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#037 - 📑 Journal Club 18

NICU journal club the incubator podcast

Happy New Year 🎉

We are kicking off the new year with a great selection of articles. In this week's episode, we review the OPTIMIST-A trial and discuss whether minimally invasive surfactant treatment will eventually replace InSurE. We also discuss two interesting papers about early markers of gut injury in anemia and how a baby's sex influences the appropriate threshold for blood transfusion. Finally, we reviewed a paper from 🇸🇪 that studied how eye tracking technology and testing done at four months corrected GA can predict ADD and cognitive outcomes at 6-7 years of life.

Enjoy this journal club and let us know if you have any feedback or recommendations.

As mentioned during the episode, Dr. Keith Barrington's blog post summarizing the various trials discussing transfusions thresholds in nicu babies is so well written and summarizes the evidence so well, that it is worth sharing:


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

Effect of Minimally Invasive Surfactant Therapy vs Sham Treatment on Death or Bronchopulmonary Dysplasia in Preterm Infants With Respiratory Distress Syndrome: The OPTIMIST-A Randomized Clinical Trial. Dargaville PA, Kamlin COF, Orsini F, Wang X, De Paoli AG, Kanmaz Kutman HG, Cetinkaya M, Kornhauser-Cerar L, Derrick M, Özkan H, Hulzebos CV, Schmölzer GM, Aiyappan A, Lemyre B, Kuo S, Rajadurai VS, O'Shea J, Biniwale M, Ramanathan R, Kushnir A, Bader D, Thomas MR, Chakraborty M, Buksh MJ, Bhatia R, Sullivan CL, Shinwell ES, Dyson A, Barker DP, Kugelman A, Donovan TJ, Tauscher MK, Murthy V, Ali SKM, Yossuck P, Clark HW, Soll RF, Carlin JB, Davis PG; OPTIMIST-A Trial Investigators.JAMA. 2021 Dec 28;326(24):2478-2487. doi: 10.1001/jama.2021.21892.

Neonatal anemia relates to intestinal injury in preterm infants. Kalteren WS, Bos AF, van Oeveren W, Hulscher JBF, Kooi EMW.Pediatr Res. 2022 May;91(6):1452-1458. doi: 10.1038/s41390-021-01903-x. Epub 2021 Dec 14.

Sex Differences in the Association of Pretransfusion Hemoglobin Levels with Brain Structure and Function in the Preterm Infant. Benavides A, Bell EF, Conrad AL, Feldman HA, Georgieff MK, Josephson CD, Koscik TR, Stowell SR, Sola-Visner M, Nopoulos P.J Pediatr. 2022 Apr;243:78-84.e5. doi: 10.1016/j.jpeds.2021.12.051. Epub 2021 Dec 27.

Maternal and Neonatal SARS-CoV-2 Immunoglobulin G Antibody Levels at Delivery After Receipt of the BNT162b2 Messenger RNA COVID-19 Vaccine During the Second Trimester of Pregnancy. Kugelman N, Nahshon C, Shaked-Mishan P, Cohen N, Sher ML, Gruber M, Marom I, Zolotarevsky A, Lavie O, Damti A, Zilberlicht A, Bardicef M, Kedar R.JAMA Pediatr. 2022 Mar 1;176(3):290-295. doi: 10.1001/jamapediatrics.2021.5683.

Visual tracking at 4 months in preterm infants predicts 6.5-year cognition and attention. Kaul YF, Rosander K, von Hofsten C, Strand Brodd K, Holmström G, Hellström-Westas L.Pediatr Res. 2022 Oct;92(4):1082-1089. doi: 10.1038/s41390-021-01895-8. Epub 2021 Dec 23.


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


babies, transfusion, weeks, surfactant, infants, anemia, paper, outcomes, group, study, preterm infants, hemoglobin, gestational age, neonatal, thought, vaccinated, antibody levels, mechanical ventilation, age, females


Daphna, Ben

Ben 00:00

Welcome Hello, everybody, welcome back to the podcast Daphna. How are you today?

Daphna 00:51

I'm doing great. This is our first and this will be the first episode that airs in the new year. So Happy New Year to you Happy New Year to all of our listeners, how exciting.

Ben 01:03

Yeah, this is going to be an exciting year. We, we've we've spoken about all the things we're going to work on this year. But most importantly, the neonatology review podcast that we're doing with Dr. Brodsky, and Martin is airing, first episode is airing tomorrow. And we have recorded episodes for the entire week. So subscribe to get access to these daily episodes, and then you'll have access to some exclusive Dr. Brown skinned mind episodes where they give you tips and strategies to take the board's. So that's, that's gonna be fun, for sure.

Daphna 01:36

I mean, it was it has been fun for us to record, actually. And I feel like I'm learning a lot, right, just by doing it. So I think I think people will get a lot out of it if you're able to listen.

Ben 01:50

Yeah, yeah, I think it's gonna be it's one of these things where it's not going to replace something you were doing before, but it's going to be like such an added value, when you're adding it on to the other things you do for studying. So that's fun. Yeah. Any special New Year's resolutions that you took on.

Daphna 02:10

So I, you know, I don't love the term resolution. But I am. And I posted about it this week on on Twitter, that I follow yoga with Adrienne, I don't know if you're familiar with that. But she has been doing yoga on YouTube for like a decade. And so she's like the biggest provider of free yoga. And anyways, during the pandemic, I found it to be a very refreshing thing to add to my day or when I was having a particularly difficult time. I think the her stuff is really accessible. And it's easy and like, for whatever level you're at, and it feels like you're part of this whatever yoga community, which to me was like such a parallel to what we're doing with the podcast. So anyways, she is doing this like a 30 day jumpstart your year yoga plan. So that's what I'm going to take on. It's my intention to do not a resolution, but my intention. And so I'm

Ben 03:14

going to always have to change the word on you. Well,

Daphna 03:18

semantics matter. And so I'm gonna keep tweeting about it. I hope people in our community will join us maybe to do yoga, maybe it's whatever they're doing to like, take care of themselves that people will talk about it so we can share ideas and share just some goodness, because it's been it's been a rough year, and it's been a rough month. And anyways, so that's, that's my intention. What you What's your intention for the new year?

