SART Fertility Experts - Recurrent Pregnancy Loss and Implantation Failure

"I can get pregnant, but I can't stay pregnant," is echoed by patients with recurrent pregnancy loss. Recurrent pregnancy loss, defined as 2 or more pregnancy losses, is discussed by reproductive medicine specialists Steven Spandorfer and Brooke Rossi. This episode includes current testing, treatment, and outcomes with recurrent pregnancy loss.

Hello, my name is Brooke Rossi and I am a practicing reproductive endocrinologist and infertility specialist in Columbus, Ohio. And we are hosting the SART Fertility Expert Podcast Series today. Today, our special guest is Dr. Steven Spandorfer.

He is an associate professor at the Center for Reproductive Medicine and Infertility at Cornell University Medical Center. He is board certified in obstetrics and gynecology as well as reproductive endocrinology and infertility. He has published numerous articles on infertility and IVF and has a special interest in complex IVF cases and recurrent pregnancy loss.

Hello, Dr. Spandorfer, and thank you so much today for joining us to discuss this important topic. Well, thank you very much. It's my pleasure to be here, and I'm very excited to discuss this, you know, what's a very important and sometimes overlooked part of what we do as reproductive endocrinologists.

Everybody, you know, I think definitely focuses in on the infertility part of things, but sometimes we lose our way when it comes to miscarriages, which basically, unfortunately, are quite painful and magnified for the patient. Of course. Let's just start by defining what recurrent pregnancy loss is.

So there has definitely been a shift in how we define recurrent pregnancy loss. Originally, it was defined as three clinical, consecutive clinical pregnancies that were lost. That has actually been changed now.

Most people would accept that two or more pregnancy losses constitute the point where we would diagnose recurrent pregnancy loss and where we would start working it up. And this comes about because studies have shown that basically after two miscarriages, the workup is pretty much the same yield as it is when you have three or more miscarriages. So that has allowed us to dial it back.

The reality is when you deal with patients, I think anybody that's had a couple of miscarriages, they want the testing. You know, the first thing that comes off their mouth, their lips, is I want all the testing done that's possible. It's hard to defer to three.

You know, the other part that probably confuses the matter a little bit more now is the ability to, you know, of home pregnancy tests and all these biochemical, as we call them, pregnancies. You know, it was a time when no one had that. Now, you know, often people are testing and finding out they're pregnant even before they actually miss a period.

So, you know, it gets a little confusing as to how do we lump that into the recurrent pregnancy loss of something we know that's very, very common in nature.

Right. I think one of the common questions that patients have are, what do we do? You know, do we count ectopic pregnancies? Do we count biochemical pregnancies? Do we count pregnancies of unknown location? And maybe you could talk about that.

And earlier you said a clinical pregnancy loss. Maybe you can help patients understand the differences in all types of pregnancies. So, you know, we have various names for different pregnancies.

A clinical pregnancy is one that is generally defined as you see something on ultrasound that shows you that it's clearly in the uterus. So that's what we consider a clinical pregnancy, at least seeing a pregnancy sac, a gestational sac, knowing that, yes, we knew it was in the uterus. Ectopic pregnancies are pregnancies that are located somewhere outside the uterus.

So most ectopics, as we know, are going to be somewhere in the tube, but they can be in the ovary. They can be even completely in the abdomen somewhere else. I would generally tend to say that an ectopic pregnancy is generally a different problem than those involving recurrent intrauterine pregnancy losses.

And so I separate those two out. The confusing part then becomes the either biochemical or perhaps pregnancy of unknown location, which are basically synonymous. Basically, when we're talking about those, we're sort of referring to pregnancies that we see a positive pregnancy test, but we don't know where the pregnancy is.

It was never seen in the uterus. It was never seen in the ovaries or in the tubes. So basically, we call it a pregnancy of unknown location.

We call it a biochemical pregnancy. But, you know, I think as we're dealing with the patients, I think even though we may not know where it is, we still sometimes have to say, look, you've had a few of these, you know, pregnancy losses. No matter how we define it, it's the same somewhat emotion for the patient.

And therefore, it does reach a point where, yes, you may not have had three clinical pregnancy losses where we saw it in the uterus, but you've had two or three of these chemicals where we don't know where it is. It's worth working everything up. And, you know, part of that workup may make sure that you don't think these are tubal pregnancies.

