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#100 - 📑 Journal Club 40

Hello Friends 👋,

We are excited to release the hundredth episode of the podcast. Daphna and I are extremely thankful for all your support and for helping us make this podcast as successful as it is. This week we have a series of high-quality papers that range a wide breadth of topics. We hope you enjoy this episode and remember to grab your CME credits for this journal club. Cheers!


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

Bloomfield FH, Jiang Y, Harding JE, Crowther CA, Cormack BE; ProVIDe Trial Group.N Engl J Med. 2022 Nov 3;387(18):1661-1672. doi: 10.1056/NEJMoa2204886.

Jensen ET, Yi J, Jackson W, Singh R, Joseph RM, Kuban KCK, Msall ME, Washburn L, Fry R, South AM, O'Shea TM.JAMA Netw Open. 2022 Nov 1;5(11):e2241943. doi: 10.1001/jamanetworkopen.2022.41943.

Bachmann CS, Risnes K, Bjørngaard JH, Schei J, Pape K.Pediatrics. 2022 Dec 1;150(6):e2022057085. doi: 10.1542/peds.2022-057085.

Abdellatif M, Tawfik GM, Makram AM, Abdelsattar MK, Dobs M, Papadopoulos DN, Hoang-Trong BL, Mostafa EM, Duong PDT, Huy NT.Eur J Pediatr. 2023 Jan;182(1):329-341. doi: 10.1007/s00431-022-04675-6. Epub 2022 Nov 10.

Akangire G, Lachica C, Noel-MacDonnell J, Begley A, Sampath V, Truog W, Manimtim W.Pediatr Pulmonol. 2023 Mar;58(3):753-762. doi: 10.1002/ppul.26248. Epub 2022 Nov 22.

Le Ray I, Kuhn P, Letouzey M, Roué JM, Mitha A, Glorieux I, Foix-L'Hélias L, Marchand-Martin L, Ancel PY, Kaminski M, Pierrat V; Epipage 2 Neurodevelopmental care writing Group; EPIPAGE-2 Infectious diseases writing group.Pediatr Res. 2023 Jun;93(7):2091-2100. doi: 10.1038/s41390-022-02383-3. Epub 2022 Nov 14.

Sabroske EM, Iglesias MAS, Rench M, Moore T, Harvey H, Edwards M, Baker CJ, Flores AR.Pediatr Res. 2023 Jun;93(7):2067-2071. doi: 10.1038/s41390-022-02375-3. Epub 2022 Nov 9.

Neonatologist staffing models: urgent change is needed.Cuevas Guaman M, Miller ER, Dammann CEL, Bishop CE, Machut KZ.J Perinatol. 2022 Nov;42(11):1556-1557. doi: 10.1038/s41372-022-01527-x. Epub 2022 Oct 7.

Mortality and neurodevelopmental outcomes of infants with spontaneous intestinal perforation: a systematic review and meta-analysis.Ang JL, Rath CP, Tan H, Patole S, Rao SC.Arch Dis Child Fetal Neonatal Ed. 2023 May;108(3):256-266. doi: 10.1136/archdischild-2022-324157. Epub 2022 Nov 3.

Higher blood pressure in adolescent boys after very preterm birth and fetal growth restriction. Liefke J, Steding-Ehrenborg K, Sjöberg P, Ryd D, Morsing E, Arheden H, Ley D, Hedström E.Pediatr Res. 2023 Jun;93(7):2019-2027. doi: 10.1038/s41390-022-02367-3. Epub 2022 Nov 7.


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

Unknown Speaker 1:01

Hello, everybody. Welcome back to another episode of the incubator. It is episode 100.

Unknown Speaker 1:19

so dramatic,

Unknown Speaker 1:21

we're live at the Carnegie Hall.

Unknown Speaker 1:27

This was actually louder than I thought it was round of applause. That was nice.

Unknown Speaker 1:32

It was not recorded. It was spontaneous from people from around the world, listening to the podcast. No, but all jokes aside, it's very exciting. 100 episodes, super nice.

Unknown Speaker 1:44

Just, I'm just, I'm just happy with the consistency we've been able to keep and not, and not just flake out. So thank you, Daphna, for making the time to record at odd hours and a time.

Unknown Speaker 1:59

This is fun, we do it, we have to do it. It's serendipitous that this is, you know,

Unknown Speaker 2:06

a week where we tend to think about gratitude. I think we have like a lot to be grateful for our team, and people who come on and talk to us also sometimes at odd hours of squeezing us into their schedule. So yeah, and just having the opportunity to do this and like engage with

Unknown Speaker 2:27

the community I have gotten. This is why people like going to conferences, right? It's because you get this open flow of ideas, you get like cited and you meet other people, and you talk about your life, but like we get to do this every single week. And yeah, I hope I hope that people even feel like a little bit of that through the recordings. You know, I think so. I think so. And the and the feedback that we got from people, in person and by email about the last episode with Dr. Lemons was was phenomenal. I mean, I think I was happy that we were able to do a good job at letting his personality shine through the episode because he's, he's a, he's a he's an amazing individual. So if you haven't listened to that episode, please go check it out. And in terms of other announcements that we have for you today, this week, we will put on sale the tickets for the Delphi conference. And we'll tell you a little bit more about

Unknown Speaker 3:22

the setup of this conference on a special episode that will be released. I don't know before Wednesday, most likely.

Unknown Speaker 3:29

Definitely not aware of it. But

Unknown Speaker 3:32

one day, we will record and release a special episode.

Unknown Speaker 3:37

But it has to happen in next three days. And I have to finish a few things on the website, but lots of moving parts, but we're going to do that. And also, this is the week where we're going to announce the winners of the neonatal network grants. So that's exciting, too.

Unknown Speaker 3:53

So yeah, without

Unknown Speaker 3:56

without much further ado, we should probably get into journal club. Yeah. Who's starting today? Am I going first? So you're going first? You always I start with questions. You start with journals.

Unknown Speaker 4:07

That's our that's our sticker. So the first paper I'm going to review today is an article that made the rounds it was published in the New England Journal of Medicine. first author is Frank Bloomfield. This is coming to us from

Unknown Speaker 4:20

the farmlands of New Zealand.

Unknown Speaker 4:23

And the title of the paper is early amino acids in extremely preterm infants and neuro disability at two years. So what are some of the notes that I took on this paper?

Unknown Speaker 4:36

I'm not a big nutrition person. So so I'm always interested in reading the background of these of these papers, because I learned and I get some refreshers on some of the of the, of the nutrition information. Yeah, I think a Background section is like an underutilized part of reading studies. So I think it's funny because when it's a BPD paper

Unknown Speaker 5:00

Like, you get like a lot of statistics and you're like, alright, they're mentioning the statistics again. But I know that Yeah, yeah. Right. But then when it's not, that's something that you have an interest in, right? Exactly when it's not your field. But but I've always been like, oh my god, again, this statistics, but now you realize, like, when it's not your field, it's kind of nice to get these little reminders. And, and, and it's a good sometimes, like you said, it's a bit of a distillation of the current evidence. So it's kind of nice to read about that. So in the background section of the paper, they wrote that a fetus receives amino acid at an estimated rate of three to four gram per kilogram of body weight per day, an amount really, that supports fetal growth and brain development. Now, insufficient protein is known to lead to a negative nitrogen balance. And that's something that is very clearly mentioned in every board review books. However, the appropriate protein intake to support the growth and development of infants with extremely low birth weight is unknown, especially in the first few days after birth. And that goes back to many different

Unknown Speaker 6:02

aspects of, of matching the fetal growth of these fetuses after they're born preterm. And it's very difficult to try to get those to understand what those rates of sort of nutritional supplementation are for a variety of different things. And so in this case, we're talking about,

Unknown Speaker 6:21

we're talking about appropriate protein intake. Now, they're mentioning these observational studies that showed an association between a higher level of protein intake and better growth and neurodevelopment. And which which have prompted recommendations for earlier and higher amino acid intake for these infants. So they designed this this trial that they call it the provide trial, which stands for the protein, intravenous nutrition on development. Definitely on a scale of one to 10 the acronym what would you read it right now? Provide

Unknown Speaker 6:56

a bad one. We should yeah, I mean, yeah, I like I like it, because it's, it's already priming you that you should be giving enough, right? provide

Unknown Speaker 7:07

it? How much is enough? That's a different question.

