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#144 - 📑 Journal Club 56




Hello friends 👋

We have a great episode of journal club for you this week. We talk about feed fortification, magnesium for neuroprotection, car seat testing and much more. We also have a new edition of the EBNEO article of the month commentary this week. We hope you enjoy this episode.

Have a nice Sunday!


 

You can find the articles discussed on today's episode below 👇


Salas AA, Gunawan E, Nguyen K, Reeves A, Argent V, Finck A, Carlo WA.Pediatrics. 2023 Sep 1;152(3):e2023061603. doi: 10.1542/peds.2023-061603.PMID: 37551512 Free PMC article.


Belfort MB.Pediatrics. 2023 Sep 1;152(3):e2023062391. doi: 10.1542/peds.2023-062391.PMID: 37551455 No abstract available.


Crowther CA, Ashwood P, Middleton PF, McPhee A, Tran T, Harding JE; MAGENTA Study Group.JAMA. 2023 Aug 15;330(7):603-614. doi: 10.1001/jama.2023.12357.PMID: 37581672 Clinical Trial.


Braun D, Kaempf JW, Ho NJ, Nguyen MH, Passi R, Burgos AE, Volodarskiy M, Villosis MFB, Gupta M, Habeshian TS, Tam HK, Litam KB, Hong QL, Dong CC, Getahun D.J Pediatr. 2023 Jun 22;261:113577. doi: 10.1016/j.jpeds.2023.113577. Online ahead of print.PMID: 37353144 Free article.


Shah MD.J Pediatr. 2023 Aug 3:113663. doi: 10.1016/j.jpeds.2023.113663. Online ahead of print.PMID: 37541426 No abstract available.


Prasath A, Aronoff N, Chandrasekharan P, Diggikar S.J Perinatol. 2023 Jun 30. doi: 10.1038/s41372-023-01710-8. Online ahead of print.PMID: 37391507 Review.


Kampmann B, Madhi SA, Munjal I, Simões EAF, Pahud BA, Llapur C, Baker J, Pérez Marc G, Radley D, Shittu E, Glanternik J, Snaggs H, Baber J, Zachariah P, Barnabas SL, Fausett M, Adam T, Perreras N, Van Houten MA, Kantele A, Huang LM, Bont LJ, Otsuki T, Vargas SL, Gullam J, Tapiero B, Stein RT, Polack FP, Zar HJ, Staerke NB, Duron Padilla M, Richmond PC, Koury K, Schneider K, Kalinina EV, Cooper D, Jansen KU, Anderson AS, Swanson KA, Gruber WC, Gurtman A; MATISSE Study Group.N Engl J Med. 2023 Apr 20;388(16):1451-1464. doi: 10.1056/NEJMoa2216480. Epub 2023 Apr 5.PMID: 37018474 Clinical Trial.


Proaño A, Flannery DD.Acta Paediatr. 2023 Aug 22. doi: 10.1111/apa.16950. Online ahead of print.PMID: 37608492 No abstract available.


 

This week, we are thrilled to welcome Dr. Dustin Flannery for our monthly EBNEO article of the month commentary written in collaboration with Dr. Alvaro Proaño;





Kampmann B, Madhi SA, Munjal I, Simões EAF, Pahud BA, Llapur C, Baker J, Pérez Marc G, Radley D, Shittu E, Glanternik J, Snaggs H, Baber J, Zachariah P, Barnabas SL, Fausett M, Adam T, Perreras N, Van Houten MA, Kantele A, Huang LM, Bont LJ, Otsuki T, Vargas SL, Gullam J, Tapiero B, Stein RT, Polack FP, Zar HJ, Staerke NB, Duron Padilla M, Richmond PC, Koury K, Schneider K, Kalinina EV, Cooper D, Jansen KU, Anderson AS, Swanson KA, Gruber WC, Gurtman A; MATISSE Study Group.N Engl J Med. 2023 Apr 20;388(16):1451-1464. doi: 10.1056/NEJMoa2216480. Epub 2023 Apr 5.PMID: 37018474


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Follow Dustin Flannery MD on Twitter




 

The transcript for today's episode can be found below:

Episode 144 transcript

[00:00:00] Ben: [00:01:00]

[00:01:00] Ben: Hello, everybody. Welcome back to the incubator. It is Sunday. We've been recording a lot of board reviews. I was ready to say neonatology review as well, but you see, I

[00:01:10] Daphna: And we never know what day it is

[00:01:12] Ben: dead on my track. I had to also remember. Um, yeah. Yeah. So, um, yeah, the reason for that is because we're, if, if you're not, if you're actively following the, um, board review podcast as well, you know that we're in the midst of cardiology.

[00:01:26] Ben: And so recently we decided to enroll our regional medical director, Dr. Rooney Toms to do a bit of cardio review for us. He's like a hotshot of neonatology. He's a neonatologist. He's a Harvard trained cardiologist, cardiac intensivist. And we're like, why are we trying to explain some of these things? When he's,

[00:01:47] Daphna: Maybe you should do the cardiology section.

[00:01:50] Ben: well, interestingly enough, Interestingly enough, we thought we thought exactly that, right?

[00:01:57] Ben: I mean, I think even when we, when I edited the podcast for this [00:02:00] week, at some point you said, really should really be doing this. And then he called me and he said, Hey, if you guys are doing cardiology, I'd love to like chime in and I'm like, say no more.

[00:02:10] Daphna: He read our minds.

[00:02:12] Ben: You're gonna be doing uh some heavy lifting so um, he goes over some very interesting things like things that to be honest with you are kind of things that I don't think about very often like How does the actual pda closes like the mechanism by which the pda closes fascinating stuff?

[00:02:27] Daphna: Super interesting,

[00:02:28] Ben: Very physiologic things as well, which I think when you think about it There's a lot of controversy about the pda but how it closes.

[00:02:34] Ben: I mean When I was listening to him, it's pretty well articulated so I wouldn't be surprised if there were some questions He goes through qpqs in a way. That's very clear. So I was very happy to be Recording with him that day you should I I know you were working that day You should definitely listen to that one when you get a

[00:02:50] Daphna: Oh, I will.

[00:02:51] Ben: it's good and um, he has some slides and stuff So we are recording. Um, we're recording video as well.

[00:02:59] Daphna: Where can, where, [00:03:00] but where pray tell can people find that video?

[00:03:03] Ben: On our, uh, small homey YouTube channel.

[00:03:07] Daphna: That's right.

[00:03:09] Ben: It's just yeah, we're not um, we're not trying to uh be the next mr Beast, but it's just very nice and very easy to upload videos on youtube. It's quite easy actually So yeah, this is why we're

[00:03:19] Daphna: And we are, we're compiling a lot of things there.

[00:03:22] Ben: Yeah, I mean the delphi talks are coming along and delphi 2024 is in the works september Uh 24 is our upcoming date for um for delphi 2024

[00:03:35] Daphna: I got goosebumps.

[00:03:37] Ben: I know we're gonna have we've Delphi.

[00:03:41] Ben: I mean, a lot of people want to want us to put Delphi again next year. So we were doing it. Then the Ted team renewed our TEDx license. So there will be a TEDx event as well. So this will be fun. Yeah, people are reaching out like I'm telling you that have like so many LinkedIn messages that It's [00:04:00] exciting.

[00:04:00] Ben: It's very, very exciting. Um, I'm revamping our website as well. So it should be a lot more info in the coming week or two and next society next week. So, um, stay tuned for that. There'll be a lot of different small episodes of us covering the next society, uh, symposium, um, small episodes talking to some of the speakers who will tell you a little bit what they are presenting about, uh, featured interview.

[00:04:27] Ben: Livestream of the poster sessions, uh, streaming of our interviewing of some of these people at this, at the next symposium. And if you're there, the incubator booth will be there. So,

[00:04:38] Daphna: So come visit.

[00:04:39] Ben: so come visit, but we're still not, um, allowed to escape journal club. So, uh, let's, uh, without, yeah, without, uh, further ado, let's begin journal club. Um, we have an ebneo commentary of Uh a commentary on the article of the month that we have this this [00:05:00] month with dustin Flannery from from chop So that'll be coming up later in the episode. But for now um, I guess I wanted to start with a paper that Has caused a lot of discussion, especially for us internally.

[00:05:13] Ben: I mean, we're always trying to, um, optimize the way we do things and, and there's been a lot of talk about, um, feeding and protocols and so on. So, uh, this paper caused a lot of discussion within our team. It's a, it's a paper published in pediatrics, Salas.

[00:05:33] Ben: And uh, it's called early human milk fortification in infants born extremely preterm a randomized trial The first author is ariel sallas as we say last author is wally carlo who was at delphi this year Whose talk will be released about the future of neonatal ventilation Uh will be released on youtube very soon.

[00:05:54] Ben: Um, this was um a trial that they actually called the [00:06:00] impact trial, so i'll get into that but The background section is actually very interesting, right? So Um, I'm going to go through a few of these things because the way the study was designed. is not something that, um, we see every day in a very typical University of Alabama fashion, where they're very sophisticated in their study designs.

[00:06:20] Ben: But what they're mentioning is that the first two weeks after birth really delineate a period of great opportunity to both prevent energy and protein deficits in babies that are admitted to the NICU, especially preterm infants born before 28 weeks of gestation. And it is during this critical period for growth and development that the provision of protein enriched, protein enriched human milk diets could prevent nutritional deficits and mitigate the effect of acute critical illness on the risk of adverse growth outcomes in these infants.

[00:06:49] Ben: Now, they're saying in their, um, in their background that a sufficient intake of protein during the first two weeks could increase protein synthesis, prevent excessive weight loss, and promote [00:07:00] growth. And then they introduced this concept of fat free mass, which is referenced throughout the paper as FFM.

