#453 - 📑 Journal Club - The Complete Episode from July 18th 2026

Hello friends 👋

Which PDAs actually need treatment? Can maternal voice and scent shape language outcomes? Should we cool at 35 weeks? And did stepping away from probiotics come at a cost? This week’s Journal Club takes on five papers that push back on standard practice. Ben reviews the SMART-PDA trial and a comparative study of PDA pharmacotherapy, Daphna covers the MIND trial on multisensory maternal interventions and a Pediatrix database study on NEC after the FDA probiotic warning, and Ben rounds out the main segment with a national look at hypothermia in 35-week infants with HIE. Ben and Eli wrap the week with Neo News on rising vitamin K refusal.

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The articles covered on today’s episode of the podcast can be found here 👇

Selective early medical treatment of the patent ductus arteriosus in extremely low gestational age infants: a pilot randomised controlled trial (SMART-PDA). Mitra S, Hebert A, Castaldo MP, Disher T, El-Naggar W, Dhillon S, Alhassen Z, Koo J, Katheria AC, Hyderi A, Kumaran K, Ting J, Surak A, Larocque J, Pepper D, Hornberger L, Makoni M, Weisz DE, Jain A, Bacchini F, Cameron-Nola AJJ, Hatfield T, Dorling J, McNamara PJ, Thabane L.Arch Dis Child Fetal Neonatal Ed. 2026 May 18:fetalneonatal-2026-330462. doi: 10.1136/archdischild-2026-330462. Online ahead of print.PMID: 42150872

Pharmacologic Therapies for Patent Ductus Arteriosus in Extremely Preterm Infants. Mitra S, Jain A, Ting JY, Ben Fadel N, Drolet C, Abou Mehrem A, Soraisham AS, Jasani B, Louis D, Lapointe A, Dorling J, Khurshid F, Hyderi A, Kumaran K, Toye J, Harabor A, Weisz DE, Stavel M, Morin A, Bhattacharya S, Lalitha R, Afifi J, Augustine S, Castaldo MP, Hatfield T, Su YC, Shah PS; Canadian Neonatal Network Investigators.JAMA Netw Open. 2026 Jun 1;9(6):e2617477. doi: 10.1001/jamanetworkopen.2026.17477.PMID: 42262753 Free PMC article.

The MIND Randomized Controlled Trial: An Intervention to Improve Neural Speech Processing and 2-Year Language Outcomes of Infants Born Preterm. Maitre NL, Kjeldsen CP, Jeanvoine A, Lukemire J, Slaughter JL, Key AP.J Pediatr. 2026 Jun 5:115187. doi: 10.1016/j.jpeds.2026.115187. Online ahead of print.PMID: 42250747

Therapeutic hypothermia and in-hospital mortality in 35-week infants with encephalopathy. Aly H, Eltaly H, Mohamed FA, Saker F, Acun C, Mohamed MA.J Perinatol. 2026 Jun 3. doi: 10.1038/s41372-026-02738-2. Online ahead of print.PMID: 42236997

Probiotics and necrotizing enterocolitis in preterm infants after the food and drug administration warning actions. Tolia VN, Bennett MM, Handler D, Canvasser J, Greenberg RG, Ursprung R, Ahmad KA, Patel RM.J Perinatol. 2026 Jun 2. doi: 10.1038/s41372-026-02712-y. Online ahead of print.PMID: 42225922

Vitamin K Deficiency Bleeding After Refusal: A Sentinel Event in a Misinformation Era. Jacobs JW, Booth GS, Wheeler AP, Adkins BD.Pediatrics. 2026 May 1;157(5):e2026075994. doi: 10.1542/peds.2026-075994.PMID: 41916583 No abstract available.

Trends in Vitamin K Administration Among Infants. Scott K, Miller E, Culhane JF, Greenspan J, Handley SC, Lo JY, Knake LA, McKenney KM, Burris HH, Dysart K.JAMA. 2026 Jan 20;335(3):272-274. doi: 10.1001/jama.2025.21460.PMID: 41359326 Free PMC article.

Babies Are Bleeding to Death as Parents Reject a Vitamin Shot Given at Birthhttps://www.propublica.org/article/more-parents-decline-vitamin-k-shot-newborns

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Watch this week's Journal Club on YouTube 👇

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

Ben Courchia, MD (00:00.737)Hello, everybody. Welcome back to the Incubator Podcast. We're back today for an episode of Journal Club. Daphna, good morning. How are you?

Daphna Yasova Barbeau (00:08.75)Good morning, good morning. You have been jet setting, huh? It's nice to have you back in town.

Ben Courchia, MD (00:12.619)Yeah, I did. We went on vacation, the one week of vacation that we take, and went to France. It was a lot of fun. And from there I went straight to Montreal for my hemodynamics training, which was something new.

Daphna Yasova Barbeau (00:29.388)Yeah. What did you learn? What was new about it? You've been doing this for a year now.

Ben Courchia, MD (00:37.045)A year now. Well, we're going to talk about it today, actually, because I think that with these two papers that I'm going to review today, I'll be able to shed some light on some of the hemodynamics things I've learned. I wanted to maybe just do a few announcements. I believe that when this episode is going to air,

Daphna Yasova Barbeau (00:39.586)Okay.

Ben Courchia, MD (01:04.833)Well, let me just check when this episode is going to air.

Daphna Yasova Barbeau (01:06.958)Let's walk it back a second.

Ben Courchia, MD (01:09.717)Let's walk it back a second. I just want to make sure that I'm not giving people the wrong information. So when this episode is going to air, there will be three days left to submit your feedback on our website for the annual anniversary of the podcast. And then you can be entered to win a whole set of prizes and so on. So make sure you do that. I think that this is quite nice.

Daphna Yasova Barbeau (01:17.322)No.

Ben Courchia, MD (01:39.213)In terms of the other thing that I wanted to mention, I've seen a lot of doctors starting to use a lot more Substack, which is a platform I don't fully understand. I understand it's kind of like—okay, I'm going to upset so many people—but it's kind of like a blog, and then you can subscribe to people's Substack. I've seen it used a lot with journalists or people who are in the news. But one of our

Daphna Yasova Barbeau (01:50.038)Yeah.

Ben Courchia, MD (02:08.343)Dear friends, Nick Embleton from the UK has started his own Substack. He has one on NICU nutrition and one on baby loss. So check him out. I think he's always been a strong voice for our community. He's a very bright mind, and he has a lot of insight when it comes to both nutrition and infant mortality. So you can go on Substack and look for him.

And subscribe. That's really it. So these were my two announcements for today. Anything else that I forgot? Otherwise, we'll deal with that tomorrow. Okay.

Daphna Yasova Barbeau (02:49.452)No, I think that's it. I'm excited to get this hemodynamics primer today.

Ben Courchia, MD (02:56.517)Yeah. So today I'm going to get to a paper that I've been meaning to review. It's published in the Archives of Disease in Childhood, Fetal and Neonatal Edition. It's authored by Souvik Mitra, who I guess is taking up a lot of space on our podcast these days, but that's not because of a lack of merit. He's very prolific. He's doing phenomenal work.

Daphna Yasova Barbeau (03:12.499)He's quite busy, this guy. Very prolific. I don't know how he gets it all done.

Ben Courchia, MD (03:22.593)But this is the selective early medical treatment of the patent ductus arteriosus in extremely low gestational age infants, a pilot randomized controlled trial. These are the results of the SMART-PDA trial. This is a very important paper, I believe, for the discussion on the PDA. And, to be honest with you, it's not an easy paper to understand. It's quite a complex design. And I think that's the—

My preface is basically based on the fact that Souvik and his team have tried to address some of the gaps in what we know and how we study the PDA. So once you understand it, it makes sense and it's easy, but I'm hoping that I can break it down for the audience. So I'm not going to give you too much background on the PDA. Most common cardiovascular condition affecting our preemies, pretty bad downstream effects of the PDA—NEC,

Bronchopulmonary dysplasia, et cetera, et cetera. Now, there are large randomized pragmatic trials that have not really demonstrated the benefit of treating the PDA. And what we use to treat the PDA are the cyclooxygenase inhibitor drugs: indomethacin, ibuprofen, acetaminophen. And for babies that are born extremely prematurely, the micropreemies, which is what we're talking about in this paper, the babies less than 26

weeks, there's still a lot of desire from a lot of institutions to treat these infants. And I think this is where the contradiction lies, right? We keep showing data that we're moving away from treatment, but for this population, the question is, well, maybe this population benefits from it. Interestingly enough, the paper mentions a survey of the Canadian Neonatal Network that shows that about two-thirds of this population

in Canada receives pharmacologic treatment for their PDA. Now, given the potential adverse effects of the medications that we have available and their waning effectiveness as we go up in postnatal age, there is a controversy as to whether doing a selective early treatment of a high-volume PDA shunt can improve clinical outcomes in this smallest infant group at the highest risk of

Ben Courchia, MD (05:47.374)PDA-attributable morbidity. And to their knowledge, they said there's no RCT that's been conducted exclusively on this micropreemie population of less than 26 weeks that employs a comprehensive hemodynamic screening strategy to specifically select and treat high-volume PDA shunts. And I think that's very important. We have a lot of data, most notably, I would say, from the University of Iowa,

where they have a hemodynamic program that helps them address the PDAs of their patients. And it's a report of their practice, but these are not randomized controlled trials. They've adopted this practice. So this is where the distinction comes in. And for people who must know, Dr. Patrick McNamara, who leads the team at the University of Iowa, is one of the senior authors of this paper. So

We'll talk a little bit about the trial. So the selective early medical treatment, abbreviated the SMART-PDA trial, is a multicenter, open-label, parallel-design pilot RCT conducted in seven Level III and Level IV centers that all have an established neonatal hemodynamics program that offers targeted neonatal echocardiography.

