What we are Missing in Pregnancy Care when we Don't Examine the Placenta, Part I: Dr. Mana Parast

The placenta is the diary of intrauterine life, so says Dr. Parast and her collegues. They are using this diary, after birth, to better understand both the trajectory of problems in birth (like IUGR and preeclampsia) as well as markers of impending morbidity for mothers (like autoimmune conditions that have not yet crossed the threshold of noticeable symptoms). Dr. Parast believes that placental pathology should be the standard of care in any birth that involved some sort of pregnancy complication, to better understand the cause of stillbirth (and potentially prevent future problems) and to guide maternal care in future pregnancies.

Check out some of the work the Parast Lab is doing here: https://pathology.ucsd.edu/research/labs/parast/index.html

Transcript

[00:00:00] For most of us when you're pregnant for the first time. And even after that, you're introduced to a whole host of new feelings, both physical and emotional and loads of mystery, especially in the first trimester. Maybe you get to hear the fetal heart rate at around 12 weeks. But what if you could know more about your baby's experience of pregnancy? Today's guest, a placental pathologist has called the placenta a diary of intrauterine life and runs a lab working on deciphering the information in this diary to better understand what has happened in pregnancy and what might happen in future pregnancies. She also liked to use this information to help predict possible health issues for both mother and baby down the road. Welcome to making sense of pregnancy. This show is a new pregnancy reference. 

I'm [00:01:00] 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 the first part of my conversation with Dr. Mona harassed. 

Today we're lucky to welcome Dr. Mana Parast. She's a physician scientist with clinical and research expertise in placental development and pathology. She is the director of the Perinatal Pathology Service and co director of the Center for Perinatal Discovery at UC San Diego. Dr. Parast, thanks so much for coming on the show.

I could keep going to list all your titles. Is there something I left off? Please don't. No, [00:02:00] that's fine. Thank you. Excellent. I'm so excited to have you on to talk about. The placenta, which is something we should all be talking about all the time. So let's get into it. , I'm going to ask you this question, realizing this is kind of a ridiculous one, but can you briefly describe your research?

Sure. , I'll talk a little bit first about,, the basic research, that I do. But I have a feeling like we're going to, maybe veer more towards the clinical translational work. So I'll end with that. But, , I have a basic research lab where I study placental development. And, the human placenta is a very difficult organ to study because placentas in general are very evolutionarily divergent.

organs. So animal models are useful to some extent, but there is a,, big limitations and using just those models to understand the human placenta. And really until [00:03:00] recently, we haven't had good models for. Studying the human placenta. And by that, what I mean is, , the majority until about, I would say 2018.

 We really didn't have, good models that represented true placental cells. We were using, for example, placental, tumor cell models, like these choreo carcinoma cell lines that a lot of researchers were using and still use. And, really, the gold standard was,, having access to placentas and isolating primary placental cells, but, those are not available to everyone.

But, basically, 2018 was known as the year of the human placenta, because basically a lot of , protocols were published for deriving stem cells from human placentas and what are called organoids, basically mini, , placental, organ like, culture models that you can continuously passage in culture and [00:04:00] model this organ.

So that really revolutionized, the research. But even prior to that, what we were trying to do was use human pluripotent stem cells. These are stem cells that can give rise to basically all the different cells and tissues in the body. And it had been controversial for a long time, whether these cells can actually give rise to not just,, cells that give rise to the embryo proper, but also, the placenta, which is an extra embryonic organ.

But our group and several other groups have really worked tirelessly over the past, , 10, 12 years to show that these models can in fact be used to model the placenta, , In the dish, and that's also been revolutionary because you can bank cells so you can take, cells from the placenta at delivery, and you can reprogram them to generate these pluripotent stem cells, and then you [00:05:00] can.

Differentiate them, direct them into forming placental cells, and in a way what you're doing is sending the cells back in time. So you have a placenta that's coming from a patient, for example, with preeclampsia, but you're trying to learn, well, what happened in this pregnancy, usually, very early on in pregnancy that made this pregnancy, be affected by preeclampsia.

So what you can do is take these cells. from this placenta where you know the pregnancy outcome and , by reprogramming them, you're sending them back in time and are able to model events early in that particular pregnancy. And that's powerful. It 

sounds like looking through a telescope.