Unknown Speaker 7:12

I'm giving it a seven out of 10. Seven out of 10. Yeah, okay. Yeah. Yeah. Okay. Okay. We're good. All right. So that was a good thing that we just did right there.

Unknown Speaker 7:22

So they looked at

Unknown Speaker 7:25

the provider, I looked at babies who were born with a birth weight less than 1000 grams, to determine whether the administration of amino acid had an additional one gram per day, starting within the first 24 hours after birth, and continuing for five days would increase the percentage of children who survived without neuro disability at two years of age corrected from prematurity. So let me get into the study design a little bit more.

Unknown Speaker 7:50

This way,

Unknown Speaker 7:53

this way, it this way, I can clarify a few things. So this was an investigator initiated multicenter parallel group, double blind, randomized control trial, they included babies who were born with a birth weight below one kilo and who had an umbilical arterial catheter. And that was interesting. They explained the reason why they wanted to have a UAC.

Unknown Speaker 8:17

Mostly because they wanted to make sure that they were able to consistently get the difference of amino acid administration between the intervention and the control group, without any factor, dampening that basically. And they excluded babies who were admitted to the NICU after 24 hours of life, multiple births of more than or have two or more infants,

Unknown Speaker 8:40

chromosomal genetic congenital disorders that affect growth, presence of inborn error of metabolism and danger of imminent death. They randomized babies, one to one to either the intervention or the placebo.

Unknown Speaker 8:54

What was the intervention? So the intervention basically started within 24 hours after birth, and continued for five days. And it involved infants receiving 8.5% Trofim eaten, which basically includes one gram of amino acid and 1.4 milligram of sodium. And I had that question, because it wasn't clear in that part of the paper, but this is in addition to your regular TPN with your regular amino acid. Does that make sense? So So those kids would get their TPN. As usual, they would order their TPN with the recommended amino acid levels in those TPN. And then in addition to that, the intervention group was going to get an extra one gram of amino acid.

Unknown Speaker 9:39

The control got some the same volume, which I think was 10 to 12 milliliters of just saline.

Unknown Speaker 9:46

They did a lot of fluid actually, for I was thinking about that. I was thinking about that soon. Interesting. I mean, that's how you do the placebo, but it's a lot of fluid.

Unknown Speaker 9:58

They looked at whether

Unknown Speaker 10:00

Were the administration of that placebo could have had an effect on some of the outcomes that they measured, especially when they did chemistries. So I don't know if I'm going to have the time to get into that. But they did look at it. And it's and I think there was one case where the placebo administration could have been the reason for some abnormalities that they saw.

Unknown Speaker 10:20

Okay, so they didn't really have a mental assessment that two years using Bailey, the best using the Bailey three, they did also some neuro exam, and they actually had other tools that they were using. So it was it was quite thorough. The primary outcome was survival, free from any neuro disability at a corrected age of two years. And then they had a long, long list of secondary outcomes. The other thing that they looked at was the incidence of refeeding syndrome, which, for those of you like me, who needed the reminder, is serum phosphate concentration of less than 1.4 millimoles per liter, and a total serum calcium concentration of 2.8 million more per liter on day five after birth. And what we'll talk about that in a little bit. So what are some of the outcomes of this study, they were able to enroll 434 infants, which were divided, equally, so 217 babies in each group. And the primary outcome, which was evaluated at two years of age was able to be achieved in about 94% of infants, which was pretty well distributed between the two arms of the study. So I think it was like, I think it was 93 5% in one arm and 94, two in the other. So so they had consistent, they had consistent

Unknown Speaker 11:37

follow up rates.

Unknown Speaker 11:39

So in terms of the primary outcome, which was survival without neuro disability at two years,

Unknown Speaker 11:45

that was seen in 47.8% of the babies who received the additional amino acids, versus 49.8% in the placebo group. So quite similar, and not really, statistically significant. Now, I'm going to go through some of the some of the interesting secondary outcomes that they looked at. And there's many more things obviously to look at through the paper.

Unknown Speaker 12:12

So this is by no means a complete exhaustive list of all the outcomes that they looked at. But some were quite interesting, looking at the rates of neuro disability, any neuro disability.

Unknown Speaker 12:23

Between the two groups, they found similar rates between the 240 1% in the amino acid group versus 37%. In the control, in terms of moderate to severe neuro disability, they found that the babies who received amino acid actually demonstrated more rates of higher prevalence of moderate to severe neuro disability. And the rates were actually quite high 16.5% in the amino acid group versus 8.6%, in the control. So if you're listening and you wondering if you heard correctly, yeah, the babies in the intervention arm did worse, quite quite impressively. So looking at moderate to severe cognitive delay, specifically there to the babies who received amino acids did worse 6.9% of cognitive, C moderate to severe cognitive delay, versus only 2%. In the control. Wow.

Unknown Speaker 13:15

Other Other aspects, I think the cognitive delay, I have to look back, I didn't write it down in my notes whether the cognitive delay was actually statistically significant.

Unknown Speaker 13:27

Doing it, I don't have it in front of me, I'll have to look it up. They looked at language score, that was also lower in the intervention group that was not statistically significant, but that trended toward lower in the intervention group. The rest of these,

Unknown Speaker 13:40

the rest of these factors of the primary outcome were the rest of them were sort of similar between the two groups. They noted also an interestingly, an increased risk for an increase an increased need for PDA treatment, that was higher in the intervention group 54% versus 42%. That was statistically significant as well, the length of stay was similar between the two group, they saw a higher incidence of refeeding syndrome in the intervention group 24% versus 16%. And

Unknown Speaker 14:11

and then in terms of growth and and and anthropomorphic measurements. Interestingly enough, the growth was a little bit better babies were able to gain more weight in the first four weeks of life in the in the intervention group, but that sort of was not sustained later on. So so there was no sustained growth benefits when it came to the intervention. The time to reach for feeds was similar between the two groups as well. And so in conclusion, they were saying how, in infants with extremely low birth weight, extra parenteral amino acid at a dose of one gram per day for five days after birth did not increase the number of infants who survived free from near with disability. They're actually in the process of collecting longer follow up data at everything six to seven years. So we're we'll be looking at for the data when that comes out. And one of the other

Unknown Speaker 15:00

conclusion is that they're saying at this time this this data does not. Sis does not warrant any change to the current recommendations of the recommended amino acid supplementation for extremely low birth weight infants.

