrombophilia workup, and we find something there. Karyotypes is another blood test that, depending on the situation, you may draw at this point, or you may wait until more. But that's another thing that can be looked at with this recurrent implantation failure. And then maybe, in extreme cases, there are some other more rare tests that aren't routinely done. But some stuff like immunological workups do come into play. But that's usually further down the road. Maybe not after two failed ones, but three, four, then we're starting to look at those types of workouts.

Kristyn Hodgdon:
What is an immunological workup entail?

Nicole Yoder:
Usually, there are people who are going to specialize in doing reproductive immunology, and they may look at like natural killer cells.

Kristyn Hodgdon:
Okay. So that's reproductive immunology. Not something that would happen at your clinic.

Nicole Yoder:
Okay. So, there are people who are specializing in that subset. And it's not often that they're going there after maybe two failed transfers, but maybe after three, four along those lines.

Kristyn Hodgdon:
Separately from reproductive immunology, how do autoimmune diseases play a role in? Is there any research there as far as if you have a thyroid condition and it's managed by medication? Is that something to still account for, or does that reduce success rates at all?

Nicole Yoder:
For example, like the thyroid-like autoimmune conditions, we always want you to be as well controlled as possible. But it certainly is true that for somebody who has one autoimmune condition, it is possible that there may be other autoimmune situations going on in your body, and that may be something that we don't have great tests for or great ways to quantify. So this is where sometimes we'll start modifying the protocol that we use to use medications that might help reduce any autoimmune reaction that your body might be having. Not necessarily because we've identified oh, here's your autoimmune issue, and here's the treatment. But it's the whole picture just seems like maybe of an autoimmune condition going on. Then maybe we're going to take a different approach in terms of the transfer protocol.

Kristyn Hodgdon:
Can you explain what that typically is for people who might be interested?

Nicole Yoder:
Yeah. So sometimes we're going to add on things like prednisone if you don't already like some sort of steroid. If you don't already have that in your transfer protocol. Now, some places will do this routinely. We do that routinely here. Some places do not. If you weren't on that, we might add something like that on. You may switch to a downregulation protocol. We try to get as much of the inflammation that could possibly be going on out of the system and switch in that regard for protocols. If you do follow up with an immunologist already or a rheumatologist or have an endocrinologist, and sometimes we'll have you go back to them and make sure that you are as well controlled as you can possibly be from their perspective as well.

Kristyn Hodgdon:
At one point, when I had one of my miscarriages early, even I think it was my chemical pregnancy, my h increased just from that, like little bit of HCG. Oh yeah. And so that's when I got referred out to an endocrinologist. I always think it's good to have an endocrinologist. Like you said, if you do have any sort of thyroid disorder.

Nicole Yoder:
Yeah. And we know that is pretty common. And for some people, it's just like a whiff of a change with that HCG. But for some people it can be really dramatic.

Kristyn Hodgdon:
Yeah.

Nicole Yoder:
And that's why it's always good to have an endocrinologist on board who's helping us manage those things because they're really the experts in the thyroid.

Kristyn Hodgdon:
Absolutely. And then what about troubleshooting for embryo issues?

Nicole Yoder:
You know with the embryo issues, one of the things that we look at is we go back to the original cycle where that embryo was made, and we look to see are there any clues about just the cycle in general and how the whole thing went. So, how was the fertilization? How were the de threes? How many of those embryos made it to day three but didn't make it to an actual embryo? Some of those things can tip us off to maybe there's an egg quality issue, maybe there's a sperm quality issue. And the tricky thing about this is there's not a lot of great. That tells us about the quality because sometimes you're like, great, we at least we got an embryo. But sometimes, maybe something about that cycle, just the quality of the eggs or the quality of the sperm, wasn't quite great. And it translates into, yes, a physical embryo is there, but it doesn't have much potential. So sometimes we do another cycle, change some parameters, maybe change the protocol, add some different techniques in the lab, and then for whatever reason, embryos from the second batch will implant, and embryos from the first just won't.

