The Surprising Role of Aspirin in Fighting Preterm Birth Risks: Conversation with Dr. Matthew Hoffman

Preterm birth is a significant problem in the world and affects one in 10 pregnancies in the US.

Any early birth anytime before 37 weeks. Could lead to a host of negative outcomes, both for the mother and the baby.

What can be done?

Today, I talked to a researcher about his work examining how aspirin taken early in pregnancy can decrease the rate of preterm birth.

Dr. Hoffman's most recent publication about aspirin use in pregnancy: https://journals.lww.com/greenjournal/citation/2024/03000/aspirin_in_pregnancy.27.aspx

Transcript

Preterm birth is a significant problem in the world and affects one in 10 pregnancies in the us. Any early birth anytime before 37 weeks. Could lead to a host of negative outcomes, both for the mother and the baby. What can be done? Today, I talked to a researcher about his work examining how aspirin Take an early in pregnancy. can decrease the rate of preterm birth. Welcome to making sense of pregnancy. 

 Consider this show a new 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 [00:01:00] 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 this show. will become your go-to source for how to make your pregnancy better. 

Today, we're lucky to have Dr. Matthew Hoffman on the show. He's a doctor and researcher and serves as the Marie E. Pinozzotto Endowed Chair of Obstetrics and Gynecology for ChristianaCare Health System. Some of his research focuses on preterm birth and in particular, he's examined the use of low dose aspirin to affect the rate of preterm birth.

Dr. Hoffman, thanks so much for coming on the show. 

My pleasure to be with you, Paulette. 

So let's talk can you define the size of the problem? How common is preterm birth? 

Yeah, preterm birth is very common. It's about 10 percent of the overall population. The other part when you pull out and again, the particular study we're talking about was an international study.

There are about 15 [00:02:00] million preterm births around the world. There's about a million deaths that result to that. Most of those are concentrated in South Asia and Sub Saharan Africa. So this study was particularly relevant there that speaks to mortality, but there's also long term health costs and consequences to children who are born too early.

Yeah. In the U. S. it seems like it's leads less to mortality and more to health issues long term for the children. 

Yeah, , I think that speaks to our neonatology colleagues, none in our successes. So we recognize that we needed to think about how do we prolong pregnancy to improve outcomes for children.

And when we're talking about preterm birth, I know that the OB community has segmented that population into different buckets, the early preterm, very early how does that break out? Do you know offhand? 

Yeah. So about 2. 3 percent or less than 34 weeks. And again, the [00:03:00] earlier are the more mortality that you see.

And again, it varies very much by country based upon resources for dealing with those. Similarly, one of the child is born determines both their short term survival duration in the NICU and also profoundly affects how they'll live their lives. Even things like the kidney. Is a third less efficient if you're born before 34 weeks and that plays out as we become adults.

Okay. Okay. Do we know the underlying mechanisms that create preterm birth, both in the population of women who come to pregnancy relatively healthy and the population who come with something significant like hypertension or diabetes?

Yeah, great question. So part of the discussion around this is we recognize that there's about a third probably higher now in the U. S. of babies that we as obstetricians will deliver [00:04:00] early mostly because of blood pressure problems or the baby being undergrown. About 70 to half are going to be spontaneous preterm birth.

This tends to skew more preterm birth labor, contractions, breaking water and younger, healthier people, and more of the latter meaning folks that we deliver and folks who are older with more chronic medical conditions. Regardless, most of us are coming to the conclusion that these things overlap each other, that there's now what we're calling either the great obstetrical syndromes or adverse pregnancy outcomes, and these reflect placental illness which we think the placenta is really the root cause of both preeclampsia, preterm birth and fetal undergrowth in a condition called abruption. which is the placenta separating too early from the lining of the uterus. We know that moms who have one of those conditions [00:05:00] are likely to recur with that condition, but equally as likely to have another version of it. Meaning if you have preeclampsia in your first pregnancy, your risk of preterm birth, spontaneous preterm birth doubles in the next as an example.

Wow. 

And we think most of this now is really maternal inflammation rather than infection. 

That's interesting. I'm only familiar with a limited set of it, but I interviewed Dr. Carl Wiener. Who's got, , the RNA sequencing test to look at predicting preterm birth early on.

