How your Placenta and Baby "Talk" to Decide when Labor Starts: Conversation with Dr. Todd Rosen

Every popular depiction of a woman in labor that you've ever seen on TV or in movies or experienced yourself contains one real truth: the start of labor is a surprise. It's a surprise because despite the many things we do know about labor, we don't know how or why it's initiated. What series of things have to happen to get labor to turn on, and why-- in one in ten births in the US-- does it turn on too early? This is the topic My guest, Dr. Todd Rosen, talks about today. He and his collaborator Bing bing Wong have developed a compelling theory about the conversation between the placenta and the fetus that may explain what the triggers are. 

Dr. Rosen's paper on the placental clock: https://rep.bioscientifica.com/view/journals/rep/168/3/REP-24-0053.xml

You can find more of Dr. Rosen's work here: https://pubmed.ncbi.nlm.nih.gov/?term=Todd+Rosen&sort=date

Dr. Rosen references the episode with Dr. Hoffman, focused on how aspirin impacts preterm birth: https://podcasts.apple.com/us/podcast/the-surprising-role-of-aspirin-in-fighting-preterm/id1779600854?i=1000684963648

Transcript

[00:00:00] , the uterus is strong, the uterus can expel a baby, but it doesn't do that until the fetus and the placenta tell it it's time To come out so we actually think that the brains of the operation is mostly the placenta.

The placenta is the decider. The placenta serves many functions in the pregnancy. It's like a kidney, and it serves as a lung, so it serves as like the gut because it feeds the baby, it oxygenates the baby, it takes the baby's waste away, it kind of does everything.

 So why can't it be a brain, and why can't it learn during the pregnancy, and why can't it decide when the baby is ready to come out? 

Every popular depiction of a woman in labor that you've seen on TV or in movies or experienced yourself contains one real truth, or at least one real truth. The start of labor is a surprise. It's a surprise because despite the many things we know about labor, we don't know how or why it's initiated, what series of things have to happen to get labor to turn on, and why.

In 1 in [00:01:00] 10 births in the U. S., does it turn on too early? This is the topic my guest, Dr. Todd Rosen, talks about today. Collaborator, Bingbing Wang, have developed a compelling theory about the conversation between the placenta and the fetus. That may explain what these triggers are. 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 it will become your go to source for how to make your pregnancy better. Please enjoy my conversation with Dr. Todd Rosen.

 today we're lucky to have Dr. Todd Rosen on the [00:02:00] show. He's a maternal fetal medicine obstetrician and gynecologist and a researcher at Rutgers Health. Dr. Rosen, thanks so much for coming on the show. 

Thank you for having me. 

We're here to talk about something called the placental clock. Which I think references the fact that something in the placenta is setting the length of a pregnancy. You wrote about this in a paper published in 2024 in the journal Reproduction. 

A proposed model of a clock that governs the length of human pregnancy, a clock that governs the length of pregnancy is, , an amazing thing to look for.  Can you tell us why finding a clock is important? 

Well, I think it's important for a bunch of reasons. First reason is , we should understand why labor happened. It's been more than 50 years since we put a man on the moon and we still don't know even the most basic reproductive biology questions.

So. Just for science's sake, and it's good to know these things, but the reason that this has been an [00:03:00] area of focus for me is that by understanding how the clock that governs the length of pregnancy works, we might be able to stop it. I know you've had other guests on your podcast that have talked about the problem of preterm birth, but to frame it slightly differently than they might have, it's the leading cause of death and disability of children up to age 5 in the United States and worldwide.

More children die from complications of prematurity than they do from birth defects or from infection or from SIDS and other common causes of early childhood death, , more than half of preterm births seem to be idiopathic. That means that we just don't know why they happen.

 When we do a careful analysis of the placenta and the baby and the uterus after the babies were born. We don't know why. That predetermined birth occurred. Some predetermined births are caused by infections, others by a weak cervix called an incompetent cervix. Sometimes hemorrhage and placental abruption will lead to that predetermined [00:04:00] birth.