Kind of exactly. Where you're looking at history. Let me ask one question before we get to the clinical work. I know there's a lot of work to grow organs in labs. Do you think growing a placenta includes challenges that growing a heart, for example, does not? 

Absolutely. , we are light years [00:06:00] behind in the placental, biology research field compared to all these other organs.

 I always, , tell people, kind of jokingly, but it makes me sad after I say it, that if you go to PubMed and do a search for any organ. Take your favorite organ, brain, heart, anything, and just do a search, PubMed gives you not just a list of articles, but, in a window on the left hand side, it gives you a little graph of how many articles have been published in relation to your search term over time.

And for every single organ, what you see is an exponential rise in the number of articles come in the, 70s, 80s, 90s. For placenta, it's a And that's really sad, and that really, to me, reflects the overall state of the field and how behind we are and how we need to catch up. 

 That's super interesting.

And to me, Just shocking. Is there an organ that's more important to civilization. I'm not sure [00:07:00] So that's a weird. It's a weird Take on what to focus on but I guess what I was imagining when I see things like that is that there's a The placenta is more complicated? 

It's, a complex question.

Yes, you can say it's more complicated, but funding has a lot to do with this. This has really been an under appreciated, Oregon for a really long time. , so the NIH, for example, launched the human placenta project. Yeah. In, 2014. And so for the past 10 years, but the, investment of funds into that project compared, for example, to the brain initiative has been significantly less, and I'm not trying to put down.

We need research in every single field. To me, the placenta. It's just been underfunded for so long that in order for us to catch up, we need more funding and then we need to train [00:08:00] people in this field, right? When you don't have funding, you don't, , as a result, you don't have a lot of people, , doing this research or even training to, to be able to do this research.

So, yeah. 

Also it may be that, , people don't understand. that some of their health issues may have arisen from the placenta, but when they have. , a heart condition, they think it's, , it's a heart condition. So that's what I'll deal with. 

You pay attention to the issue right in front of you. But in fact, the heart problem may have developed in utero as a consequence of some complication with the placenta. Everyone has a placenta.

So exactly, 

exactly. 

Should be a big market for this. So can you talk a little bit about your clinical work? 

Yeah. So on the clinical side, I'm a perinatal pathologist by clinical training. That's also a field where there's not that many of us. , I'm interested in, how, placental pathology can tell us about, what happened in a particular pregnancy, particularly with adverse sex.

pregnancy outcomes such [00:09:00] as preeclampsia, fetal growth restriction, preterm birth. And the placenta can really tell us a lot about both what happened,, with mom and then what potentially could happen with the baby, both in the immediate neonatal period, but also long term. So. I'll just quickly mention that, yeah, I think it was actually now over 20 years ago where, Dr.

Barker, made the hypothesis that basically the placenta, by setting the environment, in utero for the development of, each person, that that environment sets you up for either, normal development , beyond the womb or for development of disease later in life.

So this was all based on his studies of information that was available on birth cohorts where they found out, for example, that, , during the Irish potato famine, , there were a lot of babies that were, born small as a result of that. And,, the subsequent, rates of [00:10:00] metabolic disease, diabetes, cardiovascular disease was significantly higher in this particular population.

And so. He, came up with this hypothesis that fetal growth restriction, doesn't just affect the baby, in the immediate, , newborn period, there are complications associated with that as a newborn. Sure, but even once the baby experiences catch up growth and,, everything's, seemingly fine with the newborn.

Because their organs were deprived of nutrients, they get programmed to basically store energy, right? So that metabolic programming, is programming you for obesity, for cardiovascular disease, diabetes later in life. And these are things that, We've now known for a good, 20 plus years and, this is what we need to act on.

So yeah, so on the one side, I'm interested in, placental pathology directly and how those are associated, with, specific, adverse pregnancy outcomes. But the problem with placental pathology is [00:11:00] that, , it's a little bit like,, the placenta is delivered, bad things have already happened.

And now we're kind of looking back. And really what I'm interested in the sort of translational part of my work now is to develop biomarkers, specifically, looking at biomarkers and maternal blood that can actually predict that particular pathology or, , detect or see that developing pathology in an ongoing pregnancy.

