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#053 - Dr. Kristi Watterberg MD

NICU journal club the incubator podcast

Hello Friends 👋

We could not be more excited to have on the show this week the legend herself... Dr. Kristi Watterberg. Dr. Watterberg is a humble neonatologists who has accomplished an incredible amount of work in the field of neonatology. Whether you have read her papers or not, there is no doubt that your practice has been shaped by her work. She recently first authored the study of hydrocortisone prophylaxis on survival of extremely preterm infants without BPD in the New England Journal of Medicine. We covered a variety of topic ranging from steroids, research methodology, mentorship and her work with the Committee of the Fetus and the Newborn. We hope you enjoy this interview.


Bio: Dr. Watterberg is a Professor Emerita of Pediatrics in the Division of Neonatology at the University of New Mexico Health Sciences Center. She served as Chief of the Division from 2006 – 2011, and Director of the UNM Signature Program in Child Health Research from 2011 – 2016. Dr. Watterberg has over 30 years’ experience conducting studies exploring newborn adrenal function, its relationship to inflammation and BPD, and long-term outcomes after preterm birth. She is the New Mexico Principal Investigator for the NICHD Neonatal Research Network (NRN, 2006-2023), which has multiple ongoing observational and interventional studies. She also was awarded a grant from NIH to study adrenal function at age six in a cohort of NRN children born extremely preterm (R01HL117764; 2013 – 2019). She has mentored fellows, faculty and other learners in research and academic advancement. Dr. Watterberg has served on NIH peer review panels and is a member of the Society for Pediatric Research and the American Pediatric Society. She has been an AAP member throughout her career, and has served on the Committee on Fetus and Newborn (COFN) as a member from 2006 – 2012, and as chair (2013 – 2017).



The transcript of today's episode can be found below 👇

Daphna 0:00

Hello, everybody. Welcome back to the podcast Daphna. How's it going?

It's going really well. You know, now that the boards are over just trying to get back on the straight and narrow, I guess.

Ben 0:56

That's right. That's right. I'm very excited about the guests that we have on today. She She published she was the first author on a neonatal Research Network paper that we both enjoyed. And we said, hey, let's bring her on. And we we made some room in the schedule to have Dr. Christy Waterberg on the show. And this is very exciting to have such a timely, you know, like such a timely interview where paper gets published and we get to talk to the first author. That's really neat.

Daphna 1:24

Yeah, I think this is, especially given all the background work that Dr. Waterbrook has done. This is I think, especially exciting and important. That's right.

Ben 1:35

So, for those of you who are not familiar with Dr. Waterbrook, or her work, she is professor emerita of Pediatrics in the Division of neonatology at the University of New Mexico Health Sciences Center. She served as chief of the division from 2006 to 2011, and director of the University of New Mexico signature program in child health research from 2011 to 2016. Dr. Waterberg has over 30 years experience conducting studies exploring newborn adrenal function, its relationship to inflammation and BPD and long term outcomes after preterm birth. She is the New Mexico principal investigator for the NI CHD neonatal Research Network, which has multiple ongoing observational and interventional studies. She also was awarded a grant from the NIH to study adrenal function at age six in a cohort of neonatal Richardson Research Network children born extremely preterm. She has mentored fellows, faculty, and other learners in research and academic advancement. Dr. Waterbrook has served on NIH NIH peer review panels, and is a member of the Society for pediatric research and the American Pediatric Society. She has been an AP member throughout her career and has served on the committee on fetus and newborn as a member from 2006 to 2012. And as chair from 2013 to 2017. Dr. Waterberg, thank you so much for being on the show with us today.

Unknown Speaker 3:01

Oh, thank you for having me.

Ben 3:03

I want to start this interview. Really early. You mentioned to us in passing that you were an English major in college. And I want to know exactly how does the path I mean, to major in English, you must you must have a very brain year towards literature and and and I'm wondering how does that path lead you to medicine and specifically neonatology?

Kristi Watterberg 3:31

So in high school, I took all the science courses that were available. And when I got to college, I decided I was I was tired of that. I just wanted to do something completely different. And so I did. And yes, I've always been interested in literature and writing and that kind of stuff. So I did that in college. So then with my English degree, I got a job as a, as a proposal writer, a grant writer, for the Regional Medical Program. And I was working for a couple of doctors, and I ended up thinking, you know, gee whiz, if they can do that, I can do that. So I went back and took the, the prereqs for medical school and went to medical school, and then from there, so fascinating.

Daphna 4:12

That's really interesting. And obviously, you're using your writing skills all of the time, and in your research work. But yeah, but actually, I'm Ben and I, and Ben's very much a buff, but I were interested in like the medical humanities. And so I wonder if you use kind of your writing past, in your daily life, or in medicine and how you how you use that part of

Speaker 3 4:40

I'm actually more in reading than in writing. So I've been kept very busy over the years with kids and medicine and all that. I've always wanted to write the great English novel, you know, great American novel, but just, it just hasn't happened because so much else has happened. Okay, very good. Maybe when I retire Finally, I'm sort of semi retired at the moment but not completely.

Ben 5:07

And what's interesting is that you you entered the field of neonatology, I think in the 80s. Is that correct?