[00:07:07] Ben: And fat free mass basically Accounts for muscle bone brain and other tissues built on the protein matrix a protein enriched human milk, uh Diet is then believed that if you I mean, it's believed that if soon after birth you you have a protein enriched human milk diet You could favor ffm accretion fat free mass accretion and What is the point of thinking of FFM is that a lot of observational studies have shown that FFM gains lower, may lower the risk of long term complication, such as neurodevelopmental impairment, obesity, and chronic diseases in these infants.

[00:07:46] Ben: It's not completely surprising when you understand now that fat free mass is muscle, bone, brain, and other tissues that really make a huge difference when it comes to these long term outcomes. But there's not, [00:08:00] um, any trials as far as they're reporting that have talked about early human milk fortification on fat free mass accretion.

[00:08:08] Ben: The question the group is asking is, does a human milk diet fortified with human milk based product soon after birth increase fat free mass accretion in infants born extremely preterm. And the question is I mean, again, I am not, I'm sure that if Amy hair or mystical read this paper, they get that question right away.

[00:08:29] Ben: To me, it's a bit confusing. It's like, what, what are you trying to do? But as we go through the study design, you will understand what, uh, what the group was trying to do. So this is the impact trial increased milk protein to accrue critical tissue trial. And this was a parallel group masked randomized control trial with a one to one allocation ratio.

[00:08:50] Ben: The intervention was masked to the clinicians, to the parents, and the outcome evaluators. They included babies that were born before, uh, at 28 weeks [00:09:00] of gestation or less, and that were admitted to the neonatal unit at the University of Alabama at Birmingham Hospital. They excluded infants with major congenital anomalies and infants with terminal illness whom the decisions to withhold or limit life support had been made, um, prior to, um, prior to them being enrolled.

[00:09:19] Ben: What was the intervention? So the intervention is something that we need to go over slowly so that you can understand what they're trying to do. Extremely preterm infants fed human milk were randomized within the first 96 hours of life to receive either a fortified human milk diet, that was the intervention group, or an unfortified human milk diet, that was the control group.

[00:09:42] Ben: So what does that mean, fortified, not fortified? What does the fortification schedule look like? So in the intervention group, these infants received unfortified maternal or donor milk on feeding day one. On feeding day two, which by the way, the feeding day one is the feeding day one of this study. So within the [00:10:00] first 96 hours after birth.

[00:10:02] Ben: On feeding day two, A human milk based fortifier that increases the energy and protein content of human milk was added. In this case, the human milk based fortifier that was added was ProLacta. If you are familiar with that brand, that's the one they were using. Adding this product to human milk increased their caloric density from.

[00:10:23] Ben: 20 kcal per ounce to 24 kcal per ounces and increase their protein content by approximately 1. 2 grams per deciliter. And this practice of fortifying the feeds with prolacta on day two continued until the day when a standard, when a standard bovine based human milk fortifier was ordered. So these kids in the intervention group were fortified with human milk, um, fortified with prolacta until they transitioned to a bovine fortifier.

[00:10:53] Ben: In the control group, these infants receive maternal or donor male confiding day one. until they [00:11:00] were ready to transition to a bovine milk fortifier, which was like, um, the human HMF. So this, this control group never got the human milk, the human milk based fortifier. Now, what does the feeding protocol look like at UAB?

[00:11:16] Ben: So the feeding protocol in their unit recommends the early administration of colostrum. And i'm going some of these things are obvious, but I think As we're going to go through the results You want to know like are they doing things in a crazy way that doesn't apply hard to extrapolate and stuff So that's why it's important to go through this they administer enteral feeds, uh intermittently via bolus gavage every three hours.

[00:11:38] Ben: The initiation of enteral feeds with either maternal or genomic via orogastric tube is done within the first 96 hours after birth with 20 to 25 per day. They progress by increasing every day by 20 to 25 per day until full enteral nutrition is established, which is defined as Reaching kilo per day, and [00:12:00] you have the addition of bovine based fortifier that happens at approximately postnatal day 14 after that full enteral nutrition has been established.

[00:12:08] Ben: So once they reach 120, they get off TPN and they get to the, to the bovine HMF. Daphna, any questions about anything we said so far?

[00:12:17] Daphna: Now, I think, I mean, like you said, knowing, feeding protocols are similar, but not identical. So it's nice to know the background information. So really, the thing they're looking here is early fortification, basically, there is, which is new to the community.

[00:12:35] Ben: Yeah. And we'll, and we'll see a little bit what the impact of that study has on, on how we practice. And I think, like you said, it's important to go through all these TDS details, because if you go and you say, Oh, the, in the intervention group, the advanced defeats by five ML a day, it's like, duh, like that doesn't.

[00:12:50] Ben: Okay. So that's why it's important to show that it's fairly similar to what we are all pretty much practicing.

[00:12:55] Daphna: I mean, I think what was also neat about this study is it was like. Super clean. [00:13:00] The groups were super clean, which is uncommon in feeding studies. We see a lot of, uh,

[00:13:06] Ben: The the the the The thumbprint of dr Wally carlo if you haven't listened if you haven't listened to the interview that we did with wally carlo. He is a Methodology nut right? He's like I read all the books and i'm fascinated by all so I don't think you can Have a study published with him as the last author without everything being as you said very clean

[00:13:27] Daphna: Very clean. No, I agree. And um, I don't think you mentioned it, but that was episode 40. Dr. Wally Carlos interview with

[00:13:35] Ben: Thank you for that. So what are the, some of the outcomes that they looked at the primary? So they had the primary efficacy outcome, which was the fat free, uh, mass for age Z score at 36 weeks, postmenstrual age or hospital discharge, whichever came first. And they measure that using air displacement plethys ismography, which is if you've ever heard of the peapod, right?

[00:13:56] Ben: That little thing that measures, um, fat free mass. That's what the, that's what [00:14:00] they were using. Now. Body composition measurements were performed at 36 weeks or hospital discharge, if an infant no longer required significant respiratory support with mechanical ventilation, continuous positive air pressure, or high flow nasal cannula.

[00:14:14] Ben: I'm mentioning this because it's excluding a very interesting population from the primary outcome. They had a safety outcome, which perforation, necrotizing enterocolitis stage 2 or 3, and, um, Secondary outcomes based, uh, there was secondary efficacy outcome, and that included significant weight loss during the first 14 days after birth, weight gain velocity in grams per kilo per day from birth to 36 weeks, postnatal growth failure, moderate to severe malnutrition.

[00:14:47] Ben: F f m and kilogram and percentage at 36 weeks, uh, fat mass and kilogram and percentage at 36 weeks, and anthropometric measurements at 36 weeks p m a. So let's look at some of the results. So they [00:15:00] randomized 150 infants, and of those 31 had a gestational 3,100 gestational age of 23 weeks or less, which represented about 21% of the population.

[00:15:11] Ben: The mean birth weight was 795 gram, and the median gestational age was 26 weeks. Almost 90% of infants were exposed to at least one dose of antenatal steroid, and more than 80% of infants who participated in this trial achieved full enteral nutrition within the first two weeks after birth. So these are some of the baseline stuff, because of that exclusion criteria that I told you where they could not measure if some of the respiratory, uh, milestones had not been met, the primary outcome was measured in 105.

[00:15:41] Ben: Of the 150 infants randomized, which is 70% of the original cohort. What did they find in these a hundred, these 105 infants, the fat free mass for age Z score did not differ between the groups, interestingly enough, when they looked at, um, growth [00:16:00] parameters, length gain velocities from birth to 36 weeks, postmenstrual age were higher in the intervention group.

[00:16:06] Ben: So in the babies that were fortified early on. Decline in head circumference for HZ score from birth to 36 weeks were less pronounced. in the intervention group as well. So, in terms of these measurement outcome, the babies who got fortified did better. The risk of postnatal growth failure and the risk of moderate to severe malnutrition at 36 weeks were not significantly lower in the intervention group.

[00:16:31] Ben: Looking at some of these safety outcomes, uh, the risk of sip neck death and the combined outcome of sip neck or death did not differ between the groups. There were four cases of NEC. None of these four cases occurred during the transition from human based to bovine based fortifier. Two infants unexposed that were not exposed to bovine based fortifier developed NEC before reaching full enteral feeds.

[00:16:54] Ben: And the other two developed next several weeks after exposure to bovine based fortifiers. [00:17:00] Um, some of the, the conclusion of the trial are that it reveals that a human milk diet fortifying soon after birth in infants born extremely preterm does not increase fat free mass secretion at term equivalent, but that early provision of, uh, fortified human milk within the first 96 hours after birth may increase, may increase, I'm sorry, length, gain velocity and reduce declines in head circumference.

[00:17:27] Ben: from, uh, for ages, these scores from birth to 36 weeks. Now the there's a, there's, there's a lot to be said, and that's why I'm sort of going through the results a little bit quickly, because I think you can go over some of these other things and we can tease apart the table, but the discussion is what's interesting.

[00:17:43] Ben: So the authors are outlining a few of the limitations of the study, which I think is very honest from their standpoint. And I'm going to mention two of them. They're saying, obviously that. The primary outcome, as we said, is not assessed in the sickest of infants, right? Because if you are still sick at [00:18:00] 36 weeks and you're on respiratory support Then you don't get to get your fat free mass measured which is likely also The group that is is most likely to benefit from the intervention.

[00:18:09] Ben: So that's that's obviously a big limitation And the other limitation is that the trial is not sufficiently powered, powered to assess the potential harms of human, early human milk fortification in a single center, center study design. And so before I go into the discussion, uh, from the authors, there's a very nice commentary that's written in pediatrics by Mandy Belfort, which.

