The Hidden Conversation Between the Immune System and Pregnancy: What It Means for Birth: Dr. Nardhy Gomez-Lopez

On average in the US 1 in 10 babies is born prematurely and, in many cases, the cause is unknown; although there could be many contributing factors, nearly 40% of pregnant people who deliver before 37 weeks exhibit chronic placental inflammation, which happens when the mother's immune system attacks the placenta. 

Today's guest is trying to decipher the conversation between the immune system and a pregnancy.  If we understood this conversation, we could look for ways to predict and potentially prevent preterm birth, and in the process we are learning more about how spontaneous term labor happens (which is, somewhat shockingly, also a mystery).

Center for Reproductive Health: Gomez-Lopez Lab

article that launches this conversation:
Deciphering Maternal-Fetal Crosstalk in the Human Placenta during parturition using single cell RNA sequencing

Transcript

On average in the U S one in 10. Babies is born prematurely. And in many cases, the cause is unknown. Although there could be many contributing factors, nearly 40% of pregnant people who deliver before 37 weeks exhibit chronic placental inflammation. Which happens when the mother's immune system attacks the placenta. Today's guest is trying to decipher the conversation between the immune system and the pregnancy. If we understood this conversation, we could look for ways to predict and potentially prevent preterm birth. And in the process, we're learning more about how spontaneous term labor happens. Which is somewhat shockingly, also a mystery. Welcome to making sense of pregnancy. 

 This [00:01:00] show is a new pregnancy reference. I'm finding and talking with experts, doing cutting edge work to better understand what we do and don't know about pregnancy and what you can do to better understand your own experience. Each week, I'll be talking to scientists, doctors, and researchers who are trying to uncover the many mysteries that still exist in reproduction. Giving you the most current. Evidence-based way to approach this enormous transition in your life. I hope it will become your go-to source for how to make your pregnancy better. Please enjoy my conversation with Dr. 

Gomez Lopez.

Today we're lucky to have Dr. Gomez Lopez on the show. She's a professor at the Department of Obstetrics and Gynecology and the Department of Pathology and Immunology at the Center for Reproductive Health Sciences, Washington University School of Medicine, who's done a ton of research on the placenta, and we're so excited to have her here.

Thank you so much for coming on, Dr. Gomez Lopez. Thank you so much for [00:02:00] having me. So let's start off at the very beginning here. Something like 50 percent of the population is women, something like 90 percent get pregnant at some point, something like 85 percent actually have a pregnancy. So it seems like , a big population who'd be interested in the kind of research you do.

And so I'm wondering, what the challenges are to research about placentas. And it seems like the stuff that you are doing is critical and elemental, and why is this being done in 2024? 

Yeah, so definitely the placenta is an, an amazing and very intriguing organ, and every pregnant woman has a placenta.

So the, research on placenta biology or immunology has been going on for many, many, many years. But I think that now the techniques, the approaches to investigate the placenta. are [00:03:00] allowing us to decipher the specific contributions of a specific cell types. And that is what is novel. What is the contribution of every cell type to that specific process.

It's very difficult to investigate the placenta. In, general, studying pregnancy is really difficult. And the reason why it's difficult is because Usually, in medicine, there is one patient, and the patient represents those symptoms. And based on the symptoms and the different medical tests, then a doctor can diagnose or have more insights into the pathology of the problem.

In pregnancy, we are dealing with two patients. One patient, that is the pregnant mother, , and the baby. And the baby's silent. So it doesn't speak, it's very difficult to, to diagnose. So maternal fetal medicine is an area of [00:04:00] of medicine that focuses on high risk pregnancies. And those are the doctors that look at the placenta and the fetus.

They do ultrasounds in order to see whether , there is something wrong during pregnancy. But that seems like a small area of medicine. Okay. So, placental biologists or immunologists like myself, we usually work in, collaboration with these doctors, maternal fetal medicine doctors, in order to understand the complexity of the disease.

The reason why it's so difficult is, one, is because you have two patients, second is because they, we know very little about how the placenta works. for the main reason that we cannot monitor this organ except if we are monitoring the pregnant patient. So, I think the approaches now, nowadays, are allowing us to investigate this organ and hopefully in the future we can investigate this [00:05:00] organ in a non invasive way.

So not to wait until the placenta is delivered to know that there is a problem. 

Yeah, that makes sense to me. And also my vague understanding is that placentation in humans is different than it is in animals. So we don't necessarily have great animal models to examine as a corollary. Is that right?

Exactly. So, it's such a unique process placentation and development of the placenta that is difficult , to know whether what we find in mice or in other type of animal models is, it's happening in humans. However, animal models, mice, rats, guinea pigs Non human primates are very helpful in testing a specific hypothesis.