He said right now they're looking at 12 weeks to try to predict preterm birth, which seems like that suggests the seeds are planted for preterm birth pretty early. 

Yeah, , , the seed analogy holds up really well. So following conception, the pregnancy sits on top of the lining of the uterus. And there is a critical time period where it literally invests within the lining of [00:06:00] the uterus for the endometrium.

And we think that that process is slowed or deterred based upon mostly maternal inflammation. And if you don't achieve the terminology, something called deep placentation, meaning the placenta fully vest within the lining of the mother that you're much more likely to wind up with those conditions that we just spoke about.

We're not entirely clear why one is different than the other, but there's this critical time period between 10 and 16 weeks. So, partly what was important about the aspirin trial there have been a lot of trials of aspirin before. It's not that we just use aspirin to prevent preterm birth but that in fact we used it very early in pregnancy.

 So three questions here. The first one is you mentioned maternal inflammation. Does that mean the mother's immune system? Is that what that generally highlights? 

Yeah. We know that general vascular inflammation is problematic. And [00:07:00] if we look at the things that seem to improve outcomes in the conditions that we've talked about, they're very similar to cardiovascular disease.

So we know maternal exercise seems to have benefit in preventing preeclampsia. There's progressive information about more of a Mediterranean style diet. When you think about aspirin blood pressure control, diabetes control. If I were to take out the word pregnancy and put in the word cardiovascular disease you would have basically an analogous model.

I'll say there's also some research groups looking at some of the cholesterol drugs, Prevostatin. Pravastatin is a cholesterol drug, but it's thought largely to work through mediating inflammation, and based upon some small studies, seems to be very effective in preventing recurrent preeclampsia.

And that's still being worked through in a number of research trials. 

That's sort of amazing. I was going to ask about aspirin. When we think about aspirin, you either think about it for use with blood [00:08:00] clots or for use with, you know, sprains, you know, sprain injuries or some kind of pain. And so I'm wondering, do we know how aspirin works in pregnancy?

Yeah I can try to tease a little bit of that. So maybe to put in a little bit of different terms, you talk about COX 1, which is blood clots or stickiness of platelets, which is what blood clots are formed from, and then COX 2, which is the anti inflammatory component. The story of aspirin begins with the thought that it mostly affected platelets.

Based upon some information in the eighties, and they lowered the dose significantly trying to improve safety, knowing we could affect platelet function. What's interesting is when we look at tests of blood stickiness, if you will, it doesn't seem to correlate with the outcomes of preeclampsia growth restriction or preterm birth.

Versus we think that probably it's now [00:09:00] again, more inflammatory mediated your, your sprained ankle inflammatory Cox to pathway. Again, it's more complicated than that. But most of it seems to be very much a preventative strategy. When the placenta is investing in the mother. So we talk a lot about building healthy placentas.

When you think about prenatal care in some ways, it's backwards. We spend a lot of time seeing folks at the end rather than setting them on the right course early. 

I was going to ask about that. It's so interesting that a lot of the fundamental things are laid down in this first trimester where you're kind of on your own.

And , usually obese say, make sure you take a prenatal vitamin and make sure you have enough folate, and there's a lot of dietary restrictions, no raw fish, no alcohol, no cigarettes, things like that. But it's not proactive, I guess is what I'd say. So I'd be we're going to get to this cause I want to know how you would change maternal care.

But before we get [00:10:00] there. Will you talk a little bit about the findings of this aspirin study? 

Yeah. So the aspirin study was a prospective trial, meaning we recruited folks into the trial. We took all first time mothers. Who had just 1 baby who had an ultrasound confirmed early pregnancy between 6 and a little shy of 14 weeks.

Moms were given either aspirin 81 milligrams or an identical placebo. And then we followed them to their delivery. Again, this was done in low middle income countries through a research group that I'm involved with called the global network. Just to say places that are involved were 2 sites in India, Pakistan Zambia, Kenya, the Democratic Republic of Congo and Guatemala.