[00:18:35] Ben: We wanted to invite for this episode and and just life got in the way we couldn't we couldn't make it happen But she she writes a few things that are very interesting number one She says that this trial the impact trial reports a common sense approach to enteral nutrition Which is that rather than the typical practice of feeding unfortified milk Until the infant reaches full volume or nearly full volume.

[00:18:57] Ben: You can start human milk fortification early [00:19:00] on enteral feeding day two I think, right? Um, where you can see that this is feasible. The other thing that she's mentioning is that early fortification resulted in less weight z score decline during the intervention, as well as faster linear growth and less head circumference z score decline, suggesting better overall growth quality, which is something that we mentioned in the, in the results.

[00:19:23] Ben: They do mention, he does mention that rigorously designed and implemented studies are still needed to directly compare early fortification with human versus bovine HMF in terms of effectiveness, safety costs, et cetera, et cetera. But she's mentioning that for NICUs. that are already using human HMF. The study offers a potential strategy to shorten the treatment duration and lessen the cost by switching to bovine at 120 ml per kilo per day, rather than continuing it for longer.

[00:19:53] Ben: And I thought that was such a, an astute point because it's almost as if she was in our division meetings where we're [00:20:00] using a lot of human milk fortifier and a lot of. We're getting some backlash from the hospital about the tremendous cost that this, um, that, that this engenders on, on our, on our, um, on our babies that, that are on it for, for weeks, especially our smallest infants.

[00:20:16] Ben: And so, um, that study then, as she says, can provide a bit of a framework as to where you could still use it with a, an expiration date on it, where. You can say all right at that point. I don't really need to continue it and it's safe to uh to transition the last point I want to make that one and then I can I give you the mic because I don't have much more to Say is In the discussion, Ariel and his team are mentioning that to them, what this, this finding implies the, the, the finding that about the fat free mass and the growth is that, um, the observed differences in weight length and head circumference following human early human milk fortification, um, it really shows you that there, at least I thought that was a very scientific conclusion.

[00:20:57] Ben: That's why I wanted to mention that at least it's not related. [00:21:00] to fluid intake, that with the same amount of fluid, they're getting the same amount of fluid, but it's likely the early provision of additional enteral protein and renal solutes such as sodium, chloride, calcium, and phosphorus, while establishing full enteral nutrition that are, that are responsible for these benefits.

[00:21:18] Ben: So, um, Yeah transitioning to bovine hmf at 15 days of life appear to be air safe Starting human milk fortification a day of life to appear safe as well And might provide a good framework if your budget is limited Then you're not sure exactly how to balance the two. I thought that was a very interesting study

[00:21:38] Daphna: Yeah, I mean, to your, to your last point, I mean, every time we look at nutrition studies, right, the earlier we can get extra nutrients like protein, you know, we see benefits for sure. I think if you don't take anything away from this, you know, other than [00:22:00] like we, we see these, you know, inferences on an end of one where, oh, we fortified and some, the baby misbehaved, right.

[00:22:09] Daphna: Um, you know. I think it at least could give people some confidence that, you know. It's, it doesn't, it's probably not the fortifier, there might be something else going on, um, with the baby. The other thing, if in our unit part of your protocol is weight based, like when you reach a certain weight, in addition to gestational age, that's when you move from one product to another, um, well, maybe you, maybe you will be able to transition sooner regardless because of improved, you know, growth over that early, um, Period.

[00:22:45] Daphna: Which I think is, is interesting. Obviously we just reviewed this over the summer, is that improved growth velocity, um, has improved, you know, neurodevelopmental outcomes. So.

[00:22:59] Ben: that's, that's, that's what [00:23:00] I wanted to get to is that there's, it's, it's easy, it's the path of least resistance is not to fortify.

[00:23:06] Daphna: Yeah. Just to ride it out.

[00:23:08] Ben: you're always where it's like, oh man, let's, let's not fortify right away. Cause if the baby misbehaves, you, you feel like all the gains are going to be lost.

[00:23:15] Ben: Cause it's like, Hey, we made it. We're like at a hundred ML and, and we're almost there. And now I'm going to add the fortifier and the kid's belly is going to blow up. And now everybody's going to be concerned. We're going to go back. And you, you, you have this doomsday scenario in your head. And I think it's great for this study to show if you don't fortify these kids their growth will take a hit.

[00:23:33] Ben: And, and, um, and sometimes It's difficult for us. Um, I love this cognitive bias of what you see is all there is, right? It's like the if you see it you're by you you you're biased by it But if you don't see it, it's almost as if it doesn't exist But this paper does put it in your face of like if you don't fortify it has consequences.

[00:23:52] Ben: Um, and so yeah

[00:23:55] Daphna: more. More to discuss at division meeting, as they say

[00:23:59] Ben: Oh boy, yeah, we're [00:24:00] not done with that

[00:24:02] Daphna: Well, thank you for that. That's a good, I was, we have been waiting for that paper to come out,

[00:24:07] Ben: There was an embargo. I've had that paper. I spoke to Ariel about this paper because I knew he was working on this study. And so we were chatting with one another. I says, when is that study result? And then he's like, well, it's in, it's published. It's just, there's an embargo until I think August 8th.

[00:24:20] Ben: So I've had this on the journal club folder and I couldn't review it until today. So

[00:24:26] Daphna: Hot, hot off the presses.

[00:24:28] Ben: that's exactly right.

[00:24:30] Daphna: Okay, um, I had another, uh, article that's been, you know, uh, had some buzz on Neo Twitter. Um, prenatal intravenous magnesium at 30 to 34 weeks gestation and neurodevelopmental outcomes in offsprings. This is the magenta. trial. Um, the lead author Carolyn Crowther, um, for the Magenta Study Group.

[00:24:52] Daphna: So the question really was, does administration of magnesium sulfate at 30 to 34 weeks gestation to pregnant people reduce [00:25:00] death or cerebral palsy at two years? This was a multi center,

[00:25:04] Ben: uh, the famous mag for neural protection, basically.

[00:25:06] Daphna: that's right, that's right.

[00:25:07] Ben: So this is like, this is literally putting that on in the, back on the, uh, back on the, on the center of the, of the table. Like we're, we're wondering if mag for neural protection actually does provide neural protection.

[00:25:20] Daphna: Yeah, of note, we'll talk about the dose, right? Um, so, we'll get there, but yes.

[00:25:26] Ben: Okay.

[00:25:27] Daphna: Um, this is a multi center randomized clinical trial. It was conducted at 24 Australian and New Zealand maternity hospitals, um, and it was So participants, staff, investigators, and assessors of the children at two years were blinded to the treatment allocation.

[00:25:44] Daphna: Um, pregnant individuals were included if they were at risk of preterm birth between 30 and 34 weeks, uh, that they were experiencing a singleton or a twin pregnancy. Um, the birth was planned or definitively expected within 24 hours of recruitment and there were no contra indecree, [00:26:00] contraindications. And these are maternal respiratory depression, hypotension, absent patellar refluxes, kidney failure, myasthenia gravis. Um, they were also, um, ineligible if they were getting, um, magnesium for the treatment of preeclampsia. Um, eligible individuals were randomly assigned to the MAG group or to the placebo group using a telephone randomization service and they did a number of stratifications, um, by hospital site, by gestational age, so they did 30 to 31 weeks and 32 to 33 weeks, and by number of fetuses, singletons, or twin pregnancies.

[00:26:37] Daphna: And so the intervention was magnesium sulfate, a 4 gram bolus. or placebo, administered intravenously for 30 minutes. Um, and otherwise, the care was per protocol at the individual site. Um, but of note, this did not include a, um, what do they call it? [00:27:00] This was like a load, the loading dose. But there was no, uh, continuous, MagSulfate.

[00:27:05] Ben: Maintenance?

[00:27:06] Daphna: Maintenance. Thank you. That's, that's the word. Oh god. I have no excuse.

[00:27:13] Ben: I'm the one who pulls call!

[00:27:14] Daphna: come. The words did not come to me. Okay, so that was the intervention. Um, they obtained any clinical data from the hospital records and then surviving children were assessed by a pediatrician, um, using the third edition of the Bailey's.

[00:27:32] Daphna: scales, and again, I told you they were looking specifically for cerebral palsy, um, and so a diagnosis of cerebral palsy required loss of motor function and abnormalities of muscle tone and power, uh, with gross motor dysfunction classified, uh, using the gross motor function classification system. They also used caregiver surveys for a kind of more comprehensive evaluation.

[00:27:58] Daphna: So the primary [00:28:00] outcome was death, which was defined as stillbirth, death of a live born infant before hospital discharge, or death after hospital discharge but before two years corrected age, or cerebral palsy. So death or cerebral palsy was the primary outcome. They had a boatload of secondary outcomes.

[00:28:19] Daphna: There were 36 secondary outcomes that assessed the health of the pregnant individual, the infant, and the child. Uh, the secondary outcomes for the infant during the birth hospitalization included a composite serious health outcome score that was counted as present if any of the following occurred, stillbirth, death of a live birth, infant, Uh, before hospital discharge, severe respiratory distress syndrome, severe IVH, grades three and four, chronic lung disease, by definition dependent on oxygen at 36 weeks postmenstrual age or 28 days after birth if born after 32 weeks, proven neck, um, so diagnosis at surgery or postmortem or radiographic [00:29:00] diagnosis with a clinical history plus pneumatosis, portal venous gas, or persistently dilated.

[00:29:06] Daphna: loop, severe retinopathy prematurity, or cystic PVL. And then, so that was the composite score, they also evaluated the comorbidities independently. So I think those are of the most interest to our listeners, but they also had a variety of secondary outcomes for two years of age for the child and a variety of secondary outcomes for the pregnant participant.