Unknown Speaker 15:14

That's this. You know, it's interesting. My, my thought always in nutritional studies is is like, again, this thing about different phenotypes. Like, I wonder if they split the group by the really growth restricted baby, right, the baby who would have been nutritionally deficient, you know, would we see differences? Maybe it's worse either, though, certainly the refeeding risk would be would be higher refeeding syndrome. But, you know, like with these vitamin supplementation, it's like, if you have enough, is the extra not helpful, but if you don't have enough is more better. I don't know. That's what I would have liked to have seen. But I'm actually going to look at that right now. Because

Unknown Speaker 15:57

I'm postcard, it's hard for me to

Unknown Speaker 16:00

it's hard for me to remember, but I do think they mentioned in their growth, discussion, something about the babies who are small for gestational age.

Unknown Speaker 16:10

But I have to, I have to pull out, pull away from my notes. And I have to go browse through the paper again, and I don't want to make you wait, but I'll try to slow you you'll get back to me. Yeah, they're just such a high risk group, you know, 100% You're so right about that.

Unknown Speaker 16:30

So, all right, well, then, shall I move on while you while you search? Yeah, I may not. I may not find anything but.

Unknown Speaker 16:38


Unknown Speaker 16:40

So another

Unknown Speaker 16:42

article that has been a hot topic is this article title?

Unknown Speaker 16:48

Alright, you want it? Okay. So it's in the supplements. Okay. So it's supplement table nine. And they were saying that they did this post hoc subgroup analysis where

Unknown Speaker 16:58

the number of infants with sepsis refeeding syndrome and survival free from neuro disability were similar in the two groups among infants, regardless of their small for gestational age status. There you go. Okay. All right. I got it for you. Okay. I feel good that sorry for the interruption.

Unknown Speaker 17:17

Thank you. So, this paper entitled analysis, analysis of neurodevelopment and children born extremely preterm, treated with acid suppressants before age two years. Lead author Elizabeth Jensen, senior author, Michael O'Shea, and then this was in JAMA Network open. So they were really looking to just do that assess whether early acid suppression in the extremely preterm infant before age two, and they looked at in NICU use and then kind of post NICU use was associated with poor neurodevelopmental outcomes. So why did they think that I thought this was again an interesting part of the background information. So there's a lot of data from the adult population that suggests that PPI use is associated with a wide range of neurologic outcomes, migraines, peripheral neuropathies, visual and auditory neurosensory abnormalities. And I did not know that. Obviously, there's this concern always, we've had this concern, especially with the extremely low birth weight infant that PPIs may have some association with decreasing the immune response, certainly by suppressing the acid, but also this PBI association with immune cell activation, migration and function. And so there was a plausibility for a link between acid suppressants and preterm infant neurodevelopment, especially in an infant who may already be at risk for kind of dysregulated development. So the study design and this is another paper from the Elgin study the extremely low gestational age newborn study, which as a reminder was a multicenter longitudinal cohort study of infants born before 28 weeks gestational age between March 22 of 2002 and August 31 of 2004.

Unknown Speaker 19:17

About 79.5% of the original cohort was eligible for a visit at the 10 year mark, which is now

Unknown Speaker 19:28

and of these 74% participated in the visit at 10 years, and the neurodevelopmental assessments at 10 years included the school age differential ability scales, the developmental neuro psychological assessment, the autism diagnostic observation schedule, the social responsiveness, scale and the child symptom inventory, or for attention deficit hyperactivity disorder, depression and anxiety.

Unknown Speaker 19:54

So the inclusion criteria was acid suppressant use so they collected data on acid suppressant used

Unknown Speaker 20:00

During the NICU hospitalization through abstraction of the medical records and then again at evaluation at 12 and 24 months corrected age from parents survey data, and any documentation of a PPI or a

Unknown Speaker 20:21

I forgot what this stands for. h2.

Unknown Speaker 20:26

Basically an h2 blocker within the first 24 months of life constituted early life exposure to acid suppressants.

Unknown Speaker 20:34

Do you mean a proton pump inhibitor? No, not a proton pump inhibitor. The h2 receptor antagonist drugs that histamine blockers basically are slightly different than a ppi.

Unknown Speaker 20:49

Okay, so, PRI the primary let me start tell you about some of the baseline data. So the demographic distribution of those exposed and unexposed acids presents were generally similar. But those exposed to acid suppressants were more likely to have required mechanical ventilation at 36 weeks that was 11.3% versus 6.3%, were more likely to have white matter damage already documented 22.4% versus 18.7%. And we're more likely to have experienced feeding difficulties at 12 months of age 26.5% versus 20.2%. So I thought that was interesting, especially

Unknown Speaker 21:32

the data on the white matter damage.

Unknown Speaker 21:36

So acid suppressant use was associated with reduced full scale IQ, which equated to a decrease of 4.35 points on the full scale IQ. Obviously, there's some discussion about the

Unknown Speaker 21:50

clinical significance of this decrease, but they also showed reduced verbal IQ, reduced nonverbal IQ. And in addition, children who used an acid suppressant also had reduced scores for the working memory and inhibition, inhibition. And they observed no association between acid suppressant use and this inhibition, switching sub tests. Also, for looking at classifications of cognitive function, the risk of moderate to severe impairment relative to low, normal or normal cognitive function was higher for children who used acid suppressants early in life with a adjusted risk ratio of 1.4. And then when they looked at the neurodevelopmental and mood disorders, acid suppressant use was significantly associated with autism spectrum disorder with an adjusted risk ratio of 1.84, as well as an association with epilepsy and adjusted risk ratio of 2.07, but not ADHD, anxiety, or depression.

Unknown Speaker 22:52

They also performed in propensity score matched analysis, they use 328 of the 521 exposed infants to match with an unexposed infant.

Unknown Speaker 23:05

And the assessment of the association between acids to present use, according to timing, suggested marginal differences, although the direction of association remained consistent across all exposure period. And what did they mean by that? This is when they were looking at when did they get the acid suppression. So acid suppressant use in the NICU was associated with a higher risk of autism spectrum disorder, adjusted risk ratio of 1.85, whereas neurocognitive impairment was associated with use after discharge, or in the NICU and post discharge periods combined.

Unknown Speaker 23:40


Unknown Speaker 23:43

does this change my practice? What is my takeaway? I mean, we don't use a lot of acid suppression therapy already, right? There was like this shift in the community as of what, five to 10 years ago anyways, but they're still I mean, they're still babies getting acid suppression. And

Unknown Speaker 24:01

we have to think about the long term risks. And I think actually, there are probably potentially way more term babies getting acid suppression than even in the NICU because of this kind of cultural shift. But again, this study wasn't describing term infants just describing the

Unknown Speaker 24:23

low birth weight infants, thoughts.

Unknown Speaker 24:27

I mean, it's interesting, because you, you, you hinted that this right, we sort of know to stay away from from assets requesting medications, but which also means that when we use that usually, like, it's not really elective, you know? Yeah, right. And I think we are using them as kind of a last resort, but there are still some babies that seem to benefit.

Unknown Speaker 24:57

Exactly. And so and so the question is

Unknown Speaker 25:00

Um, the babies who we ended up giving those. So

Unknown Speaker 25:05

the one things that the paper maybe

Unknown Speaker 25:08

the paper, it didn't really have the opportunity to do, which is to tease apart like the different types, the indications for starting them, and so on. I think I think that that's interesting, too. That would be interesting to look at. I mean, they do mention that, obviously more studies on this, like, they're not really being very categorical in their

Unknown Speaker 25:27

Yeah, they're, they're not saying like, Hey, you should, you should stop at all with this saying, like, hey, we need to look at this more closely. And I think they're absolutely right about that.