 Overdistension from having twins or triplets or maybe having too much fluid in the uterus is another cause of predetermined birth. But sometimes it just happens and it keeps happening to women and we don't understand it. I did a lot of this work with a colleague, Bing Bing Wam, we spent a bunch of time chopping up placentas and testing some ideas.

 We think that maybe a good portion of those preterm births we can't explain are just because the clock that determines the length of pregnancy just ticks too fast. And if we understand the mechanisms behind that clock, Maybe we can prevent some cases of preterm birth and load and reduce that burden on children's health.

I was surprised by that statistic in your paper that half of those preterm births are unexplained. That's a giant number. 

Yeah, preterm births affect about 10 percent of all pregnancies. It's much more common if you're black. And if you're white, I'm not understood.

 So I practice clinically in addition to doing research. And, most of the time we just, we get the [00:05:00] studies back and there's no explanation for why a woman delivered early. 

Yeah, it's   

 Really important work to be focused on. . 

So one thing you talk about in your paper are what I'll term the players involved, like the fetal membranes, the placenta, and the mom. So those three players we think, contribute something to the clock. Is that right? 

 Yeah, actually, it's kind of funny, so, a lot has been focused on, , the mom's contribution to when women, deliver, I'm not saying this in any an interrogatory way, but I think women are , the muscle in this case, they have the uterus, the uterus is strong, the uterus can expel a baby, but it doesn't do that until the fetus and the placenta tell it it's time To come out so we actually think that the kind of the brains of the operation is mostly the placenta.

The placenta is the decider. The placenta serves many functions in the pregnancy. It's like a kidney, and it serves as a lung, so it serves as like the gut because it feeds the baby, it oxygenates the baby, it takes the baby's waste away, it kind of does everything.

 So why can't it [00:06:00] be a brain, and why can't it learn during the pregnancy, and why can't it decide when the baby is ready to come out? Yeah, so this hormone that we've talked about, CRH, is produced by the placenta. That's a marker for the clock, and that's where our investigation began, trying to understand how that was regulated, , as a first step to understanding, how the placenta does this thing, where it figures out it's time for the baby to come out. 

Just a quick note here, CRH is the abbreviation for corticotropin releasing hormone. In an adult, it's released by the hypothalamus and responsible for initiating the body's stress response. In the placenta, it serves other roles, and we'll get into those.

 Calling it a brain is so interesting and, , I have three questions to lay on what you just said. The first thing is, if we're using CRH, as this measure of, , how long the pregnancy has gone on,

is there a time in the near or distant future when you think this will be used to predict a delivery [00:07:00] date? 

Yeah, so it's not a great predictor this data has been around since the 1990s I'm a guy named Roger Smith working out of Australia worked most of this out and they did a really cool study I think the lead author was a guy named Mark McLean And what they did in Australia was they measured women's blood levels?

Serially as a pregnancy went along and what they noticed was that the CRH levels Increased exponentially as pregnancy advanced, and that's a pretty big thing. That's good to know. , before that, somebody figured out if the placenta that made it, but then with the kind of really super fascinating finding was that they showed that, , if you check series levels early in pregnancy, , let's say, 28 weeks, and they're low.

Women would tend to deliver late and if they were high at 28 weeks, they would tend to deliver early. So something happening super early in the pregnancy, was predicting when a woman was going to deliver. And actually in their paper, which was published in one of the first years Nature Medicine was published, , they coined that term the, the [00:08:00] placental clock that was Dr.

Smith and his colleagues who did that. , but clinically it's not a terribly useful test. There are now tests that are available that are doing a better job at predicting preterm birth, but there's nothing that will tell us like if I run a test at 20 weeks or 24 weeks that I can predict within even a week when a woman might deliver a pregnancy naturally.

Okay. Okay. In your paper you talk about The ratio between the size of the placenta and the size of the fetus and how as that shifts over time and the fetus grows big enough to, overtake the size of the placenta or at least catch up to it, that sends some kind of stress signal?

 Is that what you think is going on to tell the placenta it's time to go? 

Yeah, that's one of the important steps that leads to the onset of labor. To express , a way that makes sense to me and maybe helps people understand what we were thinking and what we think we've shown in our lab.