[00:29:28] Daphna: Um, so between 2000, January, 2012 and February, 2018, um, they randomized and enrolled 1, 433 pregnant people and, uh, that included 1, 679 infants alive at entry. There, uh, were 51% or 858 infants randomized to MagSulfate and 704 or 50. Sorry, seven in under four individuals, mothers, 49% or 821 [00:30:00] infants randomized to placebo.

[00:30:02] Daphna: Uh, the mean age of the participants was 30. 6 years, um, and they give us some other, uh, demographic data. But overall, the two groups were similar at trial entry. Almost 95% of participants in each group received the allocated treatment. Of the 1, 679 infants at randomization, 40% were born at 30 weeks gestation to less than 32 weeks gestation, 55% were born at 32 weeks gestation to less than 34 weeks gestation, and 5% were born at 34 weeks gestation or later.

[00:30:37] Daphna: There are 1, 660 children eligible for the two year follow up. And in general, um, for the infants at the two year follow up, the baseline characteristics were similar at trial entry, um, for that follow up population. So, for the primary outcome of death or cerebral palsy at 2 years, this occurred in [00:31:00] 3. 3% of children in the magnesium group and 2.

[00:31:02] Daphna: 7% of children in the placebo group. Um, a risk difference of 61 or adjusted risk ratio of 1. 0. One, nine, and not statistically significant. In the sensitivity analysis, using data from all the sources, the pediatrician, uh, the, the psychologist, the caregiver questionnaires, and the caregiver, it included one additional case of cerebral palsy, um, reported by the parents, um, but overall, um, this did not change, uh, the statistical significance.

[00:31:34] Daphna: There were 12 deaths by two years corrected age in the magnesium group versus seven deaths in the placebo group. This is a risk difference of 0. 48 or risk, uh, adjusted, um, risk ratio of 1. 5. There was no between group differences in the proportion of children who had cerebral palsy, 1. 6 percent in the magnesium group versus 1.

[00:31:57] Daphna: 7 percent in the [00:32:00] placebo group. For the other childhood outcomes at two years corrected age, there were no significant between group differences for death or neuro or any neurologic disability, death or any major neurologic disability, any of the individual neurosensory impairments, or the distribution of the severity of neurosensory disability.

[00:32:22] Daphna: And then they looked at them stratified. So for children born at 30 to 32 weeks gestation, the rate of death or cerebral palsy at two years was 3. 3%. Um, the 32 to 34%, uh, was, uh, 3. 4% and 0. 8 in the greater than 34 week groups. Interestingly, children exposed to magnesium are more likely to have overall behavioral scores within the clinical problem range, 10% compared with children in the placebo group.

[00:32:54] Daphna: 6%. Um, at two years of, sorry, and this was [00:33:00] statistically significant. At two years, there were no significant between group differences for body size, blood pressure, use of health services, or respiratory morbidity. For the secondary outcomes occurring during the birth hospitalization, neonatal respiratory distress syndrome was less likely in the magnesium group, 34%, um, versus 41% in the placebo group, uh, adjusted risk ratio of 0.

[00:33:24] Daphna: 85, and this was statistically significant. The number needed to treat was 21. Chronic lung disease was also, uh, less common in those, uh, babies in the magnesium group, 5. 6% versus 8. 2%. Adjusted risk ratio of 0. 69. The number needed to treat was 37. There were no significant between group differences in any of the other secondary outcomes.

[00:33:50] Daphna: There were no serious cardiovascular respiratory adverse outcomes from the study infusion. Um, But there were some adverse events that we [00:34:00] frequently see in mommies getting, uh, magnesium. And they were obviously more likely in the magnesium group compared with the placebo group. And magnesium was more likely to be discontinued than the placebo.

[00:34:12] Daphna: Fewer individuals in the magnesium group had a cesarean delivery. Um, No between group differences were seen in the indications for the cesarean delivery. There were no between group differences in the risk of postpartum hemorrhage or need for a blood transfusion. However, more participants in the magnesium group had a major postpartum hemorrhage.

[00:34:33] Daphna: So overall, the study takeaways, um, were that administration of IV magnesium sulfate prior to preterm birth at the 30 to 34 weeks gestation did not improve child survival free of cerebral palsy at two. years.

[00:34:52] Ben: Sorry, it was muted, um What I mean, I think this sort of shifts the the criteria. No, what [00:35:00] do you think about that?

[00:35:02] Daphna: Uh, you mean what would be our, what is our threshold for, uh,

[00:35:07] Ben: I I think yeah, I think it moves the needle towards using this in um before 30 weeks

[00:35:14] Daphna: Yeah, it's interesting, right? We saw something similar with, with, uh, beta methasone, right? Uh, the antenatal steroids in this kind of closer to late preterm group.

[00:35:26] Ben: Because you also want to believe that, um, we, we, we have come a long way when it comes to, um, the care of these newborns, where hopefully unless there's something else going on, cerebral palsy in a baby that's born at like 32 weeks, you hope that our rates are now much lower. Um, and so maybe that makes, that makes sense overall.

[00:35:49] Ben: No, I mean, that's, that's the, yeah,

[00:35:52] Daphna: Yeah, that's the goal, right? And we, we will do whatever we can to try to make that happen. It's, it seems way easier to give [00:36:00] things. prenatally than postnatally or to make decisions about those things. But I think these are important studies. Um, I, the only thing of note again, is that, you know, the, the current regimen for fetal neuroprotection is the loading dose of four grams, um, followed by one gram per hour maintenance dose.

[00:36:18] Daphna: So, you know, there's some debate in the community if we, would we see something differently if we, we had the different, Regimen,

[00:36:27]

[00:36:45] Ben: Okay. All right. Um, should we um, we are um doing the article of the month, we're gonna Cue the jingle for our ebneo commentary. So here it goes.

[00:36:59] [00:37:00]

[00:37:16] Ben: Dustin Flannery, thank you very much for making the time,, to be, with us this

[00:37:23] Dustin: Thank you so much for having me today.

[00:37:26] Ben: You are, uh, an assistant professor and attending neonatologist at the Children's Hospital of Philadelphia at the University of Pennsylvania. You're a clinical researcher studying perinatal infectious disease. You are very active on Twitter.

[00:37:37] Ben: You're a great follow if people are still coming on the platform. Um, and it's, and it's, uh, it's great to, uh, finally have you on the podcast. I met you for the first time at ESPR not too long

[00:37:49] Dustin: Yes, that's right, up here in Philadelphia. It's great to finally meet in person all my Twitter friends.

[00:37:54] Ben: That's right. That's right. It felt, it felt always, it's always very weird. I saw you, we saw each other and it's like, we know [00:38:00] each other, but it's yet, we still haven't met, we're meeting for the first time.

[00:38:03] Ben: So it was, it was an interesting experience, but, uh, I can attest that, uh, you are just as nice as you are on Twitter. So, uh, people should not be afraid to approach you when they see you at conferences.

[00:38:12] Dustin: you so much. Yes,

[00:38:14] Ben: Thank you.

[00:38:14] Ben: Dustin, you're here to discuss with us a very important article that came out in the New England Journal of Medicine. Not too long ago, the article is called Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants. And there's a lot of talk about RSV vaccines these days.

[00:38:34] Ben: Um, and I guess usually we'd like to start off by Asking our our guests to maybe summarize the paper But I think we were talking off air about this. There's this paper comes after a long history when it comes to Uh rsv vaccination. Do you want to go? Do you want to go over that a little bit before we dive into the paper?

[00:38:55] Dustin: it's so important to understand the context of this [00:39:00] study and related studies with the history of RSV vaccine. But I have to preface this conversation in full disclosure. I am a neonatologist. Yes. I do study, um, infectious diseases and neonates, but I'm not an infectious diseases expert. I'm not an immunologist, a vaccinologist, a virologist, an obstetrician, or a trialist.

[00:39:23] Dustin: So I'm very happy to weigh in on this study, which I think is super, super exciting. But I definitely need to give that disclosure.

[00:39:32] Ben: We appreciate that dustin, but with that being said, uh, the floor is yours

[00:39:36] Dustin: All right, Ben. So we know that RSV infects nearly all Children before they turn two years old. It's a leading cause of pediatric hospitalization and pediatric deaths worldwide. Um, and each year, more than three million Children get admitted to the hospital for RSV. And more than like a hundred thousand die from severe RSV [00:40:00] infection.

[00:40:01] Dustin: And you know, this is a neonatal based podcast. We know that children born preterm, those with certain health conditions, they're at the highest risk for severe RSV infection. Um, and from a financial standpoint, RSV in the U. S. Alone cost more than 1 billion per year. And so clearly this is important. A vaccine that could prevent or minimize severe infection from RSV would have a really serious impact.

[00:40:30] Ben: And we've all done pediatric residency, so we all remember when RSV season begins and you're in the ER, you're on the floor like this and or in the PICU, this is, this is, this is a very scary time for us because RSV is, is, I mean, we have symptomatic management and it's, it's not always successful. So I think, I think I can speak on behalf of all of us when we remember those days of, uh, RSV season in the pediatric floor and, and, and these.

[00:40:55] Ben: These were not

[00:40:56] Dustin: Yes, absolutely. And even in some, uh, you know, intensive care [00:41:00] units, including my own, um, The hospital becomes so overburdened with RSV and other respiratory infections during the cold season that we actually admit many of these babies to the NICU, especially the former preterms with apnea or require mechanical ventilation.