Speaker 3 5:14

Yeah, I finished my residency in 83 Started my fellowship then

Ben 5:18

what it is like I was I was curious to ask you what was it like to enter the field of neonatology in the 80s as as a woman, obviously, this is still something that we're we're working on, I think, as a society to make sure that there's equality. And my wife was a physician. I see this every day, the highs and the lows, but I'm wondering in the 80s, what was it like for you, and how did you navigate that world?

Speaker 3 5:43

I was lucky enough to be in New Mexico. And so the university that I ended up going to for medical school was the University of New Mexico. And it's a very different environment, the entering class in 7677, whatever that was half women. And I was also lucky enough to have very strong mentor and, you know, models in both pediatrics and neonatology. So Luann Popeil is here, and was an influence on me at that time. And Alice Cushing, who was the chair of the department, what acting chair, she was, in and out very strong women as role models. And so it was an atmosphere that was very conducive to developing a career as a woman in medicine. And when

Ben 6:33

you mean when Pepe Oh, you mean like the puppy off from the puppy or classification? Yes, yes. Yes.

Speaker 3 6:40

So she was she was actually doing her landmark study, by taking kids babies down to the CT scanner, while I was a medical student, I believe, and she had to fight that getting funding because people said, You can't do that you're gonna kill babies, taking them down there and back, and she ended up being able to do it, and she didn't kill any babies. And it is, it is probably the most or one of the most cited articles still,

Ben 7:10

very much. I think I cited that article during my fellowship paper when I was most. Yeah, go ahead.

Daphna 7:18

No, I am. You know, we hadn't planned to talk about this so soon. But since you brought it up, we'd love kinda to hear your perspective about, you've told us a little bit about the mentorship you've received. But your thoughts about those of us in mentoring roles? And what's kind of the job of the mentor? How do you pick a good mentor? You know, things around mentorship.

Speaker 3 7:45

So as a fellow, I had two different mentors who ended up leaving, and that was, that was interesting. I mean, they still provided support, but they ended up leaving before the projects were done. So for the next mentor, I picked, I married him, and that that really worked much better.

Daphna 8:04

So you know, where he, where he is all the time

Speaker 3 8:06

when I know where he is. And he was extremely helpful and in connections that he had that I didn't have.

Ben 8:12

But you don't necessarily marry your mentor every single time, right?

Speaker 3 8:16

No, it's probably not the best idea. That worked for me. But I think, you know, I think it really taught me what a mentor means to a fellow or a resident, because, you know, you start something with them. And then if they disappear before the project is done, it creates a much more difficult process. So it's, I've, I felt very strongly that if you start something, then you need to continue with that fellow until you get to the end of the road with it. So it's a combination of expectations and support. You'd have to provide support for the fella to accomplish what you know, they can, but you also have to have expectations of them. Excuse me, that, that they have to fulfill. And it's a it's a rocky road, because there's a lot going on during fellowship, even for people who don't have kids.

Ben 9:08

And it's a bit easier now because of zoom and emails and stuff. I'm assuming it must have been much more difficult when you were a fellow and maintaining communication must have been almost impossible once you have your mentors. Right.

Speaker 3 9:20

Right. Well, the one mentor that left stayed in New Mexico but just left neonatology. And but the other one went to went to Hopkins and the FDA and stuff like that. So yes, it was a difficult process. We did manage to maintain contact and we published papers together. So you know, it was certainly a valuable experience, but it was difficult. I can imagine.

Daphna 9:43

It's so interesting that you mentioned that you had these kind of disruptions in mentorship because I feel like mentoring in medicine is changing. And before I feel like some people picked a place because they chose a mentor. And then they, you know, did did the work their mentor was was doing and they you know, they teamed up for potentially a career. And now it seems, especially the way GME is sometimes you end up at a program where you haven't picked a mentor or you haven't picked an area of study. And then you have to find somebody where you are. And then it seems like this team approach to research is not the same now as it was, you know, even a few decades ago in terms of kind of pairing up with your, with your mentor.

Speaker 3 10:40

Right, I agree with that. I think there again, the University of New Mexico was sort of unique in that process at the time, because you didn't go into somebody's lab and pick the project that they had put in front of you, you know, it's still it was and is still a place where you come and see what's there and then sort of try and find your path within what's available. So, when I did a fellowship, I chose neonatology out of Pediatrics, because that's where all the questions were, you know, I was going to be a general pediatrician in a small town, but I realized I just couldn't know enough about everything. And so on rounds, and in the neonatal unit, there were questions that were not answers. And that to me, that was the most interesting part. So then, when I did my fellowship, I was immediately interested in bronchopulmonary, dysplasia immediately. It's just like, so sad those babies. And so I was doing a project. I was interested in nutrition and how that might, you know, relate. This is many years ago, obviously, less less sophisticated then. So I was writing down a series of patients who had developed severe BPD. And I was interested in their nutritional intake, but I was also putting down their respiratory settings at the same time. And so I came across the most interesting words in science, which is That's funny. That's odd. What what is that about? And that's where, I mean, it's not the finding, it's the question. That's the most interesting. And what I found was that for all these little guys, it wasn't just respiratory distress syndrome that didn't resolve. They had an initial RDS with high and 502. And then it came down. And then it went back up at the end of the first week. And so I looked at that and said, you know, this is something different, this is not just a continuing respiratory problem. And so I started looking at what's going on there. And in conjunction with my colleague, Susan Scott, who is double boarded and endocrine and neonatology. We looked at the step back from the inflammatory process. And your own endogenous anti inflammatory mechanism is, is mainly cortisol. I mean, there's lots of other things in there. But that's the most widely spread the most widely effective molecule. So that's why I started looking at cortisol in these babies. And I didn't start looking at steroid therapy and babies, I came at it from a completely different angle, which is what is the adrenal function like and the preterm infant, and that's how we made the first sort of discovery in that area, which was that the babies who went on to develop VPD had a much lower cortisol concentration at the end of the first week of life. And I've found that I could start predicting babies who are going to get BPD by looking at those kids who got a septic workup at the end of the first week, because they were getting sicker. And so you know, that's just coming at it from a physiology point of view, rather than a therapeutic point of view. It ends it ends up being, you know, treating with hydrocortisone, but not in the same way that dexamethasone was.