 Okay. So this is amazing and full of questions here. So thing number one is Barker hypothesis or what's the term for it? Yeah. Developmental origin of health and disease. So super fascinating. I remember the first time I read it, I was like, this can't be right.

This is so insane, but it makes total sense. Actually the environment in which your liver is developed affects how your liver develops. So true for all your organs. , my question about that is, as we learn more about epigenetics, do we think we can change? the way that your liver behaves, even if you were in a [00:12:00] pregnancy where, , mom didn't get enough nutrition or something like that.

 That's a really great question. I think that's the, , 250 million question is, yeah. How do you, first of all, how do you detect that? Are there markers for identifying, how somebody's. , liver or, muscles are, , programmed and then what do you do about it?

, ideally,, there would be, either something that we could, if we can't do something in utero, then, , in knowing, for example, how this baby is, programmed at birth, there would be, , either diets or, , whatever regimens that are recommended, , because, of course, you can also just as , you can, potentially we can change the environment,, in utero should be able to actually.

maybe more easily change your environment, after, you're born and, then alter, , the course of, health and disease in that individual's life. So that would be ideal, but I feel like, , we're sort of at the beginnings of that, even just trying to understand, , how these, , epigenetic marks [00:13:00] are, laid down and how they can change.

Okay. So what I think I hear, which is hopeful is that , uterine environment definitely matters for how your organs are formed and the health trajectory that you are on. But as we study more about it, we can tailor your environment in the world so that you can be as healthy as you can possibly be.

So that's fantastic. I'm wondering, one thing I've heard you refer to the placenta as a diary of uterine life, which is so poetic and beautiful. And it sounds like our goal is to learn how to read this diary as well as we can. And I know that I have seen before that, for example, people who have gestational diabetes or gestational hypertension are at higher risk for having those conditions later in life.

But it sounds like those episodes also leave a mark on the placenta. And I'm wondering if it's possible to differentiate within that broad group [00:14:00] of people who have hypertension, some who are more likely to have problems down the road, and some who are less likely or That's like a pipe dream. 

No, absolutely.

, there is research, , coming out, , looking at, , a specific lesion, , that's associated with maternal hypertensive disorders of pregnancy. That's called decidual vasculopathy or decidual arteriopathy. This is basically, when you're looking at the placenta, you can see both fetal vessels.

in that organ, but also, , some of the maternal vessels that have, , sort of stripped off, , the uterine lining that come out with the placenta. When you look at those maternal vessels, if they have, , inflammatory cells surrounding them, , and in particular, if there is a severe form of this, , lesion called atherosis, where there's foamy macrophages in the wall, that lesion actually looks very much like atherosclerosis. 

For those of you playing along at home atherosclerosis. Is maybe a term you've heard that refers to the [00:15:00] circumstance in which plaque builds up on the walls of the arteries. And at least in the internet depictions of them, it looks like gunk clogging the tube. That is an artery. And again, just as a reminder, plaque is a buildup of fat and cholesterol and it can cause high blood pressure or hypertension.

Wow. 

And so when you see that severe form of decidual vasculopathy, in particular, there is research coming out that yes, those patients are the ones that are at risk,, that are most at risk of cardiovascular disease later in life. Now, the studies are limited. A lot of, and this is, really sort of my pet peeve and, what I'm trying to,, change, , in terms of,, getting people to appreciate placental pathology.

Placental pathology, right now, the majority of the work that's that has been done, that is being done, are retrospective studies, right? Again, the placenta comes out, , as pathologists or even as OBs who want to do research, what we do is, , we get together and we say, , you could, for example, say, let's [00:16:00] look at all of our patients with preeclampsia at this particular hospital and let's look at their pathology.

Or sometimes, , we do the converse study. So let's look at, for example, all the patients with decidual vasculopathy. And then, , look and see what proportion of them had maternal, , hypertensive disorders, for example, or in the case where they did, they correlated this with, with development of cardiovascular disease, it was looking at decidral vasculopathy and in a cohort of patients that have been followed for, , a long time And, the ones that, that were developed cardiovascular disease were determined , and evaluated, but, these all end up being retrospective studies, which are great in telling you,, kind of laying down a little bit of a foundation in terms of, what lesions, Mean and what there is, they're sort of associations with particular outcomes.