Four were in Canada, three were in the US. One point about the trial and how it was ultimately analyzed: what they did is basically conduct a Bayesian analysis throughout the study to inform whether the SMART-PDA approach was the right one.

And the Bayesian analysis was so striking that they basically had to stop the trial and just publish these results as is, as a standalone trial, because of the unwillingness of multiple participating centers to randomize their micropreemies to the control group, meaning the

Ben Courchia, MD (08:11.028)non-treatment group. So I think this is important. And I'm going to tease this a little bit, because I'm not telling you what this Bayesian analysis has shown. I think that when I tell you, you will understand why some people said, no, I'm not doing that. So in terms of the participants, we're talking about infants born below 26 weeks of gestation who were enrolled, obviously with consent from the parents.

Daphna Yasova Barbeau (08:12.846)Mm-hmm.

First.

Ben Courchia, MD (08:37.408)Infants with antenatal or postnatal major congenital anomalies, congenital heart disease, or babies that were on the palliative care track were obviously excluded from enrollment. All babies who were enrolled got an echo done within the first 72 hours of life. And infants with a PDA, any shunt severity documented on the initial screening, regardless of prior exposure, were eligible for randomization. Infants in the SMART-PDA

protocol got an echo every 72 hours for up to seven days of age to categorize the PDA shunt severity. I'm going to describe to you what the SMART-PDA algorithm is, because I think this is where this trial really adds a lot to the conversation. We've been discussing how we can categorize what's known as a hemodynamically significant PDA.

And I think they're doing a very good job at describing that. The way they're doing this is that they have three categories, putting the PDA into buckets. You can have mild, moderate, severe—and we have mild, moderate, severe categories for both clinical signs of the PDA and echocardiographic markers. So the clinical signs of a mild PDA are that you require less than 30% oxygen and that your mean airway pressure is less than eight centimeters of water.

I'm going to keep going through the clinical criteria and then I'll tell you about the echo criteria. The moderate PDA is needing 30 to 50% oxygen and requiring a mean airway pressure of 8 to 12. There is reduced urine output and systemic hypotension, which is defined as a blood pressure less than the gestational age in weeks at birth, which we know has pitfalls, and that's by convention. And then we have the severe

clinical PDA, which is requiring more than 50% oxygen, more than 12 centimeters of water of mean airway pressure, profound or recurrent pulmonary hemorrhage, acute renal failure, and hemodynamic instability to the point that you're requiring more than one cardiotropic agent. So, so far, so good, Daphna. This is pretty straightforward. It makes sense.

Ben Courchia, MD (10:57.384)Then let's talk about echo findings. I feel like before I did hemodynamics, I did not really understand the true assessment of a PDA. And so I think it's always good to buff up on that particular aspect. So the point here is that the size of a PDA does not necessarily mean that the PDA is hemodynamically significant. So a mild PDA has a size of less than 1.5 millimeters.

A moderate PDA is 1.5 to 2.5 millimeters, and a PDA above 2.5 is considered severe. But that's not sufficient. It is also about what else that PDA tells us. So for a mild PDA, we're looking at a left atrium-to-aortic root ratio of less than 1.5 and a left ventricular output of less than 200. So what could be confusing is, why are we looking at the left atrium?

Why are we looking at the left ventricular output as a way of assessing the PDA? So this is my pearl from hemodynamics that you can take home. The point here is that the output of the left ventricle is the direct product of pulmonary flow. Right? So when you talk about Qp:Qs, the output of your left ventricle is

the direct consequence of Qp. And when your PDA shunts from left to right, you are donating a lot of your systemic output to the pulmonary flow, to the pulmonary vasculature, which means that all this flow is eventually coming back to your left heart. And that's what's causing your left atrium to be flooded because of that excess pulmonary flow.

which leads to your left atrium enlarging, which is why your LA:Ao ratio increases. So that's why an LA:Ao ratio of 1.5 or more is abnormal, because it signals that your left atrium is enlarged from all this returning blood volume. And if your left ventricular output is high, you might think that's good—my left ventricle is working well. But basically, what that means

Ben Courchia, MD (13:18.22)is that your left ventricular output is high because it's dealing with a lot more blood flow than it needs to. So when you look at this, a left ventricular output of less than 200 is good. So that's a mild effect. A left ventricular output of 200 to 400 mL per kilo per minute, that's moderate hemodynamic significance of the PDA. And a severe would be a left ventricular output of more than 400. Does that make sense?

Daphna Yasova Barbeau (13:45.539)Yeah, I think that's really helpful, right? So backflow into the left atrium, more flow now moving into the left ventricle. Yeah.

Ben Courchia, MD (13:54.016)Exactly. The other thing that they looked at was transductal peak velocity, so the velocity across the duct. And obviously your severity went up based on an increasing level of transductal peak systolic velocity—meaning, sorry, decreasing peak systolic velocity. Because what you have to think about is that if the velocity across the PDA is high,

The way Gabriel explains it is that he mentions a hose where you hold your thumb to the end of the hose. If it's just squirting very fast, that means there's restriction of the PDA. But if the PDA is wide open, the flow is not going to be going super fast. It's more going to be like flow going through an unobstructed outlet. And so that's—

Daphna Yasova Barbeau (14:44.163)Yeah, and I think it's hard sometimes for people to understand. The flow volume is increased, but the flow velocity or the rate of flow is decreased. Yeah. But the problem is the flow volume.

Ben Courchia, MD (14:56.193)Exactly.

Ben Courchia, MD (15:02.529)Exactly. You got it. And then the last piece of the assessment is diastolic flow in the descending aorta.

So obviously in diastole, if you have a significant shunt, you will get steal, which means that the flow in the descending aorta during diastole will be reversed or absent.

Daphna Yasova Barbeau (15:26.563)Sure, that makes sense. Reversal on the aorta, bad.

Ben Courchia, MD (15:31.352)Yeah, exactly. Okay, so let's go back to the procedure. So pharmacotherapy, when it was indicated, was provided in the form of either ibuprofen, 10 mg per kilo once, followed by 5 mg per kilo times two every 24 hours. The administration route was decided by the team. And if there was a contraindication, then they could use acetaminophen given as 15 mg per kilo per dose q6 for three to seven days. Again, IV or PO. Infants randomized to the control arm—

So the control arm here did not undergo any further echocardiography or PDA treatment, regardless of their clinical signs in the first seven days, after which the decision on PDA management was made at the discretion of the treating physician. So basically, the control arm is no treatment for the first seven days. And I'm going to put this in context, by the way, because as you remember, the recent recommendations from the American Academy of Pediatrics have been

that we don't want to treat the PDA in the first two weeks. So we're doing something that doesn't follow that recommendation specifically, but again, it is guided by echo and it's in a population that we don't have a lot of data on. So what is the management plan? The plan is that you will treat babies if they have moderate signs of a PDA on clinical and echo findings, or if they have severe signs of a PDA on echo and anything

on the clinical. So if you have severe echo findings, you treat no matter what the clinical says. If you have moderate echo findings, you treat only if the clinical aspect is moderate as well. Make sense?

Daphna Yasova Barbeau (17:07.001)Got it.

Ben Courchia, MD (17:07.831)All right. In terms of outcome measures, the outcome measure was the proportion of eligible infants enrolled, right? Which is very bizarre when I read it, because it's not what we're used to. We used to say mortality, some form of clinical outcome. But here the idea was, can we actually do a trial like this? And it goes back to a lot of the issues that people have had running PDA trials, which is that you put people in groups and they cross back and forth, no matter what the investigators want. You have kids

who are in a group where it says, hey, you're not going to treat, and then they get treated. And then you're like, well, what do I do with that? And then you try to maybe use intention to treat or something like that, but it pollutes your data quite substantially. And so here the idea was, could we potentially do that? Is that going to work? Is this model going to work? Obviously, they did have secondary clinical outcomes that included mortality, procedural PDA closure, PDA pharmacotherapy, open-label rescue pharmacotherapy, BPD,

postnatal corticosteroids, pulmonary hemorrhage, duration of invasive mechanical ventilation, IVH, PVL, and so on and so forth, ROP, NEC, et cetera. They also pre-specified safety parameters that I will let you review. I feel like I'm extending myself too much, but I want to get into the statistics. This is one of these papers where you must understand the stats. And so what they did is that

they used this Bayesian framework and not the usual p-value approach. And that was deliberate, because it's a pilot trial like this one, and they have about 100 babies. So it was not really powered for statistical significance. So the Bayesian analysis answers the question we actually cared about, which is: given the data, what is the probability that the SMART strategy—SMART being the approach of the paper—is better? And so

instead of looking at whether it's significant or not for every outcome, they treated anything above 80% as a meaningful signal. What they then did is this thing called the win ratio, which is how they built their headline composite outcome. And a traditional composite outcome treats every component as equal. So death is the same as, say, ROP. But in the win ratio, you rank the outcomes by importance, which is also why it's interesting, because you had

Ben Courchia, MD (19:32.281)in this paper one of the authors, Fabiana Bacchini, who we've interviewed on the podcast, who represents parents. And I think this is key in this paper: what is the outcome that matters to parents, and how does that influence how we treat? And so in this case, they had these ranked using this win ratio. And it started with death being the top outcome to be considered, second

pulmonary hemorrhage, third sepsis, then NEC, then ROP. Okay?