 I could take the world's greatest placenta, Paulette, and connect it to you. And even if it was the Hercules of placentas, you would not [00:09:00] get enough nutrition or oxygen to survive. , you need to be out of your mother's womb so you can breathe air and eat food. The baby's going to grow inside the uterus,, and maybe 7, pounds.

Thank you. But the baby needs to continue to grow, to be a full sized adult, 140 pounds or whatever we grow it to be. The placenta grows much more slowly, and it begins to sense that it can't give the baby what it needs forever. So, at some point, the placenta has to recognize that the baby's getting too big.

For it to supply it with his needs and that, if you're a conscientious, well meaning placenta and your number one job is to feed and nourish, and oxygenate the baby, , that's going to stress you out. And the reason we came upon that stress idea is that CRH and cortisol. CRH is a hormone that's made by the human brain that ultimately , leads your body to make more cortisol.

So these are all part of your stress response. If I'm, , on an airplane and I'm worried about being on that airplane, my brain's going to make CRH, my adrenal glands are going to make cortisol eventually. And that'll help me deal with the stress [00:10:00] or function better in the stress.

We think because those hormones are involved And that CRH is made by the placenta. We think it's the placenta that feels stress. When we thought about these things, we thought about it at different types of levels. We thought about the biology.

We thought about the molecules involved. We thought about if we were engineers, I used to be, I'm a former engineer. How would I design a system that would work reliably and result in both healthy mom and healthy baby. One thing about stress is we always think of it as kind of a negative thing, right?

We think of stress as perhaps having a negative effect on the body, even if it's a normal adaptive response. And sometimes when there's too much stress, really bad things can happen. If you think about people that go to war. And they come back changed because they have post traumatic stress disorders, because those steroids can change your brain forever.

Steroids can cause these molecular changes in the genes called epigenetic changes that are permanent. And that may explain some parts of,, post traumatic stress disorder. If there's going to be stress in utero that is [00:11:00] involved with the onset of pertuition, we don't want to stress the baby because that's mean, right?

We want that baby to lead a long, healthy life without stress. Like really having to go through some things while it's in utero. We don't want the mom to be stressed for just basic, survival of the species, she needs to raise that child. I think, maybe now in the U. S. for 26 years or something before they launch them.

But they have to be healthy for that kid and maybe for the kids that come after them. So that if you're going to stress something, you stress the placenta. And we think this placenta begins to feel stress. And the placenta is a disposable organ that basically ends its life when the baby comes out.

We think that the placenta gets stressed, it has the permanent changes to its physiology, but it's okay because that placenta doesn't have to live past the life of the pregnancy. Am I making sense? 

CRH in an adult body does something specific. We think it does a similar thing in a placenta. 

Yeah, so you're asking one of my favorite questions, Paula, It's always opposite day in [00:12:00] the placenta. The placenta kind of does everything backwards from the rest of the body. So, for example, there are dividing cells in your body, and if you give them oxygen, they divide more.

But if you give the dividing cells in the placenta oxygen, they divide less. That's just one of the placental paradoxes or something. , In your brain, if you have a stress response, right? Let's say I get scared by something and my brain recognizes that it makes the CRH, makes my adrenal glands make cortisol.

Then the cortisol feeds back to your brain and says, Hey, I'm here. There's enough of me. And you get this negative feedback loop. The brain makes less CRH. In the placenta, it's weird. The placenta makes the CRH. that drives a baby to make cortisol, and then the cortisol goes to the placenta. The placenta's like, oh, I'll make more CRH.

It actually works exactly backwards in the placenta compared to the way that it does in the brain. And actually understanding the difference in CRH regulation during pregnancy in the placenta compared to the brain was the major focus of our initial [00:13:00] investigation. We thought that by understanding that process, it would give us a bunch of clues about what Other, other enzymes or other molecules were important in this process.

Yeah, if you think about it, it's a positive feedback loop, right? The placenta makes CRH, the baby makes cortisol, the placenta makes more CRH. And that's why you, in part, why you get that exponential rise in CRH levels as the pregnancy progresses. 