You want to check the integrity of the tube, but as well as the rest of the sort of normal recurrent pregnancy loss workup, which we'll talk about later down, you know, down the podcast here. And of course, you know, this is, you know, recurrent pregnancy loss is different than infertility. Unfortunately, some patients, a lot of patients with recurrent pregnancy loss don't have infertility, but so there are some patients who have infertility and recurrent pregnancy loss.

And, you know, sometimes the evaluation kind of overlaps a little bit as well. Absolutely. And, you know, probably when you look at the full recurrent pregnancy loss workup, you probably do hit most of the areas of infertility in and of itself, as opposed to the other way around with the infertility workup that's much more sort of focused and shorter.

It doesn't quite cover all of the recurrent pregnancy loss workups. And there gets to be this overlap where people even take it a step further when they talk about the implantation failure, particularly patients doing IVF. And definitely there are some people, even physicians that will try to equate, you know, failed IVF cycles to recurrent pregnancy loss and recurrent miscarriages and actually try to do some of the recurrent miscarriage workup in these patients that have had recurrent, you know, quote unquote implantation failures.

In other words, putting an embryo back in and it didn't work, that's considered, that's what people would call an implantation failure. You know, I think it's important to understand. I think those are two distinctly different entities.

And I personally don't try to lump together the recurrent implantation failure with the recurrent pregnancy loss patients. I mean, you know, there's pretty nice statements out of both the European Society, you know, of Human Reproduction, as well as ASRM, you know, the American Society of, you know, what sometimes we call add-ons for IVF treatments and basically doing some of the recurrent miscarriage workup for these patients that have you know, implantation failure, quote unquote, is not necessarily indicated at that point in time. So, I definitely think it's important to try to separate out that implantation failure from the recurrent pregnancy loss.

When we talk about recurrent pregnancy loss, concentrate solely on the patients that have actually gotten pregnant and have had, you know, recurrent pregnancy loss, miscarriages or whatever. So, it sounds like implantation failure is really an issue that can only be within the world of IVF because it's the only time that you really know an embryo is getting in to the uterus. And sometimes I do hear recurrent pregnancy loss patients ask, well, did that pregnancy implant? And, you know, we always need to remind them, of course, that pregnancy implanted, you know, you've had a positive pregnancy test.

So, it's important that we help them understand that they are two different diagnoses. Exactly, exactly. Tell me a little bit about, you know, if a patient has recurrent pregnancy loss, do you see any risk factors, whether it be within their family or lifestyle? You know, as you're talking with a patient and taking their history, what are the things that you're looking for that the patient may tell you? So, I think when you look at recurrent pregnancy loss, it's probably important to sort of, and I try to break it down with patients of, there are some things that are well-known and well-defined that are associated with recurrent pregnancy loss.

And then there are these other sort of areas of recurrent pregnancy loss that are a bit controversial. And then there's this third sort of category of things that people do that probably, as I described it, most people that are RAIs don't touch. But there are definitely, you know, some doctors out there that do some other testing that is, most of us consider sort of out there and not part of the recurrent pregnancy loss.

So, you know, as you go through that workup, that sort of also tells you like what type of things, you know, we should be asking the patient as we get there, and particularly like family history or other issues that run within it. Many of the things that we look at within recurrent pregnancy loss are not necessarily things that recur within families. But, you know, as we talk about, you know, what are the things? So, from the workup standpoint, certainly we all talk about getting, you know, chromosome or karyotypes on both the two partners.

So, you want to check the chromosomes of both the male and the female partner. And in that, we're looking for, you know, even though the patients themselves can be normal, sometimes we can actually have structural, you know, basically where our chromosomes sort of rearrange themselves. And basically, we can still be normal, but that leads to a higher rate of miscarriages.

You know, if you think about a chromosome, it has lots and lots of genes on it. So, you could pluck a piece of, you know, chromosome two and stick it on chromosome six and, you know, flip the other piece back over. You may have all your genes.

You can be completely normal, and most of these patients are. And yet, when they go to, you know, create a sperm or an egg, basically as the, you know, you're taking half of your chromosomes and combining with the half of your partners. Basically, you can have this rearrangement where all of a sudden now the chromosomal composition, the number of genes is abnormal, and that can lead to miscarriage.

So, that is actually, you know, something that can run in families. But basically, by and large, that's a test that you absolutely need to get, you know, getting a chromosome test on both of the partners to evaluate and see if there looks like there's some sort of abnormality that they may have. Yeah.

And so, we call it a balanced translocation to see if maybe a woman has a greater chance of having a genetically abnormal pregnancy than other women her same age. Right. Either partner can have that.