Okay, well that brings me to my next question, which is that one of the ideas that I saw in your research is this idea of a cell atlas for the placenta. So can you tell us why that's important and what that is? 

Yes. [00:06:00] So, what I was mentioning earlier was, we don't know enough about the placenta, and I think that the, any scientific problem can be seen as, why we don't understand a specific problem is because we don't understand the communication in this specific problem, right?

So, I see it like in a language. So, when you don't understand a different language, it's because you don't understand the meaning of that language. So the place we saw it in this way, the placenta is communicating with the mother. The, the fetus is, is a way of the fetus communication with the mother.

But we don't understand this language. So when you don't understand a language, you go to a dictionary and a, a glossary that tells you a specific eh. War means so and so and so in your own language. So what we were trying to do is establish a glossary or an atlas of the specific [00:07:00] cell types that the placenta has so then we could then investigate what is every cell type telling us and whether we can identify signals for every single cell type in this atlas in the maternal circulation.

So this is kind of a general question. Do we have this kind of atlas for other organs? Yes. 

And recent advances in next generation sequencing have allowed , the investigation and the, description of several atlases in the brain, the lung, in many organs, because now we can decipher different cell contributions in a specific organs.

Ourselves, we have been focusing on the placenta. 

Okay, so that's super interesting. So the process that you are going through, other scientists are using for different organs. Exactly. Okay. So as I understand it, we don't know the mechanisms that [00:08:00] initiate spontaneous labor yet. But from some of the papers that you've written, I'm wondering what you would say the placental role is in labor.

 Do we know if it's initiated by the mother or the baby, or can we describe Who contributes how much? 

Yes. We actually have done in vivo experiments in mice, because this is the only way that we can test this hypothesis, is to know what are the drivers that initiate parturition. And the only way that we can test that is if we can induce partion.

Yeah. So in mice, we inject a specific inflammatory molecules that will initiate partion and so on. So we know that labor is a complex process, so it's mediated by the uterine tissues, the cervix, as well as the placenta. Then the placenta has some membranes that are surrounding the amniotic cavity.

These called, these are called extra placental membranes. or choroid amniotic [00:09:00] membranes, and these fetal tissues also contribute to the process of labor. When we did experiments in mice, we Proof that both the mother and the fetus contribute to the active process of labor. Because when you remove this specific inflammatory signaling in the mother, the process of labor, , the percentage of mice that enter into labor are lower than when they have the two components.

And the other way around, when you remove it in the fetus, the, it's just half of it. So it seems that the mom and baby are contributing equally to the process of parturition, at least to the one initiated by inflammatory stimuli. 

So do we think that the chemical conversation going on for a spontaneous full term labor is different than the conversation that goes on for a preterm labor or a premature rupture of membranes or things like that?

Yeah. So that, that's a very important question [00:10:00] because we want to understand. normal parturition because it's the culmination of all these processes, the myometrium, the cervix, and the placenta, right? But we know that the preterm parturition or spontaneous preterm labor is basically the activation of this common pathway, but earlier.

Now, the difference between normal parturition, on time parturition, after seven weeks of gestation in humans, and preterm parturition is what triggers that preterm parturition. So, spontaneous preterm labor is a syndrome, and it can be initiated by inflammation, by infection, by placental damage. By maternal characteristics, such as having a short cervix.

So the reason why it's so difficult , to say preterm parturition is just early parturition is because it's a syndrome and it can be initiated by multiple factors. And we, [00:11:00] in our lab, we focus on the inflammatory infection driven mechanisms. But there are other factors that may not be mediated in the same.

pathway that we are investigating because they are driven by different etiologies. 

So there are a lot of different routes that may lead to preterm labor. But what I heard in there was that none of those routes are necessarily under the direct control of the pregnant woman. 

Exactly. 

So many women say, , the baby came early and what did I do wrong?

Did I eat sushi? Did I run up the stairs? Did I carry something too heavy? But the process itself is much more complex and much more integrated with a number of different things that you have no control over, like your immune system, right? What's going on with your immune system?

There's not much you can do , if we could control that, you would never be sick, right? Like 

that would be amazing. 

So can we talk a little bit about RNA sequencing? When I was reading your paper, I guess how I understood it [00:12:00] was that if you're looking at. Placentas that are delivered, you're looking at almost like , a series of text messages.

, so you have a static conversation at one point in time, and I'm wondering how that translates to the dynamicism of this process over time, you know, whether that conversation looks different at 35 weeks or 36 weeks or, or how do those things relate to each other? Yeah. Yeah. 