Ben 03:48

Mine, my new year? Intention is started before the New Year. I don't do New Year's resolutions. By

Daphna 03:55

the way. I didn't assume that you wouldn't. Honestly.

Ben 03:58

There's no The idea is that if you have an improvement you want to do on yourself, do it. You don't plan you just do it. So I started I got a chess coach. So I am on a on a path to better myself as a chess player.

Daphna 04:17

I know because your your your chess practice came up on the podcast calendar

Ben 04:25

on the other calendar of the podcast. So yeah, so I found the a chess grandmaster located in Croatia, who's coaching me every Sunday. So this is very, very exciting stuff. Yeah. So anyway, all right. Should we do some journal club? Let's do it. All right. All right. I'm going to begin if that's okay. So the first paper I think we should talk about is one that got a lot of buzz on Twitter, and it was published in JAMA. And it's the optimist. The optimist a trial. I think there's Optimus Prime and there's the optimist a trial. The the paper is called effect of minimally invasive surfactin therapy versus sham treatment on death or bronchopulmonary dysplasia in preterm infants with respiratory distress syndrome, the optimist a randomized clinical trial. This is a, a large group of authors that include some of our friends from Twitter, but I'm afraid of leaving someone, so I'm just going to skip right past that. But this was a very interesting paper, right? So so the group the so the optimist group tested the hypothesis, that administration of surfactant via thin catheter would reduce the incidence of the composite outcome of debt or BPD. And some of its components. So, right. So the first question I had was, is this Lisa, right. But I guess, Lisa is a is also a term that was been coined to define the same principle basically, right, that, instead of providing surfactant to a baby via an endotracheal tube, you will use a thin catheter, while the baby is still connected to some form of non invasive support, whether it is CPAP or an IMV. And then you would administer aliquot of surfactant through that 10 catheter. And then, and then pull it out without ever to ever having to catheterized the trachea. Right. So So that's so I guess, yes, it both of these terms seems to be exchangeable and synonyms. So this was an international multicenter clinical trial that involves 33 centers, in a multitude of countries, including Australia, Canada, Israel, New Zealand, Qatar, Singapore, Slovenia, Netherlands, Turkey, the UK, and the US. The participants had to meet a few criteria, they had to be born between 25 weeks and 28 and sick 28 weeks and six days, they had to be admitted to the NICU obviously, and they had to be supported with CPAP, or non invasive positive pressure ventilation for rds, and prior to intubation, obviously, so the infants were then deemed eligible if they were on the CPAP level between five and eight centimeters of water, and that their financial requirement was 30% or greater, within the first six hours of life. The so that's that's something that's very, very important, right? This idea of saying, well, CPAP 30% Is that a criteria? Right to give surfactant, but they have good data to show that it was it was not picked at random. And I think it's the paper is very dense. I don't want to spend too much time on that. But that's been addressed, if that's one of the questions that's popping up already in your mind. And I don't mean, you definitely mean anybody obviously, listening. They, the mentioned the fact that caffeine was not really controlled for meaning it was at the discretion, and they assumed that some of the babies were on it as part of the standard management. So then they randomized and every baby receiving mist, right, which is minimally invasive surfactant therapy, and the match them one to one with a sham group. Interestingly enough, so then you wonder, what is the sham treatment? So basically, Brad Manley from Australia was actually describing on Twitter where that was meaning that they would sort of put it very

Daphna 08:40

helpful to get that behind the scenes look, the studies Yeah.

Ben 08:46

So so they would, so they would block the isolette I guess, or the pod or whatever, the room, and then the either the mist or the sham would happen behind closed doors. And if you had a sham, then they would just like manipulate the baby's head, but they wouldn't do anything, right. They wouldn't put a catheter and do nothing, but they would just let the baby be right. The intervention was obviously the administration of surfactant using mist using the Hobart method, which I thought was something very fancy. They have a link to a YouTube video that's actually very well done. But honestly, it's just a, a sort of cardiac catheter that's being passed the vocal pass by the vocal cords. And so there's nothing really revolutionary about the Hobart method. I was I was if you're wondering, they had no, they had no admin, they had no protocol for administration of sedation, and atropine or sucrose were allowed. And then they gave surfactant in three to four Alec Watts away the 10 second pause When each, it's important for us to mention that our episodes are sponsored by kz, which manufactures surfactant. And we want to disclose that obviously as a as a as a conflict of interest. But we Qasim wants to make sure also that none of the views that we're going to discuss are representative of their opinion. And they're not involved. And they're not giving us any any pointers or anything to say about this trial. So that's important also for us to clarify. So. So then who got intubated? Right. I mean, that was the big question. And so in both groups if the fit to reached 45% or greater, or if there was a severe or recurrent apnea or persistent respiratory acidosis, then they were eligible for intubation. And once intubated surfactant could be administered based on clinical judgment. And so that's where the, the trial end, the outcomes are critical. So the primary outcome of the study is death or BPD. At 36 weeks postmenstrual age, or physiological bronchopulmonary dysplasia assessed at 36 weeks. So how do they define bronchopulmonary dysplasia? It was, if at 36 weeks, they were supported by mechanical ventilation, CPAP, or high flow nasal cannula at a rate of two liters per minute or more. Or Possibility number two, they were receiving supplemental oxygen with an effective if I were to have 30% or greater. Or number three, they were receiving oxygen with a net fire to less than 30%. But it did not pass a room air trial. So these are the primary outcomes. The secondary outcomes included six clinical, clinical and safety outcomes. And they included pneumothorax and need for intubation within 72 hours, great three or four ivh deaths during hospitalization, or major morbidity, and each of these were considered separately. So there are samples, they share their sample size calculation, but they were not able to reach their, their, their sample, because of COVID. There was a lot of issues associated with COVID and enrollment. So they had to stop a bit short. They enrolled infants between 2011 and 2020. And they basically were able to get 488 infants, the infants, of those 485 were included in the primary analysis, the median gestational age was 27.3 weeks, and, and 49.7% were female. Interestingly enough, the baseline characteristics of the study infants overall were similar, but the frequency of male sex incomplete or no steroid exposure, and multiple birth within the gestational age stratum of 25 to 26 weeks, were each 12 to 14%, higher in the Miss group. So I think that's important to clarify. Okay, shall we move on to results,