Ben Courchia, MD (20:10.19)So, in terms of results, let's get into them now. So now we can understand a little bit what we're trying to do. They enrolled 116 out of 185 potentially eligible infants, for a recruitment rate of 63%. Of the 116 babies that were enrolled, 104 infants, or 90%, were randomized. In the randomized cohort, the mean gestational age was 24.3 weeks, with a standard deviation of

0.8 weeks. The birth weight was 714 grams. Breaking down that arm, 51 infants were allocated to the SMART arm with a mean gestational age of 24.4 weeks and a birth weight of 726 grams, and the other arm 24.2 weeks and 702 grams, so quite similar.

In terms of treatment characteristics of the 51 infants that were in the SMART arm, 45% received pharmacotherapy after their first echo, 17.6% after their second, and one patient after their third echocardiogram. The median age of pharmacotherapy initiation was two days, and

12 infants, or 24% of the cohort, never received pharmacotherapy at all. Of those receiving pharmacotherapy based on the SMART-PDA protocol, 25 received ibuprofen and eight acetaminophen as their primary pharmacotherapy.

Those are the 53 infants; 64% received PDA pharmacotherapy during their hospital stay at a median age of nine days, so after that initial seven-day period. And with regard to procedural closure, 9.8% in the SMART arm and 13% in the control arm underwent invasive PDA closure. So in terms of clinical outcome, they say that the Bayesian analysis showed that the SMART approach

Ben Courchia, MD (22:26.286)was associated with a reduction in pulmonary hemorrhage, with a relative risk of 0.07 and a probability that the SMART approach is better than control of greater than 0.99. So let me just reframe that for you. It means that the Bayesian analysis showed that the SMART approach had a likelihood of reducing pulmonary hemorrhage

by 99%. And I'm just going to let that sit for a second, and go to the next one. It also sh—Yeah, okay, yeah, okay. Very astute observation, my friend. It also sh—

Daphna Yasova Barbeau (23:02.179) That's a lot of percents. Thank you, thank you. We've only been doing this journal club for five years, you know. I've got—

Ben Courchia, MD (23:12.404)Uh-huh. It also showed a clinically meaningful probability of benefit with regard to NEC, with a relative risk of 0.39 and a probability that the SMART intervention is better than control of 0.92, which is about 92%. Which now makes you understand why

when that data came out, a lot of the centers were saying, I'm not staying, I'm not leaving my patient in the control arm, right? That doesn't make sense to me, because you're telling me that the likelihood of reduction is so much higher. So when we're talking about this, right? I think this is really quite

It was quite incredible. And that's also where that Bayesian analysis looks at the hierarchy, right? We're not talking about death, we're talking about pulmonary hemorrhage, which is your second outcome, and NEC, which is your fourth outcome in that hierarchy. Does that make sense?

Daphna Yasova Barbeau (24:31.991)Got it.

Ben Courchia, MD (24:32.879)Yeah. So for the other outcomes, the estimates were imprecise and centered around one. So I'm going to skip that. And with regard to pharmacotherapy-related outcomes in the SMART arm, 3.9% developed oliguria, and none developed GI bleeding within the initiation of treatment. So I'm going to leave this there for a second. The conclusions are that the trial—

the first to exclusively enroll infants born before 26 weeks' gestation, suggests that the sickest micropreemie with a high-volume PDA shunt identified through early comprehensive hemodynamic screening may benefit from pharmacotherapy. Future trials should examine the role of such selective pharmacotherapy strategies in the highest-risk infants, as specifically highlighted as a research priority by the American Academy of Pediatrics in the clinical report on PDA management.

So this is very interesting. And I think that, to me, what's very innovative is the approach of the Bayesian analysis, the win ratio that they did, and the outcomes we're discussing. So one of the things that, to me, is very

very peculiar is that we're not talking about the closure rates of these PDAs, right? That, to me, is the question lingering through the paper. It's like, well, how many of them got their PDA to close? And they purposefully don't; that's not important, right? That's not really what they're looking at. But it is something that people might say: well, did it work? Did it close the PDA? And so on and so forth. And I think this segues quite nicely to another paper that Souvik is

publishing, this time in JAMA Network Open, called Pharmacologic Therapies for PDA in Extremely Preterm Infants. And we're going to talk a little bit about that, where it's a bit of a comparison. But do you have any questions or thoughts on the first one, about the SMART-PDA trial?

Daphna Yasova Barbeau (26:34.873)Well, phew, that was a big one. Well, I think, in our practice, this question about did it close the PDA? Right, maybe it doesn't close the PDA, but it has enough effect on the PDA that we still get a positive impact. Or it makes that PDA more restrictive, so it becomes less hemodynamically significant. But yeah, potentially the goal's not closure, right? And I think what's cool about this is

we know that exposure to the PDA is bad. But every time we try to prove that closure makes that exposure better, we've failed to do that. But I think what was lacking was a standardization of what's hemodynamically significant. And not all the studies were functioning off the same page of music, I think. So that's interesting. I wonder.

Ben Courchia, MD (27:27.289)No, no. And the definition of a hemodynamically significant PDA, plus the implementation of those definitions into a randomized trial format. Yeah.

Daphna Yasova Barbeau (27:36.109)Right, for sure, for sure. And I'm going to ask you, as a burgeoning expert in hemodynamics: what do you think will be some of the concerns about this study? What do you think the "we don't need a closed PDA" group will say about this study, including some of your colleagues in Montreal, right?

Ben Courchia, MD (27:59.463)Well, I think they have strong opinions on that. But I think the argument here is that this is based off a Bayesian analysis, and the fact that in the end we're not talking about a tremendously large number of babies. And while I think this is going to come counter to the fact that

Daphna Yasova Barbeau (28:06.595)That's right.

Ben Courchia, MD (28:29.894)the PDA burden is individualized to each patient in that particular format. So yeah, I think it will be interesting. And again, we're talking about the first seven days of life, and we don't know if the PDA has been closed or what the effect of that was on the PDA itself. I think this is where people are going to say, I want to see the data bear out on the patients.

Daphna Yasova Barbeau (28:57.697)All right, I can buy that. Carry on.

Ben Courchia, MD (28:59.216)Yeah. So in JAMA Network Open, basically they prospectively compared the relative effectiveness of different PDA pharmacotherapy regimens in extremely preterm infants, those born before 29 weeks of gestation. So a little bit more mature population than the one we just spoke about, which was less than 26 weeks. So I'm going to try to go relatively quickly, because it's already been 30 minutes. But the

They conducted a multicenter, prospective, observational comparative effectiveness research trial in 19 tertiary centers in Canada. Infants born less than 29 weeks were included. They had to have a large left-to-right shunt at the PDA. Infants who received indomethacin in the first 24 hours of life for IVH were also included. And they had

four predefined interventions for the participants: standard-dose ibuprofen, adjustable-dose ibuprofen, indomethacin, and acetaminophen. These were the primary pharmacotherapies. The primary outcome was failure of primary pharmacotherapy, meaning needing additional medical or surgical intervention following an initial medication administration. The secondary outcomes included receipt of a repeat pharmacotherapy course, surgical closure, moderate to severe

BPD, necrotizing enterocolitis, IVH, sepsis, and so on and so forth. In this study, they had 1,356 infants between 2020 and 2023, mean gestational age 25.4 weeks, mean birth weight 828 grams. Of these patients, about 1,100 received PDA pharmacotherapy,

whereas 259 did not receive pharmacotherapy and were conservatively treated. Among the participating NICUs, eight used standard-dose ibuprofen, eight used adjustable-dose, three selected acetaminophen, and one selected indomethacin. And again, the decision on how to treat these infants was left at the discretion of the different centers.

Ben Courchia, MD (31:24.202)So let me just get to the drug-dose effectiveness cohort. Okay, let me talk about the treatment effectiveness and primary outcome. So among the 1,100 infants who received PDA treatment, 42% experienced failure of the primary pharmacotherapy. In addition, 41.6% received a repeat pharmacotherapy course,

and 4.1% underwent interventional PDA closure. Importantly, there was no difference between the four regimens in terms of which one failed the most. So the comparison between all four treatments seems to be relatively the same. With regard to secondary outcomes, and using the standard-dose ibuprofen arm as the comparator, mortality odds were higher among infants who received acetaminophen,

with an adjusted odds ratio of 1.37. And mortality odds were lower among those receiving indomethacin, with an adjusted odds ratio of 0.4. Sepsis odds were also lower among those who received indomethacin, with an adjusted odds ratio of 0.21. Interventional PDA closure odds were lower among those who received adjustable-dose ibuprofen. And there was no difference in adverse effects, specifically post-treatment serum creatinine, bilirubin levels, and liver function tests

with any of the pharmacological interventions.

We already talked about that. When it comes to looking at other clinical outcomes for these infants who received PDA treatment, pre-discharge mortality was 14.5%, moderate to severe BPD 65.9%, NEC stage two 11.6%, and definite sepsis following initiation of treatment 22.8%. Then they compared the

Ben Courchia, MD (33:29.011)kids who were treated as one big cohort versus the ones who were not treated. And here we have the treated group, which is about 1,100 infants, being compared to the 259 infants who were not treated. I'm sorry—right, did I say that correctly? The 259 infants who did not receive treatment. So for pre-discharge mortality,

the rate was 14.5% in the group that received treatment versus 15.4% in the group that was conservatively treated, meaning those that did not receive treatment. And that difference was not statistically significant. When we're looking at moderate to severe BPD, the rate was 55.2% in the treated group

versus 32.4% in the conservatively managed group. For NEC, the rate was 11.6% in the treated group and 6.2% in the conservatively managed group. And for definite sepsis, the rate was 22.8% in the treated group versus 21.2% in the non-treated group. When compared with

those who received pharmacological treatment, infants who received PDA therapy had higher odds of moderate to severe BPD, with an adjusted odds ratio of 1.91, and higher odds of NEC, with an adjusted odds ratio of 2.15. And the inverse—well, they did an inverse probability weighting, but I'll skip that for now. So I'm going to get to the sensitivity and subgroup analysis, and then I'll close out for today.