And, you know, I think it's important to emphasize that, yes, we can't change that. But yet, that is a situation where one could do IVF and you could actually test the embryos to see if they are quote-unquote balanced, which is what the partner would have, hopefully, or unbalanced. And you can actually significantly reduce one's risk of a miscarriage by doing IVF and testing that.

So, you know, that is obviously something we want to test for, not something we can treat, but something we can, you know, deal with and recognize as a way to try to reduce the risk of a miscarriage. And sometimes that even, I mean, even that testing, even if the patient's decided not to do IVF, they still at least have an answer for what's going on. And, you know, sometimes it can predict, my understanding is that depending on the translocation, it kind of can predict the risk of having an abnormal pregnancy.

And that's a lot to a patient who, you know, at least understanding what's going on is really important. That is true. It does give you some ability to predict based on the translocation, based on who has it, and also, you know, it does give answers.

In fact, when you mentioned about giving answers, that's probably the very first thing I tell most patients is that, you know, this problem is tough. Lots of people have miscarriages, you know, much more common than people think. You know, I actually tell every patient, I'm like, if you went to a Starbucks, had everybody close their eyes, and had all the women raise their hand if they've had a miscarriage, everybody raises their hand.

Yeah, I say a similar thing. It's all my patients sit there and say, I don't know anybody that's ever had a miscarriage. I'm like, it's because no one talks about it.

And then once they've had one, they don't even talk about being pregnant until they're like, far, far along to their showing. And so I think that's important. But the other part of it that I always tell patients as I come in, as we sit down, even before I've started taking a history is, you know, we're going to take a full history, I'm going to do a full workup.

And there's about a 50% chance to find absolutely nothing. And it's important for understand that. And that's because, and this is why the topic is so confusing, is that, you know, often most miscarriages are something wrong with the embryo itself, and not the person carrying the embryo.

So there's nothing wrong with the patient herself. It's that the embryo itself was abnormal that led to the miscarriage. In fact, I always quote this study that we did when I was a fellow at Cornell many years ago.

But basically, we went and looked at miscarriage, you know, after seeing, you know, positive fetal heart rate in singleton pregnancies, you know, we looked at what the miscarriage rates were. But more importantly, we actually went back and looked at how many of these that miscarried after a heartbeat of a singleton, how many of these were chromosomally normal or not normal of the embryos. And what we found basically is those over 40, not surprisingly, like 80% of them were chromosomally abnormal, under 40 was like 70%.

So most miscarriages were still chromosomally abnormal. And most patients that come in to me with a history of a couple of miscarriages don't often have had testing of these embryos. So basically, in their mind, they feel like they had normal embryos that they lost.

But the reality is, you know, it was probably the embryo that led to the miscarriage. And therefore, that explains why, you know, over half the time we find nothing. And I think that's probably one of the most important things for patients to understand.

Because often patients come in, you know, and you can't overlook the psychological part of this. Patients come in, they feel like a failure. They feel like, I am letting my partner down, I am letting my parents down, I'm letting my family down, I can't have a baby, you know.

They say things like, why is my body rejecting me? What's wrong with my body? And it's themselves and they don't have to. I've heard more people say, God is punishing me. And it's like, I don't think it works that way.

What type of God or who you believe in is the way it is. But that is the emotional complexity of what we deal with. So, you know, going back to the workup.

So, we talked about the workup. Yeah, what's the other testing that we do besides the karyotypes? So, we also want to do testing on the uterus itself. So, some people can have, you know, there's a couple of type of abnormalities within the uterus that could lead to miscarriages.

So, some people could have scar tissue in their uterus. So, a patient that's had a few miscarriages sometimes has actually had, you know, surgical procedures to remove it and sometimes ends up with scar tissue in the uterus. So, if you have scar tissue in the uterus, it can lead to a higher risk of miscarriage.

So, certainly you take in history, you want to ask, you know, have you had surgical procedures? Doesn't have to necessarily be just a surgical procedure to remove a pregnancy. It can be, you know, whether she had fibroid surgery previously or some other surgery. Other things in the uterus that can cause miscarriages are definitely fibroids, particularly fibroids which are abnormal growths.

You know, the uterus is a muscle. So, it's just a cell, basically. It's like a growth of an abnormal cell in the uterus.

It's not cancer, generally, but basically grows and pushes its way into the inside of the womb, inside the cavity, as we call it. That can lead to a higher rate of miscarriages. That's very common.

