Tracking Placental Inflammation in a Pregnancy While its happening: Dr. Yong Wang, Part II

Last week we talked about the technology, originally used to look at inflammation in the brain and heart, applied to the placenta. This amazing form of MRI, which is both non invasive and safe, allows for real time information about inflammation in a pregnancy in progress. Today I'll finish my conversation with Dr. Yong Wang about what he and his team found in the study that used this technology in pregnant patients.  

Transcript

Paulette: Last week we talked about the technology originally used to look at inflammation in the brain and heart applied to the placenta. This amazing form of MRI, which is both non-invasive and safe, allows for real time information about inflammation in a pregnancy in progress. Today I'll finish my conversation with Dr.

Y Wang from Wash U. Medical school about what he and his team found in the study that used this technology in pregnant patients. Welcome to making sense of Pregnancy. This 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 [00:01:00] it'll become your go-to source for how to make your pregnancy better.

Please enjoy the rest of my conversation with Dr. Yong Wang. We'll pick up where we left off last week talking about the optimal timing for DBSI scans in a pregnancy and how those currently don't line up with routine OB scheduling for pregnancy checkups.

Dr. Wang: So this is again, one of the advantages. If you have a tool which can imaging placental inflammation safely so that that way you can apply that repeatedly over pregnancy because pregnancy is a highly dynamic process and it really require a longitudinal follow-up. So DBSI really fulfill this, , ideal target because we are pretty safe.

We are , using the, , water within our body. As a probe to study the inflammation. So ideally, , we want to scanning, , the patient to be able to understand the key developmental transitions and the critical decision points. So we really [00:02:00] prefer, if possible, to scans at eight to 10 weeks of the gestation to capture early implantation process and how new, , placental inflammation may play the role in this process.

Also 16 to 18 weeks during major placental VA vascularization stage, and also 24 26 weeks while many complications first manifest, and later on at 32 or 34 weeks for late pregnancy risk assessment. So those longitudinal time point ideally will capture the major phases of the placental immuno development while providing very clinically actionable informations for clinical decision making.

But current schedule, , we show in the paper at 12, 20, 32 to 36 weeks, all while they are very convenient because patient come in for real regular, uh, OB cares, but may meet some early pathology processes that began in the first trimester, which is quite challenging to image. But that will be our probably next step of work [00:03:00] to add on early stage imaging.

Paulette: Yeah, I was hoping for a scan, a really early first trimester scan to see more of the immediate results of implantation. I, maybe you can't do anything with, there is no placenta, but maybe you can't do anything that early. But I, I wonder if, , your schedule makes more sense than the OB schedule right now.

, I don't know what the current schedule is organized around. Right. Since there's not that much to do. Right. You're just checking on everything. 

 , or maybe a better way to say that, is that the current OB schedule is organized around the technology. We have to detect trouble and progress in a pregnancy, and as we get more exact technology like this diffusion, MRI and have more biomarkers, the OB visit schedule may might reflect different possible intervention points.

Dr. Wang: I think maybe in the future, , this beyond this, regular clinical care, for high risk patients with history of, , preterm birth or other known histories of placental dysfunctions, [00:04:00] they maybe could come for actual visits.

Just for this placental assessment. 

Paulette: Dr. Wang, I wanna change the OB schedule. As we develop more in pregnancy and OB care. M many more, visits will be shifted towards that first trimester once we know what's going on, since that's when the seeds are laid for problems we deal with later.

And then you, we could all just come in at the right time for our MRI at eight weeks. Right, 

Dr. Wang: right. I think at least for, maybe not the timing for general, population screening, but for high risk patient, it may make more sense to study the, the baseline testing, the first visit earlier. 

Paulette: So when you're looking at the group with inflammation in the group without inflammation, , do you need to know how things change over time?

For example? Yeah. Could someone just come in at one point and get a scan and you would be able to tell that there's inflammation? Or do we need to know that it is different from what it was before? 

Dr. Wang: , This is an excellent question. So we are also very interested to [00:05:00] know not only what happening at one particular time, point, what happened, but we also want to know, uh, what's the time dynamics because we know pregnancy is a highly dynamic process things could happen during pregnancy, right?