Daphna 12:50

let's do it.

Ben 12:52

Okay, so the primary outcome, the primary outcome of death, or BPD, occurred in 43.6%, in the missed group, versus 49.6% in the control group, and that difference was not significant. So for their primary outcome missed did just as well as control. And this is now where things are getting a little bit dicey. Looking at each individual outcome alone, death was reported at Oak hearing prior to 36 weeks, was present in 10% of the missed group versus 7.8% in the control group, and that was not statistically significant. The p value was point five one. So higher death, but not statistically significant. Looking at the incidence of BPD, alone at 36 weeks, it was 37.3% in the midst group versus 45.3% in the control group, and that was significant P value was point 03. The one thing that's important to mention in these results is that when you're looking at the primary outcome of death, or BPD, the confidence interval is quite wide. So when you're looking at the relative difference of the two outcomes 43.6% in the MISC group versus 49.6 in the control group, that difference of 6.3% the confidence interval range from minus 14% to 1.6%. So that's, that's that's,

Daphna 14:25

that's quite large. And across is one, right? Yeah.

Ben 14:29

Yeah. Which is why also, I mean, they didn't they didn't report that as clinically significant. So that makes sense. But still, you would want your confidence interval. For people studying for the boards you want the confidence interval to be narrow. secondary outcome the need for intubation within 72 hours was reduced in the midst group 36% required intubation incident within 72 hours versus 72%. In the control, the incidence of pneumothorax requiring drainage was higher in the control group 4.6% versus 10.2 per sent. And the incidence of other key clinical and safety outcomes was not statistically different between the groups. So they looked at other stuff, I think that we should just mention that we're not really part of the primary outcome or the secondary outcome. But treatment with missed was associated with a reduced requirements for intubation at any time. So 54.8% versus 81%. It, it reduced the incidence of PDA requiring medication 35 versus 45%. And in the need for oxygen therapy at home in survivors to hospital discharge 14% versus 22%. The requirement for surfactant therapy via ET tube was also reduced after treatment with missed 32% in the Miss group 68% in the control group, quite a large difference. And the missed group should also reduction in four of six continuous secondary outcomes. So when they looked at the number of days, certain things were required, right, so mechanical ventilation, it was one versus four days, between missed and control, the number of days on CPAP was reduced 17 days for missed 22 for control, mechanical ventilation plus CPAP was 25 days for Ms. 32. For for controls, and all forms of mechanicals, respiratory support 40 days versus 45 days. So these are some these are the outcomes, then they did a lot of other stuff, looking at subgroups. And I think what was very, very interesting was to look at the subgroups and the different gestational ages. So looking at the outcome of death, prior to 36 weeks, there was a signal a statistically significant interaction in the relation to the treatment effects. So control group was favored at lower gestational ages, and Ms group was favored at higher gestational ages. And that was significant, which were babies that were which makes sense, but it makes everything so much money. So and so let's just repeat that for a second. Right. So for the outcome of death, it was better to get intubated and get surfactant when you were at a lower gestational age compared to higher gestational ages, but not for the composite outcome of death or BPD. Or for the outcome of PPD alone. So if you wanted to reduce death in the lower gestational ages group, it's unclear whether whether it doesn't appear that misters better. The need for intubation within 72 hours of birth was 49% for the missed group, versus 72%, for the control group within the gestational age of 25 to 26 weeks, and 29% versus 72%, in the ages of 27 to 28 weeks. So you basically see the difference prevailed, but they were more intubations at the lower gestational ages. So like they were less likely to sustain themselves after Miss, which makes sense. Yep. I've been speaking for a while now. Before I go into the discussion, what what are your thoughts?

Daphna 18:13

Yeah, well, I mean, it just goes to show you how important your outcomes are, right? What we're defining as success. And what is important to you. So there are obviously some things that are improved with mist, and two minute minimally invasive surfactant treatment, and that they are probably it's probably most likely to be beneficial in slightly older babies. So they're able to tolerate the procedure get enough of what they need and move forward. And it may not be as successful in the babies of lower gestational age, where we're all trying to find out like what is the optimal treatment course to minimize some of these significant morbidities. And I think it just shows that these little those early early early babies, the babies who are most at risk, are still at risk, no matter what, what we do for them. But I think there are definitely some signals here that that there is a benefit of mist into in certain populations of babies for sure.

Ben 19:28

Yeah, I agree with you. I think this is something that that is. I mean, people are talking about this as like the paper of the year already. Hot Topic. It is a hot topic. I think it shows that the non invasive, less invasive surfactant administration is not something that will be a novelty and that will only applied to a select group. I think it's going to probably end up what we're seeing now. Is that Yes, if you have a 22 weaker I don't know if this is the right, the right path, but it seems from this Paper that for the broad majority of babies admitted to the NICU, this might be the way to go.