[00:41:16] Dustin: But let's talk a little bit about this. It's really disheartening history of RSV vaccines. So RSV was discovered in the fifties and pretty soon after a vaccine using an activated form the virus was developed and tested in multiple trials. Um, but really concerning these trials showed that young children who were naive to the virus, meaning they had not been infected before, um, who received the vaccine.

[00:41:45] Dustin: They really had an enhanced response when exposed to the virus. Um, instead of a decreased response, they had a much higher risk of hospitalization related to RSV and tragically, two toddlers in these studies died. Um, [00:42:00] and so this really halted RSV vaccine development for quite some time.

[00:42:06] Ben: So you're saying that they, they, they got that initial vaccine back in the sixties and they actually did worse, uh, when, when infected with

[00:42:15] Dustin: Correct. Um, and one, one article I read cited that. 80% of Children who got the vaccine and had never been exposed to RSV required hospitalization when they received or when they were exposed to the virus. So you know, this is a really scary part of vaccine science. You know, you create vaccines to prevent serious infection and bad outcomes.

[00:42:40] Dustin: But when the vaccine actually is contributes to worse outcomes, that's just really scary for the field.

[00:42:48] Dustin: But fast forward a few decades, scientists now have a much better understanding of this virus's structure, specifically, this pre fusion form of the F protein. Uh, has become a [00:43:00] target for more modern vaccines. Multiple RSV vaccines targeting this pre fusion F protein are in development, including the bivalent Pfizer vaccine in this, uh, Kampmann trial we're going to discuss today.

[00:43:14] Ben: Mm hmm.

[00:43:15] Dustin: And so, um, I'd like to start with a PICO question, uh, when I think about randomized trials. You know, I love randomized trials because on paper they seem so straightforward. They ask specific questions, specific exposure, specific outcomes, and the statistics aren't so complicated, unlike some of these observational studies we do, where we try to adjust or account for all of the things, uh, that we can't replicate in a trial.

[00:43:41] Dustin: Um, and so this, this trial is fairly straightforward, of course. You know, every study is a bit complicated. I was, uh, browsing through the supplement. It's over 400 pages long, uh, the protocol on the supplement. So, um, we'll just kind of get right into the PICO question here. So they asked in pregnant women at [00:44:00] 24 to 36 weeks gestation.

[00:44:01] Dustin: Does a single intramuscular injection of a bivalent, and by bivalent they mean RSV A and B, pre fusion F protein based vaccine compared with a placebo decrease the risk of medically attended severe RSV associated lower respiratory tract illness by medically attended. They just mean you required, um, interaction with the medical field or a medical provider.

[00:44:29] Dustin: And they have pretty clear definitions of what they mean by severe RSV based on symptoms and respiratory support requirement as well as admission to the ICU. They also, um, as a second primary outcome. Ask the same question, but for medically attended, non severe, uh, RSV associated lower respiratory tract illness.

[00:44:53] Dustin: Um, this gets a little bit confusing when you're just reading the article quickly because they don't say, uh, severe and non severe. They just say [00:45:00] severe and then, uh, just medically attended.

[00:45:03] Ben: Yeah, you have to keep track of when it says severe or not. That's true. I got, I got myself, uh, tracking back several times. They're like, wait, what were they talking about?

[00:45:09] Dustin: Yes, I almost wish they just labeled it as severe and non severe because it can get a little wordy and confusing. Um, and so this is an interim analysis. This was a phase three, double blind, one to one allocation, randomized, placebo controlled trial. And this was done in 18 countries over four RSV seasons in two hemispheres.

[00:45:33] Dustin: Um, and they included 73, 92 healthy pregnant women. Again, who were between 24 and 36 weeks gestation at the time of injection with vaccine or placebo. They looked at two, um, they looked at two primary outcomes, again, medically attended severe RSV associated. lower respiratory tract illness, [00:46:00] and then medically attended non severe lower respiratory tract illness.

[00:46:04] Dustin: Um, and this interim analysis, uh, reports on these outcomes at 90 and 180 days after birth. So, so three and six months. And for these endpoints, uh, they use their sample size calculations, um, to come up with, uh, a lower boundary of the confidence interval. greater than 20% as their definition of meeting success criterion for vaccine efficacy.

[00:46:29] Dustin: They also had a couple of secondary and exploratory outcomes, which I won't get into detail here. Um, but importantly, they also included safety data, uh, adverse event data for both the pregnant women and the infants. So what were the results? Um, the maternal and infant demographics and clinical characteristics were pretty similar between the two groups.

[00:46:52] Dustin: Um, about half of the women, uh, were enrolled in the United States. Uh, that was the country with the highest enrollment. [00:47:00] South Africa was number two median maternal age, 29 years and the median gestation at injection. was 31 weeks and three days, which is important. And we'll talk a little bit about more later.

[00:47:13] Dustin: Um, two thirds of the women were white and nearly all the 94% were born at term gestation and had a five minute Apgar score. greater than six. So again, this is an interim analysis, and the reason is because the data monitoring committee recommended early trial termination because the success criterion was met for the first primary outcome, medically attended severe RSV associated infection at both 90 and 180 days after birth.

[00:47:45] Dustin: For the other primary outcome, the non severe the statistical success criterion was not met. Um, there were similar incidences of maternal adverse events and infant adverse events in both groups. Both were low. Um, [00:48:00] importantly, 11 safety end point that gets highlighted a lot in in the lay media is that five per 6% of births in the vaccine group group.

[00:48:10] Dustin: We're at less than 37 weeks compared to 4. 7% in the placebo group. So this is about a 1% difference, not statistically significant. Um, and we'll talk about why that is still of some concern. Um, and so they concluded that the results of this trial, which importantly was sponsored by Pfizer, uh, suggests that maternal RSV vaccine.

[00:48:35] Dustin: could really be a game changer in prevention of severe pediatric RSV disease across the globe. Um, and just back in May, a U. S. FDA advisory committee voted in support of approval for Pfizer's uh, pre F RSV vaccine during pregnancy in order to provide infant protection. And the vaccine is currently under review by the FDA and we expect some more information really any day [00:49:00] now.

[00:49:02] Ben: Thank you for reviewing for reviewing the article. Um, you wrote a very nice commentary for the ebneo team that will be available in acta pediatrica. And I am wondering what is your main takeaway from this paper as a, as a clinician? Um, I think, I think that's, that would be that your input is quite, is quite valuable when it comes to that.

[00:49:26] Dustin: Sure. I think my main takeaway is again, related back to the context here, the reality that a maternal RSV vaccine could soon be licensed any day now after more than half a century of research. And this is just really particularly remarkable in context of that really disappointing and tragic RSV vaccine history.

[00:49:50] Ben: What do you think is going to be, um, the approach? And I think we're stepping outside of our jurisdiction here when we're talking about the administration of the [00:50:00] vaccine, um, and regarding the timing, considering the efficacy end points, uh, of the trial, looking at, let's say 90 days, 180 days, I think. Right.

[00:50:14] Ben: I think that that would put probably a certain, uh, apply certain window as to when the, the pregnant individuals could be, could be potentially vaccinated.

[00:50:23] Dustin: Yes, absolutely. Uh, really an important issue to resolve is the optimal timing of vaccine administration during pregnancy. We very well know that infants born at the lowest gestational ages are at the highest risk for severe RSV disease. And so they may not benefit from maternal vaccine if it's And, you know, given routinely late in the third trimester.

[00:50:47] Dustin: Um, and so even in this trial, uh, the vaccine was administered between 24 and 36 weeks. Uh, but it takes about two weeks to really develop an, uh, robust immune response in the pregnant woman. [00:51:00] Um, and then we know that, uh, really the, uh, the highest antibody transfer occurs during the third trimester. Um, and so it's a little bit unclear how this vaccine could benefit babies born at lower gestation.

[00:51:15] Ben: I have a suspicion that it's probably going to start later in pregnancy and that our preemies are probably going to suffer from, from our just. From our lack of knowledge at this point, and eventually it will, as usual, trickle back down to the preemie. So as we, as we understand it better and it's, and it's sort of a phase four post marketing type of situation in term and late preterm, then we'll, we'll try to see how could that affect our, our preemies and what are the effects in terms of immunity over, over how long.

[00:51:45] Ben: And, and I think what I'm trying to say, I guess, is that we, we most likely will continue to see data being published on this subject specifically.

[00:51:53] Dustin: I think you're absolutely right. And again, the median gestational age at injection was [00:52:00] about 31 weeks. And so again, that would not benefit our youngest babies born, you know, much earlier. Um, and so I think you're right that, uh, That it's possible that if the vaccine is given a little bit later, it will still have a huge impact because since most babies are born term, uh, most babies who develop RSV infection are in fact term.

[00:52:22] Dustin: And so there will still, I think, be a huge benefit, but we'll need to think more carefully and do more research to figure out how we can benefit our tiniest babies.

[00:52:33] Ben: You mentioned something in your review of the article that, um, obviously, I think is going to be, sadly enough, will probably be a huge point of discussion, which is the slightly increased rate of premature delivery, uh, in the vaccine group. And if people are interested and, and the, um, the paper will be available, uh, the link to the paper will be available on the, on the website, but you can look at figure four.

[00:52:55] Ben: And I think it's in, uh, it's in, it's in, um, It's, uh, [00:53:00] rectangle B on the on figure four, where you can clearly see that it's not statistically significant, but obviously it's always the same. It's a bit of noise, and it's not clear whether this there's a signal there. Um, do you think that component of the results of this study will dominate the public discussion?

[00:53:18] Ben: Or do you feel reassured based on the data that that there's most likely nothing there?

[00:53:23] Dustin: Yeah, it's a really interesting question, and it is something that the public has sort of latched on to, as well as some of the experts. If you read the testimony, uh, and the articles, um, about the FDA advisor discussions, uh, there, there are some, some vaccinologists and infectious disease experts, uh, who are very worried about this.