So the trajectory is more important and meaningful than a single point measures. So we found that dramatic differences that were detectable throughout pregnancy. On placental inflammation in cases with placental inflammation, immuno cell infiltration was nearly doubled that the healthy placenta, so specifically at early pregnancy, like 11 to 13 weeks.

Inflammation cases shows 4.8% immuno infiltration versus 2.8% in healthy cases. But when they reached the later pregnancy, this gap widened to 7.25% versus 4.75%. So importantly, this differences were statistically significant and clinically meaningful. So they represent quantifiable biomarkers that could [00:06:00] enable early stratification and interventions.

Which I think is quite important to study not just one point, but the trajectory of the placental inflammation over pregnancy. So that can help us to understand the eventual pregnancy outcome for one particular patient. 

Paulette: And while you're talking about that, what I'm thinking about is 

 I interviewed Dr. Matthew Hoffman, who ran this enormous multi-country study that looked at healthy first time mothers. Because , the largest amount of preterm births happens among first time moms. So for that first time, we don't know who's gonna run into preterm birth and who won't, and they administered low dose to aspirin early in the pregnancy and found that the group that took the aspirin experienced fewer preterm births.

Yeah. So I mean, if you find something at eight weeks, conceivably, you could actually treat it.

Dr. Wang: Yeah, we could, we could use this novel treatment or, and then we can monitor the treatment effect, right? Yeah. At this moment we, we just give them medicine. We just ask [00:07:00] them, do you feel better or any symptoms? But with this, we have a quantitative measurement safe, so we can quantify whether this treatment is good enough or we need to adjust the dosage.

Yeah. So to reach the maximum treatment effect to prevent even the, the very bad outcome after say eight, nine to 10 months. 

Paulette: It's super interesting to hear that even at the earliest scan, people who have, placenta characterized by inflammation have it early on and it just gets worse than people who don't have it.

And that makes me wonder whether. They're coming to pregnancy with something that is, going to be a problem and is currently below the threshold. So there are no markers yet, right? 

Dr. Wang: Yes, yes. So this, we are trying to building a, a better normal baseline. Like say what is normal looks like, right?

Paulette: Yeah. 

Dr. Wang: And then that may help us to understand what is the normal relative values during pregnancy. What's the placental immuno infiltration? Because we know [00:08:00] that even in normal. Pregnant process. The placental immuno infiltration are changing over time. So that is play a lot of roles in, for example, people seeing initiating the labor, you know, for normal delivery.

But we need to know what's happening , in the healthy groups. We, we already see that. There are plenty of variabilities in terms of immuno infiltration range from about two to 6%, depending on the gestational age. So with this normal atlas was established, we can better tell whether one patient was significantly beyond this normal range at certain time of pregnancy and whether we need proper treatment or monitoring on in those patients.

Paulette: Yeah, that was something I was gonna ask you about on my wishlist is, , using this MRI to, to better predict labor. If labor is an inflammatory condition, maybe you could, use this to measure how much it has changed, you know, at 38 weeks or 39 weeks to see how close labor. 

Dr. Wang: Yeah, absolutely.

This is has been [00:09:00] a research hot, hot spot in the field. So about preterm labor, what really triggering labor and preterm labor. There are different hypothesis. One of them are really the inflammation, I mean during pregnancy, maybe a major player of this. So this is, I think still in my mind, is one of the most exciting potential applications of our technology.

So labor actually is indeed considered an inflammatory process, including massive immuno cell activation. And inflammatory mediator release and the DBSI could provide unprecedented insight into this inflammatory, concise preceding labor on site inhuman longitudinally. We could potentially identify women at risk for preterm labor, maybe days or weeks before clinical symptoms appears enabling preventive interventions.

I mean, maybe just like you mentioned, maybe some simple treatment may help some of the patient already. Also, in addition, we could distinguish between normal preterm labor inflammation and the [00:10:00] pathological inflammatory states that, , might require different management approaches. So this could transform our understanding of , what is the labor normal physiology, , and also what is the normal delivery timing.

So we are preparing a new, actually a new paper using the data. , We collected in the similar cohort. , Based on the placental imaging technology to study how the placental inflammation in patient, , who experiencing the pre preterm labor. So that, give us better, , pictures on, related to your question 

Paulette: that, that's super interesting.

And right now for this paper, the sample was not enormous 'cause we're trying it out. Yeah. But in the patients who had inflammation, were any of them preterm? 