Unknown Speaker 25:34

And the question becomes, yeah, because the babies that we do give them, they give these acid suppressing medications to the they're very often in a pinch and need to go home and have difficulty with feeding and so on, which in their data was not really clear that this was the case. So again, there may be different indications in their group. But the question is, what would have happened if they had not received it? So like the

Unknown Speaker 25:58

Yeah, this? Yeah. So and do do we know that development is probably better at home than in the NICU? Yeah, probably. So I have a feeling.

Unknown Speaker 26:08

I have a feeling that I'm going to keep giving us at suppressing medications when I feel like it's absolutely needed. And unlike before, I'm going to have like this little tension in my back as I put in the order a little bit more more pronounced than before, because I'm like,

Unknown Speaker 26:22

do we really need to do this? Do we really need to do well, and I think, I think maybe one thing a good takeaway is, if you're going to trial, something like this, and it's not better than Stop it, right? So a lot of times once babies get started on acid suppression therapy, and you're like, wow, that's bad. I've Margeaux it's not bad. It's not really better. But let's just leave it on. Let's see if it works, if we leave it for longer. But maybe hopefully, we can stop doing that. You try it. If it doesn't work, you get off of it. I had a I had a medical school professor who used to give us this sort of

Unknown Speaker 26:56

this this thing about like, using medications that had some some issues associated with them. And she was saying, first step is to say no, then start slow. And then and then be quick to say no more.

Unknown Speaker 27:13

Yeah, that should be on a t shirt. Something. Yeah.

Unknown Speaker 27:18

Maybe it will.

Unknown Speaker 27:20

Alright, so since you're, you're doing neuro cognitive,

Unknown Speaker 27:23

neuro, the mental outcome stuff. I'm going to go next to a paper that was published in pediatrics. Not too long ago. When was that published? Actually, December isn't the December issue. Okay.

Unknown Speaker 27:38

In any case,

Unknown Speaker 27:40

I always feel like I'm behind in terms of the papers because these these journals always have like, the December issue out November 20. So it's like, it feels like you're always feel like I'm in December. Yeah, I know. This episode is so proudly sponsored by rocket meat Johnson. Recommend Johnson is dedicated to the research and development of nutrition products that help support baby development at every stage, including an extensive Enfamil portfolio for premature and low birth weight. infants learn more at HCP dot meet So this paper is called relative age and psychotropic drug use in preterm and term born children and young adults. first author is Christine strand, Buckman.

Unknown Speaker 28:23

And this is a paper coming to us out of Rooney's homeland, Norway.

Unknown Speaker 28:29


Unknown Speaker 28:31

where are my notes on this paper? There they are. Okay. So

Unknown Speaker 28:37

the, the Background section was very interesting for many reasons. So number one, there's some interesting data about the fact that, as we probably are familiar with preterm babies are at high risk of

Unknown Speaker 28:49

being diagnosed with ADHD, psychiatric problems, social cognitive disadvantages, compared to full term babies who were born full term infants who were born at full term. Now,

Unknown Speaker 29:00

they then go into sort of the school system in Norway, and I think it's everywhere is different. But in Norway, kids get placed into a grade based on the calendar year in which they are born. So, which, interestingly enough, is the way it was back when I lived in New York, but in Florida, for example, I think there's like the deadline of September 1, right? Am I correct? If not, you probably know this, but it's something like that. Something my kids not close enough. So we never, we never had an issue because my daughter, my daughter was born in December. So in New York, she was supposed to enter first grade, but then we went to move to Florida and they said, well, she's supposed to stay in kindergarten and not move to first grade. But so we had to look at was she allowed to continue on was that kind of she was she was able to get here but the cutoff was like September something my daughter's December. But in Norway, it wouldn't have been an issue because she's in the right calendar year. Now whether why they're mentioning all these things is because they're saying that it creates something on the corner

Unknown Speaker 30:00

logical age relative to the other classmates that they define as, like the relative age effect. And they're saying, if you're in a class with somebody born in January, and you yourself is born in December, there's like a significant difference between that child born early in the year versus the kid born later in the year. And, and that difference can can cause a lot of socio neurodevelopmental issues.

Unknown Speaker 30:26

And they're showing in the background section that younger age in a school class increases the risk of being diagnosed with ADHD and prescription of psychostimulant. Which,

Unknown Speaker 30:39

as like, that's, that's nuts. I didn't know that. Yeah. Now that's where what they're trying to get to is, what if you're preterm is there like the double burden as they say, because now not only are you in the class, and you may be born later in the year, but now you're also born preterm, so you're even smaller. So the the, their goal was to assess separately, preterm interim born infants, for the importance of relative age in school on mental health indicated by psychotropic drug use in adolescence and young adulthood.

Unknown Speaker 31:14

So far, so good, because these were concepts that I had to sort of wrap my head around. And they're not your usual Pneumatology stuff. Correct? Right. This is the into our general pedes. But but it matters, it matters. Of course, it matters.

Unknown Speaker 31:30

Okay, so then let's go into the study design. So this was done using some of the Scandinavians social healthcare system using this medical birth registry of Norway. And this birth registry also provides data on all prescribed drugs dispensed by pharmacies, and they can follow these kids way into young adulthood. So they looked at babies born between 1989 and 1998. And the reason the data collection was so far back is because they have followed up kids until they're like early 20s. And they looked at babies born between the gestational age of 23 weeks to 42 weeks, and the birth weight with a minimum birth weight of at least 400 grams. They excluded babies who had some congenital birth defects. And one of the criterias was that they had to be alive at 10 years, which is when they started looking at some of these outcomes.

Unknown Speaker 32:23

So these individuals were followed between 2004 and 2016. With Annual Registration from the year they turned 10, until the year of their 24th birthday, in immigration. So leaving the country death, whichever one occurred first. And then they categorize babies into a preterm group, which was considered a baby born between 23 and 36 weeks or term 37 to 42 weeks.

Unknown Speaker 32:50

Now, in terms of the relative age, so they redefined that in the study design, which I think was important, and it's measured basically by the month of birth in the year, and categorized into month intervals. So they're looking at kids born, for example, January, February. So individual individuals born in January or February, for example, were defined as relatively older, having a higher or having a high relative age, whereas those born in November, December, were defined as relatively younger having a low relative age. So if you're still was trying to understand this concept of relative age, I think that explains it pretty well. The primary outcome of the study was the need for psychostimulants for ADHD. And then secondary outcomes include prescription status of for other categories of psychotropic drugs, which are antidepressant, hypnotics and zeolitic. anti-psychotics.

Unknown Speaker 33:41

Okay, so then let's get into some of the results. So the number of individuals that they were able to assess was 488,470 people. So large data, obviously, as you would expect from this large database.