The per-protocol sensitivity analyses were largely consistent with the primary analysis. They demonstrated higher mortality odds with acetaminophen, with an adjusted odds ratio of 1.47. They also demonstrated, with indomethacin, lower mortality, with an adjusted odds ratio of 0.16, lower sepsis, and higher BPD odds.

Ben Courchia, MD (35:47.476)Turning to the subgroup analysis, the notable findings include lower mortality odds with indomethacin within seven days of birth, with an adjusted odds ratio of 0.16, and higher BPD odds with indomethacin, both within seven days, with an odds ratio of 2.7, and after seven days. In addition, in the subgroup of infants born before 26 weeks—now we're talking about the same population as the SMART-PDA cohort that we were discussing—

indomethacin was associated with lower mortality and higher BPD odds. And in that same subgroup analysis by gestational age, adjustable-dose ibuprofen was associated with lower BPD odds in both gestational age subgroups. For infants below 26 weeks, the adjusted odds ratio was 0.33. And for infants at 26 weeks and above, the adjusted odds ratio was 0.38. The conclusions are that,

in this large multicenter comparative effectiveness research study, it really shows that the primary PDA pharmacotherapy failure rate was high. We're talking about 40%, and similar in extremely preterm infants, regardless of the medication that you choose. The use of acetaminophen seems to be associated with increased mortality odds, but this result should be interpreted with caution, again because of potential confounding by indication or contraindication.

Although no pharmacotherapy choice, as we described—i.e., ibuprofen, acetaminophen, or indomethacin—stood out as more effective. Overall, infants who were exposed to pharmacotherapy had higher odds of moderate to severe BPD and necrotizing enterocolitis, but lower mortality odds compared with infants who were conservatively managed. Future studies should approach—

and should investigate approaches for identifying extremely preterm infants at high risk for PDA-attributable morbidity, and infants most likely to respond to medical therapy. This is a great linkage to the other paper that we just reviewed. I'm going to want to stop here. I'm exhausted.

Daphna Yasova Barbeau (37:57.495)I'm sure you are. Okay, so where does this leave us?

Ben Courchia, MD (38:01.203)Well, I think it's very interesting, because now you see that this approach of just saying, hey, we use acetaminophen and then we treat everybody based exactly on what the PDA size is—it's not good. There's actually a great editorial in JAMA Network Open that I'm inviting everyone to read, authored by Marjorie McConey,

Daphna Yasova Barbeau (38:07.161)Yeah, we treat everybody. Everybody is—

Daphna Yasova Barbeau (38:16.878)Mm-hmm.

Ben Courchia, MD (38:30.078)which basically makes this exact point: that the burden of a PDA is individualized. A 1.5-millimeter PDA means nothing to me unless I understand how it is affecting that particular baby. And there are some babies who are going to respond very differently to a 1.5-millimeter PDA, and their intervention should thus be different. And I think that when you go back to the intervention, right?

They're talking about including babies who basically have a PDA that's above 1.5 millimeters. That's the inclusion. And it highlights how, if your goal is to just measure the PDA in size and give a medication hoping that it will close, this is not the right approach, because number one, your closure rate is extremely poor, 40%. And the outcomes are not clear-cut. It's not like you give the medication and suddenly mortality, morbidity, everything goes down.

So I think that, to me, this reinforces what we just saw with the SMART-PDA trial, which is: I don't really need to know what the closure rate is. I don't need to know the diameter. I need to have a better assessment of which patient I'm talking about, and then tailor my treatment to that particular physiology. So I think this probably made things more complicated for everyone, but—sorry.

Souvik's email address will be in the description, and you can email him.

Daphna Yasova Barbeau (39:56.205)That's right. That's fine. People can address that with him personally. No, I think this is helpful. I think it again just underscores this individual approach to medicine, right? We want to be able to give all the babies the same thing and have good outcomes. And that's

Ben Courchia, MD (40:02.311)Yeah.

Daphna Yasova Barbeau (40:18.519)I think that's what they're telling us. It's that we can't do it that way, especially for the PDA, but probably for a lot of the other things that we've tried to do in neonatology.

Ben Courchia, MD (40:22.834)You can't, yeah.

Ben Courchia, MD (40:28.744)Yeah, and to me, it's fascinating that the same outcomes we were talking about, specifically when it comes to NEC, really can swing one way or the other, depending on whether your approach is a bit shotgun-y, where it's like, I'm just going to look at the size and treat or not treat, versus a little bit more tailored. Whereas in the SMART-PDA trial, the data is sort of predicted, right? The SMART-PDA approach in the first seven days of life does have

significant implications for the reduction of that specific morbidity. So yeah.

Daphna Yasova Barbeau (41:03.885)Yeah, for example, this reversal of flow in the aorta. Like, if the intestines aren't getting enough flow, it stands to reason that you'd be more likely to get NEC. So, okay. Yeah. You sure have.

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Daphna Yasova Barbeau (00:55.368)For sure, for sure. All right. Well, you've had enough time to talk about your papers. It's my channel. I have this article entitled the MIND, M-I-N-D, Randomized Controlled Trial, an Intervention to Improve Neural Speech Processing and Two-Year Language Outcomes of Infants Born Preterm. It's in The Journal of Pediatrics. The lead author is, say it for me. Maitre. Did I get it?

Ben Courchia, MD (01:00.163) Mm-hmm.

Ben Courchia, MD (01:19.583) Nathalie Maitre. Maitre. Yeah.

Daphna Yasova Barbeau (01:24.646) I'm not sure. The Duolingo is not doing as much for me as I thought in my French practice. Maître. Did I say "ray"? Yes. Okay. Senior author Alexandra Key. And this is a really interesting paper,

Ben Courchia, MD (01:29.262) Ha ha, Nathalie.

What? Yeah.

Daphna Yasova Barbeau (01:43.168) because the first line of the background says, "Despite advances in neonatal care, infants born prematurely still have high rates of developmental delays and impairments." And I thought that was interesting, because we recently released episode number 448, Are NICU Outcomes Actually Getting Better Over Time, with Dr. Camp. And the answer is no.

"No, but" is the answer, I guess. And we got a lot of feedback on social media about this, because people said, wow, we've made so many advances. Look at what we're doing. We're saving these little babies. And we had to respond that that was the point, right? Mortality has decreased significantly. We had a great talk in the first Delphi, out of Japan, that mortality has decreased significantly, but

the neurodevelopmental outcomes are not changing. We're really not moving the needle on developmental outcomes. And that matters to families. So, anyway, I thought that was an interesting highlight. What they tried to do in this study, they recognized that maternal voice is very valuable. Maternal voice while holding is the gold standard of developmental care. But

for example, here in the United States, it's really difficult for us to have parents at the bedside. So could we create a proxy for parents at the bedside? That gets to the rest of the background. And I quote, "singing during NICU kangaroo care increased exposure to coached parental singing and was associated with better outcomes."

"Later in admission, parental singing and reading positively influence linguistic outcomes of former preterm infants." And so this underlies how important exposure to infant-directed voice is. Infant-directed voice means the type of language, the type of talking we use with infants, which is a little different from the intonation, the flow that we use with adults. So that specific infant-directed voice is really important

Daphna Yasova Barbeau (04:05.732) in shaping auditory processing of language. And of course, systemic and structural factors in the NICU limit parental presence, and that makes live infant-directed voice by caregivers, familial caregivers, really difficult. So the MIND intervention, multisensory support to improve neural processing and development, MIND,

was a way to try to expose babies to their parents' infant-directed voice and holding, even if the parent wasn't there. I'll explain exactly what the MIND intervention looked like, but they compared that to their quote-unquote enhanced standard care, where infants heard just recordings of maternal voice, but without

these other components. Okay, fine. Let me just tell you what the other components are for the MIND. So I'll tell you about the caregiver voice recordings. Mothers were trained by a board-certified music therapist to do infant-directed speech and singing.

And then they recorded these, and they made recordings that they were able to play that included lullabies, nursery rhymes, and children's books. They were able to play this from speakers. So this passive caregiver voice recording is standard of care. All the babies are being exposed to these voice recordings of their mothers, and it's not just voice recordings, specifically infant-directed

voice recordings. So the control group was hearing these caregiver voice recordings via a customizable speaker placed near the baby's head. And the nurses were instructed to do this one to two times a day. Specifically, they were instructed to activate the speaker when the infant was in a quiet alert state. Now, the MIND intervention includes this pre-recording of mommy's

Daphna Yasova Barbeau (06:25.564) voice that's inventoried, but it additionally includes smell. So moms wore cotton t-shirts for an hour in the NICU, and then the cotton t-shirt was cut up into pieces. Part of the MIND intervention included exposure to a piece of this cotton t-shirt. So during sessions, babies were exposed to their mother's scent

and the therapists held the infant against their chest. They were wrapped in a Zaky, which is like a kangaroo care binder, and the infant's head was on their mommy's scent cloth. We have, yes, we have. Perfect. Yeah, that's a great interview. So basically, one group just got the recordings, the other group

Ben Courchia, MD (07:07.63) We interviewed the creator of the Zaky, if I'm not mistaken. I'll find the episode number, but keep going.

Daphna Yasova Barbeau (07:23.432) got the recordings while therapists were holding them in the Zaky binder, in a quiet alert state, and wearing a piece of their mother's scent cloth. So basically, they're trying to convince the baby that it's being exposed to its mother, even when the mother can't be present, versus not being held,

not being contained in the binder, and just being exposed to their mom's voice through the speaker. Does that make sense? Did I explain that right? Do you think so?