Dr. Wang: Yes. I mean, uh, I think at least around 50 to 60% of them have preterm because Oh, wow. In this paper we talk about inflammatory groups, , based on their, , postpartum placental pathology report.

, In a new paper, we are doing prospective prediction of which patient [00:11:00] may have preterm labor based on their placental information findings. , Which will be quite exciting. So that eventually, if we can establish that method. We can maybe. Develop a, a, a temporal spatial signatures of placental immuno changes during early pregnancy and use that a strong predictor of the pregnancy outcome, including preterm labor.

Paulette: Is the prediction based on, one scan or multiple scans? 

Dr. Wang: , in this moment, we are including multiple scans 'cause we think that. At least one or two scans, uh, additional to the first baseline scan can give us a better idea what's the trajectory will be. 

Paulette: Yeah. That would be interesting to see because you said that inflammatory placenta start off more inflammatory than the normal ones.

Dr. Wang: Yes. 

Paulette: Maybe you only need one, but also the inflammation grows faster for the inflammation group, so, 

Dr. Wang: exactly, exactly. So the post, the initial scan. And maybe the following scan give you a measurement of the changing rate, like what's the changing direction or [00:12:00] changing rate? Maybe some patient may be normalized after first scan, right?

Yeah. And second scan will make sure it, it is different in, in their developmental direction and changing rate, which is very informative. 

Paulette: So the other thing I was struck by in this paper is you have like a 17 ways to validate this technique. , We don't have to talk about all 17, but maybe you can just walk us through a little bit how, you know, you're measuring what you think you're measuring.

Dr. Wang: Yes. This is a, in my mind, the most important component, how we . Make sure this is the data we want to, to use to make sure the technology works. And what we do is that we basically, um, , take the human placenta. , Tissues after delivery. So we will perform the ex vivo DBSI imaging on this piece of tissue using specialized, small animal scanner to mimic our in vivo scan in the same way.

And then we use the same tissue. We do very [00:13:00] careful quantitative histology staining and the studies to try to preserve as much as we can the shape of the, of the tissue. So that we can register our quantitative pathology findings of immuno cells inflammations, and so we can register to our ex vivo DBSI scans.

So this type of work will allow us to do very strict voxel to voxel cell comparison between DBSI, inflammation, biomarkers, and histology, inflammation measurements. So by, by comparing to, , the histology quantifications, so as we show in this paper, we can establish our confidence that our DBSI measures are truly reflect.

The histology identifiable pathology related to inflammation. So we have compare, , between different DBSI biomarkers with different type of histology, inflammation, biomarkers, and they give us pretty good linear correlations. So we are have our initial confidence that, [00:14:00] and diffusion MR like diff, DBSI can reflect those immuno cells infiltration in in human placental tissues.

Paulette: So when you're comparing the placenta after delivery to some of the scans taken during delivery, are those things only correlated with the latest scan? I realize the placenta contains the history of the pregnancy. Yeah. But there is dynamic change. And once you get the placenta, it's kind of like an autopsy, right?

Like it's just, you're 

Dr. Wang: Exactly, it's, it's a fixed point in 

Paulette: time. 

Dr. Wang: Yes. So the inflammation changes. That's why we need longitudinal scan. Right. To study how that changes. But for the validation purpose, we only need one time point even after delivery. Yeah. We want to make sure what we measure is really what's happening in the tissue.

So it is a, it is a calibration or it's a validation using, tissues from multiple patients, like. 10, 20 patients. Each patient, we have a whole placenta. And from this whole placenta, we take multiple pieces from different locations and each pieces we [00:15:00] do multiple histologies and, different standing quantification and compare with our DBSI measures.

So after this detailed validation that can help us to make sure validate this imaging method are truly measuring something related to immuno cells, for that time point, like postpartum measurements. 

Paulette: The other thing that's interesting about that is, it gives you a sense of the kind of information you're getting in a pathology exam.

Yes. It really, it really is like this is what was happening at the end of pregnancy. 

Dr. Wang: Yes. Yes. So that's at very end of the, , pregnancy. It give you the idea, a snapshot. Like a Yeah, a total of what happening at that time point, whether your imaging are telling you the same thing. 'Cause it is almost impossible to do any placental biopsy during pregnancy, but some of the placentas are acquired.