[00:53:43] Dustin: And I think it's... stems from the fact that there was a similar signal regarding an increased incidence of preterm birth reported in the GlaxoSmithKline RSV vaccine trial back in 2022. But a couple of things I want to mention here. First, [00:54:00] the proportions of preterm birth in both arms of the current study were much lower than the overall U.

[00:54:05] Dustin: S. preterm birth rate. And so we looked at CDC statistics data from 2021. Again, which overlap with this study. And the preterm birth rate in the U. S. is 10. 5%. And so when you look at the preterm birth rates in the two groups, 5. 6% in the vaccine group, 4. 7% in the placebo group. So both significantly lower than the national rate.

[00:54:31] Dustin: And so, you know, what do we make about this 1% difference? I personally don't feel too alarmed about this, but I also don't think it can be ignored. Especially in light of the GlaxoSmithKline, uh, earlier data. But something else that needs to be discussed is an important limitation of this study. They only included healthy pregnant women.

[00:54:53] Dustin: And so pregnant women at high risk were excluded. There's a long laundry list of what conditions that [00:55:00] includes, uh, but it definitely includes women who are most likely to deliver preterm. And so how do we interpret these results in context of that?

[00:55:11] Ben: I think it's going to circle back to our initial question, which is as we're figuring out when to give the vaccine, we'll probably solve that problem by just giving it maybe at 34 weeks and, and really making the risk of, of preterm delivery less of an issue when you're delivering closer to 35, 36, rather than if you're delivering at 32 weeks, when it's still quite significant, despite especially considering us and other developed countries, very good outcomes for these babies.

[00:55:37] Ben: So I think it'll be interesting to see how, um, The inclusion criteria for for or the recommended inclusion criteria for the vaccines are are being laid out. And also, um, how does the timing, uh, could potentially resolve, uh, resolve this

[00:55:52] Dustin: Yeah. Absolutely. And just two more comments about the timing issue. One is just because a vaccine [00:56:00] becomes available during pregnancy and is approved and found to be safe doesn't mean pregnant women will accept it. Um, and, you know, I think we have a higher acceptance of vaccine during pregnancies ever since the H1N1.

[00:56:14] Dustin: epidemic and obviously the COVID 19, uh, where pregnant women are becoming more willing to accept vaccination or in pregnancy, but rates for both of those vaccines are still quite low. Also, uh, we need to understand the dynamics. of interactions with other vaccines administered during pregnancy. Um, a recent study suggested that co administration of the pre F RSV vaccine, as well as Tdap, led to a reduction in the pertussis component antibody response uh, when uh, compared to just Tdap alone.

[00:56:48] Dustin: And, and so these are things that need to be sorted out as we develop optimal maternal vaccination strategies.

[00:56:55] Ben: Going a bit further beyond this paper. I think what's also going to be [00:57:00] interesting is, um, are going to be the recommendations when it comes to this to this specific vaccine in light of the recent, um, FDA approval of the nirsevimab for young infants. And I think now that we have multiple prongs of approaching and preventing RSV, how will these work in tandem or not?

[00:57:21] Ben: Um, I'm, I'm going to be curious to, uh, to see what happens. Do you have any thoughts as to what do you, what, what the future holds in terms of our approach to preventing RSV, whether it will be more towards the maternal side with the paper that we just discussed, or maybe just, Trying to vaccinate infants earlier on to prevent severe disease in the first couple of months of

[00:57:40] Dustin: Yeah, it's a really interesting question, and I'm excited to see how this pans out over the next decade, you know, after many years of only having one potential strategy, which is the Synagis, which is expensive. which really limits the patient population who, uh, [00:58:00] can, uh, receive it. It's also requires monthly injections.

[00:58:04] Dustin: We know that compliance is quite low. And so, uh, really it's, it's sort of fascinating that all in the same time period, uh, now we're, we're starting to have additional strategies. And so, like you mentioned, the FDA just approved, uh, Bayfortis or Nercivumab, Allop, Uh, for the prevention of RSV in neonates, uh, during their first RSV season.

[00:58:27] Dustin: And this is just a one time monoclonal antibody injection, and so really may be advantageous over surfactant. And so, uh, clearly now there's a market for RSV prevention. We have different, uh, prongs that we can use, and it may just, uh, need to be an individualized approach.

[00:58:45] Ben: That's right. That's right well, it looks like this is going to be a topic of discussion in the coming weeks and months and years and We we thank you for coming on the show and to the ebneo team for publishing this this great commentary We'll make it [00:59:00] obviously available on the episode page and they're always available obviously on the acta piatrica website Dustin, thank you for making the time to be with us today.

[00:59:09] Ben: Best of luck.

[00:59:10] Dustin: Thank you so much for having me.

[00:59:11]

[00:59:13] Ben: Okay, that was great. I think Um the article of the month for october which we'll look at Another vaccine, which by the way, you said you were going to talk about that statement from the AP.

[00:59:25] Ben: Um, maybe that's the right time now that we've done the Um ebneo commentary um Is going to be dustin will come back with karen popolo. So that's very exciting

[00:59:39] Daphna: All right. Do you want me to do it? Hold on. I have to find it.

[00:59:41] Ben: yeah, yeah, you can. But basically, right, I mean, while you queue up the statement, there's

[00:59:46] Daphna: Yeah, I'm gonna find you the whole, the whole statement,

[00:59:48] Ben: there's been a whole, there's been a lot of discussions about the newly approved RSV vaccine. And I know that we as a unit have had, like, conversations [01:00:00] about, like, who do we give it to? Uh, what's the recommendation?

[01:00:05] Ben: And is there like is there some time where we're going to have to wait before we use it and so on and so forth But uh the ap sort of put an end to all that discussion and came out with Uh a recommendation, um, which is pretty straightforward. I mean, do you

[01:00:18] Daphna: I have it right here. Thank you for the reminder. I did say I wanted to, to review because it was released just this, uh, the 15th of August. Um, and like you said, it's looking at the long acting monoclonal antibody nircivimab. And, um, it, the AAP recommends a single dose of nircivimab. I'm going to learn to say it,

[01:00:40] Ben: Near

[01:00:41] Daphna: nersevumeb for all infants younger than 8 months born during or entering their first RSV season and infants and children aged 8 through 19 months who are at increased risk of severe RSV disease and entering their second [01:01:00] RSV season.

[01:01:02] Ben: Right.

[01:01:04] Daphna: So I agree, pretty straightforward.

[01:01:07] Ben: Yeah, just give it,

[01:01:08] Daphna: Just give it.

[01:01:10] Ben: just give it.

[01:01:11] Daphna: Um, but yeah, I mean, the recommendation is out there. So now it will be a scramble to who can get it done.

[01:01:19] Ben: Yeah, which is interesting because, um, I think there's been, there, there has been a, um, a reduction of the threshold to move forward with vaccines. So for example, our healthcare system has like a whole process, um, to approve medication, right? Which once they become available, there's like a process, which makes sense.

[01:01:40] Ben: But now you have these recommendations that come out and they're like, yeah, it's approved, go. And. Yeah, I think institutions will have to adjust to implementing and distributing these medications pretty fast after they're approved, um, because they have a dramatic impact. So, uh, yeah.

[01:01:58] Daphna: I think the, I'm [01:02:00] hopeful, right, that everybody can get it. But at least for our high risk population, that it will be... Less of a, less of a burden to get it for the high risk population, which it sometimes still is, you know.

[01:02:12] Ben: I hope so. Okay. I have another very, I have, I'm, I'm blessed with some very cool articles this week. The paper I found in the journal of pediatrics is called discontinuation of car seat tolerance screening and post discharge adverse outcomes in infants born preterm.

[01:02:29] Daphna: I, you have also been awaiting this paper.

[01:02:31] Ben: Oh, yes. So I'm going to try to pace myself here.

[01:02:36] Ben: First author is David Braun, and this is a paper from a group out of California. So the background is very interesting. They're talking about the range of assessments that we utilize to determine readiness for discharge. Such as postnatal age. We check that they have no apneas. We check that they're able to feed.

[01:02:55] Ben: And they're mentioning how since 1991, the AAP has recommended that for preterm infants, they have to [01:03:00] undergo car seat tolerance screening. And it's not really formally been evaluated for. efficacy. It was recommended as a quote, practical attempt to reduce the frequency and severity of cardiorespiratory events experienced by infants born preterm seated in car safety seats and to minimize potential neurodevelopmental sequelae.

[01:03:22] Ben: So since then, there are some studies that have been done in hospital and hospitals using car seat testing that have raised a range of questions about individual aspect of the car seat testing elements. There's no real study that has compared utilization of car seat with non utilization of car seat on the rate of post discharge adverse outcomes.

[01:03:43] Ben: And people are questioning whether we should still be doing this. And I think we reviewed a paper not too long ago by Eric Jensen that even addressed that question, but. In 2016, the Canadian Pediatric Society withdrew its recommendation for [01:04:00] CAR C testing. In 2020, uh, an article by Davis and colleagues discussed the need for additional AAP guidance to decrease the variability in CAR C testing screening and to facilitate effort to understand if it's clinically important.

[01:04:14] Ben: In 2022, there's, there are two institutions in the U. S. that reported that they no longer utilized. car seat testing. And in a survey of hospitals performing car seat testing, the response to the question, is the car seat tolerance screening a good way to assess cardiorespiratory readiness for discharge in at risk infants?