We recorded a little under 12, 000 women. Approximately 6, 000 in each group. Those who took aspirin had a decrease [00:11:00] in all the things that we would hope that they would have a decrease in. So they were less likely to have a stillbirth. At 14%, They were less likely to have a preterm delivery before 37 weeks by 11%.

But we were particularly enthralled to see that the group who was before 34 weeks was less, 25%. And a trend for even the earlier kids in under 28 weeks were reduced by about 28%. But it was pretty profound. Is the early preeclampsia before 34 weeks, there was a 62 percent reduction reduction in those moms who had preeclampsia having very small babies.

When you think about preterm birth. And I spoke about inflammation, particularly early. Early preterm birth and early preeclampsia are probably mediated by inflammation. And a lot of what we did is [00:12:00] we shifted children who would have been born 30 weeks to now 35 weekers, if you will. So again, important outcomes, particularly on a population health level.

The other part is we followed it from a safety standpoint. So, so no differences in health care utilization, no more bleeding issues, no complications, no more side effects, except for a tiny difference in allergies of 0. 3%. And then just to say, we recently published this past year. Follow up on these children when they had reached 3 years of age, looking at neurodevelopment and there was no difference.

If anything, there was a slight improvement just to call attention to 1 of my old friends and colleague, Jim Zhang went back and looked at a group in the 50s and 60s that was recorded and people would take aspirin randomly and they recorded it. Close to 60, 000 [00:13:00] women and those moms who took aspirin for just usual reasons had about an 18 percent decrease in learning disabilities.

So aspirin may, may also be helpful. We know children born premature have more learning disabilities and also moms, even if they have preeclampsia term, their children are more likely to have learning challenges. 

Wow. So one thing that I am thinking of while you're talking about this is in your study, I thought you gave the aspirin from the first trimester to the edge of the third trimester, and I'm wondering if we think it has a different effect on the placenta in the first trimester than the second because the placenta is totally different.

Yeah so what we think we do is, is we, so we talk about the early process of de placentation. So we think that builds the healthy placenta, and then we know the placenta ages in the same way that we know that if we [00:14:00] build healthy children and then we help stave off inflammation, we're less likely to have cardiovascular disease.

So if you will, probably helps build. a healthy start between 10 and 16 weeks, and then prevents the weathering of the placenta. Getting maybe a little too deep into this preterm birth is probably a little bit more of a weathering of the placenta effect and preeclampsia is a little bit more of a failure of de placentation.

Although there's some weathering component there as well. 

But for people with preterm birth, their placenta is experiencing some kind of different environment than for women who don't have preterm birth. Even though at the end of nine months, , if you make it that long, the placenta is done.

Right? So something else is going on there. 

Yeah, no. I mean, if you think about the placenta, it's an organ that's designed to last for 40, 41 weeks. 

Yeah. 

No other, our kidneys aren't designed to expire in 41 weeks. So it's very differently programmed. Yeah. [00:15:00] 

Yeah. 

And we know that when we look at it the same group that we did, the aspirin study looked at placentas of stillbirths and preterm births, And what you see is inflammation and weathering of the placenta, to use the word simply, in preterm births and stillbirths versus much less in term births.

And then when you look at it on the mom versus the baby side, it's almost exclusively, you see most of the lesions on the mom's side, . So again, it seems to be where the placenta meets the mom, where much of the issue occurs, going back to the idea of de placentation.

So we think it's the mom's immune system that is reacting to that interface in a way that is not optimal. 

Yeah, . And again, that sort of also speaks to the idea. If you look at moms who have one great obstetrical syndrome, they often have chronic inflammation and then it portends into the next [00:16:00] pregnancy.

And that's why we tend to see it recurrent. So I'm not that I ever want to blame moms for anything but it does seem to be on the maternal side where we have the most opportunity. 

 So I asked almost every researcher I talked to I know everyone says pregnancy is a stress test and I'm trying to tease out whether we think issues in pregnancy.

uncover underlying issues in the mom that wouldn't otherwise be present or create them. But it sounds like you're saying uncover. 

That is my general leaning. You know, I think what we're picking up and again, whether it's preterm birth or preeclampsia, we know that puts people on a pathosclerotic tract, if you will from that perspective.

So we think so, maternal side, again, chronic inflammation. I'm uncovering that, if you will, in those stressors based upon the function of the placenta that's inhibited by this. 