Daphna 20:07

I mean, reducing mechanical ventilation, reducing intubation significantly. And, you know, I think when we talked about cumulative stress in the NICU, when we talk about bonding in the NICU, you know, there's definitely some advantages to, to avoiding longer times present, intubated, or in relation.

Ben 20:32

And remember, these are babies that were very, very small, right? I mean, we're talking about

Daphna 20:37

the lay preachers, right, these are this is a moderate preterm. No, this

Ben 20:42

is 25 to 28, like, like 30 and above are not even included in this study. So this just goes to show. So this is this is, I think, a massive paper. And, and despite this, I mean, again, the big debate is this whole increase in mortality, right? I mean, this, this 10%, this 10% mortality in the MS group versus the 7.8%, in the control. And again, I think this is something that that could be of concern, and people are saying that the outcome of death or BPD, is not such a great outcome to look at, you should probably look at it individually. So you can make of it whatever you want, I think the problem becomes Are you trying to replace insure altogether, and that's not the point here. The point here is to show this as a very, very viable alternative, and also indicate that at lower gestational ages, you just have to be more cautious about who you select for this procedure. That's enough for this paper, I think, yeah, I

Daphna 21:41

think you did a good job of discussing what is a complicated, it's just

Ben 21:49

every result, every result, you'll read it and you're like, Okay, I get it. And then the next result attenuates. Don't just read before, and it's like, ah, what about now.

Daphna 21:59

So I hope we'll get, you know, a bigger study, maybe two, so that we know

Ben 22:05

maybe, I think also, I want to share with you guys that they have some supplemental material that is super, super helpful. And I would recommend you perusing it, it shows you some of the catheters that they were using, it also shows all the data for some of the outcomes based on the gestational ages. And so that's super super. Yeah,

Daphna 22:23

I think they were really transparent about what they did, how they did it, how other hospitals or other units can, can begin to integrate the practice. And so I think it was for sure any, any paper. Okay, well, shall we discuss? Anemia a little bit? We've got two papers actually on any.

Ben 22:49

So excited about those papers.

Daphna 22:50

So here, I'll do one and you'll do one. How about that? Okay. So I'll start with this paper, which I thought was super cool, right? Because anemia when I want to talk about how do you know which one I picked?

Ben 23:03

You're gonna see the sex differences would

Daphna 23:06

be great. Okay. Okay, good. See, you never know, you never know. But anyways, obviously, there's this on going area of concern about anemia and transfusions and neck. And so I'll get into it, but I thought this was a neat paper. It just so happens. We had been talking about this in our unit in the last month, so I thought it was particularly interesting. So this comes from the Society for pediatric research. Neonatal anemia relates to intestinal injury in preterm infants, lead author, will Amin, cow, cow, Tarun, and for anybody who's everybody's, anybody whose names we we mispronounce, you, let us know so we can do.

Ben 23:57

I feel like over time, we will have offended 51% of the neonatal community

Daphna 24:02

by saying their names, but we want to do better. So you just give us the feedback you let us know. And we'll do we'll do better next time. For sure, for sure. So, this is a paper out of the Netherlands. This came from actually a combination of two prospective studies performed and ethnic youth in the University Medical Center, grown again between July 2018 and December 2020. So they looked at infants born before 32 weeks of gestation within the first week of life, and they were exclusively looking at infants who had not yet received any red blood cell transfusions before enrollment. And what they wanted to look at was, did anemia or severity of anemia relate to intestinal injury, and so what they use to To look at intestinal and injury was the concentration of i, f a VP, or protein that's found in the epithelial walls in the epithelial cells sorry, of the small intestine, and has already been correlated with intestinal injury, a number of studies looking at nak, and the concentration of this marker. And so they wanted to see, could we look at early signs of intestinal injury by looking at the concentration of this marker in the urine of preterm babies who are anemic, and the other thing they went ahead,

Ben 25:38

and this is the intestinal fatty acid binding protein, thank you, the eye fhbp We won't say that again for the rest of the episode. So