[01:04:35] Ben: The answer was yes, in only 39% of cases. 45% said they were unsure and 26% of people said no. There was another, which is not, it's not wrong. Another physician survey reported that 66% agreed with the statement that CAR C testing was medically necessary and 58% did not have sufficient equipoise to support a randomized control trial of CAR C [01:05:00] testing.

[01:05:00] Ben: So with that, the group

[01:05:04] Daphna: But that being said, 2016 was a long time ago for our, our friends who already made the decision in Canada.

[01:05:12] Ben: Yeah, well, well, you'll see that our friends who are publishing the paper were not that far off. So the Kaiser Permanente South, Southern California, uh, group has 4. 7 million members, socioeconomically diverse, uh, and they have an integrated healthcare system and they basically discontinued car seat testing on infants born preterm since December, 2016.

[01:05:33] Ben: After a thorough little I'm quoting here, by the way, thorough literature review and provider discussion. And so this system wide practice change gave them the opportunity to assess the impact of car seat testing discontinuation on post discharge adverse outcome And so I had heard about this that they no longer do car seat testing And it's funny because kaiser is so big that I had heard they don't do it in california anymore Which i'm sure doesn't reflect the [01:06:00] all of california but yeah, so They did a retrospective cohort study that included all the infants that had a gestational age of less than 37 weeks, i.

[01:06:09] Ben: e. that were born preterm, uh, born to patients who received pregnancy care and delivered at one of the 14 hospitals managed by the Kaiser Permanente healthcare system between 2010 and 2021. They excluded the infants who died during the admission, obviously, and who were discharged from other hospitals.

[01:06:25] Ben: The infants were classified as two things. They were either quote unquote NICU admissions, which means that they spend some time in the NICU or they were non NICU admissions, which means they got their care in the nursery or postpartum area. The exposure of interest was the hospital level discontinuation of CAR C testing utilization.

[01:06:41] Ben: This was followed. By and I think that's important obviously to mention because they didn't just stop willy nilly. This was followed by a broad anticipatory guidance initiative, standardized nursing training, and associated educational material for educating parents and caretakers on the safe use of the infant car seats.

[01:06:59] Ben: Instruction [01:07:00] included minimizing unnecessary travel by car and avoiding the use of car seat as a bed for infants outside. The car the primary outcome of interest was the composite the composite rate of infants with any of the following events in the 30 days that followed discharge and we're talking about discharge from the birth admission that was Death number one, 911 call triggered transports, meaning needing emergent transport from they said either home residence or quote unquote, any scene.

[01:07:31] Ben: And they looked at readmissions associated with diagnostic code grouping for respiratory disorders, apnea, apparent life threatening illness of brief unresolved, unexplained. events. They stratify the primary outcome as well by gestational age categories and by NICU admission, whether the kids were in the NICU or not.

[01:07:51] Ben: Um, you can read more about the, the, the methodology, but let's get into some of the results. So the final sample size after they apply all the exclusion criteria was [01:08:00] 41, 264 infants. There's two study periods, right? There's the car seat epoch, and there's the. No longer needing car seat epoch. Um, across those two study periods, 49.

[01:08:12] Ben: 9% of the infants were admitted to the NICU and When you read this at face value like holy moly, are they admitting 49? But remember 49 of all the babies born before 37 weeks So you're hoping that like you're 35 36. Maybe they're they're born. They're fine. They go to nursery So the high admission rate remember it's we're not including the full terms in that because they don't need car seat testing the number of infants discharged by the hospitals assigned NICU levels where they had 513 discharged from level ones which are pretty much like nurseries 7, 527 from level twos and 33, 000 from level three slash four.

[01:08:50] Ben: Um, patient level car seat test rates were 49. 4% in, uh, the car seat [01:09:00] testing period and 0. 1% in the discontinuation period. So it's quite interesting to see, um. The variation where basically the graph at some point all hospitals just stop using the car seat test and yeah So anyway, the unadjusted post menstrual age and postnatal age at discharge did not change significantly between the two epochs So it's not like kids got like yeah If they started suddenly discharging their kids much earlier and then suddenly they had more issues with readmission Maybe that could be the cause so I think it's important to mention that didn't really didn't really matter didn't change when they discharged these kids.

[01:09:39] Ben: Among those receiving car seat testing, 3. 4% failed their initial car seat tests. So let's get to some of the key results. There were no statistically significant differences between the car seat test screening and discontinuation periods in the adjusted odds ratios of any of the adverse outcomes that were studied. [01:10:00] Um, again, these outcomes were death, 911 call triggered transport and readmissions. Um, The unadjusted rates of the primary outcomes in the total study were 1.02% in the car seat testing screening group, and 1.06% in the discontinuation group, so really not even close. There was no statistically significant differences that were found in the unadjusted rates, crude ORs, and adjusted ORs of the primary outcome stratified by gestational age or NICU admission status when comparing carc testing and discontinuation periods. Another interesting result among the individual components of the primary outcome So looking at each one separately the unadjusted rate of death in the discontinuation period was significantly lower than in the car seat period so actually death, uh went down from Point one point one two percent to [01:11:00] point zero two percent.

[01:11:01] Ben: So if anything And that was sort of uh That was, uh, that was significant in the, uh, in the unadjusted, uh, analysis. No statistically significant differences were observed in other unadjusted rates, or any of the components adjusted ORs comparing CAR C testing versus no Car Seat testing. The, the conclusion of the paper are that After this healthcare system discontinued CAR C testing in infant born preterm, 30 day post discharge adverse outcomes did not increase, now, in the spirit of the choosing wisely initiative, the value of the CAR C testing as a standard pre discharge assessment for all infant born preterm deserves further evaluation and research. And, I don't know why this is the week of commentary.

[01:11:43] Ben: So there's a nice commentary as well written by Malika Shah in the Journal of Pediatrics. And she's published on the impact of CAR C testing. And so, you know, it reminded me when you submit a paper for review. And the findings go slightly [01:12:00] against what one of the reviewers has already published about Like you wonder like is it worth resubmitting?

[01:12:05] Ben: I'm dead in the water so Dr. Shah actually, um writes a very nice commentary and she says that the conclusion have to be interpreted with caution for several reasons Right because I have to say I read this paper and I went on call and I was like we should stop it I'm

[01:12:23] Daphna: You're like, yes.

[01:12:25] Ben: yeah because right How many failed the car seat test and you're like What am I supposed to do with this?

[01:12:33] Ben: You just keep them in the hospital a bit longer you repeat it until they pass and it's like It's it's it has a significant burden. Anyway, so what dr Sean is saying is that the study does not give any details regarding the unit submission criterias nor describe the standard practicing and monitoring period for discharging an infant with a history of apnea for example So you don't know for what I guess for example if their units We're discharging kids after a [01:13:00] Brady and apnea already said that was a monitoring period of 15 days Yeah, then yeah, maybe they don't have a lot of post discharge outcome But if you're using a three day watch then maybe it's you you cannot apply it.

[01:13:10] Ben: So I think that makes sense I was just giving these as an example, obviously, uh, she was, she's saying how, uh, without clarity on the care received by the infants in the studies, results cannot be attributed to the discontinuation of the car seat tolerance test or generalized to other population. She's referencing, I guess, one of her paper that showed how nearly one half of the infants born between 34 and 36 and six who failed their infant car seat tolerance test in the newborn nursery had apnea of prematurity.

[01:13:41] Ben: In the supine position, and the, and I guess what she's hinting at is that there are some kids that just go through their admission unnoticed. They're sort of late preterms. You don't really look at them too often. You know, like they don't, they don't force you to gravitate towards their bedside, [01:14:00] like a 20.

[01:14:00] Ben: Too weaker, right? Uh because they're fine. But but are they though like could you unmask something? And I think that's a very astute point that she's that she's making she's saying how the the number of calls made to 9 1 1 both during and after the car seat study period are Small and the calculation of statical statistical significance may be vulnerable to small deviation In the observed number of outcomes and though she said no individual individual gestational age group reached statistical significance in the study It's notable to see that for infants born between 34 and 36 and six, it almost approached significance. She's saying how more than 70 percent of infants born premature are born in the late preterm period Many are cared for in the well baby nurseries with little additional attention outside of routine newborn care And she's saying that the author's conclusion that physicians should reconsider routine infant carc testing has the greatest implication for these infants who often receive no cardiorespiratory monitoring outside the [01:15:00] CAR C test tolerance test during the birth hospitalization.

[01:15:02] Ben: This continuation of the CAR C tolerance screen may adversely affect this often overlooked population, and it is premature to do so. So I have to say after reading that you're sort of, it's, it's, it's throwing a bit of cold water on the whole, uh, on the whole fire. But, uh, what an interesting conversation.

[01:15:21] Daphna: I mean, it's just a really good reminder that the late preterm is not a full term infant. That's what, that's my takeaway. What do we do about the car seat test? I don't know. But that the late preterm is not a full term infant.

[01:15:36] Ben: I Think um, so I've been thinking about this since um, I finished reading the the the I finished reading the commentary last night, but the my my takeaway from this has been do we need to be a bit more? Deliberate about who do we want a car seat testing on and not just like 36 and sick car sick You must have a car seat test,[01:16:00]

[01:16:00] Daphna: Yeah. I

[01:16:00] Ben: And and maybe

[01:16:01] Daphna: It's not just um, it's not just acuity, right? It's time spent in the NICU So I think probably some of these kids just cycle in and out their short quote unquote short stays So they didn't even have enough time to uh, reveal themselves

[01:16:17] Ben: It's that's exactly what the commentary is saying how much of a of a sample do you have to even to even look at that And so I think that's that's super interesting

[01:16:25] Daphna: Yeah, I think it's it's interesting right that they weren't seeing this It's approaching significance in the smallest babies, which are the babies that we most worry about. But because we've had this time to watch them, we aren't putting them in the car seat test till they've already like done their, you know, their countdowns.