But if you really want to do personalized medicine and obstetrics, what you really need is incorporation of placental pathology. into [00:17:00] prospective studies. And the comparison that I do here is with, , with cancer. So in, in oncology, 50 or so years ago now, oncologists and pathologists got together and, basically, you know, grading systems and staging systems came about such that when a patient has a new diagnosis of cancer, , not only that there's clinical staging of the disease, right?

So somebody. The clinician, oncologist, the radiologist look at, the size of the tumor, where it's located, what organ it's impinging on, then the tumor comes out, the pathologist looks at it, there is a grading system, how bad does this tumor look under the microscope, what type of tumor is it, you have ovarian cancer, some of the ovarian tumors are malignant, some of them are benign, some of them are borderline, so there are specific criteria that's associated with all of these things.

So you take all of this information and this all came about because there were prospective studies. Okay, now let's follow these patients. What [00:18:00] happens to them? What happened? , how did we find out that borderline tumors are in fact borderline? Because, , they had, , some sort of outcome that was, between a benign and a malignant tumor, right?

So these prospective studies helped. That's understand, what the specific pathology is associated with. So now, if God forbid , you have an ovarian mass and you have it removed and the pathology comes out, , X, Y, and Z based on that, and based on all those studies that the prospective studies that were done, we could give you an individual, based on your clinical staging and your pathology.

 Type of tumor grading. We can tell you this is the treatment that you think that you need. This is what we're worried about. This is your recurrence risk, right? All of that. We haven't done that in obstetrics, and that's what we need to do. If we incorporate placental pathology into, so patient had preterm birth.

What's her risk of recurrence? We have all of these, be it treatment or recurrence risk or things in obstetrics that are very [00:19:00] non specific because we haven't brought that power of pathology , into these studies. 

Yeah, , for better and worse, your description of it makes it sound insane.

 Why have we not done that? And you have the power to give a relatively young woman in her thirties, say, insight into the fact that she's on a track right now to develop hypertension and take steps to change that as opposed to All men who only understand that they have hypertension when it hits. 

A pregnancy is known to be a stress test, right? So it's not just about, okay, well, , X, Y, or Z happened with your first pregnancy. Now what's the recurrence risk for your next one? But what about, you as mom, , what are you at risk for in the future?

Or even more so if we actually, followed the babies, what is the baby at risk , in it's, pediatric and then later on in its own adult, adult life. 

Yeah. It's an amazing amount of information we're leaving on the table, literally. 

Exactly. 

So we talked about how you [00:20:00] predict, hypertension later on, I heard you talk somewhere else about predicting underlying autoimmune conditions, and I just want to emphasize that the benefit of this is you as the mother who are pregnant do not know that these conditions are waiting for you.

You have not seen symptoms yet, but these things can be picked up by examining your placenta. So can you talk a little bit about autoimmune? 

Yeah. So I can talk about, autoimmune disease.

 , I usually tell people that the majority of what placental examination does is currently with the information that we have is a little bit of context of what happened, , in this. , last pregnancy, for example, findings that correlate with hypertensive disease with gestational diabetes with, immediate neonatal outcomes like fetal growth restriction, macrosomia, et cetera.

But the one thing that, placental pathology could potentially be very useful, is, identifying potentially, moms that have an underlying autoimmune disease, which can. Also then subsequently increase the [00:21:00] risk of, , the adverse pregnancy outcome that they had, which is usually fetal growth restriction.

And , this may not be outright, , really severe fetal growth restriction. It might be mild. But, especially, in a patient, we get a lot of placentas where the indication for a placental examination And is fetal growth restriction or sometimes it's fetal growth restriction with a question mark,, was this baby just small, or is it in fact, , a growth restricted baby.

And so that's really important. I mean, I would say that, , if anyone's listening and, if there was ever a question of, , was my baby small, was it, was it in fact feel growth restriction? What is the recurrence rate? Placental pathology can really tell you a lot. , very generally speaking, placental pathology can be divided into vascular lesions and inflammatory lesions.