Unknown Speaker 33:57

And the figures are actually quite interesting. So figure two in the paper, is this this graph. And it shows the annual psychostimulant use by categories of birth month throughout the year, showing that there's a gradually higher proportion with psychostimulant prescription with increasing birth month from January February to November December for both preterm and term born either male or female. So if you go in figure two, you have two graphs, one for males, one for female, and then on each graph, you have two lines, a red one and a black one. The red one is the pre terms. The black one is the term kids. And what you see is that the psychostimulant prescription does increase quite linearly from the B from early in the year all the way to the later in the year. I have to say that for females, the lines are kind of close to each other. Not really, that different. However, for the males, it's actually quite impressive. That there's this

Unknown Speaker 35:00

significant difference. I'll tell you a little bit about that. The prescription for boys born in November December was 1%, higher from for preterm

Unknown Speaker 35:12


Unknown Speaker 35:14

for preterm born and 1.3% higher for term born compared to two boys one earlier in the year. So, for girls, it was much less it was point 5% And point 4% respectively.

Unknown Speaker 35:26

For term born in November December, the adjusted odds of psychostimulant prescription compared with peers born earlier in the year was 1.8, at age 10 to 14 years, and 1.17 at ages 20 to 23 years.

Unknown Speaker 35:47

Within preterm born, the corresponding results were 1.39 at age 10. Through 14 years and 20 through and 1.34, between the ages of 20 to 23 years old,

Unknown Speaker 36:01

a relatively younger term and preterm groups were more often prescribed antidepressants and anti psychotic drugs at 10 to 14 years compared with peers born earlier in the year. But this did not really persist later, at later ages, like when they were looking at it from like 20 to 23 years old. In terms of the other four anti, the other four psychotic drug groups that they were looking at. They were no relevant changes. And if you go look at some of these, at these are, I forget how these graphs are called the

Unknown Speaker 36:33

whatever, I'm just not going to try to tie. But if you look at the psychostimulants, and they have it broken down by by gestational age, so they have the pre terms, and they have the terms, what you see in the term groups is that the odds of being prescribed psychostimulants between 10 to 14 years of age, the odds ratio is 1.8, as we've mentioned, and that sort of slowly goes down, as you get to the older age groups, so 15 to 19 years old, 20 to 23 years old, and it's almost like in a stepwise fashion. And the difference between the babies were born later in the year and earlier in the year sort of

Unknown Speaker 37:08

is reduced. In terms of the pre terms, you don't see that trend at all, it's quite consistent. It's not as pronounced. So like the odds ratio we said was 1.8, in the term kids that tend to 14 years. So in the in the babies that were preterm, the odds ratio was like 1.4. So not as significant, but it stayed like that, throughout the different age groups, it was 1.4, a 10, to 14 years 1.3 at 15 to 19 years, and 1.34 at 20 to 23 years. The confidence interval

Unknown Speaker 37:41

does get a little bit wider as you get to the older age groups. But I thought that was an interesting trend. So the conclusions of the paper are that preterm children born late in the school year have increased risk of psychostimulant prescription compared with preterm peers not previously studied, this relative age effect seems to persist into young adulthood, in contrast to findings for term born children. So I thought this was this was very interesting data. And I have a feeling that you know, sometimes you read a paper and you're like, Oh, my God, one day, I'm going to have to present on prematurity something and this is data that actually speaks to people because that's ridiculous. Yeah. And, again, this is like a large birth registry of almost almost half a million individuals with data up into their early 20s. So very, very interesting paper.

Unknown Speaker 38:33

Yeah, provoking. I mean, we know that the preterm infant is at increased risk for for ADHD. So it makes sense that, you know, to look at the medication trends, but this is interesting. And it turns out, I mean, there's so much we don't understand about, you know, our, our environment, right, like, your, your, your birth, but it's, it's, it definitely spoke to me because my daughter, like I said, she's in she's a December, girl. And, and so she's like, the smallest kid in her class, everybody thinks she skipped a class. And, and it's and, and it's fine when you're like, six, seven years when you're six, seven years old, but like, as you get to like, these 10 to 14 years of age. It's a it's it's such a hinge type of age group, that that this is, this is this could be, this could be an issue. And so it's true that when you say I had something I thought about from my daughter who was born full term, who's doing fine who has no issues, thankfully, but like, I was like, Oh, you're right. It's the right like if on top of that, your former preacher. Holy smokes. Yeah. Yeah, the additive kind of effects.

Unknown Speaker 39:43

Okay, I'm gonna take a different a different trajectory. That's fine. That's it. That's it. We didn't close that chapter for today.

Unknown Speaker 39:51

I have this article association between neonatal phototherapy and future cancer and updated systemic review and meta analysis.

Unknown Speaker 40:00


Unknown Speaker 40:01

anyways, I just feel like we can't.

Unknown Speaker 40:04

I'm so curious about this question that we had. We have to review them when they come up.

Unknown Speaker 40:11

Lead author Mohamed Dillard up dilla Teef.

Unknown Speaker 40:17

Yes, I did it, I did it. And this is in the European Journal of Pediatrics. So, the study design is, again, a meta analysis using a database search

Unknown Speaker 40:30

using an outcome variable only if it was found to be present in at least two papers, because when we talk about childhood cancer, there lots of different kinds of cancer. So a lot of papers are only looking at one kind of cancer or the cumulative risk. So it's, it's hard, I guess, to follow the data, so to speak. So the outcomes were any type of cancer, leukemia and its subtypes and non Hodgkins lymphoma, as well as cancers of the liver, skin, bone, nervous system, kidney, eye, and orbit.

Unknown Speaker 41:04

And most of these are quite small. Thankfully, since the different types of childhood cancers are still rarer than other childhood diagnoses, but it did include some recent large studies, including the 2022 paper out of Israel that showed specifically phototherapy was associated with him adipocytic cancers and leukemia with a hazard ratio of 2.29 and specifically for hematopoietic cancers 2.51, but did not show an association with solid tumors and lymphoma. It also included the Digitali at all paper published in 2021 in pediatrics, which used a huge cohort study of the Kaiser California hospitals and did not find any association. It also included a 2020 Iranian paper that used a large larger case control study that did not show any increased risks, except that the risk of cancer was increased by 55%, when it was accompanied by male gender, maternal age greater than 35 years during pregnancy and smoking by Father. Interestingly. So their inclusion criteria they had a total of 7,343,592 participants and from eight different countries Sweden, the US, UK, Canada, Denmark, Taiwan, Iran and Israel. They included 15 articles, seven were case control studies, and eight are cohort studies. And in terms of quality six case control studies, and three cohort studies were a fair quality while one case control study and the remaining cohort studies were of good quality.

Unknown Speaker 42:36

So let's get into the outcomes, any cancer so they use six studies to do the analysis of the combined data. And as for the unadjusted data, there was no statistically significant association between exposure to phototherapy in the neonatal period and the future development of any type of cancer. Now, it's ratio of 1.1. But there was a statistically significant association

Unknown Speaker 43:00

in the neonatal period, and the future development, any type of cancer when using the adjusted analysis.

Unknown Speaker 43:10

Then in terms of any hematopoietic cancer, three studies contributed to this analysis, there was a statistically significant association between exposure and the nail period and the future development of any Hamato poetic cancer odds ratio one point or nine and comparable results were found in the unadjusted data analysis. Any leukemia, five studies were included there was a statistically significant association between exposure to phototherapy in the neonatal period and the future development of any type of leukemia odds ratio 1.35 is also true in the unadjusted data analysis.

Unknown Speaker 43:47

myeloid leukemia, they use three studies, and there was statistically significant association between exposure

Unknown Speaker 43:56

for myeloid leukemia and odds ratio of 2.86. In both analyses, there was no statistically significant association between exposure to phototherapy and the future development of lymphoid leukemia, non Hodgkins lymphoma, kidney cancer, skin cancer and nervous system cancers.