Okay. Okay. That makes sense. Now I realized there are many paths to prematurity.

 There are people who have, or are currently working on, testing, that can be done in the first trimester to predict preterm labor. So I don't know whether that preterm labor is, is going to predict the 50 percent we can't explain, or if that's going to lead to one of the preterm labors we can explain, but it makes me wonder whether this defect in the placenta that causes this too fast clock happens super early on like conditions [00:14:00] like preeclampsia where, the seeds for preeclampsia are planted very early on in the pregnancy.

Yeah, so I listened to your podcast with Matt Hoffman, and he talks about the great placental syndrome all the time. The placenta is the source of all good in pregnancy, but it can also, when it malfunctions, lots of bad things can happen. Preeclampsia, stillbirth, , fetal growth restriction is a major cause of problems in pregnancy as well.

You can get things like the placenta can invade too far into the wall of the uterus, and that can cause an accreta. You can have pregnancies called multiple pregnancies. Placenta can be a source of significant disease in the pregnancy, there's a commercial test available on the market now that looks at a ratio of some placental proteins, and if those were abnormal, that can predict a preterm birth and.

To me, that test predicts the kind of preterm birth that I'm most interested in the one that we think we have the most chance of impacting. So your question is spot on and perfect that, , our ultimate goal. We're running a clinical trial now, [00:15:00] and we're running a certain way, but we are looking for funding to employ one of these tests.

I think we're going to get it, say if you have a test that predicts preterm birth and this one's done at 19 or 20 weeks, there's some that are being marketed, they're not on the market yet, but there's some studies to show maybe you can do it even earlier than 20 weeks. But we think those are the markers that the clock is ticking too fast.

And though, and those are the patients that might be eligible for treatment. 

What would the treatment be? 

Right. So the reason, we played with all these molecules all the time is because we were trying to figure out what enzymes, what processes are important. So we have, we've implicated this pathway or the NF kappa B molecule and NF kappa B.

is a super important transcription factor that's preserved across all species from Drosophila all the way up to humans. It's involved in eventually every cell in your body. Actually when it's activated often it's not a good thing, like it's important in inflammation, it's important in [00:16:00] cancer.

Actually weirdly enough it's actually part of memory. , and that's a good thing. There's a couple of cells in your body, like your brain and your immune system where and if capital B will be turned on constitutively, that means it's always turned on without response to any kind of stimulus.

And it's healthy when it does that. And it's part of the memory process. What we found in the placenta is that's what happens to that. This end of capital B molecule. is turned on. It's just, there's two, there's a few different pathways, but which could be turned on. And the pathway is called the non canonical pathway.

So we think this pathway is super important in this whole process, right? NFKB activation leads to remodeling of certain genes that leads to more CRH production and other agents that are important for the onset of partuition. And if we can inhibit the things that we think are part of that process, that maybe we can have an impact on these.

preterm births that occur because the clock ticks too fast. So we look for drugs that can inhibit this enzyme called NIC or NF kappa B inducing kinase. And there were no commercially available [00:17:00] drugs. So we ran our own screening study of other drugs that have been.

 Used for other indications, we screened more than 1200 drugs. And after a process, we found this one drug called sulfasalazine, which is used in the treatment of inflammatory conditions. It used to be used very commonly for rheumatoid arthritis. It is still used for diseases like ulcerative colitis and inflammatory bowel disease because it's been used for those drugs or those indications for so long.

There's actually a lot of experience with the drug in. pregnancy. , and going back through some of the old literature where they were looking at how pregnant women did on these drugs, which by the way are very safe, like class B FDA drugs. , they show that almost no women who got the sulfasalicine delivered preterm, like out of 280 women in these two retrospective studies, zero women delivered before 34 weeks of pregnancy when they were getting the drug, which is far less than expected.

And actually far less than women who had the same diseases, presumably healthier because they were on no medication. Like 70 percent of those women delivered preterm. So [00:18:00] we're testing this drug sulfasalazine. We think it inhibits this, the NF kappa B pathway. And we're hopeful that that will yield results.