Daphna 25:48

now, you know. And then the other thing they wanted to look at was basically the, the regional oxygen of the intestines or overlying the abdomen, and the splink, Nick fractional tissue extraction. So did anemia change, kind of oxygen delivery and oxygen use in the intestines, which I thought was a nice correlate to what they were doing. So they used a case control study, which was a little different than a typical case control study. So they use what's called a nested case control study design, where basically, they select several healthy controls for each case, but they may not know the case, yet to begin with, so they took this proportion of babies, all within anemia, so they had some exposure, so anemia, and then they want they follow them to see which babies were acquired red blood cell transfusion. And then then they have the cohort, the selected matched controls for those cases, who then required backrow, both transfusion, which I thought was a neat way to look at things. So let's get started. So the other thing I wanted to mention is that they did exclude samples after confirmed neck diagnosis, to prevent looking at really neck induced intestinal injury. And they defined a neck as an abdominal radiograph, where they either had NUMA ptosis, or portal venous gas, or both. They also described what their red blood cell transfusion threshold was, which I thought was very helpful, because obviously, this changes widely between country between unit. And so I thought this was very helpful. So I think we should go over those. So the hemoglobin thresholds were eight millimoles per liter, or 12.9 grams per deciliter for infants on the first day of life, and infants on ventilator ventilatory support during the study period. For infants on other respiratory support, say plus CPAP. They use seven millimoles per liter or 11.3 grams per deciliter. And then for infants during the first four weeks through otherwise, clinically stable, they use six millimoles per liter or 9.7 grams per deciliter. And after the first four weeks in babies who are otherwise clinically stable, they use 4.5 millimoles per liter, or 7.3 grams per deciliter. And so, again, depending on where you practice, I think this is more conservative than then some places, especially in those first four weeks of life. But you'll have to think about that in relation to your own unit. So their study protocol, they collected urine twice weekly during the entire study period to look at the i FA BP and they placed this sensor to look for regional saturation of oxygen on the central abdomen. So during the first two weeks after birth, they measured that continuously every day for at least eight hours. And then they calculated the splink Nick fractional tissue extraction for each baby. In addition, they collected a variety of clinical variables including the presence of the PDA, which is something that I was interested in looking at. So in total, they enrolled 140 infants. 40 infants received a red blood cell transfusion during the study period at a median of 10 days after birth. And then the selected controls from the remaining remaining 100 infants for 36 cases. So in total they include 72 infants In this kind of injured individual study, there were no major differences in baseline characteristics except for the prevalence of mechanical ventilation, and a confirmed PDA in cases. So for babies who require transfusion, there was a higher prevalence of mechanical ventilation and confirm PDA, which I think we should keep in mind. And then the median postnatal age to transfusion was 11 days. So let's get into the i f, a BP. So median levels. Yeah, that's the median levels were higher in cases than in controls on subsequent time points from seven to five days until 24 hours before red blood cell transfusion. So what that means is, even for some babies, five to seven days before the need of transfusion, they had higher levels of this protein in the urine, which is, I think, kind of impressive for almost a full week. And they started to see that increase. And they also, like I said, looked at the regional saturation of oxygen, and at 24 hours, but not before that time before packed red blood cell transfusion cases had lower saturation than controls. And looking at all the infants, the hemoglobin level correlated with this regional saturation 24 hours before transfusion, which I thought was pretty interesting. And then after adjustment for the presence of the PDA, which I told you something I was in particularly interested, and they looked at mechanical ventilation at the time of measurements, they still saw similar results, so I thought that was very valuable. And then they looked at all the infants as a group, the levels of urinary i fhbp, correlated negatively, with hemoglobin levels on subsequent time points from seven to five these until 24 hours before red blood cell transfusions, and levels of the urinary protein also correlated negatively with the regional saturation 24 hours before transplant transfusion. In again, all infants, they adjusted for the presence of the PDA and mechanical ventilation, ventilation for all babies at the time, points measured, and they still again, all of the data bore out. And so in both cases and controls, lower regional saturation variability, 24 hours before transfusion, correlated with higher i fhbp levels, but not prior to 24 hours. But I thought that it was interesting that basically all of the things they were looking for correlated, so anemia, babies with all babies with anemia had lower regional saturations in the 24 hours prior before transfusion in the cases. And that lower hemoglobin levels were correlated, both with the saturation and the urinary i f a PB levels. So I thought that was interesting. It doesn't quite change my practice yet. But you know, globally, I think we're starting to use lower red blood cell transfusion thresholds. And so I think this just goes back to, you know, individualizing care based on week of gestation, acuity of baby and already risk for intestinal injury. Your thoughts?

Ben 33:53

Yeah, I think this was really cool. I mean, I think I'm going to try to ask next week, our labs if we can actually measure this because I look at these graphs, and

Daphna 34:04

I think we can measure this in our lab.

Ben 34:07

What are you talking about? What is that thing you want to measure? But it's impressive how the, the, the fhbp increases, progressively over time as the anemia so like you have these two, these two graphs where you see the hemoglobin of the cases go down and the ABP just increasing and then you correlate that with a decrease in localized localized saturation. That's it's kind of impressive.

Daphna 34:35

Basically linear goes by like it's, it's really cool. And,

Ben 34:39

and it goes back to that that dilemma that you were mentioning earlier in the discussion, which was the idea of gut of transfusion related gut injury. Is this the chicken the egg is it's the anemia that causes the gut injury, and by the time you transfuse, you've already injured. I think this this adds more water to the well of saying, yes, the anemia is actually the culprit here and and is the main reason for gut injury. So I think this is interesting. And yeah, this was, I thought this was fascinating. The other thing

Daphna 35:07

that I think is super valuable is anytime in our little babies we can look at anything through urinary measurements is so much so valuable, especially because this was changing on a day to day basis. So being able to get a lab value from urine instead of blood, I think is especially going to be because anemia, right? We can draw less you don't want to draw more than that's super, super valuable. So very cool.

Ben 35:38

Okay. Shall we move on?

Daphna 35:40

Yeah. You want to do the other paper?

Ben 35:44

Okay, okay. So, the other paper on anemia that we're discussing is called sex differences in the association of pre transfusion, hemoglobin levels with brain structure and function in the preterm infants. I thought you were going to pick this one because it dealt with anemia, sex differences, brain MRIs. So I thought this was right up your alley. And this is from first author, Amanda Benavides from University of Iowa. So this was a very cool study. This was a, the University of Iowa was part of the top trial. And if you have, have we reviewed the top trial,

Daphna 36:25

I don't mean that as a standalone paper, no, fine.

Ben 36:29

But it was basically a paper looking at transfusion thresholds for babies and they came up and they were looking at high versus low. And they outlined very interesting data looking at lower threshold transfusion thresholds based on whether a patient was quote unquote, sick versus not sick. So and Keith Barrington has an amazing blog post summarizing both the top trial and the other trials like the pines and all the other ones that have the Ethno, and all these other trials that have come out. So I will link Dr. Barrington blog post, because I think that's a good place to start for anybody interested. And Dr. Bank is going to come on the show soon. So

Daphna 37:09

they're very excited about that.