Controversially is what if you have a polyp? And a lot of women have polyps in their uterus. You know, there's some studies that have suggested that polyps may actually be associated with miscarriages. It's not as definitive as the data that's there for fibroids or scar tissue, but it's possible.

And generally speaking, you know, if somebody's got something in the uterus that's not normal, you want to take care of it. It's a simple, generally surgical procedure to remove it. A step further are birth, you know, congenital anomalies of the uterus, particularly what's called a uterine septum.

And the best way to describe that is that for most women, you know, when you're inside your mother carrying you halfway through the pregnancy, you know, the uterus is really two completely separate tubes that actually come together in the middle of the pregnancy and fuse. And so there's, you know, if you think about it, if you have two tubes that fuse, you always have something dividing it in the middle. And generally speaking, that gets resorbed back by the body, but not always.

So sometimes you have a piece of that sort of line, that tissue still there called a septum. And if you have that, that is associated with miscarriages as well. So that is something else we can surgically take care of and improve.

So you certainly don't want to overlook the uterus in these situations and the uterine cavity, specifically looking for those anomalies that could be going on within the uterus itself. And the septum, you know, the septum, of course, would have been there since birth. It wouldn't have changed and it's not going to go away.

It's also not going to get worse if it gets repaired. And sometimes we, you know, we may do a fallopian tube test or an HSG to see it. We may do a saline ultrasound, maybe an MRI.

Those are all the ways that we may, you know, image the uterus and look for the exact length of the septum to see if it is reasonable to remove. And yeah, it is a quite simple surgery that we can do to remove it. So see, we talked about the uterus, the karyotypes, what other kind of testing would we be? So some other testing is, so when we get to, you know, there's this whole sort of group of things called blood clotting autoimmune type testing that we want to do.

As I described it, there are basically three that are very well known to be associated with miscarriages. That's looking for things that are called like anti-cardiolipin antibody, lupus anticoagulant, and a beta 2 glycoprotein antibody. These are, all three are basically autoimmune antibody basically that are definitely associated with the recurrent pregnancy loss.

Particularly though, not the very, very early ones. It's really more associated with once you've seen a heartbeat, sort of late first trimester miscarriages. And these are, you know, basically three simple blood tests we can get.

And all of these are treatable. And that's important to understand, you know, whether it's with baby aspirin or blood thinners like globinox or heparin you may have heard of. But basically, these are definitely things that are treatable.

And these should not be, you know, omitted as far as part of the workup. You should definitely look for these. Can we call that like the antiphospholipid syndrome? Yes.

We can call it, well, once you have, if you have these and you have the recurrent miscarriage, that becomes the definition of antiphospholipid antibody syndrome. And that's what that is overall referring to. There's a lot of, a lot of my patients want to get tested for other things.

Right. Want to get tested for MTHFR and these different things, those things that we should be considering. So basically, when we get those blood tests, and, you know, look, we sometimes do in our practice, what we often do.

Next thing you know, you're getting 18 tubes of the autoimmune blood clotting tissues. You know what that testing, you know what that patient's had. That's usually when the tech is yelling at me that she can't believe she had to draw so much blood out of the person.

But you are getting things like the MTHFR. You're getting things like prothrombin gene mutation, factor V light and protein S and protein C division. And you don't have to know the names of these.

But the problem with these things is that, first of all, they're very common. If you look at like the MTHFR, which some, you know, basically a third of all Caucasian women have a mutation in the MTHFR. That's a lot of people.

Now, do you see a third of all people having recurrent miscarriages? No. In fact, probably most of the evidence would refute most of the association between these two. It's very weak at best.

And like, for example, that one I always give, you know, talk about because, you know, basically you're looking at how that may affect what's called homocysteine. It mostly deals with acid metabolism. And a lot of these studies, to understand, came from risk of stroke in men in VA hospitals.

So. It sounds like our patient population. Yeah.

So you can see that we're extrapolating sometimes. People extrapolate a lot and say, well, if this causes blood clots in these patients, then this is probably what's causing miscarriages. But I think the association is not absolutely there.

And most of the evidence would point away from this. All these blood tests for these autoimmune and clotting tests, I think the evidence with those is very weak, other than the three that we mentioned that are more associated with the antiphospholipid antibody syndrome. Now, when you talk about other blood type things and autoimmune stuff, there's definitely some evidence, particularly like for thyroid in a patient that has thyroid antibodies, and a very out of control thyroid, you know, underactive thyroid, that there's probably some association with miscarriages.