That's the trial that we're doing now. We have an FDA investigational new drug approval, and we are running that clinical trial now. 

 So that's amazing. I think of NF kappa B as like an immune system regulator, and I didn't know about its memory function.

It makes me think of Dr. Hoffman's work one thing Dr. Huffman said is, the aspirin was successful in shutting down a significant fraction of preterm birth , they also at the same time thought, why doesn't it shut down? Why doesn't it shut them all down? 

Yeah. So Matt and I've talked about this quite a bit. We, serve in the same research consortium and we've been colleagues working together for like 15 years.

 There's , multiple, multiple different processes that go on in the onset of partuition. , the aspirin inhibits inflammation that occurred, like the final end stage for that we think happens is that after this clock's been activated that, that the canonical and if government pathway may get activated to be that final step that triggers labor, [00:19:00] but.

And that, and aspirin, the drug he's been studying so extensively and has published quite a bit on, , has been shown to inhibit the canonical NFKP pathway. But we think it's the non canonical pathway that's important. It's not, we're not mad at each other about this. , we're just studying different parts of the process.

He's published his papers in amazing places like the Lancet. It's incredible the work he's doing, but I will bet you that we may see a greater effect. From the well, I can't i'm not gonna bet you anything the self isolating is doing a different thing Yeah, and like matt's already proven that that the aspirin reduces preterm birth risk by about 10%, give or take.

 In our group, we're hoping to see a bigger effect. We're doing a, , basically a phase two trial right now. , looking at biomarkers to see if , in a woman's body, if we see the same effects we saw in the lab. And then if that study shows a positive result, then we'll move on to the bigger clinical trial once we get that funded. 

. I'm wondering if you [00:20:00] in the course of this study ran into any surprises, anything you found that surprised you? 

, yeah. One thing that surprised me, it's just taken us so long to figure things out. I remember I was a fellow and I came up with these ideas and I was studying it.

When I was in NYU and then I left research to just do clinical medicine for a while, and I came back to it about 10 years later. But when I thought of these ideas, I'm like, Oh my God, this is going to happen. Someone's going to figure this out in the next week or something like that.

I just, I kind of panic. Yeah. So now 20 years later, we're starting to get there. , I think it was funny, so Bingbing, Wong, and I used to bet on things all the time, and I don't like to bet unless I'm pretty sure I'm going to win. And so we had seven consecutive bets about what the result of our experiment would be, and I think I won those seven bets.

But the eighth bet, I was pretty sure, , this one thing was going to happen, and this was like the final trigger for labor, and I was absolutely wrong. And I actually, I got, yeah, so I, I think I had to buy him. Beer or something. So the, thing that [00:21:00] surprised us and we, and this work started with Carol Mendelson's work in a knockout mouse model is that so far we've just talked about the placenta saying, Oh, the baby is getting too big.

It's time to get, get it out. But that's not a great system. If I was an engineer designing the labor system or whatever you want to call it, . for the pregnancy clock, I would want to have a fail safe system. Some babies are completely healthy and ready to come out when they're four pounds and other babies like born to diabetic moms may not be ready until they're 12 pounds.

So if we're just relying on the size of the baby to be the one thing that drives labor, that's not enough. So Dr. Mendelsohn figured out in mice, in this one weird knockout model that she made, but like it really informed what we did. That the mouse pup sends a signal to its mother that okay, I'm sure I'm ready to come out and.

Mouse partuation and human partuation are completely different, CRH, which we've talked about, doesn't matter in the mouse for this purpose. , you can make a CRH knockout mouse and they'll still deliver exactly when they're [00:22:00] supposed to. , but what it does do is it knocks out the corpus luteum, that's, , the ovary that makes progesterone.

And when the corpus luteum goes away, progesterone levels drop. And the mouse goes into labor. So we looked for some of those similar things and through a series of experiments we did something called transcriptomics and proteomics. And we look to see the difference between a very near term pregnancy, like at 35 or 36 weeks.