You're muted, but I see you saying yes. Great. Okay. So they always assessed infant readiness. These sessions were attempted before or after routine care. Sessions were discontinued if the infant did not engage. Part of the engagement was using this PAL, the, what's it called, pacifier-activated music player. So by the baby sucking on the pacifier,

Ben Courchia, MD (08:06.743) Yeah, I was muted, but I said very well. Yes, you did that very well.

Daphna Yasova Barbeau (08:36.166) that's what activated the speaker to do its thing in both groups. So either the baby was being engaged just with auditory stim, or engaging on the pacifier with auditory and the additional sensory smell, touch, and proprioception. Okay. And it was also discontinued, obviously, if there was any autonomic instability, which they defined, and they made sure that consecutive sessions were at least

three hours apart. The goal dose was two to three times daily over two to three weeks, with a goal of achieving 20 sessions. And they considered them compliant with the study protocol if they were able to get in at least 12 sessions. I'll argue that it will be hard for a therapist to do this three times a day, just as potentially difficult as getting parents at the bedside, but it's an interesting concept.

And then, what were they measuring? They were looking at auditory event-related potentials. These are ERPs, using EEG, collected within 72 hours of the first and the last study session. So they took a baseline of ERPs for the babies, and then at the end of the two to three weeks of sessions, they got an additional measurement. And so they were looking at these auditory event-

related potentials. So what is that? What is an ERP? They use the scalp electrodes from the EEG, and they're looking at a measurable brain response. And then, specifically, what they're looking at, and I'll get into this, is something about consonant contrast. So is the baby able to distinguish that

the B sound is different from the D sound, which is different from the P sound? So those were the things they were comparing. And in terms of the leads they were using, based on previous studies, using the 10-20 EEG system, they used a left frontal lobe lead and a right frontal lobe lead, F3 and F4. Yes, we're following so far.

Daphna Yasova Barbeau (11:01.096) And

Ben Courchia, MD (11:01.611) Yes, I'm following. I would have a question about the significance of that, in terms of, why is it, the fact that the baby can differentiate, you said the B sound and the other sound, or something. Yeah.

Daphna Yasova Barbeau (11:10.656) Yeah, perfect. So that speech sound differentiation, consonant differentiation, is a fundamental building block for language development. So they're trying to see, at baseline, do the babies have this differentiation? Does it get better with the intervention? And, hopefully, is there a difference between the MIND intervention and their standard control of just the auditory sound?

Now, there are some units where babies aren't getting exposed to language at all. So the bare minimum is getting babies exposed to language. But how does that change with maternal infant-directed voice, and then the MIND intervention, maternal infant-directed voice, maternal smell, and being contained by being held on the chest? Phew. So there, I guess.

What they're trying to prove is, if we can improve these building blocks of speech, how does it improve speech outcomes at two years? So again, they looked for these ERPs, they looked at the differences between the pre and post, between different babies. And, I gave you the wrong consonants earlier, the consonants are B, G, D,

G and B and D. So they were looking at the different consonant contrasts. And then they looked at the two-year behavioral measures. They looked at 22 to 26 months corrected gestational age, the Bayley Scales of Infant and Toddler Development, Third Edition, and they used the PLS-5, the Preschool Language Scale, Fifth Edition, to look at outcome convergence. So did any of the markers in the infancy period

predict outcomes at two years? Okay. I spent a lot of time working through that. I think we're good here. In total, 120 infants were randomized to the intervention MIND group. 108 completed the intervention. 100 had EEG data available at both assessment points, and about an 85% follow-up rate at two years, which again is pretty remarkable.

Daphna Yasova Barbeau (13:32.275) They had 122 infants in the control group. 116 completed the control intervention, 98 with EEG data, and again, an 87% follow-up rate at two years for the control group. Importantly, no infants failed their hearing screens during those first two years. They did have some pretty impressive COVID-19-related attrition, but they were able to mitigate that.

The major baseline characteristic differences showed just that the mean educational duration for mothers in the control group was one year greater than in the intervention group. This was statistically significant. And the control group had a slightly shorter delta EEG. So the time between the pre- and post-EEG time points was slightly shorter, with a p-value of 0.049. Okay, so what did they find?

They found that there was a significant difference at post-EEG assessment between groups. They saw improvement in both groups, but, as I'll get into, more improvement in the MIND group. They found differences in the locations, so the different frontal leads, F3 and F4, and in the time window. So I didn't mention this, but they also looked at different time points

past the intervention, in milliseconds. They used two different time points from the exposure to the auditory stimulus. So at the subject level, the ANCOVA revealed significant differences between groups across the temporal lobe locations over time. And, same thing, the contrast-level ANCOVA, looking at the different consonant contrasts, also showed

differences between the groups. What did this look like at two years? There were direct positive effects of the MIND intervention on the Bayley receptive and expressive scores, even when controlling for gestational age and maternal education. All of the scores are here, but I'm not sure that everybody's that familiar with them. You should just know that the scores improved.

Daphna Yasova Barbeau (15:52.627) And there was also improvement on the Preschool Language Scale five auditory comprehension and expressive communication scores. And the scores represent small to medium-sized effects, about 0.5 standard deviations on the scaled score measures for both the Bayley and the PLS-5, which across published literature is a clinically meaningful effect size.

So at the participant level, the total effects modeled showed the intervention effects on speech sound differentiation. So improvements in speech sound differentiation on the pre and post also predicted better scores on the two-year language outcomes. The MIND effects on differentiation of especially the B and G consonant contrast, measured in the frontal locations,

were significant for every single language score. So if babies were able to have that differentiation, especially for B and G, they had improved scores across the board at two years. So their overall conclusion is that the MIND intervention, language plus scent plus touch and proprioception,

had a much larger effect on speech sound differentiation than enhanced standard care. And this improvement in neural effect mediated better performance on the two standardized measures of receptive and expressive language at age two. So I think this is really exciting. Maybe people are like, yeah, no duh, that makes sense. But I think it underscores that, one, exposure to language is really important. Two,

infant-directed speech is really important, and every single one of us can do that every time we engage with the baby. There's no reason you can't tell the baby, good morning, hello, you're so cute, you're so strong, in baby voice and baby speak every time we enter the isolette. So every single one of us can do that tomorrow when we go into the NICU. And that the combination of kangaroo care,

Daphna Yasova Barbeau (18:08.693) and being held and being talked to, and smell, and vibration, all at the same time, probably has a much bigger impact on development than just exposure to any one of these things in isolation. And of course, being near their familial caregivers is optimal. It looks like we can do a proxy with therapists, but we're pretty, we're pretty

aggressive, I would say, with developmental care in our unit. And there's no way that we would be able to have therapists do this three times a day. So

Ben Courchia, MD (18:43.827) Yeah. But to correct you on one thing, the meaning was not what was tested. You could say whatever you want. You could even read out the news. You can just open your mouth. Yeah.

Daphna Yasova Barbeau (18:47.273) Please.

Daphna Yasova Barbeau (18:52.381) I can say whatever I want. That's true. That's true. That's not what was tested.

Daphna Yasova Barbeau (19:00.189) That's right. That's right. Yeah, you're absolutely right. What you're saying is, it doesn't have to be lullabies. It doesn't have to be a baby book. Yeah.

Ben Courchia, MD (19:09.85) For sure. Sometimes I've seen it, I've done it myself. You're roaming around with students and you say, let's get away from the bedside, let's not bother the baby. And it's like, no, speak around the baby. It's good. Yeah

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Ben Courchia, MD (00:35.986)Okay, so the paper I'm reviewing next was published in the Journal of Perinatology. It's called "Therapeutic Hypothermia and In-Hospital Mortality in 35-Week Infants with Encephalopathy." First author is Hany Aly from Cleveland, Ohio. Lots of interesting people on that paper as well.

Daphna Yasova Barbeau (00:45.231)Mm-hmm. Oof.

Ben Courchia, MD (01:00.982)Obviously, we know the devastating effect of HIE on our neonates. And the criteria for therapeutic hypothermia, which is, to be honest with you, the only evidence-based intervention that we currently have available for these babies, is indicated for infants who are 36 weeks of gestation or more and who have moderate to severe HIE. The safety and efficacy of hypothermia in infants who are born before 36 weeks is uncertain.

Recently, we reviewed a paper that was published in JAMA Pediatrics on a Bayesian probability approach to babies receiving hypothermia between 33 and 35 weeks, which showed that there was an increased signal for mortality in that population. And the question really lingered as to maybe 33, 34 weeks, okay, but what about 35 weeks? There were a lot of questions about whether the data

was really strong for that specific gestational age. Importantly, as the authors mention, current evidence remains inconclusive regarding the safety of therapeutic hypothermia in infants who are born at 35 weeks. And a recent international survey of 88 centers demonstrated substantial practice variation, with many centers continuing to offer cooling at 34 to 35 weeks despite findings from the randomized trial. Notably, 22 centers reported in-hospital mortality rates lower

than those observed in the trial, and therefore did not find sufficient justification to alter their practice, citing more favorable outcomes in their multicenter experience. In addition, several small single-center studies have reported mixed results. Consequently, robust population-level data remains limited. The purpose of this study is to conduct an epidemiological analysis using the National Inpatient Sample, the NIS

database, covering 2016 to 2022, to examine hypothermia utilization and outcomes among infants born between 35 and 36 weeks with HIE. So basically, they took the data from the NIS looking at the infants specifically during that 35th week from 2016 to 2022. I'm not going to get into what the NIS is. It's a very well known database from the Healthcare Cost and Utilization Project, HCUP,

Ben Courchia, MD (03:28.014)and the Agency for Healthcare Research and Quality, the AHRQ. Infants that were included in the study basically had a gestational age of 35 weeks. They compared them to infants who were 36 weeks and more, and they had to have a diagnosis of HIE and receive therapeutic hypothermia. So whenever we have these database studies, I think the methods are pretty straightforward. I'm going to let you review that,

and I want to get into the results. So the sample of patients who met inclusion and exclusion criteria was 1.4 million infants. Of these, there were 493,000 infants in the 35-week group. Of them, 2,354 had a diagnosis of any degree of HIE. They had about 900,000 babies in the 36-week group, and of them, 3,900 had any degree of HIE.