Kristyn Hodgdon:
And will people forgo genetically normal or good-quality embryos just to do another round?

Nicole Yoder:
Yeah, sometimes people do.

Kristyn Hodgdon:
When do you sort of recommend that? Because I just feel like just due to the cost sensitivity of the whole process, it's so hard to it's also, I think, ethically hard for a lot of people, like you worked so hard to create those embryos, like to get them. But I'm at the point I still have two embryos in the freezer, and I'm terrified to use them because I've just had bad luck. But it's like to get rid of them is like, equally.

Nicole Yoder:
Like equally gut-wrenching, right? Because you don't want to write them off as bad just because they came from that cycle or something like that. But yeah, sometimes people do that. Obviously, this is easier in a world where there would be like unlimited resources, time, energy, and effort are no big deal, then be like, yeah, just make a new batch. Let's try from that batch. But sometimes that when we it depends on how many you made per cycle. So if you only make two embryos in one cycle, yes, we're obviously going to use all of those. But if you happen to make a lot, and maybe we've gone through 3 or 4 in that particular cycle and nothing is working, then maybe we discuss if you're up for it and have the means to make it happen, maybe another cycle with different maybe you make some health tweaks. Maybe you have your your partner wherever the sperm source is, make some tweaks on their side, see if we can up that sperm quality a little bit. And maybe the embryos have come from a different batch or just more likely to implant.

Kristyn Hodgdon:
Yeah, absolutely. What about diagnoses like PCOS and endometriosis? Can those affect implantation at all?

Nicole Yoder:
Certainly, those two things are, PCOS is basically a very complex metabolic disorder, certainly can have, but certainly can just have an altered metabolic environment that both the ovaries and the uterus. And so for people with really classic like a lot of those symptoms, we really want to be working with a dietician, with your endocrinologist, make sure everything is in as tip-top shape as we can because if the metabolic environment is off, that certainly can have an effect on implantation, which goes hand-in-hand with just overall maternal health. If your body is signaling, this is not the optimal time for an embryo to be implanting. Because I'm not super healthy right now, that can be enough to tip the scales on it not going.

Kristyn Hodgdon:
I'm so glad you said that because I think a lot of times we see the Western medicine versus Eastern medicine or like it has to be and or. But I think in a lot of a lot of times, it can be both and you can use like a dietician to help complement your fertility journey in addition.

Nicole Yoder:
Absolutely.

Kristyn Hodgdon:
More traditional medicine.

Nicole Yoder:
Absolutely. Especially in cases like PCOS, where we know that there's insulin resistance, we know that getting yourself in the sort of best dietary condition you can is only going to be helpful because in not for any fault of your own, it's just like the way your belt just needs maybe a little extra tweaking on the dietary side to get the metabolic sort of balance where it should be.

Kristyn Hodgdon:
Yeah, absolutely. And what about Endo?

Nicole Yoder:
The endometriosis that's certainly can have an effect on implantation. With endometriosis, it's really a tricky diagnosis that can affect really every single component of the reproductive tract. So eggs tubes, and uterus, they're all in this environment that is filled with more inflammation than there really should be. And that certainly can translate to egg quality issues, which might translate to the embryo quality or also decrease chances of implantation. And this is we've already mentioned this, but this is where you might change the protocol that you're using. So you might do what we call that typical downregulation protocol to help decrease that inflammation as much as we can before we're doing a transfer.

Kristyn Hodgdon:
I've always been curious about at what point do you offer up surgery for endometriosis after failed transfers versus the downregulation protocol.

Nicole Yoder:
Can we have between like patient and the provider? And it also depends on do we have the ability to make more embryos. Do we not? So, if we suspect or know you have endometriosis and you only have very few embryos to work with, the chances are going to make more very low, and probably going to be moving towards like suggesting surgery sooner. Now, if you have a lot of embryos and we can work through them, then I'm going to avoid surgery because surgery does not go without risks in itself. You can certainly have scar tissue develop from surgery. You can have surgical complications. There's recovery time that goes with that. But if we can do surgery and remove some of that endometriosis, and we think that's really going to have a positive effect, then yeah, maybe we're going to go that route. But I usually like to give it the old college try without surgery before jumping straight to that. But again, that is a personal preference and you may feel differently.