Ben 13:53

And so and so is this. So this is where I guess this is the inception of your work on on hydrocortisone and the potential benefits it might have. Right for BPD. Was there I am obviously very familiar with your 1999 paper. But I'm wondering, had you done any work before on hydrocortisone in that area to in relationships specifically to

Speaker 3 14:18

show the 99 papers, the pilot studies, right? Yes, yeah. Well, that came out of this first work where we looked and thought and saw that, you know, cortisol concentrations in these babies were lower in the ones who went on to get VPD. So the question then became, obviously, if we give them a little bit of hydrocortisone at that period, can we make a difference in their outcome? And so we didn't start out to treat them with high doses, we started out to try and replace their own adrenal insufficiency. And that's where we did the initial pilot study and then the the big study but before that we published on the relationship of chorioamnionitis, to respiratory distress syndrome and to BPD and the sort of paradox If you have less respiratory distress syndrome, but more BPD why? Why might that be? And it's because of the increase in inflammation from Korea and the United with the second hit of being intubated after birth. So yeah, we did we did that work published in 95.

Ben 15:17

And a lot of the work you've published has become like, knowledge. It's it to me, it's quite fascinating. So for example, what every neonatologist thinks about when they are thinking of giving steroids with indomethacin, and the association with perforation, that was the work you did in the in the early 2000s, the late 1990s. That's the paper. That's the paper that showed this this this this association that we were not aware of beforehand.

Speaker 3 15:47

Right. Right. And that was devastating. I have to tell you, I mean, that was my first big randomized multicenter trial. And it was stopped about halfway through because of the increase in spontaneous perforations. And so I didn't sleep at night for for a very long time looking at that, but ended up being able to say, yes, we showed that you should not give hydrocortisone and at the Matheson together, and we probably saved a whole bunch more kids from getting a spontaneous perforation. And I've dealt with that in that way.

Ben 16:22

And yeah, so So that's, that's what was gonna be my question. Is this how you you mitigate the frustration of this happening to your code? Versus Oh, if I had not published this finding many other people out there, even though that number is probably unknown to you, you can assume that you've done and the net effect is positive, rather than negative. Right, right. Sorry, definitely. You were gonna say something.

Daphna 16:46

I was gonna say, I think that's absolutely true. And I think it brings shed so much light on how even if the work that you set out to do doesn't go exactly as you anticipated, there's so much to learn from every single study. And that was groundbreaking. And I think it saved countless lives by having that knowledge, which we didn't have before.

Ben 17:12

So my question to you then was, you go through this, this phase where you had this initial pilot study, and the results are promising, and they're pointing you in a certain direction? And then you do this paper from that that was published in pediatrics in 2004, looking at this prophylactic use of hydrocortisone. And I mean, for the people. I mean, first of all, we'll put the link to the to the paper in the show description. If you haven't seen this paper, you should read it like, as researchers, you may like I feel like not many people get to work on the paper of this magnitude to begin with. It's like it's it's, it's, it's, it's a big deal. And then you see this, this association with the perforation, but on the other hand, it was almost serendipitous. I mean, it didn't really it created a an obstacle where the trial had to be halted, but it was not the question you were trying to answer. So I am wondering if, as a researcher, you feel a bit of frustration, where it's like, well, this this, this PDA business derailed the trial, but but like, I still want to find out what hydrocortisone prophylaxis can do to BPD.

Speaker 3 18:18

Right. And I have to tell you that the results of of that particular trial halted the research in this area for a long time, obviously. And it it did that despite the fact that you could see that in the absence of indomethacin, there was no effect of hydrocortisone on spontaneous perforation. But we had to wait for the French study. It was supposed to be a Canadian and a French study friends of mine. We talked about developing this and doing it without indomethacin and stuff. And it finally got done in France, but not in Canada. We had to wait a long time for

Ben 18:51

I wanted to then backtrack a little bit because in between 2004. And are you when you're talking about the French study, you're talking about the premiere lock trial that came out in

Unknown Speaker 19:02

Bolivia study. But in

Ben 19:03

between, we have two little studies from Italy and Finland, right where they're there. They're almost like the initial study you published in 1999, where the numbers are very small, but they are showing that that maybe hydrocortisone can help. So as a researcher, when those studies come out, how does that make you feel like are you saying I should really try to push again on this topic or? Yeah, well, actually

Speaker 3 19:32

the finished study, what do you study? They stopped because of the reports of increased perforation in our study, and been sante I don't know. I think he had only planned to do a small pilot study at that time and then and then my study was published and everybody stopped. They were all at the same time. And so then we stopped until the Premier League study came out and then we were able to put together I still think this is an amazing accomplishment. I have To say, we were able to put together data from Italy, Finland, France and the US into an individual patient data meta analysis. And I'm so proud of that accomplishment. It took a year to get all the data use agreements in place. I mean, that was, it was a huge issue. But I was still able to work with Michelle Schaefer who had done the statistics for my original study. She had moved to Washington. So I flew out there. And we'd worked together for days putting together all this stuff and making sure we had the right information. And getting that published. And I just, I'm very happy about.