In preterm labor patients. , Which is maybe at 26 weeks, 

Paulette: right? Yeah, 

Dr. Wang: So those give us a, a, better, platform. We can study maybe at a [00:16:00] different stage of the pregnancy, whether we can validate our, , InVivo measurements. So that's something, , we are keep doing. We are collecting tissues, keep validating.

And the validation data also serve as a ground truth for us to improve our imaging algorithm. So I think I just only view that as a validation, but we see that as a source or data we can improve our algorithm to make it better. 

Paulette: It is amazing and , it also shows kind of what we have not understood about pregnancy for all the months before delivery.

Yes, right. There's so much going on and there's a lot changing and, this is an amazing look at what's actually going on. 

Dr. Wang: E exactly. It, it just give you something invisible to our clinicians, physicians, considering , the special, , things we in this patient cohort, we need to make sure it's very safe to the mom and to the fetus.

At the same time, we want to monitor this highly dynamic pregnancy processes, , with high [00:17:00] accuracy and specificity. , So we are thinking that, uh. For example, one of the ongoing project was funded by heal initiative is to study how the placental inflammation changes in patients who has opioid exposure and how those placental inflammation may impact the fetal brain development.

So this is ongoing study. We already see very interesting data with this technology. , We can tell very different, , immuno response during the pregnancy in the patient who has exposed to opioid. Uh, so there's a different studies, like similar like this, but this tool give us opportunities to study, follow them,, in a very personalized way, longitudinally during pregnancy.

So I'll say in the next couple years, we will generate more insight about what happened during pregnancy in terms of placental immuno response, 

Paulette: It's just amazing to me. , And , I'm wondering, right now we do placental pathologies looking at what we think are the consequences of like contaminants.

Dr. Wang: Right? 

Paulette: We [00:18:00] can't see that in the scan. 'cause that's even smaller, 

Dr. Wang: right? Because like you mentioned this is, we look at the postpartum tissue. What Yeah. What is the final, outcome, but what happened in the middle, right? Right. We cannot do. Biopsy, but you can think of this technology is a in vivo pathology study, which can be performed at any time point during pregnancy in a very safe way.

So about 10, 15 minutes, MR. Scan, you can do almost like a virtual pathology on a patient who need help. 

Paulette: I can't believe it's that quick. , If I were a patient to go through this MRI scan. I would not have any sense of whether it was A-D-B-S-I or a weighted or a regular old MRI. Right. My experience is the same no matter what.

It's just the overlay of technology after the scan. 

Dr. Wang: Exactly. So on the patient side, you won't feel any difference. I think maybe only thing you can tell, 'cause when you lay down in the scanner, you can hear this grading noise, right? So different type of [00:19:00] grading noise may sound differently. So from there, maybe you can tell, okay, this is maybe T two star with IT images.

This is T two. This is A-D-B-S-I. But other than that, you don't feel anything different. 

Paulette: So now, 20 years ago or so, I, , was in an MRI scanner when I was pregnant Yes. To look at it was actually an inflammatory issue. Hmm. But it's the easiest thing I did in pregnancy. 

Dr. Wang: Hmm. 

Paulette: You just lay there and , MRIs can be a little claustrophobic, but for this one, unlike other MRIs, I have experienced.

They let my husband come in with me and , oh, keep his hands on my feet. 

Dr. Wang: That's great. Just so you 

Paulette: felt like grounded, which was really nice. 

Dr. Wang: That's also, it's amazing to know you experienced MRI during your pregnancy 20 years ago. Yeah. 'cause 20 years ago, people still , suspect that MRI may not be completely safe for pregnant woman.

But over the 20 years, a large amount of clinical trial demonstrate MRI is safe, really safe for all stage of [00:20:00] pregnancy. And also the MRI Scanner is much better now after 20 years and it's becomes quieter. The barrel size is much bigger, 

Paulette: so, oh, that's nice. That's ideal. Yeah. You don't feel 

Dr. Wang: too constricted in the, in it.

You can listen to music, all those type of things. You can keep talking to, your friend outside in the control room. So I think it'll be much more user friendly, particularly for our pregnancy woman cohort. 

Paulette: Yeah, that is ideal. , While I was being moved into the, scanner, like I might not fit.