In terms of hypothermia utilization, fewer infants in the 35-week group received hypothermia. In the 35-week group, 19.8% received cooling, compared to the 36-week group, where 889 infants, 22.4%, received therapeutic hypothermia. This yielded an adjusted odds ratio of 0.84 and a

significant p-value of 0.01. Respiratory distress syndrome was significantly associated with the 35-week group, which is not so surprising, while persistent pulmonary hypertension of the newborn and thrombocytopenia were more associated with the 36-week group. Coagulopathy was more strongly encountered in the 35-week group compared to the 36-week group. The median length of hospitalization did not differ between the two gestational ages in infants with HIE, and that was about 15

days. So let's talk a little bit about in-hospital mortality. The overall in-hospital mortality among 35-week infants with HIE, regardless of whether they were cooled or not, was comparable to that of 36-week infants. That was about 10%, 9.98 versus 9.99. So very, very much the same. Infants in the 35-week group with HIE who received cooling had significantly higher in-hospital mortality

Ben Courchia, MD (05:51.865)compared to the 36-week infants with HIE who received cooling. So mortality was seen to be higher. That was 10.3% mortality in the 35-week infants compared to 6.8% in the 36-week infant group. P-value 0.04. In-hospital mortality among the 35-week infants did not change with versus without therapeutic hypothermia. 10.3%

versus 9.9%, which shows that it doesn't seem like cooling really made a difference on that mortality ratio. The use of therapeutic hypothermia was associated with a significant decrease in in-hospital mortality among 36-week infants compared to those who did not receive cooling, 6.8% versus 11%, with a p-value of less than 0.001. The p-values are obviously very strong because we're talking about a lot of babies.

And again, just to show that the data is pretty strong, in-hospital mortality for babies who were 37 weeks with HIE who received cooling was significantly lower than for those who did not receive cooling. Because again, if you had seen that cooling did not make a difference across all gestational ages, then you say, okay, well, maybe it's not the gestational age that's the issue, maybe it's the data. The median length of hospital stay did not differ significantly, as we said.

And interestingly enough, they looked at coagulopathy. Since 35-week infants who received cooling had higher rates of coagulopathy and in-hospital mortality when compared to 36-week infants, and we know coagulopathy and coagulation disturbance is a risk factor for babies who are born at 35 weeks, the authors repeated their regression analysis, adding coagulopathy as a confounding variable. After controlling for coagulopathy in the regression model, TH was not associated

with in-hospital mortality in 35-week infants, meaning that it doesn't seem like it's coagulopathy that's leading to an increased mortality in that particular group. It was then important to identify whether coagulopathy existed in HIE infants regardless of their exposure to therapeutic hypothermia. And coagulopathy in that 35-week infant group was significantly increased in those who received therapeutic hypothermia, 28.7%,

Ben Courchia, MD (08:17.651)28.7% versus only 18.4% coagulopathy in those who did not receive therapeutic hypothermia. So clearly that side effect that we know from cooling was seen in that group. They did a mediation analysis, which didn't show any correlation between coagulopathy and inpatient mortality. And I said I would do this one relatively quick, but that's really it.

So the conclusions of the article are that although the role of therapeutic hypothermia in 35-week infants remains uncertain, its use was not associated with increased in-hospital mortality. In this national cohort, therapeutic hypothermia was associated with an increased risk of coagulopathy. However, mediation analysis did not support a significant role for coagulopathy in in-hospital mortality.

These findings underscore the need for careful risk stratification and heightened safety surveillance when considering therapeutic hypothermia in this population. Prospective studies are needed to define eligibility thresholds and monitoring strategies before routine use can be supported. Until more definitive evidence is available, close monitoring and early management of coagulopathy remains prudent when TH is administered in this gestational age group. I thought this was very interesting. I know you have a lot of thoughts on that.

Daphna Yasova Barbeau (09:39.706)Yeah, very interesting. And just to clarify, because I think it can be really confusing if you don't have the tables in front of you, there was a significant difference in mortality between the 35-weekers and the 36-weekers who were treated. So that was different, 10.3 versus 6.76. But if you look at the 35-weekers as a group themselves, and look at mortality for those who were treated and untreated, that's where there was no difference.

Ben Courchia, MD (09:56.046)Yeah.

Ben Courchia, MD (10:08.427)No difference. And that's what the first line of the conclusion really mentions when they say, although the role of therapeutic hypothermia in 35-week infants remains uncertain, its use was not associated with increased in-hospital mortality. It was also not associated with a reduction in in-hospital mortality. And so when you're 35 weeks, whether you get cooled or not, based on the data from this database, it doesn't really impact your ultimate outcome, which is survival.

Daphna Yasova Barbeau (10:09.123)And mortality. Yeah. Yeah.

Daphna Yasova Barbeau (10:22.863)That's right.

Daphna Yasova Barbeau (10:32.291)Yeah, and it was hard to get into this, but degree of HIE in babies who were treated and untreated, fortunately or unfortunately, there's a difference there too. In those who were treated, moderate HIE was 34.1% versus 25%. That was not statistically significant. But severe HIE was 7.28% in those treated, 12.8% in untreated, and that was statistically significant.

Same thing, unspecified HIE, which I guess is unspecified, 37.7% in the treated, 45% in untreated, and that was statistically significant. So it looks like there was potentially some improvement in the HIE diagnosis, even in the 35-week group. So it adds definitely another layer to our conversation

about 35-weekers and therapeutic hypothermia, for sure.

Ben Courchia, MD (11:33.367)Yeah. And I think that what this paper is actually opening the door to is that we potentially can't address HIE in the 35-week infant, and maybe even younger than that, the same way we address it in a 38-weeker. For a 38-week infant, you're going to say moderate to severe, I'm treating, or I'm doing this, I'm doing that. Maybe for 35-weekers there are certain classifications that will matter more.

Maybe mild, moderate, severe will not be treated the same way. And I think that this matters tremendously. So.

Daphna Yasova Barbeau (12:10.883)Yeah, and I think the last thing, people in units will say, well, now what are we supposed to do? I think that's when we really have to have good shared decision making with families, good documentation of those discussions, especially in light of the current AAP recommendations and guidelines.

Ben Courchia, MD (12:30.103)Yeah, I think this data comes to support what the AAP has published, in the sense that it's giving you caution about cooling below 36 weeks. But it's not definitive by any means. And I think that this is where, if you're going to deviate from that, like you said, shared decision making, review of the data with the family, and deciding together is going to be key.

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Daphna Yasova Barbeau (00:09.996)I think we've had an action-packed week, haven't we, of information? But this is a really neat article. It's entitled "Probiotics and Necrotizing Enterocolitis in Preterm Infants After the Food and Drug Administration Warning Actions," in the Journal of Perinatology. Lead author Veeral Tolia and senior author Ravi Patel.

Basically, using the Pediatrix Clinical Data Warehouse, they wanted to look at NEC.

In two ways. They wanted to look at NEC between high-use centers of probiotics and low-use centers of probiotics. And then look at how the incidence of NEC changed before and after the FDA basically prohibited the use of probiotics. We've done a couple episodes on that, if anybody wants to take a listen to that discussion.

Including some things with the NEC Society as well, and people who are international, not in the States, who have continued to use probiotics. Okay, so I think this is exciting because people are asking, how are we going to study probiotics? But this is certainly one way that we are able to do this.

Ben Courchia, MD (00:12.288)It's for sure a clever use of the Pediatrix Data Warehouse. Granted, for disclosure purposes, we work for Pediatrix. But it's true that when this FDA memo came out and it suddenly dropped, the opportunity to have a pre and post dataset that's accumulating in real time was quite nice. I spoke to Veeral about it, and he was telling me that he was looking into this, and I was actually eager to see what the data would show.

Daphna Yasova Barbeau (00:15.759)Yeah. For sure.

Daphna Yasova Barbeau (00:22.16)That's right.

Ben Courchia, MD (00:42.072)Granted, our center was not part of that at that time. Yeah.

Daphna Yasova Barbeau (00:42.32)Yeah.

Daphna Yasova Barbeau (00:48.266)Right, right. When our center became part, when our team became part of Pediatrix, it was after this data collection.

Ben Courchia, MD (00:55.232)Mm-hmm. Though we were using probiotics before the FDA memo came out, in our units. But I do feel like we have a baseline rate of NEC that is quite low, thank God, so I don't know how much significance our data could have contributed.

Daphna Yasova Barbeau (00:59.812)In our unit.

Daphna Yasova Barbeau (01:13.158)So it was a multicenter retrospective observational cohort study of preterm infants discharged from their group of NICUs from October 1st, 2022 through March 31st, 2025. And if you're not familiar with the Pediatrix Clinical Data Warehouse, it is a multicenter clinical database which uses prospective collection of clinical and outcome data. Basically, all of our notes are extrapolated.