Ben 20:35

Yeah, I think it's quite an accomplishment. And I'm so interesting. It's so interesting, the path that the study of hydrocortisone took all of you. I mean, it started right in the in the US, then we Europe. And then the French shot. I mean, I wanted to ask you about the French, obviously, because this study comes out and it's it's in the Lancet, and it's earth shattering, right? I mean, they're saying, Yeah, survival without BPD is is much lower if you're giving prophylactic hydrocortisone and

Unknown Speaker 21:04

much higher. Survival without BPD.

Ben 21:07

Sorry, that's what I meant to say. I apologize. I apologize. And not only that the neurodevelopmental outcome that came out of that study were phenomenal. I mean, it was it was not even that the that it there was no impairment, it was actually better to

Speaker 3 21:22

actually we showed that in our first study, too. It wasn't significant, except for a couple of things. But it was significantly better in several respects.

Ben 21:30

And then, but then I thought to me, when I was reading the criminal trial, I thought, I'm wondering, what was your thoughts on how they defined BPD? Because I think it was a tiny bit different from what other studies have done in the past. And it was a very much a physiologic definition of BPD. And then my question, I guess, I guess my question is, you, by the time the criminal trial comes out, are you are you thinking, Alright, this is it. This is the study, I had this, this puts this issue to rest? Or are you still working on the on the trial that you recently published with the neonatal Research Network, I'm just curious as to how this unfolds.

Speaker 3 22:10

So there's just basically two different things I started working with. Well, I started getting accidentally introduced to the French folks in 2000, when we were there on vacation, and they asked me to give a talk at one of their hospitals there. And so ever since then, I've been friends with Bono table and Tila cause, and Olivier. And so gelila Cause is sort of the the character in here who made this all happen talk about mentorship. He, he was from France, who's in though in Canada, but he just sort of kept agitating to get this done to, you know, with Olivier to put it together, he tried to get it together in Canada, but because of, I think because of the previous study was unable to get funding for that there. But you know, it's just, over time working together with people continuing to talk to each other, and then gently just says, you know, you need to do this, you need to do this. And so the that study got done, I see.

Ben 23:09

And, and so, for the for the for. So when this episode airs, I think we will have reviewed the study on the journal club, and we would have brought up the results to the to the audience, but for for the people who haven't had the chance to pick up the New England Journal. Well, so the findings, the findings of the of your latest publication were quite interesting. Do you want to go a little bit into what this study showed? Yeah,

Speaker 3 23:34

it was disappointing, of course, but not unexpected. I spent a lot of my career going around and talking about how the dexamethasone is a bad drug and the dose was way too high. And I've tried to you know, talk people out of using it or at least into using a smaller adults. And so let's Doyle tried to do the right study when he did the dark study that he had planned to enroll 800 babies in that study. And because of the increasing recognition of the neurologic adverse effects of dexamethasone, in high doses, point five per kilo to start his study, which used a lower dose point one five per kilo to start and a shorter course in time couldn't enroll the patients. So you know, he just he could not get people to enroll in a study of dexamethasone, even though that was the right study to do. And so he was stuck with like 70 Kids and it looked like yes, you could get the endotracheal tube out but it's not clear even in that study, whether it made a difference to BPD in the end. So I think that starting in the first week with dexamethasone was a bad idea. It was too strong of a drug it promotes apoptosis and the hippocampus in other spots in the brain. But people in in Medicine Unit ology all of us, it's either yes or no, it's Uh, you know this or that you have to develop a sort of more nuanced view of what to do. And so I think that it was important to do this hydrocortisone trial. And I think that it's it showed you can use that to excavate babies. When when Lex did the Dart trial, there was a bigger difference in the extubation, between the two arms of his study than between ours, but that was only 70 kids, and we had 800 kids at like, 19 different places. So I think we need actually, another dexamethasone trial, if we're going to do that.

Ben 25:39

That's interesting.

Daphna 25:40

Yeah, I was gonna ask what, what is the future of this work without, without giving away too many secrets, I suppose. But you know, other other questions that need to be answered?

Speaker 3 25:54

Well, it's really interesting to me, before I even talk about that, it's really interesting to me the different takes that people have on the same data. So a lot of people say, Well, you know, it didn't change the outcome of survival without BPD. So let's not use it. Other people say, Well, look, you can get them off the ventilator, people, babies hate being on the ventilator. You know, we hate seeing babies on the ventilator, maybe people will use it for that reason. And I think that's something that, that folks are just going to have to figure out in their own mind. So I think the future of this work is, personally, I think, you know, the inflammatory processes set in the first week, we looked way back, as I was starting out, I looked at the tracheal aspirate of babies who go on to get BPD. And there's a lot more inflammation there than there is in the babies who go on to recover without it. So I think that you get sort of set in the path and the first week or so I think you can modify it with other therapies after that, but I'm not sure that you can. Oh, sort of make it not be there. If you start in later, so I'm not sure honestly.