Unknown Speaker 44:15

So, I mean, I thought this paper was interesting, just because I think the question is still out. But one thing that is there's been a thread in some of the articles we've reviewed, is that, um, the author's pointed this out in their discussion is that there's a concern that hyperbilirubinemia itself may be the risk factor for development of certain cancers. And I think this is particularly important since the guidelines just changed. And we are tolerating much higher bilirubin levels. So I guess we'll see.

Unknown Speaker 44:52

That is so interesting. Yeah. Kind of terrifying. I didn't I didn't have the chance to read the full paper so I didn't get to that part of the

Unknown Speaker 45:00


Unknown Speaker 45:01

Discussion, that kind of discussion. So now.

Unknown Speaker 45:05

I mean, there's there's this paper in the in pediatric research. That is a special article looked at models of bilirubin neurological damage lesson learned and new challenges. I didn't read the paper yet. But I'm curious if they do mentioned how some of the effects of bilirubin on bill, because I know that in the paper just by browsing it quickly, I know that they're talking about bilirubin accumulation in the brain. So that's very interesting. Nonetheless, I think when the new pediatrics when the new guidelines came out for the phototherapy threshold, my concern was like, Oh, my God, like you're afraid you like, as we're going to roll this out. And we're going to find out that more kids need exchange transfusion, and we're going to start seeing more connectors and stuff. But it's that data, that kind of data about like, childhood malignancies that make you say, You know what, maybe that's not so bad that we're increasing the threshold.

Unknown Speaker 46:02

And, and it would be very interesting as those guidelines as soon as those guidelines have changed, and those thresholds are now

Unknown Speaker 46:09

much higher, then hopefully, we'll see if the rates of cancer are higher or lower, and then we'll be able to get our answer. It's terrifying. Now it feels like it could go either way. Right? Yeah. But um, these odds ratio are not like, Man, those I mean, right? Yeah. If it's your kid, like an odds ratio of 1.24. And as a ratio of 1.49 1.35. These are like two tuple or byla. It's like one like 25% 50%. And it's like, it's crazy. It's crazy. So hopefully,

Unknown Speaker 46:44

hopefully, hopefully, hopefully, sorry about that.

Unknown Speaker 46:50

It's just like, you know, this is, this is like a large data set. What was that? Like?

Unknown Speaker 46:55

Seven 7007? Millions, I guess, right? 7 million.

Unknown Speaker 47:02

You're like, how many babies? Did I say no, let's keep phototherapy one more day. That's right, one more day.

Unknown Speaker 47:08

But I mean, to our previous conversation, when you have the baby who you say, um, yeah, it's just the little baby, right? Oh, let it's going up, down. Let's just leave them on, you know. So

Unknown Speaker 47:22

these are the times where you say,

Unknown Speaker 47:26

we'll see. Okay.

Unknown Speaker 47:29

I have a few Lightning Rounds paper, but I have one more that I reviewed. And this is a paper that I was made aware of by, I think one of the authors on Twitter. This is a paper that was published in pediatric pulmonology. And it's called outcomes of infants with severe bronchopulmonary dysplasia who received tracheostomy and home ventilation.

Unknown Speaker 47:50

It was a it was a first author is Dr. Ken Jiri. And this is from a group out of the US.

Unknown Speaker 48:01

Where's my where's my list of papers? There it is. And this is coming from I think, I think Kansas, I'm not gonna say Kansas before I tell you.

Unknown Speaker 48:12

Kansas University Medical Center, look at the postcard remembering the location.

Unknown Speaker 48:17

Okay, so what is the background of the paper, right?

Unknown Speaker 48:22

We know that babies who have severe BPD, who are receiving invasive ventilation at 36 weeks have a significantly greater risk of needing a tracheostomy for continued assisted ventilation. Now, it's true as the author's mentioned that there's no clear guidelines among institutions on how to decide when to offer what criteria to use optimal timing data on parental acceptance of tracheostomy plate placement. For the purpose of long term resolution, there's, there's really not much guidance for that. And so in the US, they're reporting I mean, they're they're quoting a report. This is a tracheostomy placement in the NICU for infants with severe BPD ranges from like 2% to 37%. And that just goes to show you that there is not a good consensus as to what is the approach should look like. Additionally, there is also a wide variety variability among centers in terms of the outpatient follow up that is being provided to the infants with severe BPD receiving tracheostomy. And that's true that, I mean, we can speak for ourselves here. They don't have like a medical home, we in our, in our institution, and in our community, there's not like a medical home for these babies with BPD. After they leave, they go see their specialists and they go see their consultants. And we're, we're confident that these people are talking to each other, but it's not a unified

Unknown Speaker 49:41

it's not a unified home.

Unknown Speaker 49:44

So what they were trying to do, and they they had they had ambitious goals. They wanted to know what are the respiratory outcomes? Yeah, because when I'm going to tell you all the things they the aims were quite long. So you're like holy moly, that's, that's, that's a tall order. So they said what are the respiratory

Unknown Speaker 50:00

outcomes of infants with severe BPD who receive tracheostomy and who were followed by a dedicated hospital based neonatologist led, inter and multidisciplinary, Family Centered Medical Home. They basically have a BPD group that is identified to care for their BPD patients in the hospital. And that team follows these kids outpatient up to four years of age.

Unknown Speaker 50:24

So they wanted to report some of these outcomes. But they also wanted to describe the medication exposures, as well as the rates of rehospitalization of infants with severe BPD receiving tracheostomy.

Unknown Speaker 50:37

And they wanted to describe also the growth patterns of these chronically ventilated infants at home.

Unknown Speaker 50:44

And they wanted to identify biological and clinical factors in these infants that may be favorable for tracheostomy decannulation. So that's a tall task. I know. Right? I mean, that's I didn't say I didn't say that the they didn't say anything negative, I just said they they set the bar pretty high. So

Unknown Speaker 51:02

the study design is pretty straightforward. It's basically retrospective review of data that they're collecting prospectively in their unit. So they basically did a cohort study of infants with severe BPD receiving tracheostomy who are discharged from the Children's Mercy Kansas City level for NICU and followed by what is known there as the infant tracheostomy and home ventilator clinic. The it HB clinic from 2004 to 2017. inclusion criteria, obviously, were severe BPD patients with a tracheostomy. Interestingly enough, the diagnosis of severe BPD was based on the original 2001 definition.

Unknown Speaker 51:42

Which, I mean, we did a whole neonatology review series on the definition of CPD, and you can go listen to that, but I was expecting maybe for them to use a more recent definition. And they collected a ton of data, both demographic and clinical. And because we're already into like, what, 45 minutes into the podcast, I'm not going to read all the all the different variables, but I'm going to try because there's a lot of results that I want to go over. So it's there, I'm not doing the methods justice, but it's retrospective review. And they just have a ton of data.

Unknown Speaker 52:16

So 246 patients were tricked before one year of age between 2014 2017. Now

Unknown Speaker 52:25

they were able to include 98 Babies based on the diagnosis based on other factors. And the median gestational age at birth of these infants was 25 weeks median birth weight at birth, median birth weight was 710 grams. So they still remain, you know, these small, less than 750 gram babies. Okay, so

Unknown Speaker 52:46

I think I'm going to preface all the results by saying they're not really disclosing

Unknown Speaker 52:54

too much about like, how they're doing what they're doing, but they have data on 100 patients with severe VPN tracheostomy. So I'm just going to report their findings, right? So the median age at tracheostomy was four months, which is about 43 weeks post conceptual age.