Again, you know, basically, we often will treat sort of subtle abnormalities in the thyroid. But again, this is based on not a great study, based on some poor evidence. But, you know, as one of our medical endocrinologists once said, you know, if you give every patient 20, you know, a very low dose of thyroid replacement hormone, you won't hurt anybody.

Yeah. So that is often something we screen for and definitely something we treat if we find it. What about any other any other hormone testing? Like, do you screen for diabetes? Do you look at the levels, anything like that? We do screen for diabetes, usually getting a hemoglobin A1c level, which is a long term sort of measurement of diabetic control.

The reality is, you know, if you look at like William Kutteh's study, you know, and his group did a really, you know, very well done study where they looked at like 1000 consecutive patients in their clinic with, you know, two or three consecutive miscarriages, and they had the full workup. You basically find this so rarely in patients. It's part of the workup.

It's definitely associated, you know, if you have out of, again, out of control diabetes, it is associated with recurrent miscarriage. Now the question is, what's the likelihood of somebody having way out of control, you know, diabetes, and you not knowing it, and being an infertility patient? Not that high, but it could happen. You know, I think what's associated somewhat with the diabetes, and this is also something that I definitely talk to patients about is the weight.

Obviously, they're overweight, obese patients are more at risk for having diabetes. And there's definitely associations with weight, particularly obesity and miscarriages. I do, you know, you have to be very gentle in that discussion.

And the one thing I do find is that, you know, sadly, doctors don't often discuss it. We did a lot of research looking at the, you know, looking specifically at BMI or, you know, weight, and not just IVF outcome, but miscarriages. And one thing we found in doing the background for some of the research we did is that if you actually look at doctors, when you see patients that are overweight, you know, BMI, very high BMI is obese, probably less than a third of doctors even mention it, let alone sort of suggest they should try to do something about weight loss or anything like that.

So I think that, along with the diabetes part of it that comes into play, you know, for a patient, you know, it's worth mentioning. And again, it's hard because basically somebody who's, you know, significantly overweight to tell them, okay, why don't you get down to your 120 pounds? That's not going to work. Right.

And they've also often already have been trying and it's very, it's hard for them. Yeah. Right, right.

So I think that is, you know, that is also part of it and something worth mentioning and talking to patients about, but it's not the easiest topic or situation to deal with in that sense. A lot of my questions, a lot of my patients will ask about, they want to know about their immune system. They want to know, should they have, you know, extra immune testing or who can do that? Or they start talking about all these different tests.

What's the, what's the recent research and data say about immune systems? So, you know, basically the immunology system gets blamed for everything, you know, and the reality is that as I try to describe it to patients, I'm like, look, there's definitely some autoimmune things like the antiphospholipid antibodies that we're looking at that are associated with miscarriages, but there's a whole host of other things that people sort of do that are not. And I always give the classic example of the natural killer cells. There's definitely a group of people that will definitely test everybody for natural killers.

What are natural killer cells? Natural killer cells are, are basically white blood cells that basically everybody has in their body throughout their body. I describe them as, if you've ever seen the movie Natural Born Killers with Woody Harrelson, that's what comes to mind. You know, these are cells running around killing everything, but that's not what they do.

They actually serve just a normal function of maintaining your body's immunologic integrity. And when we, when we talk about natural killer cells and, you know, basically there's a very well done study out of the UK, which showed that, you know, there was no correlation, like when you have blood drawn for your natural killer cell levels, there's absolutely no correlation between what's in your blood and what's going on in the pelvis. And so basically a lot of these people that are really pushing these theories are sort of drawing blood, you know, in a patient, instead of saying, oh, you have high natural killer cells, therefore we need to give you X, Y, and Z. But the reality is that the fundamental biology of what they're doing doesn't make sense.

And then, you know, they're concocted, come up with treatments that basically, again, I'd say most people disagree with and don't make sense, have very strongly come out with, you know, both the European Society and the American Society, as I mentioned before, very much strongly against even testing for natural killer cells, let alone trying to treat, you know, for it as well. I think the majority of these immunologic tests, whether it's looking at HLA matching or, you know, and these are just blood type matching, basically, or any of those things have really been somewhat discounted. You know, the biology and the research is just not there to support it.