Ben 37:13

So this study, aimed to evaluate the impact of transfusion status on optimal brain structure and function in a subset of neonates from the top trial who participated in that trial at the University of Iowa. Neonatal transfusion hemoglobin levels were used to predict brain structures from terminal equivalent MRI, and functional outcomes at 12 months, corrective gestation, utilizing the Bayley scales of infant and toddler development. So basically, I read the objective twice, and I couldn't understand what they meant. They basically looked they were basically looking at the the hemoglobin prior to a transfusion being given. And depending on how low that pre transfusion hemoglobin was, what is the impact downstream on brain MRI and, and neurodevelopment. So inclusion criteria were babies with birth weight less than 1000 grams or less and gestational age, above 22 weeks, but less than 29 weeks. And they had to be for the less than 48 hours of age and enrollment and blood sample. From the study where they were not drawn specifically for the study. They were like leftover blood samples and stuff like that. So that's important for them to mention. And hemoglobin obtained directly prior to each transfusion, termed that's what they call their pre transfusion. Hemoglobin was used as a marker of the degree of anemia prior to transfusion in each infant. So yeah, and so, lower pre transfusion. Hemoglobin is therefore associated with lower lower transfusion threshold strategies. Whereas higher pre transfusion hemoglobin was generally associated with higher transfusion thresholds. They did unsedated MRIs at approximately term equivalent or at around the time of discharge, whichever one came first. And then they looked at a variety of different things. White matters, cerebral gray matter on myelinated, cerebral white matter. Venous venous blood cerebellar. Cerebral cerebellar ser rebels, her gray matters through rubella, white matter, basal ganglia and a lot of other stuff. Cognitive function was assessed at 12 months corrected age using the Bailey three. And that's pretty much it. So they collected patients from 2013 to 2017. And, and that basically, it was interesting, right? Because they had like three cohorts of babies in the end, because they had the babies on whom they were able to get continuous hemoglobin measurements. Then they had the both of those, they had the babies who they were able to get an MRI on. So they started with 124 infants, they had longitudinal hemoglobin values for 97 of these. Then they had brain MRIs for 29 of them and they had daily three for 30 From them, so you have these common things in the Okay, so there were no significant. So let's talk about some of the results. Okay. There were no significant differences in neonatal brain structure or baseline 83 cognitive performance between males and females in the sample size. And I think that's the main thing I forgot to mention. They were comparing males versus females that I should have mentioned that it's in the title and everything.

Daphna 40:32

But then now you've mentioned and now it's mentioned.

Ben 40:35

So I'm going to go into the results. So bear with me, there were no significant associations between pre transfusion hemoglobin and total intracranial volume cerebellar tissue, gray matter or, or white matter in males or females. However, pre transfusion, hemoglobin was significantly positively associated with white matter in all infant participants. That is, the higher the pre transfusion hemoglobin, the greater the white matter volume. So that already is pretty earth shattering. However, and listen to this, this was exclusively driven by the males. As pre transfusion, hemoglobin was positively correlated with white matter volume in males. And for females, there was no relationship of pre transfusion hemoglobin with white matter volume, resulting in a significant sex interaction, F 8.26. With a p value of 0.01. A post hoc sensitive, they tried to do a post hoc sensitivity analysis, but they were their sample size was too small, so they couldn't do it. So I'm going to skip that. Let's look at pre transfusion hemoglobin and now cognitive outcomes. In every case, the estimated trends for males and females went in the opposite direction for cognitive outcomes. Elevation of pre transfusion hemoglobin were associated with descriptively lower performance on four out of five, barely three subscales in female, including cognitive expressive language, and fine and gross motor function. That is an increase in preterm in pre transfusion hemoglobin was associated with lower scores on the Bally three gross motor function in females only, but not males. Females had lower mean belly scores with higher pre transfusion hemoglobin, but males mean barely scores showed no association with pre transfusion hemoglobin level. A post hoc sensitivity analysis was subsequently conducted in which the same regression analysis and sex interactions were performed after excluding infants diagnosed with any grade of ivh or PVL. This analysis did not change the results of any cognitive subscale, or composite outcome, a composite score regressions, or sex interaction significance, the conclusion and the state this black on white Taken together, these results suggest that males with lowest hemoglobin levels would have the worst outcomes, while female with the highest hemoglobin levels may have the worst outcomes. And this is a case of a paper where the graphs are freaking gold. And they're all going in both directions. Meaning males basically need don't do well with lower transfusion thresholds while female do better. They don't do this. They do better. Yeah. And yeah, and it poses a lot of philosophical questions, I think. So what were your small sample small sample size? Right? small sample study? Yeah,

Daphna 43:49

a small study, especially they didn't have all of the outcome measures for all the participants, right. So that's something that we have to keep in mind. But this really shakes up the it's really shakes things up, right. And again, goes back to individualized medicine, especially by sex. And it relates to the study we just talked about. And it relates to the study that we looked at maybe a few months ago about transfusions for preterm babies, by sex of donor. So there's something about red blood cells and sects that I think we just don't fully understand yet. But it shows that blank, maybe blanket transfusion guidelines are missing something is something big. I also don't know what this means for girl babies who have good hemoglobin level.

Ben 44:54

I think I mean, again, I can't help myself but you wonder if nature has predisposition for females to tolerate anemia, anemia better, because of just the nature of being a female. I think this this, the fact that we could perceive those types of things in prematurity and in infancy would be mind boggling. But I think again, I think this warrants more studies. This is so cool not to be studied.

Daphna 45:21

Yeah. No, it's, it's, it's super interesting. super interesting. So everybody should take a look at the graphs for sure. Oh, we're gonna post those graphs. Lots of graphs this this week.

Ben 45:34

And good ones to

Daphna 45:36

assure picture's worth 1000 words, as they say. So, actually, this next paper had some really good and supplementary graphs also in JAMA maternal and neonatal SARS, cov, two immunoglobulin G antibody levels at delivery after receipt of the Pfizer, but bn t u 162. B two messenger RNA COVID-19 vaccine during the second trimester of pregnancy. And I think this was such a just in time article, right. So,

Ben 46:13

I've been asked that question so many times, so many people call me like, hey, my wife's pregnant, you should get a vaccine. It's like,

Daphna 46:19

yes, it's

Ben 46:20

ended debate one, so

Daphna 46:21

we're not sure. But let's let's, let's take a look at saline after a year kugelman. This is coming to us out of Israel, which is not surprising. Israel has been doing the bulk of the pregnancy and vaccination research in the last

Ben 46:40

few years. I think they're trying to force those as well.