Unknown Speaker 53:11

Which is interesting, because some people may say that's kind of early, some people would maybe want to wait until closer to like 46 weeks, you know, maybe even 52 weeks. But it's not surprising when we're going to talk about some of their their outcomes, which are quite good that the earlier you trach. If you know that the trick is necessary, some of these outcomes usually are better. They found a significant increase in the number of infants with severe BPD, who received a tracheostomy per year over the study period. I thought that was very interesting, because that meant that as the team got comfortable with the way they were managing these babies, it looks like they were more comfortable recommending tracheostomy and the curve is actually quite impressive, where it's sort of, you have the number of severe BPD patients on the Y axis. And it's like maybe two, three from like 2004 to 2007. And then it jumps to like 10 to 12 a year. And then it sort of stays between like eight and 12 during that period until 2017 When it goes back down to six. So the question is, do we become desensitized with the implications of a tracheostomy? And we just recommend it more frequently, or are we just more more comfortable with the outcomes and believe that this is the proper way to go? That's I think, was a fascinating statistics. At age four years, 52% of the patients were D cannulated. With a median age of decannulation. At about 32 months, that is something that parents asked you all the time. How long is the tree going to be in? And I'm sorry to say but I was expecting that at four years, the rates were going to be higher.

Unknown Speaker 54:48

Because only 52% At four years. Because you know, I try to the parents are asking me you know, the parents sometimes know that the trach is something the old people get, in which case sometimes it stays in

Unknown Speaker 55:00

For a long, long time, but you tell them no in the baby like eventually it comes out. But it's a difference if it comes out after a few months versus three to four years. The median age at which the babies were quote unquote liberated from the vent was 24 months, so two years until they fully came off the vent. 36% of infants required upper airway surgeries in the form of Supraglottic, Supra glottal, plasti, tonsillectomy, adenoidectomy, or laryngotracheal reconstruction. So not an insignificant number there as well. Tracheal Bronco, Malaysia was slightly less prevalent in those who were D cannulated. By four years of age that was not really statistically significant. But tracheal Branca Malaysia, decreased one's odds of decannulation by 65%.

Unknown Speaker 55:49

Have a little side there, I put low emojis for myself. So like I had the one with the with the head blowing up, you know,

Unknown Speaker 55:58

like that emoji

Unknown Speaker 56:01

65%, I would not have guessed that number. Use of diuretics decreased. So they were looking at the use of certain medications. So the use of diuretics consistently decreased over the three years, up to three years of age. And then he sort of stabilized the use of Gi medications, since we were talking about it through from discharge through three years was 39% at discharge 47% at one year, 44% at two years 35.7% at three years of age, which was quite impressive, because that's even if we don't give it to them in the NICU. They get it. Yeah, about 85% of these babies required rehospitalization. 67% of them had one to four rehospitalization event. The majority of these rehospitalization happened in the first 24 months of life, most common cause for it was some form of respiratory complaints.

Unknown Speaker 56:53

The numbers I mean, this is this is obviously, a large number of readmission. The fact that it was in the first 24 months is not surprising, the fact that it was respiratory is not really surprising. In terms of growth, Z scores for weight and weight for length showed consistent growth from NICU discharge through three years of age. And I think that speaks to some of the papers that have been published on trying to recommend tracheostomy sooner rather than later. Because you really can get a much better growth outcomes if you don't let them sort of fall off the curves before you proceed tracheostomy

Unknown Speaker 57:25

service survival to h4 for years was 99%. And the one death that was reported was complications of a baby who basically self D cannulated. And passed away so it sounded terrifying.

Unknown Speaker 57:40

factors impacting decannulation were so so you were you were more likely to be de cannulated early if you had a fitness if the race of the patient was white, if you were event free by year two, and if you had public insurance.

Unknown Speaker 58:00


Unknown Speaker 58:02

Finally, the presence of pulmonary hypertension and rehospitalization event were not associated with the odds of decannulation by four years of age, which I was puzzled by that.

Unknown Speaker 58:18

What else did

Unknown Speaker 58:22

the conclusion of the paper are basically that infants with severe BPD, who had when they went tracheostomy had excellent survival rates, and that liberation from home ventilation and decannulation are likely to open by year four? Likely because it's 52%. It's barely a coin toss.

Unknown Speaker 58:38

But that was interesting data. That was data to look at. And you can we're gonna pull some of these graphs because it's actually quite interesting. Yeah. Yeah, I mean, I think it's, it's a moving target, right, just like you said, but it's important for anticipatory guidance for families. And I think it begs the question of meeting with your local teams, right, and finding out what are their kind of outcomes and practices.

Unknown Speaker 59:05

Okay, all right. I have one more. All right. I have one more and then I had some rapid review also. Okay. This was entitled early skin to skin contact and risk of late onset sepsis and very and extremely preterm infants. Lead author Isabel Loray. And this is coming to us from I always say it wrong, we need your French accent here. Okay.

Unknown Speaker 59:30

The epi pas group there you go. I did it at the Bosch you're ready to come on the French podcast now.

Unknown Speaker 59:39

I'll tell Gabriel that you're coming now that you

Unknown Speaker 59:43


Unknown Speaker 59:45

be pushed to do that'd be pushed do group you were doing so well. Why did you why did you?

Unknown Speaker 59:54

That was pretty good. Okay, this isn't pediatric research. So what's the question they wanted to evaluate the association

Unknown Speaker 1:00:00

between exposure to early skin to skin contact and incidence of late onset sepsis and extremely in very preterm infants. I think this is valuable because in lots of units, this concern about infection is a stated reason why people are not doing well much kangaroo care at all, but certainly early kangaroo care. So the study design, and this is a use of the EPA pouch to cohort it, which again, as a reminder is a prospective national population based cohort study out of France that had an inclusion period from March to December of 2011. With plans for follow up at 12 years, so we're again almost there.

Unknown Speaker 1:00:41

So their intervention they used questionnaires regarding skin to skin to develop this quote unquote, kangaroo mother care KMC score for each infant. And they were particularly interested in exposure to early skin to skin care, which was defined as initiation before day four of life,

Unknown Speaker 1:01:00

which is difficult in some units non existent in others.

Unknown Speaker 1:01:05

And then their primary outcomes. They wanted to look at late onset sepsis, which is considered in case of bacteremia, or positive CSF culture beginning after day three, and requiring five or more days of antibiotics. And then they looked at this other class of Lonnie late onset neonatal infections defined as an episode beginning after day three and require five or more days of antibiotic administration associated with any positive bacterial culture, blood CSF, tracheal, aspirate cutaneous lesion, urine, conjunctiva, stool, peritoneal fluid, or osteo articular fluid, which we don't get very often,

Unknown Speaker 1:01:44

or some other catheter.

Unknown Speaker 1:01:48

So I did want to mention one thing as we talk about the result data because I think it is pertinent that more than 10% of the data was missing for two variables, duration of Central or peripheral venous catheter missing 13%, and oxygen therapy a day three missing 13%. And so obviously, the use the need, and the prolonged exposure to central lines is a risk factor, obviously presents us for sure.