And I think basically, fundamentally, both the American and the European societies have really come out strongly against doing the testing for either of these, let alone the treatment for them. Yeah. It sounds like it's maybe an area of future study, but definitely not well-established enough to be testing for a pregnancy plus patient.

Now, there are some other areas. So, you know, basically the whole notion of chronic endometritis, for example. So this is a chronic underlying infection of the uterus.

It's not really typically symptomatic. Usually when you think of an infection of the patient, they have pain or symptoms, but patients can have what's called, you know, a chronic underlying infection in the uterus. How would they have gotten that? So basically, usually it's from having some sort of intrasurgical procedure, but the reality is it can occur just via infections, like, you know, whether they've had some other infection of the uterus or the tubes or something like that along the line.

What about at the time of delivery, if they had chorioamnionitis or infection during delivery? I don't know. I don't know. I don't know if anybody knows that.

I don't know if anybody's actually done studies that followed them. Like after a miscarriage, tissue or that sort of thing. Definitely sometimes with that.

In fact, we actually did a study, I think, looking at people that had retained product. Like, in other words, a patient had a miscarriage, they didn't pass everything. When you removed it, about a third of them actually had a chronic underlying infection.

And it's probably not as much as an infection as we think, as much as it is an inflammatory reaction within the uterus. But that's also quite controversial because, you know, the question is, how do you diagnose it? But in the world of pathology, it's very, you know, different pathologists say different ways to treat and different ways to diagnose. There is some evidence, it's again, not the greatest evidence, and it's hard to do these, you know, well done trials.

But sometimes if you diagnose it and treat these people with antibiotics, sometimes they get better and actually improve their outcomes as far as miscarriages. Sometimes people say to me, because I sometimes will look for chronic endometritis in people, and they'll say, well, I don't have any symptoms of this. And I say, well, it might be the symptom that you're having.

Like, you're symptoming me that you're having miscarriages. So, you know, I think once you get down to the bottom of the list where everything's been negative, sometimes people do look for these. The other thing that's a little interesting also that's a more, a newer topic, and actually, you know, very recently, AUA, which is the American Urological Association, in combination with ASRM, came out with a statement.

And it's looking at the male side of things. So, you know, we talked about from the man, yeah, we talked about his chromosomes, you want to make sure he didn't have that rearrangement, the structural rearrangement of his chromosomes. But the other thing from the man that's a little controversial, but there's a little more evidence pointing towards it now, is looking at what's called sperm DNA fragmentation.

So, basically, this is sort of looking at the, and it really has more to do with, you know, the DNA repair system of the sperm. And some men basically have, you know, abnormalities within the testicle or within, you know, within the male tract that may lead to more DNA abnormalities that can lead to sort of what's called DNA fragmentation. And basically, there is some evidence that men that have, you know, some significant abnormalities within their sperm may actually have higher rates of sperm DNA fragmentation, which may be associated with miscarriages.

So, you know, I have started sort of testing, you know, looking, and if it's significantly elevated, you know, I definitely will send the man to a urologist to see if there's something they can do to help improve whether it's, you know, antioxidants, lifestyle. Right, like obesity, smoking, these are things that— Yeah, exactly. Exactly.

In fact, actually, smoking, in fact, for both, I mean, it is interesting. I really almost never see smoking from patients anymore. I hardly have, you know, smoke.

That's good. Yeah, no, it's surprising. I mean, so I practice in Ohio, and you practice in New York, and you'll have to remind me of what the laws and infertility coverage is.

But I just want to make it a point to let patients know that, you know, the codes for infertility and the diagnostic codes for recurrent pregnancy loss are different. So even in Ohio, where we have a lot of patients who don't have infertility treatment coverage, they can still have their testing for recurrent pregnancy loss covered by insurance. You never want a patient to be nervous about how much the evaluation may cost, because it's often would be covered by their insurance.

Yeah, no, no, totally. I think it's the same thing here. I mean, basically, the codes are different.

And I think that, you know, many patients that—even the patients—because most of our patients actually have coverage for diagnosis of infertility. Yeah. It's treated.

As opposed to the recurrent miscarriage patients, I think a lot of them actually have coverage for not just the diagnosis, but the treatment short of like, you know, when they move on to IVF or something like that. But the other possible treatments that we may do, you know, for patients are often covered, you know. So let's talk about that next, actually, because I was—my next question was going to be, what are some of the treatment options that you offer patients who have recurrent pregnancy loss? So I think the first thing, which you sort of touched on earlier on, is lifestyle things.