Into the clinical database. Okay. In this group, they included all infants 23 to 29 weeks gestation at birth, and they excluded any infants with major congenital anomalies. All right. So it's a short paper, which is lovely. They looked at 17,279 infants.

7,000 infants were pre the FDA warning, and 6,711 were post the FDA warning. They had a washout period of about 3,500 babies. These infants were collected from 347 NICUs. They excluded 24% for major congenital anomalies. This is a pretty high rate of

congenital anomalies. But anyway, the remaining cohort was 10,083 infants, 5,268 pre-warning, 4,815 post-warning. The demographic characteristics were similar. The only significant differences were seen in maternal race and ethnicity compositions and breast milk exposure in the low-use centers. So just to

clarify that. Yeah, I'll tell you. So there was a difference in race and ethnicity. In the high-use centers of probiotics, they had, let's see, for example, fewer Black infants, both pre and post, compared to the low-use centers. They had

Ben Courchia, MD (03:10.67)Yeah, what does that mean?

Daphna Yasova Barbeau (03:36.878)more Hispanic infants in the high-use centers.

Pre-implementation, they had actually the same number of Hispanic families in the post-implementation period. There were slightly more white patients. This is probably not even significant. And then other/unknown, so they had more other/unknown in the high-use centers compared to the low-use centers. And then,

looking at breast milk at discharge, the high-use centers, so high use of probiotics, they had more breast milk at discharge and they had more any breast milk during hospitalization than the low-use centers. But of note, the breast milk at discharge and any breast milk during hospitalization is not different in the pre and post

for high-use centers. Does that make sense? So when we're comparing high-use centers to themselves, there wasn't a difference. It's not like they started getting more breast milk along the way. I think that's important to note.

Ben Courchia, MD (04:50.124)Yeah. High-use centers, you said, are people who use probiotics in more than 80% of the eligible cases.

Daphna Yasova Barbeau (04:58.054)Yes, sorry. Thank you for clarifying that. Okay, so the results. Probiotic use decreased from 86%, so more than 80%, to 6.9% in high-use centers, and from 13% to 0.1% in low-use centers. This was statistically significant for both groups.

That makes sense. If you weren't using a lot of it, you were like, okay, we'll just get rid of it altogether. But a big change, obviously, in those high-use centers. Yeah, it's like a roller coaster. Sure.

Ben Courchia, MD (05:31.0)That graph that shows that precipitous drop, the power of the FDA, right? It's interesting that the publication of a single document. Look at that. This is absolutely insane.

Daphna Yasova Barbeau (05:45.72)Yeah. Wow. Especially when you should acknowledge that many of the therapeutics used in the NICU are not FDA approved in the age group in which we use them. Yeah.

Ben Courchia, MD (05:57.343)Yeah. But what I'm saying is that it's an administrative event backed by a single case. Fair enough, it's not just an administrative event, but wow. Eighty-six to seven percent. Dang it. Okay.

Daphna Yasova Barbeau (06:02.755)A lot of power, yeah.

Daphna Yasova Barbeau (06:10.79)Yeah. So then they looked at the incidence of NEC. The incidence of NEC among infants in high-use centers increased from 2.7% to 4.4% post the warning. And it was pretty constant, 3.6% both pre and post, in the low-use centers. Yeah. So what did that look

Ben Courchia, MD (06:34.654)Use, yeah.

Daphna Yasova Barbeau (06:40.646)like? It really included all NEC. So it went from 2.7% to 4.4%. The medical NEC went from 1.7% to 2.7%, which was not statistically significant by itself. Surgical NEC went from 1% to 1.7%, which again was not statistically significant by itself. They also looked at SIP, so spontaneous intestinal perforation.

Ben Courchia, MD (06:45.559)Yeah.

Daphna Yasova Barbeau (07:08.422)Two percent to 1.6% in the high-use centers, which was not significant. They also did not have a statistically significant change in bloodstream infection or the composite outcome of NEC or death. But for all NEC, there was a statistically significant increase in those high-use centers who decreased their use after the warning.

In the low-use centers, there were no differences for any of the outcomes. There was a, people hate when we say this, there was a trend, a p-value of 0.06, for bloodstream infection, but actually it was 9.7% pre the warning, when they were using more probiotics, and 11% post the warning. So a slight increase there. Okay.

Ben Courchia, MD (07:39.49)Mm-hmm.

Daphna Yasova Barbeau (08:03.494)They then used a difference-in-differences approach to look at NEC. So the pre and post difference in NEC was 1.64% in the high-use centers and negative 0.02% in the low-use centers, for an unadjusted difference of 1.66% with a p-value of 0.044.

The model-estimated difference in differences, so after adjusting for infant characteristics and any breast milk exposure, was 1.18% with a p-value of 0.045. So still statistically significant. And I told you about the differences in medical versus surgical NEC. So they conclude this was a natural experiment involving over 10,000 extremely preterm infants,

and centers that discontinued routine probiotic use following the FDA warning experienced an increase in NEC incidence, while centers with minimal probiotic use showed no change. The clinically important findings suggest that rapid discontinuation of probiotics following regulatory warnings and actions may have had unintended consequences in this population vulnerable to NEC.

Thoughts?

Ben Courchia, MD (09:21.057)Yeah, I think that it's a bittersweet result, right? I feel like the signal is there. There's definitely an increase, specifically for centers that used it more. We were one of those centers that used it more. We were not included in that study, but we are a center that used a lot of probiotics.

Daphna Yasova Barbeau (09:31.694)Agreed. Yeah. You're like, aha.

Ben Courchia, MD (09:48.792)And I worry that people are going to say, 4.4% is still pretty much okay. And they're going to say that's fine. And I don't think that's fine. I'm very worried that this is going to remove an opportunity for excellence, where we were at 2% NEC rates for a network of units, right? That included how many, did you say, in total for this particular

Daphna Yasova Barbeau (10:17.284)Babies, 10,000 babies. Yeah. That's right.

Ben Courchia, MD (10:19.097)10,000 babies, 347 NICUs. That's really good. That's really good. Why can't we do that? And like we said in the episode where we actually discussed the memorandum from the FDA, it's frustrating that there's not a great path for probiotics to return to the NICU. And it's frustrating to see that people around the world continue to use them and we're in a little bit of a holding pattern when it comes to that. So.

Daphna Yasova Barbeau (10:47.918)Yeah, there are studies in other, let's say our neighbors in Canada, where the use of probiotics did decrease their rates of NEC, and so they'll continue to use it.

Ben Courchia, MD (11:01.837)Absolutely. Yeah. So it is what it is. And I don't know whether this is going to move the needle. I hope it does.

Daphna Yasova Barbeau (11:13.2)Well, this is not the only, what's the word, major institution looking at this, right? We have other databases, so hopefully they will look into that as well, and then collectively we can maybe take that information to make change.

Ben Courchia, MD (11:34.435)Yeah. But to answer the question, I think it was both also worrying. It's like, oh my God, it really should show a difference, right? When I was talking to Veeral about this, the question is, what if it doesn't show anything? Then how are we going to interpret that data? So I'm happy that it does show a difference. And I'm happy that it shows a difference in the direction that we physiologically postulated.

Daphna Yasova Barbeau (11:48.347)Hmm.

Daphna Yasova Barbeau (11:51.92)Yeah.

Ben Courchia, MD (12:04.091)So I think that this is where data leaves us and where advocacy picks up, where now it's about us advocating for our babies. So like Ravi had mentioned, and I forget who we interviewed on this, but the data's there. The next step is no longer an RCT. The next step is advocacy.

Daphna Yasova Barbeau (12:13.028)That's right. Well, for the science, weren't,

Daphna Yasova Barbeau (12:31.704)Yeah, and I think it just goes to show that we need everybody, right? All the people doing different types of scholarly work. We can't move forward without all the types of scholarly work, which is interesting. But alas, here we are today.

Ben Courchia, MD (12:37.23)Yeah.

Ben Courchia, MD (12:49.391)All right. We will leave you off now. Tomorrow we'll be back with Neo News. Eli and I are reviewing data on the administration of vitamin K, so a very polarizing topic. Stay tuned for that.

Daphna Yasova Barbeau (12:59.106)Oof. As I present our new vitamin K refusal form this afternoon. That's on me. That's on me.

Ben Courchia, MD (13:05.497)Finally.

Listen, better late than never. So it is much better. Just so you know, now people are going to email you saying, could we see your vitamin K refusal form? So be ready to email that around.

Daphna Yasova Barbeau (13:14.298)I was preparing for journal club, okay? So.

Daphna Yasova Barbeau (13:22.478)When it is official, I will be happy to share it.

----

Eli Cahan (00:01.955)we're going to talk about something that we never talk about on this show, just kidding: vitamin K. A couple of really interesting articles have come out recently on vitamin K and the way in which vitamin K is finding itself, perhaps, in the crossfire

of culture wars. And Ben, this article that you picked was a really interesting kind of article in Pediatrics that was one dose case review, one dose op-ed, and one dose medical mystery. The article describes the case of hemorrhagic consequences, coagulopathy associated with

vitamin K. And after the case presentation, the first line in the next paragraph in this article reads: this presentation of hemorrhagic symptoms should not be a diagnostic mystery, which I find to be quite a striking line. This presentation should not be a diagnostic mystery, because it's basically saying we're in a world now where this needs to always be on your differential.

The article goes on to describe some of the statistics about the difference in risk of hemorrhagic consequences with and without vitamin K. And it says that without vitamin K, the risk of this syndrome occurs in approximately one in 14,000 to one in 25,000 infants. With intramuscular vitamin K prophylaxis, the incidence falls to less than one in 100,000.