Ben 27:03

Well, after reading the New England article. My question to you then was, to me what all this evidence points to is a form of risk assessment. I have a feeling that from all the data that you've published in the past from the premier lock trial, from from this trial, this trial didn't have a specific name, correct. It's in the papers called hydrocortisone to improve survival without bronchopulmonary dysplasia but didn't have like, is it going to be one of these things where we're going to do a risk strategy? Do you think we're going to end up with a risk stratification, where chorioamnionitis, for example, would be an important factor, the degree of inflammation soon after birth will be a big factor and based on this risk stratification, then we will decide whether to use or not hydrocortisone?

Speaker 3 27:53

I think so I think people are already trying to do that we're going to present an abstract at this upcoming meeting talking about, you know, is there a differential effect based on the baseline risk? That kind of stuff, I certain that that will be true that the problem is that when you get down to 2324, even 22 weekers, the risk for developing chronic lung disease is almost unimaginably high. You know, if you start out being intubated, it's sort of you'd be surprised if they don't end up with some kind of oxygen requirement at 36 weeks or more.

Ben 28:29

And going back to some of the of the, of the, of the secondary findings that you've mentioned, especially shorter invasive ventilation earlier, extubation. Do you think that there, there's going to be a need to study these outcomes as primary outcomes in future studies? Or do you think that there's enough data right now to to use at least hydrocodone maybe not as a as a as an agent to reduce survival as an agent to residual BPD, but maybe to have these outcomes of less time on events and earlier extubation?

Speaker 3 29:04

I think I think people will, will put their own imprint on it. I think some people will say I want to do this to get that baby off the ventilator, I think it's worth it. And we've shown that it doesn't have any adverse neurodevelopmental or growth outcomes, at least at two years. We are following these babies to five to six years in a long term outcome. And we're doing pulmonary, pulmonary function outcomes in a subset of babies at certain centers that have that capability. So we're going to be able to say more about that school age outcome, you know, in a couple of years, but I think everybody's just gonna put their own take on it, depending on what they're actually what their biases and their background is.

Ben 29:41

So then let me ask you this question. This is this is now I'm just calling an audible here, but how do you feel about I think, the spin that people are putting on the evidence so I think people will read the New England Journal article and we'll say, Oh, that's it hydrocortisone. Let's put that to rest. And we're no longer going to use it. Where do you think that as a field, we could collectively do better in how we read into the data? Because we especially now with Twitter, you get to hear all sorts of opinions, where some people will see that it's so interesting, because it's the same data. And you have some people that say, Oh, I think that's it. hydrocortisone is done for we shouldn't use it. And some people are saying no, but look at the secondary outcomes. And like you said, everybody is seeing it differently. Is there you think, a way that as a as a, as a as a field, we could be better at looking at data more objectively and make better conclusions?

Speaker 3 30:40

Well, I have to say that I think that neonatology has gotten a lot more sophisticated in its interpretation of data over time. And I think people are less inclined to jump into some new therapy just because they think it's going to work. We have a long way to go. You know, we don't have as many patients as the adults do. We can't do studies of 10,000 adults, you know, or 10,000 babies. And we have to deal with what we have. But I think it's very interesting to me, that the adult studies will will say that a therapy is significantly better, if it creates a three to 4% difference in outcome. Whereas when we do a study of 800 babies, which is what the vitamin A study was, and our study was, we say, well, we're going to look for, you know, 10 percentage point difference. And if we didn't get that, then it's not significant. If you look at the confidence intervals for survival without BPD, it's really tilted towards using hydrochloric, even though it doesn't end up in the traditional frequentist significance of point oh, five. So I think we have to get a little more sophisticated. In our reading of these things. A couple of people within the network are very interested in Bayesian analysis, we've published some articles. With the using Bayesian analysis, the most recent being the nest study looking at laparotomy versus strain for intestinal. And

Ben 32:06

we reviewed that paper and we loved it.

Speaker 3 32:09

I'm so proud of Marty for getting that thing done. You know, that's another one that took years years to do. And it required the cooperation of pediatric surgeons as well as the anatomic judges. So it was an uphill climb that one.

Daphna 32:26

I have a question you. You know, you spoke to how medicine is so nuanced. And, you know, we talk a lot on the show about individualizing. Care and medicine. So how how do we balance that with? You know, this other concept that standardizing care saying a unit has better outcomes? So how can we do both?

Speaker 3 32:53

Oh, I think we can do both. And first of all, I think that standardizing care or creating guidelines so that you have a consistent approach to the babies, and so that you don't change from day to day, depending on who's attending, I think that is hugely beneficial, has been shown to be beneficial for, you know, acute lung injury, and just all kinds of things in different populations. I think that's a different than saying your approach to each individual patient should be tailored to that patient. So if you have a nutritional guideline, you you do this approach with all the babies, and it's been shown that that leads to faster enteral feedings, and you know, better growth outcomes. However, you have to look at each individual baby still to say, well, that one, you know, he's not doing so well with that. And this one, maybe they need this kind of another. So I think that within the guideline of approaching all the babies in a standardized way, so you don't have this, you know, oscillation of care, depending on who's giving the care. But at the same time, realizing that babies are different, some do have chorioamnionitis babies that are delivered after preterm labor are very different than those who are delivered after preeclampsia, or, you know, the ones who are SGA are very different than the others. So I think those those two things need to be melded together.