Daphna 46:43

Yeah. They're kind of always just ahead, right? Yeah, anyway, so this, they looked at kind of mother infant diets between May 2021, and July 2021. So what they did is they enrolled pregnant women over 24 weeks of gestation, who had received a second dose, or first and second dose of the Pfizer vaccine, and we're not known to be previously infected with the COVID virus. And then, again, any women who had reported previous infection or who didn't receive both vaccine doses were excluded. So they obtained a maternal blood sample to look at Scarlet SARS, cov, two IgG. And then they drew an umbilical cord blood sample within 30 minutes after delivery, to also evaluate, evaluate SARS, cov to IgG. And total, they had antibody titers measured for 129 women, those women were a mean age of 31.9 years, we, which becomes important when they look at the data, and they looked at 114 neonates born at a mean gestational age of 39 weeks. So the mean gestational age and administration of the first and the second vaccine doses were 21.9 weeks and 24.9 weeks, respectively. And the mean duration from the second vaccine dose to birth was about 14 weeks. And that will become important as we move forward. But what was amazing was that all maternal and all newborn IgG tests had positive antibody results. 100% of moms and 100% of babies had positive IgG, which I thought was already kind of cool. Then they talk about median levels of antibodies, which again, I think across the board, across patient groups, we still don't know how to use IgG levels. We don't know what that means for production. But it was reported here, the median level of IgG antibodies was 1,185.2. For the women, the mothers and 3315. For neonates, which this is I think the next really interesting point that neonatal titers measured approximately 2.6 times higher in maternal titers across the board. So maternal titers were correlated with neonatal antibody titer. So as the moms antibodies were higher babies had higher antibodies, but still, overall as a group 2.6 times higher, the baby antibodies in the mommy antibodies. So the other thing they wanted to look at was do the titers differ with maternal age, gestational age at the second dose and duration from the second vaccine to birth. So these were things that they were looking at. So for all of us, older women, so for you Each one year increase in the mother's age, the maternal and neonatal antibody levels changed by a negative 3.9%. So as mothers is pregnant mothers were older, their antibody levels were lower, does this hurt

Ben 50:15

you so much.

Daphna 50:16

They're always picking us older. Not pregnant, I'm just saying it's picking older women,

Ben 50:24

okay, and you're not old adult, you make it sound like just 75.

Daphna 50:28

But anyways, this is consistent with other data that antibody levels with age with increasing age are decreased. So that's interesting to know. In addition, for each one week increase in the gestational age at the time of the Second vaccine dose, the maternal and neonatal antibody levels increased by 10.5%, which is very cool 10.5% and 9.4%. So 10.5% increases for mommies 9.4% increases for the neonates. However, furthermore, for each week that passed since the second vaccine dose, maternal and neonatal antibody levels changed by minus 12%, which is important to note. And so for each week, that changed, or so each week that passed since the vaccine dose, as as a dyad, maternal and neonatal antibody levels changed by minus 10%. So it was interesting that the antibody levels were increased the later in gestation that you got it however, there is maybe some evidence of of waning immunity, the longer you go from, from the second vaccine. So I thought that was interesting. They talk about this a lot about in the discussion, they don't give us a definitive threshold time for optimal vaccination. So obviously, that's the question everybody wants to know is when is the right time to get vaccinated? I think this paper shows, you know definitively that there's benefit to vaccination in in pregnancy and and potential protection with increased antibody levels in in neonates, but I don't think it still answers the question about when should we get it and then they talk about that their recommendation, the authors of the paper still that women get it early, as early as possible in pregnancy to prevent complications of COVID-19 during pregnancy? Thoughts?

Ben 52:41

Yeah, I have I agree with with your assessment. I think this paper is super valuable, because I've had acquaintances that have asked me about vaccinating during the pregnancy. And there was that data, right, that came out people are aware of the fact that if you're vaccinated after you deliver, and you breastfeed, those antibodies will cross into the breast milk. And, and I've heard this before saying, Well, I'm not going to sway, vaccinate during the pregnancy, just wait, and and I'll pass it on to the baby, for during breastfeeding, but then the paper makes a good point. And showing that yes, it is in the breast milk. But babies who have been breastfed from mothers who have been vaccinated have no sign of antibodies in their serum. So somehow it's found in the milk, but not in the baby. And so I think this is where this paper is so important, because it actually shows evidence of antibodies present in the baby at birth, which, yeah, which, which, to me, it, it makes, it puts a lot of big incentive on the parents, because technically, think about this if you don't get vaccinated during the second trimester, and how is your baby gonna get those antibodies for? Not until, like, whatever age the vaccine is approved for? I think it's five years, right? Five years. So so it's, it's, I mean, I'm seeing this from the standpoint of a pregnant, expectant mother and I'm thinking yeah, like the second trimester is your is your window to actually get vaccinated so that you can actually protect your baby and give your baby some immunity? Considering that the breast milk is not really working out too well, and raising the sealer Amanda

Daphna 54:23

value. So the next cohort really to to get approved is the six months to five years, right. So I mean, that that less than six month, there's less than six months, babies are really this this, this is the best way to get. We don't know what level of protection yet, but presumably something

Ben 54:45

and if you're, and I'm sure that we're not the only ones I mean, you and me have been seeing a surge in the number of pregnant mothers showing up to l&d with COVID Positive

Daphna 54:56

especially in the last week, right the last two weeks. Yeah, yeah. Well With with the increasing cases nationally, so

Ben 55:04

yeah, so yeah, that was fun. That was that was like that paper. Do we have time for one book?