So I'm wondering if, if the [00:17:00] mom is bringing this to pregnancy unknowingly because we have not tested for that yet. At some point in the future, once we understand this better, if you could test a woman before she were pregnant to see if she would be likely to have these issues in pregnancy, provided you had a test fine enough to measure some kind of inflammatory issue that is not rising above the threshold for testing at this point.

Yeah, I mean, just to say there, there is a test that we, we are part of some of the early discoveries looking at blood work at 19 weeks. It's it is commercially available and FDA approved. It does look at placental function and also sort of hormone handling. And we just completed a study where we took women who had high scores, meaning more likely to have preterm birth, gave them aspirin and progesterone.

And compared them to an historical cohort and what we saw was about a 3rd [00:18:00] diminution of the early preterm births again. There is a group in Columbia that is looking at the back of the eye. They've published on this, and it turns out you can see vascular changes. In the back of the eye that seem to predict.

Some of these outcomes again, they still have a lot of work to do. But to your point looking at moms early having tests that are early and putting in interventions early is I think where many of us are trying to head. 

That's amazing. So if you look into someone's eye, the back of the eye is a sensitive enough place where you can see the evidence of vascular changes that suggest that there's an inflammatory process going on.

Yeah. No, there's been a revolution in I imaging based upon artificial intelligence. So a retinal scan can tell your gender, can tell your ethnicity. Tell if you're a smoker, whether you have anemia, whether you have an elevated test for [00:19:00] diabetes and at least the early studies that have come out of that group suggest that they can accurately predict preeclampsia.

Wow, 

again, still a lot of work to do there. They've done about a 1000 people. But it turns out, if you think about it, the back of the eye has blood vessels. And we can look directly at the blood vessels in the back of the eye. 

That is amazing. And, and also amazing that you have confirmed that aspirin, which is relatively cheap and easy to administer is something that has a profound effect on the development of the placenta and the progress of the pregnancy.

That, that seems like amazing luck. Hard work. Hard work. I'm just saying, look, and that that's the answer, 

You know, it's, it's part of the answer. So, you know, we reduce reduced early preterm birth by 25%. We're asking the question, why didn't reduce it? 100%. Is it a dose [00:20:00] phenomenon? We have a trial that's funded to look at higher doses.

There's another group. So I'm looking at a particular the at risk group women to deliver before 35 weeks in the prior pregnancy, there is a group led by Ohio State, who's looking at people who are now currently recommended for the prevention of preeclampsia. There is a group at Penn that is doing a preconception intervention.

So there are a bunch of folks looking at dose as part of the issue from that perspective, but certainly celebrating the 25%, but there's still 75 percent to go. 

That's super interesting. How common is the use of aspirin in pregnancy in the U. S.? Do you know? 

Yeah, this is a lot of the controversy right now.

One of the problems is the guidelines are oriented towards preeclampsia, not talking about the risk of stillbirth and preterm birth. There was a study that came out of the [00:21:00] group the Duke group in 2019, looked at 2019 birth certificate data. And based upon current guidelines, it says that over half of women should be on baby aspirin.

The question that many people are asking, myself included, if there's no side effects, if babies have long term normal. Neurological development, if not maybe a little bit better, if we looked at larger numbers should it be like prenatal vitamins? 

Yeah. Yeah. That's super interesting. And I guess I would ask in your ideal future, what would preterm prevention look like?

You know, I think probably again, it's going to be a mixture of blood work and, or looking at things like the back of the eye. Some more assessment of physiological function of the placenta and whether that's markers of maternal inflammation, whether that's markers of placental function and then [00:22:00] if you will, catering doses part of the studies that all of us are doing that I mentioned, dose escalation, or just simply doubling the dose You know, if somebody weighs 100 pounds probably different than somebody weighs 300 pounds.

Yeah. 

Somebody who has a lot of inflammation probably needs more. 

Yeah. 

But we don't really know how to do that level of personalized medicine yet because we don't have as much refined diagnostics. 

That's super interesting. So what that sounds like to me is that there would be more careful care in the first trimester.