They also cite statistics showing that infants who do not receive IM vitamin K are estimated to be about 81 times more likely to develop late-onset coagulopathy. And they go on to describe the place of vitamin K in broader decisions that patients may be making. They say patients who decline intramuscular vitamin K are not making an isolated choice about one intervention.

Eli Cahan (02:23.531)Refusal often co-occurs with refusal of other newborn preventive services, including ocular prophylaxis and the hepatitis B vaccine. The American Academy of Pediatrics has noted that parental objections to vitamin K generally fall into three broad categories: belief systems, infant welfare concerns, and outside influencing factors. And those outside influences can include friends, celebrities, and healthcare professionals.

Ben Courchia (02:50.028)And social media should have been on there.

Eli Cahan (02:52.121)And social media. Maybe celebrities are on social media, but you can define that anyway. The article also cites a recent JAMA study showing that the proportion of infants not receiving IM vitamin K increased from about 2.9% in 2017 to 5.2% in 2024. Exemplary of a bit of a sea change in how people are thinking about immediate postnatal care,

Ben Courchia (02:55.5)Maybe.

Eli Cahan (03:20.635)including the first two interventions that hopefully any healthy baby would get. Ben, what do you make of the trend in the data around vitamin K? What do you make of this really interesting article, and what do you make of the broader conversation around vitamin K?

Ben Courchia (03:36.291)Yeah, thank you, Eli. I think it's a very interesting topic. I think that it's important for us to be up to date on what the data actually shows. So I want to re-emphasize one number that you quoted. The relative risk, obviously, that infants who do not receive intramuscular vitamin K are estimated to be 81 times more likely to develop late-onset vitamin K deficiency compared to those who do. I think that this is a very important statistic for

us clinicians to relay to families. And in terms of when bleeding does occur, so let's say there is some vitamin K deficiency bleeding, then what we really worry about, specifically in the first six months of life, is intracranial hemorrhage. And intracranial hemorrhage occurs in 30 to 60% of late-onset cases, with a mortality rate that can be as high as 20%,

and 40% who suffer long-term neurological injury. So the expected consequences of a stroke, basically. And so I think that these numbers should be memorized. Again, 81 times more likely to develop late-onset bleeding. If you have late-onset bleeding, you have a 30 to 60% chance of having an intracranial bleed. If you have an intracranial bleed, you have a 20% chance of dying, a 40% chance of having long-term

neurological sequelae. All of this could be prevented with one single shot at birth, which to me is staggering. What's very interesting about what you described, the fact that decisions are made in conjunction with other decisions, I think is an interesting one, because this mistrust in the system also sometimes has a halo effect and leads to mistrust, for example, in formula usage. So very often, parents who will refuse

vitamin K will also be parents who will say, we just want to exclusively breastfeed our baby. We're not going to give any formula because formulas contain all these nasty things. And that's one point where, actually, no problem, right? If you want to exclusively breastfeed your baby and you're going to do it well and you're going to provide enough nutrition, then that's great. That's actually a very good decision. But where we often forget is that the fact that you're exclusively breastfeeding is actually a risk factor for

Ben Courchia (06:02.22)developing vitamin K deficiency bleeding. And so it is an interesting scenario in which you're making a bunch of decisions together, sometimes driven by the same motivation. One of them is actually not quite good, about exclusively breastfeeding a baby, but also having a direct amplification factor on your second decision of not giving vitamin K. And I think that this is something that to me is interesting from a decision theory standpoint, where

really, that's increasing the risk of seeing negative outcomes. What I think is also interesting is that you mentioned the trend, right? You mentioned the increase from about 2.9 to 5.2% in the span of what, seven years. I kind of agree with some of the discussion points on this subject that it's probably an underestimate.

Again, the sampling bias of these studies obviously is that you're capturing a lot of hospital births, but it's not clear that this is actually well representative of the current true incidence of refusal of vitamin K. And I am very eager to see the follow-up to this study, because I suspect that there's going to be an inflection point where we're going to find out that it's going to

grow exponentially. I don't know about your experiences as a fellow, but at least for me, covering the nursery, it is routine for us to see patients refusing vitamin K supplementation and injection. And to that point, I also want to mention for all the clinicians out there that when you are seeing patients in the nursery or in the labor and delivery suite, when you are documenting on these patients, there is an ICD code for refusal of vitamin K. And I think that

it's a nice thing to put in the problem list, because it's obviously something that, as these papers mention, you want to potentially leave that thread in for outpatient follow-up and for other people to also keep track of this. Because like you said in the beginning, it should not be a diagnostic mystery. But yeah, it's hard, because we've been trained under the assumption that everybody got vitamin K, and now it's going to be, I have to remember that I have to tease

Ben Courchia (08:27.415)my patients apart, between the ones who did receive it versus the ones who did not receive it. And sometimes it's hard if it's just one sentence in a long discharge summary. But that's why I like this problem list idea, where it's actually on the problem list and you'll remember that and obviously be more aware of it, and make the pediatrician aware of that as well. So these are my thoughts on this subject.

Eli Cahan (08:51.917)Yeah, spoken like a true medical director. It's interesting. When I've seen infants in the follow-up clinic, it's one of those things that if the baby isn't born at your hospital and you have all this challenge getting the baby's records, and maybe it's not on Care Everywhere. If you're on Epic, and even on Care Everywhere, sometimes it's almost impossible to divine where the medications are.

Ben Courchia (08:54.767)[laughs]

Eli Cahan (09:20.341)It's one of those that I feel like I am guilty of, that if I don't see for or against, I assume they got it. And I think if you have no other takeaway from this conversation, I think we need to question that assumption, right? It's kind of like if you're thinking about Haemophilus influenzae in parts of the country where vaccine rates are lower, we just have to keep this on our differential.

And I want to highlight, there was an amazing story on this that just makes plain what denials of vitamin K look like, in ProPublica by Duaa Eldeib, who is a dear friend and wonderful mentor and colleague to me. Duaa wrote about a series of infants who arrived healthy, passed their newborn screens, and in some cases made it to their two-week visits without concern.

Ben Courchia (09:46.639)Mm-hmm.

Eli Cahan (10:15.703)And then, without warning, their systems began to shut down. Sudden seizures in a seven-week-old boy in Maryland. Apnea in an infant girl in Alabama. Vomiting and lethargy in a baby boy in Kentucky. Bleeding around the umbilicus in a Texas newborn not yet two weeks old. These are all cases of vitamin K refusal. And I think the article does a really nice job synthesizing

the conversation in the Pediatrics article, as well as in the JAMA research letter, all of which is to say these conversations have high stakes. It is not the kind of thing where, if the family does refuse on day of life one, we can say, well, as long as that kid looks okay by day of life three, when mom is going to get discharged, then we're out of the woods. Late-onset coagulopathy is a real thing. There are babies

who are dying or suffering very severe morbidity from it. And it is all of our prerogative in the NICU to start having these conversations, and in the newborn nursery to start having those conversations, including that even if the family doesn't get the shot with us, there still may be an opportunity for them to get it at their early discharge clinic or at their next visit. And I think, as the gateways into this system for new families as well as expanding families, this is

unfortunately a trend that we're going to have to pay more attention to diagnostically, and hopefully something that, using communication as an intervention, as we've talked about previously on the podcast, may be a good opportunity for us to own that responsibility.

Ben Courchia (12:00.803)Yeah. And I think it highlights the fact that this is really going to force us as a field to move from a checklist approach, where you say got it, didn't get it, to really having a structured conversation, starting with the obstetricians, where we're going to have to start having discussions and counseling about this very early on, so that it's not something that we address after the baby is born, when the parents have made up their mind. It's a bit more of a structured approach to counseling,

with very clear handoffs between teams, where obstetricians can sign this out, just like they're signing out the gestational age. We can have conversations about that and we can sign this out to the outpatient world as well. So let's see where this takes us. The 5% threshold has been crossed and the graph is not pretty. We'll post that on social media, but yeah.

Eli Cahan (12:50.701)Yeah. By the way, you know what 5% means? One in 20, right? How many babies are in the nursery? We have 40 babies in our NICU. We have 30 in our step down. We've got lots in the nursery. That's like one per early discharge clinic, at least.

Ben Courchia (12:54.799)[laughs]

Ben Courchia (13:07.727)Yeah, that's what I was saying earlier. When you say one in 20 for our nursery, that kind of means maybe one every other day, if you were to do like 10 patients a day. But I feel like I see multiples every day. I think this data stopping in 2024 is going to be staggering when we start accruing 25, 26, and eventually 27, because it feels like it's way more.

Eli Cahan (13:35.885)Yeah, it definitely has not gotten better since 2024. Last thing I'll say, Ben. I love that you commented on the opportunity to start these conversations early. I have a habit now in my prenatal consults of talking about vaccines, especially for these micropreemies. When we're talking about the pulmonary consequences of prematurity, often I find myself talking about the importance of vaccination, both of that child when they're at an appropriate age and appropriate weight, but also of the family. And vitamin K may

Ben Courchia (13:37.751)No, no.

Ben Courchia (13:53.593)Yeah.

Eli Cahan (14:03.575)I think it's a great idea that maybe this is something we should add to our list of things that we're talking about in the immediate postnatal period.

Ben Courchia (14:07.883)Yeah. And then unfortunately, the patients that we get tend to get their vitamin K. I feel like the rates of refusal in the NICU are probably lower than they are in the well-baby nursery. So I think it really is going to be incumbent on the obstetrics world, but we'll see. Why not? They're excellent. So there's no reason why they couldn't get that.

Eli Cahan (14:27.447)Well, we'll keep a pulse on this. Thanks, Ben.

Ben Courchia (14:27.567)All right, Eli. I'll see you next time.

Bye.