Daphna 55:09

So I hope so. Yeah. Let's do one more. Which one are you going to do

Ben 55:14

one more quick one. I want to do this visual tracking. In pre German

Daphna 55:18

very cool paper, not the one I thought you were gonna do.

Ben 55:21

This paper is called visual tracking at four months and preterm infants predict 6.5 year cognition and attention. first author is yova. Fredrickson cow. And this is from a, a group out of Uppsala in Sweden. So the reason I picked this paper is that I did a lot of research as a college student on it. I know that. Yeah, so my dad, my dad is a painter. And he's, he's an artist. And then we decided that we wanted to look at how people look at different paintings we had, like, we rented an eye tracking device, and we put people in front of famous, famous paintings, and then we would watch where their, their motions, their fixations and stockades went, and it's super, super cool. I have some very nice pictures. Actually,

Daphna 56:09

for anybody who hasn't picked up on it yet. Dr. Cortes is quite quite the renaissance man. Right, a jack of all jack of all trades. You name it, he's done it.

Ben 56:19

Yeah, I mean, I've dabbled, I think, go sell, don't sell me expertise that I don't have. But anyway, this was a very cool study where basically, they looked at visual tracking of preterm infants. And they, they collected data on babies were born between 22 and 31 weeks, that happened between 2004 and 2007. And, again, we're running a bit out of time. So I'm gonna go quickly, what they did is that in the clinic, they had a sort of smiley face and the placed an eye tracking device on the baby. And it would basically measure several things. And it would move the smiley face in a sinusoidal pattern, or a triangular pattern, and they would monitor how well the baby could track that object. And there's a few things obviously, that are difficult to read through the paper, because it describes eye tracking movements. And it's kind of it's kind of difficult. But basically, you have smooth pursuit, which is where if your head stays straight, and you track an object without moving your head, that's smooth pursuit, you have head movements. So obviously, you're moving your head to keep up with an object that's moving in front of you. And then finally, you have these these things called stockades. And that's basically when you're jumping, your eyes are jumping from one place to the next to catch up. So imagine that an object is in one place disappears, appear somewhere else, as your eyes are jumping to that new place that's called a stockade, meaning whatever is in between those two points, your eyes don't really see what's

Daphna 57:52

I like to think about it, if you're watching somebody who's watching something out of like the window of a moving car, and you see that their eyes will jump. for them. It looks like it feels smooth, but the cicadas are are jumping from one point to the next.

Ben 58:08

Yep. So they did that at four months. And then they did the Wechsler at six point five years. And let me just so so the define this thing called the gain, right, the relative proportion to which the infant followed the object. And so that means that the baby was always sort of in sync with the movement of the object. So looking at Gaze gain, and smooth pursuit gain at four months were strongly related to all Westeros parameter at six and a half years, gaze gain for the triangular ensign is orbital motion patterns related similarly to the cognitive scores as well. And for the center's auto motion pattern timing related to some of the also met up sorry, I forgot to mention, they also did surveys for attention deficit disorders. So that also was related. There were no statistically significant differences in association dependent on motion pattern and visual function was tested by an ophthalmologist. And that did not influence the result. So in conclusion, the ability to attend to and to smoothly track a moving object in infancy seems to be a marker or an early marker of cognition and attention at six to seven years of age. And I think that's pretty cool. I mean, it's pretty cool technology. It's pretty cool idea. And it's kind of nice that we have these. We have we have the study.

Daphna 59:30

Yeah, I think just for people's reference, if you're not familiar, or you can't recall, you know, the tracking development that in typically developing infants, so not necessarily the preterm infants, attentional abilities to track appear soon after birth, and then smooth pursuit eye movements typically start to develop within two months of age and so that's why they used four months to kind of allow for that Some of that catch up because of the prematurity. So I thought they use the right time point. And then looking both at the Wechsler and AD D measurements at six and a half years, I thought was pretty valuable. So

Ben 1:00:14

yeah, neat. Yeah,

Daphna 1:00:17

I think that's all we have time for.

Ben 1:00:18

Now, that's all we have time for. This was fun journal. I'm happy that we kicked off the year with this group of articles. I was afraid that there was going to be pretty bare bones out there considering the holidays and certainly

Daphna 1:00:28


Ben 1:00:30

that's always something. Before we close the show, we're going to announce this week, the winners of the giveaway very exciting. So look out for the Twitter account to announce the winners of the iPad Pro for the incubator giveaway and of the of the books that we're giving away as well. And of the Brodsky and Martin series for the other podcasts, which you should subscribe to. I received the iPad Pro, it's at home, my daughter

Daphna 1:00:59

wants it was very sad that it was for her. And then maybe the only other thing we should mention is that we've got a really neat interview next week with Mary Coughlin about trauma informed care of of neonates and families. So I hope that you will all join us to to have a more mindful approach to babies and families to start off the year. Maybe that will be somebody's intention to have a more mindful, she's

Ben 1:01:27

dynamites. She's very cool, and I enjoy that.

Daphna 1:01:31

Okay, have a good one.

Ben 1:01:34

See you later. Bye. Thank you for listening to this week's episode of the incubator. If you liked this episode, please leave us a review on Apple podcast or the Apple podcast website. You can find other episodes of the show on Apple podcasts, Spotify, Google podcasts, or the podcast app of your choice. We would love to hear from you. So feel free to send us questions, comments or suggestions to our email address NICU You can also message the show on Instagram or Twitter at NICU podcast. Personally, I am on Twitter at Dr. Nikki spelled Dr. NICU and Dafna is at Dr. Dafna. MD. Thanks again for listening and see you next time. This podcast is intended to be purely for entertainment and informational purposes and should not be construed as medical advice. If you have any medical concerns, please see your primary care practitioner. Thank you


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