So certainly weight control, if you can, not smoking. Those things definitely are helpful. There's even been some evidence that sort of, you know, TLC helps.

Yeah, yeah. You speed up the level of patients, letting them come in when they need to see you, answer questions, right? Yep. I think there's—there goes—there's a lot to be said for the psyche that we don't totally recognize.

And so, you know, we're lucky as a group. We have three full-time psychologists that we could probably have 10 more if we need them. But I definitely push patients to see them and speak to them because I think, you know, sometimes the communication between the couple is not perfect.

And basically, everybody sort of, you know, the blame, it's just so much—it's so hard to deal with sometimes. So I think that that's important. From a treatment standpoint, you know, we can do things.

Some people put people on Empiric, you know, which is just, you know, without real great medical evidence. Sometimes people put people on a baby aspirin, like sometimes you'll use for heart disease, a very low dose, which is the 81 milligrams of aspirin a day. Sometimes people will actually also give patients progesterone after they ovulate.

Both of those are probably fairly innocuous therapies that don't really have a lot of side effects to them. We don't really do a lot of testing for progesterone anymore. You know, there was a time where we used to bring people in and check their progesterone levels.

But then, you know, we've learned that progesterone levels, if you had a catheter and kept checking it every 10 minutes, it's like up and down every, you know, it's released in a pulsatile fashion, so it goes up, it goes down. You don't really get great measurements. We used to also do the biopsy of the uterus, but that also has been fairly discounted too.

You can use a progesterone level to see if somebody's ovulated or not, but you can't say if somebody's progesterone is good or bad, which is something to ask about. Right, right. And look, there was a very famous reproductive endocrinologist that made her career off of moodle phase deficiency, of which now most people sort of say, well, we're not even sure it really exists.

So I think definitely, you know, both of those are fairly easy to give. I think the patients that end up going down the road of the MTHFR and have that, often I will say, take some extra folate, basically. The reality is it's a water-soluble vitamin.

You're not really going to overdose on it, other than maybe your pocketbook gets hurt a little bit if you're getting it from some of the expensive health food stores that are out there. If someone really had antiphospholipid syndrome, they would treat it with something else. Often once I diagnose somebody that's got really one of the main anticardiolyte antibodies, or one of those antiphospholipid antibodies, and we feel like they have the syndrome, I often will work in conjunction with one of our hematologists.

And then for those patients, there's blood thinners. Often they'll be on a baby aspirin, but often a baby aspirin plus a blood thinner, usually Lovenox these days is the medication most commonly, but some people use aspirin. And, you know, like I said, it's very treatable.

Many people freak out and say, oh my God, I need to be on this from the moment I have it, but that's not really true. It really is, you know, basically you probably, the evidence would suggest need to be on it once we see a heartbeat. Most of my patients probably are on it way before that, once they see a positive pregnancy test.

And, you know, I don't have the evidence to support one way or the other, but there's definitely treatment for that. What has been shown not to help are steroids, for example, used to give a lot of steroids for these situations. And that really hasn't been shown to help.

When you say steroids, you mean like something like prednisone? Yes, exactly. Exactly. Like common steroids that are often given, you know, to that sometimes some of the, you know, the rheumatologic patients that have rheumatoid arthritis or lupus will get, but I don't think people are doing that so much anymore.

So, you know, that, that is, those are sort of the basic sort of treatments. We talked about the surgery and the uterus. Surgically, if you need it.

And then ultimately that leads to, let's say you do the whole workup, you find absolutely nothing. Maybe you've tested one of the miscarriages and found that it was a chromosome abnormality. You know, at that point you can start talking to the patient.

At what point do you do IVF and actually test the embryos before you put them back in? You know, I think that, you know, when we get there, I think the first thing that's important to talk to the patients about is, you know, you're jumping your level of getting pregnant way above what you've been doing. You know, it's a different world all of a sudden. Instead of just, you know, having time dinner, you know, having intercourse and getting pregnant, you know, basically you're now going to a whole artificial way, you know, that's fraught with its own issues of IVF.

So I think maybe, let me make sure I'm understanding. You're saying like, so now you take a patient who, let's say they don't have infertility, they just are having losses, all of a sudden they're doing IVF when maybe they don't need to? Is that? Right. Well, in other words, you know, basically you're sort of taking somebody, it's not that they, you know, somebody that's had two losses or three losses, maybe a little bit different than somebody that's had four, five, six losses.