Like I might not, I'm just gonna make it. , 

Dr. Wang: Yes, yes. Actually, we are using for the, for this study, we are using Siemens VDA scanner, which is really designed for high BMI patients, but I'm not saying pregnant women's high BMI, but for with. Bigger body, like abdomen size, that can easily fit you in for most of them.

Paulette: Yeah. More space is ideal. I call it whatever you want. That's like a much more comfortable experience. In the beginning I'm assuming many, many people will get the MRI so we can establish what's normal and what's not normal. Yeah. Right. [00:21:00] And then it, the fu for the future of ob, GYN do we imagine?

You're only scanning people who have previous experience with inflammation or how would it work? 

Dr. Wang: Yeah, I'm, I'm thinking ' if we have enough funding support, I would like to do a really large scale, normal scanning. Because for different people with different, , races and know ages, 'cause aging is a big factor, right?

As we know when people aging, , the whole body respond to the aging differently. So, , accurate, , Atlas for different type of patients will be super important for us to more accurately identify patient who has, , really the need to be better monitored and to to be better treated at early stage. 

Paulette: . This just, it feels to me like a giant leap forward. 

Dr. Wang: , I agree. I think this is the beauty of translational innovation because this technology was originally designed for the brain imaging in the aging population. 'cause [00:22:00] we want to study neuroinflammation what's happening in the brain that inflammation may causing cognitive declines.

But we translated to study pregnant, , woman, particularly the placenta, cervix, fetal brains. It shows advantages because it's purely safe 'cause it is imaging the water already inside our body. , Not like in the brain. People sometimes using PET imaging so that you have to inject radioactive tracers into your bloodstreams to be able to image it.

Right. Uh, so, but this technology is ideally we can translate from the neurology field to OB field with excellent features of safety. But at this moment, we are demonstrating is also accurate and sensitive and specific. So I think that's the future and also the beauty of doing translational studies and translate the innovation from a different field to a woman's health.

Paulette: It's just amazing and I, I really hope that you are successful in shifting the OB schedule and I think [00:23:00] so many women complain about not having any care in the first trimester, essentially. And it, feels like we don't really know what to do and you might not make it to the end of the first trimester.

So we'll see you if you make it. Yeah. Thank you. So, so to have something like this where you're actually. Very invested in the first trimester, and there are things that you can actually do. Seems amazing. 

Dr. Wang: I, I agree. I totally agree. The early studies in the pregnancy is important because in addition to preterm labor, another condition called, , the frequent stillbirth, right?

Like people lost the pregnancy at early stage, and a lot of them mean related to the implantation. And I, I think based on the literature of animal studies and the inflammation also contribute a lot to this. Procedure or pathology pathways. So that's another reason for high risk patients. Maybe it's worthwhile to, may really have, a really early stage, early pregnancy assessment point.

Paulette: Yeah. That, that's [00:24:00] amazing. , Dr. Wang, I'm so grateful that you came and shared this with us. It, it's just, it's, , exciting to be present from a distance at the pregnancy moonwalk. 

Dr. Wang: Thank you so much. I'm very excited about this and thank you for your time. I mean talking to me. 

Paulette: In the last 20 years, lots of time and effort have been put into studying the human placenta and how it works in pregnancy. And lots of this research has been focused on examining or creating near equivalents to the placenta with 3D organoids or placenta, uh, chip technology studying animal models like sheep.

Or post-delivery pathology. It feels like a pretty gigantic leap to be studying the actual organ while it's working in pregnancy. I'm amazed by where we are now and by all the future prospects that Dr. Wang briefly mentioned, which I'm guessing represent a small fraction of what his lab is doing. Using technologies that have been honed to decipher chemical and physical changes in other parts of [00:25:00] the body, like the brain and heart, which attracts a lot of research attention and bringing them into women's health.

In particular, women's health and pregnancy, which I tend to think of as public health since it affects every baby born, is an amazing and ingenious approach. And while I'm still busy appreciating what we have, I can't help but look forward to what's on the near horizon. Thanks again to Dr.

Wang for sharing his amazing research. Thank you for listening. If you like this episode, please share it with friends and while you are sharing it far and wide, why not rate and review the show? It really helps other people find the show and share in the awe that this kind of research can bring. We'll be back next week with more amazing research.