Yeah, no, I mean that time frame to 10 to 16 weeks is really probably critical. And again, underappreciated for what it is. I think folks, the other part of it, just to be clear from my perspective, you know, we as providers like to provide medicine but thinking through the lifestyle components in a way that we can change people's behaviors how do we go about doing [00:23:00] that as the other part, we don't do this well as healthcare providers globally.

Well, that's a harder problem, right? To get someone to change how they're eating or exercising or sleeping is, you know, dramatic changes in their life, which is, which is why everyone wants a pill. 

Yeah, no, I mean, it's a fair comment, but you know we're interested to see even over short time periods from that perspective, but even as a physician culture.

We are still commonly recommending bedrest for preterm birth prevention based upon terrible data in the sixties. And in fact, the data says that women who are active are less likely to have a preterm birth. So we're holding onto legacies and our culture has to evolve. 

I interviewed a really interesting doctor in Israel.

They did a great study over there putting a Fitbit on all these pregnant women so they could actually measure how much they're moving around and how that affected preterm birth and they found basically what you said which is there [00:24:00] was no correlation between activity and the probability of a preterm earlier preterm birth.

Yeah, we have a study. We put out only an abstract form. It's still going through the process of peer review. But well, I did a study with this one same research group. We're doing the dose escalation looking at a pessary around the cervix. Terrible idea didn't work at all. But women started to open up their cervix by ultrasound.

We put Fitbits on them and those women who took more than 3500 steps were less likely to deliver early. And again, highly statistically significant. 

Do we think exercise is anti inflammatory and that is part of the pathway or it's too complicated to say? 

No, I mean, again, going back to the analogy, if this was the heart, this is what we would do.

We would talk about cardiac rehab. We would talk about blood thinners. We would talk about anti inflammatory aspirin and changing to a Mediterranean diet. It It all sort of lines up [00:25:00] together and it probably is going to require more than one intervention. 

That's super interesting. You were mentioning that you're doing other work in this area.

Do you want to talk a little bit about that? 

So we sort of talked a little bit about that. We have some proposals to again, extend looking at the fondness of the eye. Again, in that same population, the dose escalation study, looking at aspirin is another key area. We're starting to think about monitoring activity.

And treating activity, just like we do glucose where we, monitor people's glucose. Talk to them about improving their activity. Thinking about it really. The same way you would glucose. We don't do that. Again, there's more work that needs to be. Some of these are a little further along than others.

The dose escalation study is funded. Some of the others are in early proposals. Some are just in the early phases of just [00:26:00] learning. But we're sort of in. Sort of now informed based on what we've done to know where we want to head. Okay. 

That is super interesting, but you're not testing the cholesterol drug.

So I am part of the MFMU, there is a proposal to do that. They're working through some FDA clearance stuff that will go live there. We're waiting for that to then potentially also use it in the global network. The same group we did the aspirin. So we have chatted about that. What's very reassuring about that is we can't find it in the blood of the baby.

So it doesn't seem to cross the placenta. But because it affects cholesterol and cholesterol can be involved in neurodevelopment, there's some appropriate safety signals. I'll say they have gone back and that group has looked at the 40 odd babies who are randomized to that drug. And again, if anything, their neurodevelopment is more normal than those babies who weren't [00:27:00] exposed.

That is amazing. That's so awesome. Thank you so much for the work that you do and for sharing some of it with us today. 

Happy to be here. 

Thanks again to Dr. Hoffman for walking us through some of his work. And what we might do to prevent preterm birth. His studies innovation starting aspirin early and on a specific dose. It seems like the kind of evidence-based suggestion that could be put into practice relatively easily. And it sounds like, although there may be a complicated chemistry underlying the early weathering of a placenta. Inflammation is one of the likely protagonists in this premature aging. At the very least this research is a powerful counterpoint to the story. 

A pregnant woman could be telling herself about how her premature birth resulted from lifting something heavy or exercising in the wrong way. It seems to be on average, a process that starts early. And it's not dependent on a choice a woman makes, but it's also potentially a [00:28:00] susceptible to something as basic as aspirin. Thanks for listening. 

If you like the show or know someone who has experienced a preterm birth or the threat of it, please share it with them. We'll be back next week with more amazing research. ,