And they are definitely different from a predictability, you know, standpoint of recurrence. But basically, you know, you can, you know, as you start moving towards IVF, you know, it's a lot more interventional. And so I think it's always important for these patients to necessarily understand that.

And sometimes the patients will actually question, you know, they've been, you know, I'll see sometimes people for a second opinion have had like one or two losses. And somebody was recommending, you know, go straight to IVF at 33, you know, years old, you know, we'll do testing of the embryos. And they're like, why do I need that? And I'm like, you know, it's a good question.

Yeah. No. And, you know, the reality is, is that IVF comes with its own issues, you know, testing embryos, which has always, you know, when we first described and discussed testing embryos, it sounded like the best thing since the invention of the wheel.

Are chromosomally normal, right? Because chromosomally abnormal pregnancies often result in miscarriage. Right. In other words, this goes back to that thing that we talked about earlier on where most patients, particularly, you know, as you get older, you know, with increasing wisdom, as I call it, comes higher rates of chromosome abnormalities of the embryo.

But as you get older, that's more common. But the reality is, is most miscarriages are probably chromosomally abnormal. And therefore, you know, it goes back to why our workups are often negative.

And, you know, yes, we, you know, within IVF, you get the eggs, you fertilize, you grow them in the lab, you can biopsy the embryos, basically, and then freeze the embryos. And you can take those cells that you took off and test them to see if they're chromosomally normal or not. Again, it comes with a whole host of issues that's probably beyond the pale of this sort of discussion here.

But it is a way of sort of saying, okay, we have a normal embryo, we can actually put that normal embryo back in. If we go down that pathway, I think like one of the most important things that I make sure the patients understand is that, A, it's not a guarantee that it's going to work. And B, you can actually still miscarry, we can do all the testing, put a normal embryo in, and you can still miscarry.

So it doesn't explain everything. But, you know, it is a way of trying to reduce those risks of miscarriages for some of these patients. And certainly, for some patients, it is right.

You know, I think basically, for each patient, it is, you know, it's an emotional roller coaster. And some people take it a lot harder than others. And sometimes you need to go to more aggressive treatments sooner rather than later for some people.

I think as long as we're very honest about, you know, not over promising with, you know, IVF or with genetic testing of embryos. You're right. Sometimes it's what people, it is what makes the most sense for people.

I mean, sometimes I try to explain it. You know, if you think about it, three to 6% of all children by one year of age have some sort of birth defect. You know, most common birth defects are heart disease, lung disease.

Those are very common. You know, maybe you just had some so terrible, you know, defect within the heart system or, you know, that leads to a miscarriage as well. None of the testing that we would do would help correct that.

None of the treatments we do would help fix that. And so there are sometimes miscarriages that we just cannot prevent. You don't understand.

Right. Well, you know, I try to remind patients, and I hope that you agree with me on this. I mean, you know, what do you talk to people about their overall prognosis of having a baby if they have recurrent pregnancy loss? I often try to remind them it's quite positive, especially if they are getting pregnant easily.

Right. You know, I often tell people, I think, you know, part of the problem with the recurrent miscarriage treatments through the years is that the initial studies done in like the 30s and 40s were based on some guy doing a mathematical computation where he decided that after three miscarriages, 87% of all clinical pregnancies resulted in a miscarriage. So basically, you could take yams.

You could, you know, have olive oil dipped on your bagel. You could have eaten strawberries upside down in the field, and you would have decreased your risk of a miscarriage no matter what. Later studies have actually shown that basically even three in four miscarriages, probably 50%, 60% of people that get pregnant again are going to have a baby even if we do nothing.

So it's not as bad as we think. The long-term prognosis is generally very, very favorable. Of course, most of that goes back to the age of the woman.

You know, we know, you know, from IVF studies that we did that like 82% of the equation of our IVF success, we did the study where we took everything and met with a mathematician and came up with a statistical, you know, long mathematical equation. But the bottom line was 82% of our success in IVF was completely predicted by the woman's age. So, you know, we know that dictates a lot of this, but on the other hand, the overall prognosis of somebody that's getting pregnant and having miscarriages is much better than they ever realized.

That's why reassurance is helpful, and that's why a little TLC goes a long way. No, I agree. Well, Dr. Spandorfer, thank you so much for meeting with me today for our SART Fertility Expert Podcast.

We greatly appreciate your insight in recurrent pregnancy loss, and I really hope that this talk will help a lot of our patients. Thank you so much. Sure.

Thank you for having me. It was a pleasure. Have a good day.