Daphna 34:14

Yeah, I like how you speak to probably there are some subsets of phenotypes of babies that that will take us down one pathway or another.

Unknown Speaker 34:24

Right, right. Right.

Ben 34:27

Since Is there anything else that we need to talk about when it comes to hydrocortisone? Or can we know our mask?

Daphna 34:34

Well, I know, Mike, one of my questions was, so obviously these are big study, every time you do a study, it's a big study. Right? And we've spoken about how different people read the literature differently. But how do you deal with some of that, you know, some of the the chatter, you know, whether things go well or not well, or how you anticipated or didn't anticipate, I think when you're on a big public stage, so to Speak with a neonatology as a small community. How do you navigate that?

Speaker 3 35:07

Oh, gosh. I just have tried over time to talk to as many people as possible, I think. So to turn from the hydrocortisone stuff back to the adrenal insufficiency stuff, which is where I started all this. I still see people giving big doses of hydrocortisone to babies for hypotension in the first few days of postnatal life. And I've talked to try and get rid of that particular thing for years, and I finally published a paper in the Journal of Pediatrics, a couple of years back, talking about dosing of hydrocortisone, for the immediate postnatal period. But I have to tell you, people are still doing for per kilo per day instead of one kilo per day in these tiny babies, and then they come in and they asked me, you know, how can I get this kid off of hydrocortisone, we went on this tapering course for weeks. And it turns out that they started with a dose of four times what they might be starting with. And so I think it's very hard to get that kind of thing out there because Harriet Lane says, to give, gotta give this much, but Harriet Lane doesn't know these preterm babies. Right. So this, I think this is really hard. And I have to say, I've experienced this in speaking about cortisol and adrenal insufficiency to folks over the years. So I don't know if I'm getting anywhere.

Daphna 36:32

One study time, right boy study? Well,

Speaker 3 36:34

you know, I published this dosing article. Several years back,

Ben 36:39

I was in fellowship when it came out. I mean, we were using very big doses,

Daphna 36:42

we made it, we made it, we made a judge. Oh, yay.

Unknown Speaker 36:49

One thing at a time.

Daphna 36:52

The other thing I wanted to ask about, for example, one of my interests was studying the HPA axis in regards to stress and trauma in the NICU. And I got a lot, I got a lot of pushback from people saying it's too complicated. We don't understand it. It's totally dysregulated in premiums. So why even bother studying it? And obviously, I wish I had been under your mentors. Because I may have done some of those studies. I wanted to be remote, but how do you? How do you push push through that when you feel like a question really has to be answered?

Speaker 3 37:33

How do you push through I just kept pushing through. I mean, there was not many, not many people are interested in that field. You know, people would say if you can't come talk to who can come talk to us, and it's really hard to figure out anybody else at that time? Who was even thinking about working in that area. So it's not easy. No, and endocrinologist, very few endocrinologist understand the area. And like I said, I was really lucky to have a colleague Susan Scott, who was an endocrinologist and a neonatologist and we could talk about these issues together. I don't pretend to be an endocrinologist, I don't have any expertise in any area in endocrinology outside this one spot. But in this one spot, you know, I do know what I'm talking about. And so you'll find endocrinologist coming into the unit and talking about dosing for hydrocortisone, which is which is way out of line. You know, it's just that mostly they come in for adrenal insufficiency. And you know, that ch kind of a kid, and they'll get they'll talk about how you can give so much hydrocortisone and it doesn't matter. Well, yeah, it doesn't matter. You know, these these little brains are not ready yet. So in terms of the outcome, and what what we look at, I don't know if you had seen the article that we did about kids at school age out of the support study and their adrenal function. And it's been shown we showed some of this and, and other people with granola has done a lot of work in this area, that babies who are born preterm have altered HPA Axis reactivity later in life, both in infancy and childhood, and some would say in adulthood as well. So we found a blunted morning reactivity, which is the opposite of what we thought we would find. And it's very interesting, it's always good when you find the opposite of what you expect. You have to push further. No. And so it was consistent with people who suffer from PTSD, the blunting of the HPA axis in response to stress. And so one of my kind of my interests, which I am now beyond, beyond the point of starting a new study for I keep trying to interest people in this is not only to decrease the stressful activities, or stressful events that that little guys have in the unit, but to increase the positives.

Daphna 39:50

I feel like study, that's what I want. There you go.

Speaker 3 39:54

I think it's really interesting and important, I think if you could, for instance, say as An order in the unit that this baby will be read to for half an hour every day, or that will play this kind of music for every baby, if you could study the effect of that kind of thing. I think it would be really interesting. So, you know, we know that private patient rooms can be a bad thing as well as a good thing from the study they did in I think it was Washington University, where the it looks like those babies get less verbal interaction, and more alarm noise, because people will look at the alarm in a different room and say, Oh, I don't need to go in there right now, that's not anything. And so they don't get the the interaction between the nurses talking. And they don't get so much of the parents talking because there's only one family in there. But if you take that same situation, and you say that the parents have to agree to be there certain time, occupational therapy is there, you know, people have to talk to these babies, then they do better. So I think you've got to strike a good, good balance between noxious stuff, cutting down the noxious stimuli, which is what hope is with private patient rooms, and increasing the positive stimuli, which you have to be careful to do even in that situation.