Kristyn Hodgdon:
Yeah. That's something I've just always been curious about. I don't have endometriosis, but like just having all that scar tissue. I guess it just feels like you'd want to get it removed. But at the same time, you're right, like it's such an intense surgery. That's laparoscopy. Right?

Nicole Yoder:
Usually. Yeah, usually the adult laparoscopy. But as I was saying, was like the complications, like surgery to remove scar tissue, can ultimately result in more scar tissue. So it's not a completely benign thing. And that's why we tend not to use that as first line maybe these days. But it certainly is a tool in the toolkit. If you're if you see what's going on.

Kristyn Hodgdon:
Amazing. And what about when the cause is just unexplained? Again, chicken and the egg scenario. You don't really know. Like you've done all the tests, you've checked all the boxes. What's next?

Nicole Yoder:
Yeah. So when you've done all the tests and we can't find any cause for it, usually we're going to do is try again. And a lot of times we'll switch up the protocols to see if that helps. We're going to there are different adjuvants that you can add into these transfer protocols. So we're going to make sure we've exhausted all of those things. And a lot of times people will maybe have a streak of not having implantation. And then who knows why or reason you have the cycle looks maybe completely on paper like all the other ones, and that one works.

Kristyn Hodgdon:
And you do hear it all the time because two embryos I have left are like the poorest quality of the batch. But you hear, oh, I had one embryo left and it just so happened to work. And yeah, you always have that glimmer of hope that the next time will be the one.

Nicole Yoder:
Yeah. And some people ultimately, if they have done many transfers and nothing has worked, we can't find a cause. Then we have the conversation of are we looking at a gestational carrier. Is that something you would consider? Is that feasible? That is ultimately another option that some people utilize.

Kristyn Hodgdon:
Yeah, absolutely. I would do that in a heartbeat if it wasn't so costly.

Nicole Yoder:
It is. And that is unfortunately the truth of the matter. It's not for nothing.

Kristyn Hodgdon:
Exactly. I think this gave people a ton of options to ask their healthcare providers about if they are dealing with implantation failure, just for those who might not be doing IVF yet, would that just be like the rules from episode one apply where it's just if you haven't been getting pregnant in a year or six months if you're over 35. That's when you just see like implantation failure only applies to IVF, correct?

Nicole Yoder:
Yeah. To get that diagnosis. And that may be what's going on in somebody, but we don't know it until we put back embryos like we know there was an embryo made. We know that the embryo landed there and it didn't take. So that's why the diagnosis really only applies to people who have done it. But it could be that ultimately, that is the issue. You just have to do IVF to really make that diagnosis.

Kristyn Hodgdon:
But if you've had a failed IUI, it's not like you have failed implantation. It's just.

Nicole Yoder:
Yeah, correct.

Kristyn Hodgdon:
Awesome. Love it. I think this episode is going to be very popular because everyone just wants to know how to troubleshoot after a failed transfer. It's one of the most heart-wrenching experiences, I think even though it's not a miscarriage, it's I really do feel like when you work so hard to create those embryos, it does feel like a loss.

Nicole Yoder:
Yeah, it's still a loss. It's one of my least favorite phone calls to make. And yes, you're correct, it's not a pregnancy. It's still a loss.

Kristyn Hodgdon:
Yeah. Sending love to everyone dealing with implantation failure. And yeah, feel free to ask any questions following this episode that you want to see addressed, because I think we can keep going on this topic on our site and even on future podcasts. Thank you, Dr. Yoder. This was awesome.

Nicole Yoder:
Always great time chatting with you.

Kristyn Hodgdon:
If this podcast means something to you, be sure to hit follow or subscribe. This helps you because you'll never miss an episode, and it helps us because you'll never miss an episode. For everything you need to know about fertility and women's health, head to rescripted.com or follow us on social @HelloRescripted.

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