[01:16:43] Daphna: Um, and some of these kids never got a countdown and, and, and, and right. Do we pick them up in the car seat testing? Yeah. It's an interesting point. For

[01:16:52] Ben: Yeah.

[01:16:53] Daphna: Okay.

[01:16:54] Ben: Alright. Okay.

[01:16:55] Daphna: Do we have time for one more? Okay. At this one, uh, we'll wrap [01:17:00] up my discussion on, on MagSulfate today. Uh, this is in the Journal of Perinatology, Antenatal Magnesium Sulfate and Adverse Gastrointestinal Outcomes in Preterm Infants, a Systematic Review and Med Analysis.

[01:17:13] Daphna: Um, lead author Arun, uh, Prasath. So the question is, does antenatal magnesium increase the risk for adverse GI events? And they want, they asked three specific questions. Is there an association between antenatal mag sulfate and adverse gastrointestinal outcomes like neck, sip, feeding intolerance, time to reach full feeds, and GI related mortality in the preterm infant?

[01:17:37] Daphna: The second, in extreme preterm, less than 28 weeks and very preterm infants, less than 32 weeks, does the administration of antenatal magnesium have any adverse GI outcomes? So by Covid stratified by gestational age. And thirdly, is the association based on the different types of indications of MagSulfate like neuroprotection versus preeclampsia or [01:18:00] tokalysis.

[01:18:02] Daphna: Um, so they found, uh, in the system, systematic review, randomized or quasi randomized clinical trials and non randomized. reported GI related morbidities, um, when mother's of preterm infants were given mag sulfate for either neuroprotection, tokalysis, or preeclamsia. They excluded, uh, studies that did not report pre specified neonatal outcomes, um, or, That was pretty much it.

[01:18:29] Daphna: And then they used preterm infants whose mothers did not receive antenatal mag sulfate, uh, as the control group. The outcomes that they wanted to look at was, uh, necrotizing enterocolitis greater than or equal to, uh, stage two neck using the Bell's staging criteria, surgical neck, those needing surgical intervention, uh, a sip, spontaneous intestinal perforation, feeding intolerance.

[01:18:58] Daphna: Quote unquote as [01:19:00] defined by authors time to reach full feeds using a minimum of 150 mLs per kilo per day and Quote unquote GI a related mortality mortality thought to be related to neck or sip as reported by the authors They had a final total 44 articles including six randomized control trials and 38 non randomized studies eligible for the final meta analysis since we're short on time, I'll just get into the primary outcomes.

[01:19:28] Daphna: So,

[01:19:28] Ben: your time. I don't,

[01:19:29] Daphna: take your

[01:19:30] Ben: yeah, we're not rushed.

[01:19:33] Daphna: You say that, but you are forgetting our time, our time situation.

[01:19:39] Ben: true. Because I look at how much we've actually recorded, which is like 55 minutes. And I forget that we have to splice in the, the

[01:19:45] Daphna: That our listeners have been listening for longer than 50.

[01:19:49] Ben: I know, but the content is just so good. Okay.

[01:19:51] Daphna: Okay. Uh, so for medical neck greater than, uh, greater than equal to stage two reported in 40 studies involving [01:20:00] 51, 000 infants, the pooled effect estimate favored the magnesium sulfate group, but was not statistically significant between the two groups in non randomized studies, um, or randomized control trials.

[01:20:14] Daphna: For surgical neck, it was reported in five of the 44 studies involving 29, 000 infants, the incidence of surgical neck was significantly lower in the magnesium sulfate group compared with controls. Uh, there was no significance, uh, for infants less than 32 weeks, which was, um, was specified in three studies.

[01:20:35] Daphna: CYP was reported in eight out of the 44 studies. Uh, this included 34, 000 infants. Antenatal exposure magsulfate did not increase the incidence of CYP in preterm infants. For the subgroup analysis, uh, there was no difference, uh, between, uh, the groups in the less than 30. For time to reach full feeds, um, this was reported in eight of the [01:21:00] 44 studies, involved 3, 258 infants.

[01:21:04] Daphna: I told you full enteral feeds were defined as a minimum of 150 cc's per kilo per day. And there was no difference in time taken to achieve full feeds. Feeding intolerance was reported in three out of the 44 studies. This involved 414, um, infants, um, and no difference in feeding intolerance. GI related mortality was reported in only one study.

[01:21:28] Daphna: study and there was no statistically significant difference between the two groups. Uh, and this include in, this included, uh, the group stratified by gestational age. And they did these secondary outcomes. They had a sensitivity analysis performed separately for all studies, including infants less than 32 weeks of gestation.

[01:21:49] Daphna: And 17 studies, uh, including 10, 000 infants were analyzed. The incidence of medical NAC was similar among the MAG sulfate group as compared to controls. [01:22:00] Um, studies that use MAG sulfate for neuroprotection alone, 13 studies were analyzed and neuroprotection or preeclampsia, five studies were analyzed separately.

[01:22:11] Daphna: Both analyses did not show any statistical difference between the two groups, uh, by indication for MAG.

[01:22:20] Ben: Okay.

[01:22:21] Daphna: For the outcome of SIP, um, they looked again at the pre term infants and studies that used MagSulfate for neuroprotection, a total of three studies used it for neuroprotection and seven studies for less than 32 weeks were included and, uh, there was no difference between the two.

[01:22:38] Daphna: groups. For other indications like tocalysis and pre eclampsia, there were not enough studies available for meta analysis. Um, and then for outcome of time to reach full feeds with the subgroup of infants less than 32 weeks, um, and studies that used MagSulfate for neuroprotection showed no difference between groups.

[01:22:56] Daphna: So the overall study takeaway is that there [01:23:00] The study does not support any clear association between antenatal magnesium sulfate administration and adverse gastrointestinal morbidities or GI related mortality in preterm infants. Um, this does come up, I think, clinically when, when you're like, the baby got a lot of mag sulfate, the magnesium is really high, what do

[01:23:19] Ben: up a little bit clinically, you're saying it comes up all the time.

[01:23:23] Daphna: Daily. Daily comes up daily. So, so I mean, I think maybe it, may I'm in a play devil's advocate. Maybe it's not a problem because we are slower to feed the babies who received mag sulfate, but they did this balance measure of the time to full NRL feeds. Obviously it wasn't, um, done in all of the papers that the time to full NRL feeds so.

[01:23:47] Daphna: So. I, I don't know what to say.

[01:23:51] Ben: I am baffled, by the way, because I, I mean, I don't [01:24:00] know, I don't, I don't, I don't know what to make of this, to be honest, because I, I do, I do some random stuff when it comes to medical. Let me give you a glimpse as to my medical practice when a baby has been exposed, has been exposed to

[01:24:13] Daphna: gonna lay it all out there,

[01:24:14] Ben: Yeah, but I mean, I don't know what to do.

[01:24:16] Ben: I look at I try to trend a little bit the mag level I try to find out if the baby has stooled like I want to And I want to corroborate that with my exam

[01:24:25] Daphna: what, right, what, is, are there vowel sounds? Yeah,

[01:24:29] Ben: Exactly. I have this, I have this number that I don't know where it came from. That like, if a mag level is less than 2. 5, it's sort of okay. And that if it's above 2. 5, it's not okay. I think this was either residency or fellowship. I don't remember, but that's sort of ingrained in my head. And then if you're, if your mag level is 2.

[01:24:44] Ben: 3 and you're pooping, then I'm okay. Right. So I don't really have a good system and. And I do, and I'm, I don't know if I, I was not expecting to see this, um, from this paper specifically when they're saying that like [01:25:00] the incidence of surgical next is actually lower. It's like, are you kidding me? I mean, I think there was one case

[01:25:07] Daphna: re, I had to re read it a few times.

[01:25:10] Ben: right, 'cause you're like, am I, am I reading this correctly?

[01:25:12] Ben: Is that going to change clinical practice and am I going to feed aggressively a kid? That's on me that has received a lot of magnesium that has a magnesium level of like 4. 5 God knows it's very hard, but I have to say it's it is the highest level of evidence that we can have right? Um It has it has a large number of studies, right?

[01:25:33] Daphna: And a lot of babies.

[01:25:35] Ben: A lot of babies. So I guess it's going to take me a few readings, but

[01:25:42] Daphna: I thought it was all so interesting. I was glad that they did it by... indication though, the studies for different indicate, you know, the studies size, the number of studies for each indication of why you got magnesium sulfate are different, right? Because is your [01:26:00] risk factor different because you were exposed to preeclampsia and you got magnesium?

[01:26:05] Daphna: Or, you know, or is it different because you're preterm and you're infected and you got magnesium? So So, you know, we talk about, you know, what, what predisposes babies to, to certain risks, but I guess MAG as a whole may, may not be to blame.

[01:26:26] Ben: We'll see.

[01:26:27] Daphna: We'll see.

[01:26:28] Ben: That's not right. I shouldn't say that. I shouldn't say it's a freaking meta analysis. I don't know. Anyway, very, it's a, we're going to pose this paper and you're all going to go dissect it and you'll let us

[01:26:38] Daphna: Tell us what you think. Yeah.

[01:26:40] Ben: Exactly. All right, Daphna. I think this is now really all we have time for today.

[01:26:45] Ben: Um, For our audience member look out on our youtube channel. We release new videos of the delphi conference every week um, and We will have we'll continue to post Neonatology [01:27:00] review content every other week and we look forward to seeing all of you at the neck upcoming neck symposium So with that have a good rest of your day everybody

[01:27:10] Daphna: Bye.

[01:27:12] [01:28:00]


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