Yes, so the placenta is, it's a dynamic organ, as you say, it's growing as time progresses and it has different functions in early pregnancy, mid pregnancy, late pregnancy, because obviously the requirements of the developing embryo will be different.

Now, what we show in our research was that, These processes can be at least monitored in the circulation. And what we found is that this will be [00:13:00] different in early pregnancy, will be different in mid pregnancy, and that these processes may be different. And the, interesting part it's not the fact that they are happening because we knew by our developmental physiology books that that, that is happening.

The, the interesting part that we had provided with this paper was to show that we can identify these processes in the maternal circulation. 

So that's super interesting. Instead of either waiting for the placenta to be delivered or doing something invasive, which I'm assuming very few people do mess with the placenta during pregnancy, there's some correlation between RNA and the mother's blood and what the conversation that's going on between the placenta and the fetus.

Exactly. 

So that's amazing. So we could do a blood test at any point. 

That's the end goal of this is the proof of concept study that hopefully will allow us to continue doing more research. And actually we are [00:14:00] Just recently funded by the borrower's welcome fund to pursue this idea and to see whether we can utilize this information, this single cell atlas, and we can now go to pathologies because this single cell atlas was generated in normal pregnancy, normal parturition.

And now we provide the evidence in the paper that, that we can identify a subset of women who eventually deliver PRETA. However, this has to be repeated, it has to be validated, it has to be in a different type of patients and in a different type of PRETA and VAERS. So now what we want to do is to investigate these PRETA and VAERS that are.

Associated with chronic placental inflammation. And for that, we will focus on the biomarkers that we can find in the circulation that they can be in reach for that specific type of pretend. So the idea will be in a perfect world is that we will have a [00:15:00] single test that will tell us this woman. may have some type of placental disease or inflammatory disease.

And therefore we can treat her in a specific way and not wait for the, the pregnancy just to have to end in a pretend delivery. 

I mean, the way that you're describing it, it sounds like we'll look back at the way pregnancy has been handled for the last thousands of years and say, Oh my God. That is crazy that we were just blind going into it, right?

And whatever happened, happened. And then you had to respond to whatever happened as opposed to do something preventative, which is amazing. One other person that I spoke to about this kind of work is Dr. Carl Wiener. I don't know if you know his work, but he is looking at RNA sequences to predict preterm birth and he's looking early, like at 12 weeks.

And I'm wondering what you think about something like that. Can that kind of work? go on before we understand the full conversation of what, of what spontaneous [00:16:00] labor looks like. 

Well, there, there will be some type of remember that I told you that preterm birth is a syndrome. 

Yeah. 

Some of the preterm births that they may be due to processes that go wrong during early pregnancy.

Some of them, not all of them. Majority of pretermers may occur in my opinion, because something go is going on in the second or the third trimester because this is when the place is already established. But it may be that they, by looking at signals earlier in pregnancy, we can identify some women who are at higher risk.

For Britain, and the, the, the challenge in the field is not only identifying women. So we are very, very early in in in this research because we are at the moment in which we are identifying these pregnancies. So with this specific test that we generate this. Okay, we can identify women that have in this specific condition.[00:17:00] 

The next step will be to develop therapies for this specific women that have a specific subset of preterm birth. And that's the challenge because then we have to understand the mechanisms of disease in order to start. testing therapies in mice, in non human primates, and so on, you know.

So, yes, we can identify women who are, indeed, right now in the clinic, you can identify women that maybe have a history of pre temper, so they are likely to have a second pre temper but as a doctor, what do you do? You know, so , the only success story here is if you have a woman who has a short cervix as a doctor, then you can recommend vaginal progesterone.

So, this woman is given vaginal progesterone, then she has the 50 percent chances of not delivering a baby, a pregnant baby. But so far, we have not any, any other strategy besides vaginal progesterone to recommend to pregnant women who are at higher [00:18:00] risk. So I hope that we're trying to say that this is a very novel field, but we also have to be not conscious that it's not just identifying women who eventually deliver print.

I mean, to come up with a solution for those women. 

Of course, of course. What do we do even if we could find them? That is a serious and significant question. But I guess what I take away from what you're saying is that, Again, there are many paths to preterm birth. And so this test looking at 12 weeks may identify some women for whom something has gone sideways in placentation very early on.

And so maybe these are the women who deliver before 28 weeks or before 34 weeks. Maybe it, that is right. related a problem early on is related to a delivery that's much earlier and other preterm births that happen in the late second or early third trimester are things that correlate more closely to problems with the placenta in the second or third trimester as it develops as different things are changing.