Ben 41:14

I mean, you see, you're not an endocrinologist, but this is balanced, right there positive and negative. I, I wanted to, since we're still on the topic of research, I wanted to talk to you about the concept of collaborative, right. I mean, you've been very successful in accomplishing so many great things within the context of the neonatal Research Network. And I wanted to ask you, what are the the advice you would give to young investigators in being able to succeed within the context of a collaborative? How do you how do you fulfill your role effectively and not? Right? I mean, I hope my question is good,

Speaker 3 41:54

right. So I did research pretty much on my own for about 10 years, and after fellowship and developing the whole sort of framework of adrenal function in the preterm infant, and then, you know, the pilot study that we did, and then I put together my own network, to do the first multicenter trial and managed to get that funded. But I put together just, you know, friends, people that I knew from here, there and everywhere, and put that study together if people who wanted to do that particular study. So that was sort of my springboard to be able to get into the neonatal Research Network was a history of doing stuff like that. In the network, I will tell you, it can be very frustrating because it takes a long time to get things done, because you have a lot of people with different ideas and different concepts. But in the end, having all that structure and all those different voices in your head, leads to much better studies leads to much better outcomes. When you look at the the data that's collected, and it's really substantial. So one of the things the network tries to do, is to encourage fellows and young faculty to be involved to do secondary analysis of a study that they didn't do the main study, but they can do a secondary analysis of it. Or even young faculty can come in and propose their own studies within the network. So I would say that if you want to get collaborative research done, you have to get someplace where that happens. So you know, you can start out by doing stuff in a lab, you can start out by trying to do individual studies on your own chart reviews, every fellow does a targeted you that that's, you know, one of the things that everybody does. But in order to go on into collaborative work, I think it's really hard as a fellow to put together your own network, obviously. But if you can be someplace where the people there are collaborating with other folks already, then attach yourself to that collaboration, and maybe make part of it your own. I think that that's a really good way to proceed.

Ben 43:59

But it's interesting what you're saying, right? I mean, you're saying that working in the big collaboration sometimes can be frustrating because of everybody voicing their opinions, which sometimes you perceive as a roadblock, but to internalize those, that feedback eventually leads to better research.

Speaker 3 44:17

Right? It's really hard to hear, it's hard to listen to, it's hard to get through. But it's critically important to creating the kinds of studies that will stand up over time.

Daphna 44:28

And I'm also interested in in talking a little bit about some of the, you know, you've done so much international collaboration, and obviously, that's a whole other set of challenges, to do international collaboration, but but to talk about the value of of doing that working across countries across cultures, things like that. Right?

Speaker 3 44:51

Well, that's all been pretty much informal. You know, I just I made friends in France a couple of decades ago and and so realm that, you know, various relationships evolved and a new study comes out and you know, it gets done and we're able to get the data from there. I honestly have never met Dr. Bunsen T, but he's been extremely collegial and helpful and involved and stuff and the finished one I knew Miko, Hellman. And that's how I got to sort of be involved with, with pulling the finished study into our analysis patient. individual patient data meta analysis. Yeah. But it is it's really it's interesting data use agreements are becoming more difficult all the time. And more important, so getting the getting the French system to finally agree to release their data to the American Statistical folks. It took, it took Olivier a long time to get that done. But he did and it was incredibly valuable. I am

Ben 45:54

French, and I can tell you I feel the pain. We are. Yeah, we have a very rigid administration. And we don't like to share, especially not across the Atlantic. I wanted to we're running short on time, I don't want to, but I wanted to ask you about your work on the committee on the fetus and newborn? Yeah, can you tell us what this is, we see papers coming out from pediatrics once in a while. And it is the authority. But I'm wondering, I think we're, I feel this is my personal view that we're much less familiar with the committee for the fetus and newborn than we are, for example, with the neonatal Research Network. And I was wondering if you could, if you could tell us a little bit about what the committee with the committee is and what its goals are.

Speaker 3 46:46

So the American Academy of Pediatrics, aap has a number of committees and sections and councils. And the idea of the committees are supposed to be a group of experts, and they are selected by the board, to be on that committee to participate in developing policy and clinical guidelines for members of the academy. And so you are, you are nominated. And then if you are lucky enough to get on the committee, it's a lot of work. It's very interesting. It takes a lot of time, especially as chair of the committee, it takes a lot of time to get that work done. But you feel important. I mean, you feel like you're you're making a difference in writing those because you end up seeing those guidelines being cited, all over the place. And so it, it makes you feel a tremendous sense of responsibility to get it right. And so you spend a lot of time writing things or deciding it's not yet time to write things, or revising things that have already been written trying to tuck other committees into agreeing with you. It's, it's quite a challenge, it's really worth doing.