And, , a vascular lesion like, , maternal vascular problems, fetal vascular problems, they all have different recurrence rates. And then there is, inflammatory lesions, especially what's called chronic [00:22:00] volitis of unknown etiology, that has a particular recurrence rate. 

So chronic of the latest of unknown ideology, AKA V E happens when maternal T cells infiltrate the placental Villa leading to an inflammatory response that can negatively impact fetal development. Contributing to fetal growth restriction and preterm birth. It's really common. Something like five to 15% of all. 

Third trimester placentas. Have it. If your doctor knows that you had view E in a previous pregnancy, it may change the way. They approach your subsequent pregnancy.

So exactly knowing what lesion existed in the placenta that contributed to this fetal growth restriction. is important. But the one lesion that, hasn't actually been categorized, I think it's actually, looked upon by pathologists and OBs alike as being,, both inflammatory and vascular is this lesion that's called massive perivillous fibrin deposition.

And that's when the placenta comes [00:23:00] out, , and, it's sort of variably involved, when, when you slice through a normal placenta, it's a very spongy, light, tissue, lots of, vascular spaces. When you slice through a placenta that has perivillous fibrin, it's, it's very firm. , , it looks like there was kind of white lines going through the placental disc.

And this is all fibrin deposition that has happened, , In the placenta, , as a result of potentially, an underlying autoimmune condition that, once diagnosed, it can actually, so this can lead, if it's not, treated, it has the potential in a subsequent pregnancy to get worse, and it lead to recurrent fetal growth restriction, with treatment,, there is, I'm not an expert in this, but, , from, working with my OB colleagues, things like aspirin, low molecular weight heparin, these are things that can affect, the organ in a subsequent pregnancy and, decrease the risk at least or, even completely [00:24:00] alleviate fetal growth restriction in a subsequent pregnancy.

And of course, nothing to say about the fact that then mom learns that,, they actually. , have an autoimmune condition that might affect their own health, even outside of pregnancy. So that's, that's really important. 

 It's particularly important because, pregnancy is a big trip wire for autoimmunity.

So all the big, all the big hormonal shifts. So puberty, pregnancy, menopause are the three times. So it would be useful to know to a mom that you're on this track., let me ask a question. I as a person, I'm having a baby and I go in and have a delivery and it seems fine. Can I ask for a placental pathology?

Is it something that a patient can ask for? It has to be ordered by the doctor and it's not easy to get. 

That's a good question. , the College of American pathologists,, has designated a list of criteria for when a placenta should be examined. Those are simply recommendations, though they were, , I think they initially came about in the late nineties, and they [00:25:00] have most recently been updated over the last year or two, and they generally these indications for placental examination fall into two categories.

 Three categories basically, , some sort of maternal disease, some sort of, adverse, pregnancy outcome that's kind of lumped into, mom and then, , adverse neonatal outcome. So if the baby goes to the NICU, if the baby's growth restricted. And even, those indications include if the placenta itself looks abnormal, if the cord appears to be, abnormally inserted or there is something, macroscopically wrong looking about the placenta, , those are kind of like the three categories.

In the absence of that, , I'm sure a patient can ask for it. It's not from my understanding. Part and parcel of your,, coverage of your delivery. There is not an additional charge, above and beyond that. So I would say that, yeah, especially if you think, there is always, fetal growth restriction cases, the question of, was my baby really small, or, you know, I was a small baby, so if I have a small baby, maybe the [00:26:00] baby was just constitutionally small, and that doesn't matter, but, you never know, and if there is the opportunity to have the placenta examined, I would say it's good to do so. 

I'm going to stop my conversation With Dr. .Test. here for today. I appreciate it. Her proactive view of pathology as a tool that can be used to better understand the past and potential future. 

You can use information from a placental pathology to elucidate what happened in your pregnancy as well as to chart your course, going forward. If you have the lesions that suggest hypertension. You can follow up with a cardiologist to address potential issues with blood vessels or the heart. It seems like an amazing amount of information. 

We are currently failing to take advantage of. 

 It might be a good idea to ask your OB about. A placental pathology in your particular case. Thanks for listening. If you like the show, please share it with friends. We'll be back next week to hear more insights on how [00:27:00] placental information can be used in pregnancy.