So, So you could all be [00:19:00] doing this work and you're all going after a different subset and kind of the tricky difficult part is to identify which women goes in which bin. 

Exactly. 

Early on. So, yeah. 

Yeah, and I think that it's also very important. And I mentioned a little bit earlier this. I am a basic scientist.

As a basic scientist or as a computational sequence in person, you always need to work with clinicians because clinicians will have the description of the disease. If we look at the types of preterm births that are associated with early, early preterm birth, the majority of them are associated with infections.

So there is something to the mom that is occurring and early that hair. Vaginal microbiome, we call it, but the vaginal composition of microbes is somehow susceptible to some type of dysregulation immunologically, and we just actually published a [00:20:00] paper supporting that, that there is some type of disbalance in the immune components in the vaginal, ecosystem that will somehow make this woman more pregnant.

susceptible to developing pre temperature. So there are multiple ways in which investigators are trying to look at this problem. All of us, of course, not invasively in order to Right, right. Right. 

But I'm imagining when you're talking about the vaginal microbiome, maybe we could use some kind of like prebiotic suppository or something like that to rebalance that microbiome to lower the chances that that results in an early birth.

Okay. 

Yeah, so we, we are thinking , from what we have seen so far in the, field. The vaginal microbiome itself doesn't allow us to identify women at higher risk for preterm bear. When, when we subcategorize this preem in all the subsets that I was [00:21:00] mentioning to you, it may be helpful, but.

So far hasn't proven to be helpful, and maybe some people may not agree with me with that. So this is, this is my point of view, and this is the data that we have generated. Now, because of that, we started looking at the immune system in the vagina. So rather than to and it must be a very tight conversation and balance between the microbes and the immune system.

So we look at the immune system and we found that women who have a pro inflammatory vaginal ecosystem are more likely to deliver preterm. So what we would like to do in the future is to actually take. Some of these components that are missing from the regular or the normal vaginal ecosystem, and add them up in order to see whether we can minimize the risk of these women to eventually deliver preterm.

Of course, this has to be tested first in animal [00:22:00] models in order to see whether the addition of these components Specifically called the fencings are also helpful and they are not harmful to women who, who in their vaginal ecosystem. Now, I do think that there is a tie regulation between micro, we modify the immune system, the micros are going to change and the other way around.

But I just think that there has been a lot of, and this is my opinion, is a lot of research in the vaginal microbiome. And so far, we have not been able to come out with an answer. You know and a specific set of microbes that are telling us this woman is going to deliver preterm. But we have been able to, to show that then the specific cells of cytokines and specific immune mediators are allowing us to identify women at risk for preterm birth.

It's super interesting to think about using that microbiome as a knob to adjust what is going on immunologically in the mother. I'm wondering in your ideal world, how would this change maternity care? Would, the first [00:23:00] trimester have more attention? 

Well, I think that the In my opinion, again, I'm not a physician, I am a basic scientist, translational scientist.

In my opinion and with the experience that I have, I think that the women are highly monitored during early pregnancy because this is where they have , risk of abortion or miscarriage and so on. And I think they should be highly monitored during early pregnancy. But I think women should also be monitored in the second trimester and in the third trimester more closely.

In my ideal scenario, if I will be pregnant, what I would like for me to go through. Well, what I will do, for sure I will do, is I will go to my doctor constantly. I will ask questions. I will check that all the, not just [00:24:00] their concerns, are being addressed. Also, my concerns, we are the, carriers of the pregnancy.

We understand when something is wrong. 

So 

I will encourage anybody to, if there is, you feel that there is something that is wrong, you should go to your doctor and talk to him, to them, to her, and say, you know, this is how I am feeling. , That is the most important. It doesn't matter if it's the first trimester, second trimester, or third trimester, because there are pathologies associated with the entire pregnancy.

So close monitoring personalized monitoring of the pregnancy, it will be ideal. Of course, that brings up a lot of expenses and, multiple things that may be in the hospital, specifically in the United States, may not be , may not be a standard practice but I, I will tell you that.

We the Prenatology Research Branch, we have research protocols in which we [00:25:00] enroll women very early in pregnancy. This was a branch that was in Detroit, Michigan, because we serve a very high risk population. The national rate of preterm birth is 10%, 11%. In Detroit, Michigan, it's up to 60%. So it's a very high risk population. 

Dr. Gomez Lopez statistic. There got a little crunched, but it's important that you hear that. She said. The national rate of preterm birth is something like 10%. And in Detroit, Michigan, it's up to 60%. So it's a very high risk population.