Ben 47:56

How do you decide that? That was? That was my follow up? Question is, since since this is supposed to generate policies and guidelines, how do you say alright, this field, this area, we know enough that we can actually make a statement versus Oh, boy, there's not enough evidence that we have to hold off,

Speaker 3 48:13

right? It is surprising how well it sort of sorts itself out over time we do you present to the to the neonatal section of the AAP twice a year, and try and get feedback from members of the section on what they feel like they need help with guidelines that would be useful to them. And then, but it's kind of interesting, because papers, big papers come out, like the support study in terms of oxygen targets, and the support study also in terms of CPAP versus intubation, major landmark studies will come out like that, or the whole body hypothermia for HIV. And then it becomes clear that it's time to give people guidance on that, in that particular issue. A second one of the most difficult is the guideline on hyperglycemia. Oh, boy, because there there is not information. And so as David says, David, Adam, can you tasked with writing something about which we don't have enough information? Evidence is missing people need guidelines, you know, need help and trying to figure out how to do this. And so that's been a very difficult well over a long period of time. Yeah.

Ben 49:22

Yeah. My last jokey question is the initials of the Committee on the fetus and newborn is CFN is it? Is it call it or the caulk or you guys calling it the coffin?

Speaker 3 49:33

We call it the coffin but actually, I was I was trying to lighten up the things in the in the committee meetings as chair would call it COVID coffin. People try and generally call it KOFUN. But okay, so when I when I left the committee, after being chair they gave me a we were in in Arizona for the meeting at the time and they gave me a little thing with a skull on top of it. For a chair in the office,

Ben 50:04

at least at least there's a sense of humor. And that's good. That's good. Yes.

Speaker 3 50:07

I think that's really important. When you're working hard, and you're being a volunteer, you know, this is all volunteer. I think it's really important, first of all, to recognize how hard people are working on this and all the committee's. And secondly, tend to maintain a sense of humor and enjoyment about what you're doing.

Daphna 50:25

I have two more questions. My my first last question is, you know, you have always been doing a lot of things at the same time pulled in a lot of different directions. And if you have any tips for our listeners on even just like your organization of your day, your week, your projects, how does that work for you?

Speaker 3 50:50

Actually, I've talked to fellows these days about how there has been a consistent arc to my career in terms of seeing something that's really odd. And pursuing that and finding out a basis for it, you know, that the, the the adrenal insufficiency? And then if you find that, can you do something about that by giving early hydrocortisone? So then study that? And, you know, yes, there are other things in there at the same time, but it's all sort of been focused on this question about looking for a question, finding an answer. The next question down the line, is this finding an answer? And in the meantime, I've been involved in a lot of different things through the network. Yeah. Go ahead. No,

Ben 51:35

no, I was gonna No.

Daphna 51:38

No. Well, that this was my last question is and you brought me to it is that you mentioned early in the interview that you were drawn to neonatology? Because there were questions to be answered. And I wonder now and you know, over the course of your career, do you think we have more answers or more questions?

Speaker 3 51:57

Both? Both? We've gotten answers to some of the questions and those answers lead to more questions. And, you know, if you think you've answered all the questions, you're suffering from a lack of imagination. I think, you know, as I've said, I think we need to proceed from the negative parts of what the babies experienced to trying to provide more positive experiences for them. I have to say one thing, too, there was an article a number of years back that talked about preterm babies having an inverse circadian rhythm for cortisol, they had lower ones in the morning and higher in the evening. And so there was something about preterm babies where they were backwards. And I'm thinking, you know, just take a look at what happens to preterm babies during the day and take a look at what happens to them at night. What's happening is you're stressing them out to the max all day long. And so their cortisol concentrations up through the day, then they finally get a break. So their morning concentrations are low, we need to figure out how to how to cut that out.

Daphna 52:58

Okay, yeah, you're right, then there are lots of questions. If you think about that, I mean,

Ben 53:03

to give Daphna credit she does. She does decibel rounds in the NICU just to make sure that noise level right, yeah, yeah. So you're, you're preaching to the choir here.

Daphna 53:13


Ben 53:14

My last question to you, Dr. Warburg is, is I think today, fellows are very preoccupied with the choice of their research topic, right. So they're like, I have to pick something that's that's going to, quote unquote, deliver, right? I mean, you want to pick the and I am of the I think I know what you what your stance may be based on the discussion we've had today. But I am wondering if you're an advocate of just cycling through as many questions as possible and not try to pick something that on the forefront may appear to be yielding the best outcome or the most the most the most buzz I guess,

Speaker 3 53:52

I think, I don't think you can do that. I don't think you know what's going to produce the most earth shattering outcomes. I think what you have to do, in order to get you through the long slog between the idea and the outcome, you have to choose something that is interesting to you that you have a particular vested interest in, you take a look at some of the early stuff that we did was aerosol delivery to the lung. And people are talking about how much aerosol is delivered to the lung. And so we looked at urinary excretion of crumble, and I said, No, you guys, it's not 10% it's point 1%. So I think you have to look at something that is interesting to you in order to like I said, get yourself from the idea to the outcome.

Ben 54:32

All right. I love that. That's it. That's that's all I have for today then.

Daphna 54:36

Okay. Now, we were really grateful that you were able to spend this time with us obviously, you have a lot going going on given the recent publication and it seems like you always have a lot going on.

Unknown Speaker 54:50

I'm trying to cut down oh, well, you know.

Ben 54:56

Anyway, thank you so much Dr. waterway. This was tremendous fun, and I think everybody is gonna enjoy hearing your perspective on research and I think you're you have a very inspiring career. So congratulations. Congratulations. Well, thank

Unknown Speaker 55:07

you. Thank you for having me. This has been fun. Thank you. Thank you.


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