And we compared those to pregnancies at 39 weeks. And we took cord blood. Looking at what the placenta might be making, what the fetus might be making, we found some differences. And we found a couple of the last steps to trigger this whole NFKB cascade. , so that one was a surprise.

 Putting our ideas, together, we think, , The thing that drives the clock is a two stage process. Stage number one is that the baby gets big and stresses the placenta and that induces some changes in the placenta and that baby, and the placenta's ready to go. And once the placenta's ready to go, and then it receives, the placenta, like, [00:23:00] you know, Plus I'm just kind of learning, Oh, the baby's in this state.

It's okay. If it comes out, then it waits for the baby to send a trigger through the vocal cord. And that is like the final stage that activates the entire labor cascade, which then involves the membranes involves the uterus and the baby is expelled through a pretty painful process. Yeah. 

that's one thing that really struck me about your paper. I've seen other theories about the trigger for spontaneous labor, and they tend to focus on one particular pathway, and most of the papers focus on different pathways. I understand that this process is complicated, and we have to break it into smaller parts to untangle what's going on, but your view incorporates all three players, mother, fetus, and placenta.

Yeah. I've talked to some really accomplished scientists and they say, if you can understand how this molecule works, then you'll make a career and you'll get NIH funded and you'll become a professor and maybe a chair or something. But we are trying to answer this question.

Differently, we're not saying, [00:24:00] Oh, what role does NF kappa B play in this? Or what role does CRH play? We were studying these molecules to try to understand, , how this clock works. So we just looked at what had been published. We thought CRH was a good place to start, , what I learned about science is the more Okay.

The more collaborative you are, the better your experiment is going to be, the more likely you are to find your answer. So we talked to a bunch of smart people here at Rutgers. , we had some local experts, including Arnold Rapson here, who, is an expert at NFKappa BA. We ran smart initial experiments.

What was really kind of fun was that the first experiment, my whole idea, the one I came up with, working really late nights when I was a fellow, A couple of elements of it were true and it was a good basis for starting the experiments, but everything, everything I was thinking past a certain point was wrong.

And because we designed smart experiments, we actually figured out , it wasn't what I thought it was going to be, but it was something related. And we, and we got there. So keeping your eye on the prize, which is not like focusing on one molecule or one pathway, but keeping your eye on the prize that we care [00:25:00] about.

Why women go into labor? Because we want to try to prevent preterm birth eventually, , is what drove the work that we did. 

 Well, it's amazing. Thank you so much for sharing it today. I am excited for other people to, , to think about it, even pregnant women to think about it that way, 

that it is this complicated conversation between the placenta and the fetus. 

Yeah. I think that's a fair way of describing it.   

Thank you so much for coming on. I totally appreciate it. 

Thank you for having me. 

Thanks again to Dr. Rosen for taking the time to talk about his work with us today. When we were no longer taping, I asked him if working out the model of what sets off spontaneous labor has changed the way he counsels pregnant women in his practice. And he said it hasn't.

So for now, even though we've made untangling the pathways responsible for this process, On which all civilization depends, we don't yet have any better way to turn off labor when it comes too soon. And in fact, to this point he said, [00:26:00] this is why preterm birth rates have not been reduced over the last 30 years.

We clearly have methods of initiating labor when it hasn't come soon enough, with prostaglandins to open the cervix and oxytocin to get the uterus to contract, but it's complicated to figure out what the costs are here. Some research argues that induction leads to more c sections and other research counters that, suggesting it leads to fewer c sections in certain cases.

A lot of different issues can bring someone to induction and or c section, so that one is hard to unwind. All of which makes figuring out the what and the why. What flips labor on and why it happens too early for too many pregnancies. All the more important.

This work could have an enormous impact, not only on preterm birth, which in and of itself would be giant, but also on term birth. If it could narrow the window of uncertainty around delivery, timing, it could have real implications for managing the limited resources of labor and delivery practices, 

In particular, hospital beds and OB time.

 and [00:27:00] potentially impact how we carry out inductions in the future.

Thanks for listening. If you like this episode, please share it with friends. We'll be back next week with more amazing research.