And there we were offering, there are many programs www. prenatology. org but we were offering clinical care and this clinical care was the entire pregnancy. And I think that many pregnant women benefit from this program from the NICHD because they were monitored.

during pregnancy. Of course, the goal of the branch being there was to do research. However, by doing research and also monitoring patients, I [00:26:00] saw myself how many women benefit from having a constant clinical care, But not only through their first trimester during the entire pregnancy, because usually pregnant women in their second or third trimester will go to the doctor if there is a problem, right?

But if it's not, it's very difficult for you to, to go out to the hospital. 

Yeah. So, 

I think that this is personalized care, understanding that every patient is different and every patient has different needs. And not all of us fall between this normalized standard course. It's very important. So I think it's a combination of you as a mother being committed , to have a high quality pregnancy, but also as a physician to provide the best clinical care.

That makes sense. One last question I have for you about looking at spontaneous labor. Can you imagine a time in the future where once we better understand the different factors involved in [00:27:00] spontaneous labor, that we would go about inducing labor in a different way? 

For, for, for them, 

well, , if you need induction, because let's say you have hypertension or something, there's so many reasons why people get induced earlier than four weeks.

And right now it seems like Pitocin and the regiment that we have right now to induce 

 Labor. 

feels a little bit like a giant hammer. And I'm wondering once we understand that conversation better, if you think we'll go about that process in a different way. 

Yes. I think that this strategy that we are following in preterm birth like this separating the different subsets of preterm birth in order to tackle every subset of preterm birth differently should be applied to all obstetrical and gynecological syndromes.

Because if they, if there is a syndrome like you know, rest of labor or this type of different, 

yeah, 

they must be different methodologies. [00:28:00] So instead of utilizing one single strategy to do induction of labor or augmentation of labor, there must be other alternatives. But if again, there needs to be funding and researchers focus, clinical researchers focusing on this.

And I know there are some of them, but there is, there is need for more. 

But I'm wondering if you think that could be an application of your work, because if you, if you genuinely figure out. How spontaneous labor starts, which has been a mystery for all time, then we may have more sense of what the levers are that we can use to generate labor in places where it is, if you have arrested labor, it takes too long or whatever it is.

Yeah. But because it's. It depends on so many different factors. It depends on the fetus also to be well, right? So if you have 

time, yeah, 

right. So it's, it's, it's difficult because it, as I was telling you, pregnancy is such a complicated problem because if we [00:29:00] want to, Accelerate labor, then easily we can do a specific strategy.

But if the fetus is stressed, we don't want to do that. So it's a very time sensitive and balance between. What can we do to, so then this strategy it will have consequences, but what is the best that we can do to avoid those consequences? 

Yeah, that makes sense. It is very complicated. And is the future of your research to identify biomarkers or that somebody else?

Well, the future of our research is to investigate the mechanisms of disease. That is what we do, but I'm, I am in partnership , with physicians and also computational biologists. And our goal is I, I kind of have two jobs. One is the one that I want to figure out why. And the other one is, can we prevent disease?

 Why this happens and this is where I have to collaborate [00:30:00] and we have an enjoy collaborating with people with multiple expertise is because only team science will allow doing to generate a biomarker. For an specific obstetrical condition, a basic scientist or a computational biologist or a physician itself.

We may not be able to have the expertise to come up with a good biomarker. So that's , the present and the future is team science to, to work with multiple expertises in order to complement each other and to come out with not just a biomarker. A biomarker that has biological sense and is personalized for that specific type of disease.

Well, that would be amazing thank you so much for coming on and explaining some of your research. It's really fascinating. 

Thank you for having me. 

Thanks again to Dr. Gomez Lopez for taking the time to walk us through some of her work. Interest in how the immune system interacts with pregnancy. Began in the 1950s when Peter Medawar, a [00:31:00] British scientist and Nobel prize winner. Brought attention to the topic in service of questions he had about immunity and organ transplants. Since that time, lots of different theories have been floated. About how immune cells treat a fetus. Which because of paternal DNA is a foreign object in the mother's body. But developing a real understanding of what that relationship is like either through the microbiome or evidence of inflammation may, will crack open our understanding of both spontaneous term labor and preterm labor. It's an exciting field to watch. I also appreciate Dr. 

Gomez Lopez is suggestion. That pregnant people should feel empowered to take their questions and concerns there. Doctor without hesitation. I think a pervasive feeling is that you don't want to bother your doctor. Which is a thoughtful sediment, But if you feel something is off, act on it, bring it to your OB. Thanks for listening. 

If you found this conversation useful, please share it with [00:32:00] friends. We'll be back next week with more amazing research.