Unknown Speaker 1:02:18

And I wanted to talk a little about the baseline characteristics. So they did use propensity score matching, because there were some differences between infants who were exposed to early kangaroo care and those who were not, which I think we knew here are not surprising which babies were kind of quote unquote, eligible for kangaroo care, compared to others. In the whole cohort, they were more likely to have early kangaroo care if the input parents were more had this higher than you could maybe speak to this more but higher professional status or intermediate status.

Unknown Speaker 1:02:52

So I think that had predicts a higher SES probably, I don't know if you can speak to that at all. Yeah, there is, despite the social, the social network that is available in France for health care coverage, and other another support, there is still a lot of disparities across the board. And that usually reflects itself in how people get access to health care. So if you are, if you have a higher paying profession, you're able to subscribe to what they call mutual, which is basically an additional type of insurance that gets you access to more health care faster. And if you don't, then you sort of have to wait your turn in line. And at the expense of your your, your condition, worsening, which is why I often say that sometimes when we look at Europe, and we look at the healthcare system over there, it's not all rosy, there's some things that can be fixed, and we should try to figure out how to fix the healthcare system in general. But yeah, for sure. Okay. Thank you for the clarification. They also had sorry, so again, early exposure to exposure to early kangaroo care, they were more likely to have slightly be slightly older, so 30.2 weeks compared to 29.1 weeks. Interestingly, they were more likely to have preterm labor or premature prolonged rupture of membranes. So again, another risk factor for late onset sepsis, but they were less likely to be SGA. They were obviously into that vein slightly larger, less likely to require surfactant By day three less likely to have mechanical ventilation at day three and shorter durations and mechanical ventilation, also less likely to have NSAIDs By day three and slightly shorter length of duration of central catheters, again, all risk factors for sepsis. But the matched cohorts were not significantly different. So in this group of matched infants, they had

Unknown Speaker 1:04:49

300 Sorry, 3669 infants born between 24 and 31 and six, seven weeks of gestation.

Unknown Speaker 1:04:57

They had 30 564

Unknown Speaker 1:05:00

We're live at a 430 for 3422. With kangaroo care data, the median gestational age is 29.4. A total of 919 infants were exposed to early skin to skin care,

Unknown Speaker 1:05:13

and 2503 were not a total of 875 episodes of late onset sepsis,

Unknown Speaker 1:05:21

and 1417 Lonnie, late onset neonatal infection episodes were reported 626 of those late onset sepsis episodes were due to any staff 533 were cons 93 were Staph aureus, and 11 were Mersa. Other pathogens were Enterococcus, gram negative bacilli, Candida and other.

Unknown Speaker 1:05:46

So risk the primary outcome the risk ratio for late onset sepsis occurrence for infants exposed versus not exposed to skin to skin care was point eight. And in the secondary outcome, the incidence risk ratio for late onset sepsis for infants exposed versus not exposed to skin to skin care was estimated at point eight, seven poor 1000 catheter days and 1.01 per 1000 hospitalization days, the risk ratio for late onset neonatal infection occurrence was similar one and the risk ratios for late onset sepsis due to cons and late onset sepsis due to Staph aureus. Also similar point nine one and point seven, seven, respectively. So all that is taken to be said that they did not find a difference in late onset sepsis or late onset neonatal infection with this early skin to skin care within the first four days of life. So I think, in general, the needle is moving in terms of care.

Unknown Speaker 1:06:52

Yeah, I mean, how many times have we heard that?

Unknown Speaker 1:06:56

Oh, we're going to hold off just because, you know, worried that this might this might cause this might cause late onset sepsis. So no, I was very happy to see that paper. Absolutely. Okay. It's time for rapid review. rapid review. So I'm going to do we're gonna we're gonna alternate. Is that okay? Sure. Okay, so I wanted to then we're talking about late onset sepsis. I wanted to talk about this paper that was published in pediatric research wasn't big research. I think so. Anyway, it's called evolving antibiotic resistance in GBS streptococcus, causing invasive infant disease from 1970 to 2021. So quite impressive. first author is Elizabeth Mary Sue Brosky. So brusque Zebrowski, and this is coming out of Texas in the US. So

Unknown Speaker 1:07:48

they basically tried to define the frequency of antibiotic resistance over time in a collection of invasive GBS isolates derived from infant early onset disease, late onset disease or late late onset disease, which here they call it ll OD.

Unknown Speaker 1:08:04

A. This was a multicenter retrospective review of infants born between 1970 and 2021 with GBs isolated from the blood, CSF, cellulitis, or bone,

Unknown Speaker 1:08:17

which I'm assuming is a is a is a synovial aspirate, I hope.

Unknown Speaker 1:08:23

All isolates were stereotyped and antimicrobial susceptibility testing performed using Disk diffusion. And the results were quite interesting. So that the most common serotype in our they had in our 2017 isolates were serotype three

Unknown Speaker 1:08:40

and that was present in about 1000 sample, which was about 55% of the of the of the of the isolates. Then second in line came one a 22% one B 9%. And then

Unknown Speaker 1:08:54

two 7.2% which, right there was something I remembered for the boards that serotype three right is the one that they don't say this is a total of 46.8% of the isolates were from infants with early onset disease 48% point 48.3% From late and 4.7% from late onset disease. All isolates were penicillin susceptible, and compared to strains isolated before the year 2000. Before y2k strains isolated after the year 2000 showed significantly greater frequency of erythromycin and clindamycin resistance. So erythromycin resistance went up from four to 32% clindamycin from 1.5 to 17.5. That's not very good.

Unknown Speaker 1:09:43

You're right.

Unknown Speaker 1:09:45

No like exactly so they basically the conclusion is documented the rapid and significant increase in clindamycin, erythromycin resistance, as

Unknown Speaker 1:09:54

clindamycin may be considered for severely allergic

Unknown Speaker 1:09:57

for severely penicillin allergic women needing

Unknown Speaker 1:10:00

UBS intrapartum prophylaxis, obstetrician, pediatrician and neonatologist should be aware of this disturbing trend. So, yeah, they have some cool graphs. Maybe we'll try to put some of them on Twitter. That was a cool paper. That sounds good. Okay, I just wanted to highlight some of these.

Unknown Speaker 1:10:19

Kind of this was a correspondence in the Journal of Perinatology. And especially because we will have an episode in early next year. Year, we invited the women in neonatology advocacy group who's a target for the year was talking about neonatal staffing models. And this is a question we get all the time to the podcast email we see on Twitter and is like very much on the physician, social media groups. And so I would just direct people to read this. It's entitled neonatologist staffing models, urgent change is needed. And that's again, the women in neonatology advocacy group kind of introducing

Unknown Speaker 1:11:11

their plan for providing a toolkit and benchmarking staffing models, so I people were asking about it, and it is being worked on. So I thought that was a nice introduction. And we can't wait to release that episode early next year. Yep, we listened to it. It was good.

Unknown Speaker 1:11:31

It's good.

Unknown Speaker 1:11:33

There's a lot of fun.

Unknown Speaker 1:11:34

It was, it was super interesting to record with Lanka, with Christine. And with Carrie, the

Unknown Speaker 1:11:44

especially for me, there was a lot of things I was not aware of, and that they were able to really

Unknown Speaker 1:11:50

put in light some of these trends and some of these issues and you're like wins, like when you think about it, like you're totally right. This is something we need to talk about.

Unknown Speaker 1:11:58

Yeah, so I can't wait for this episode to be released. Okay.

Unknown Speaker 1:12:04

All right. I have one more. I have a few more. Okay. There was this paper in the archives

Unknown Speaker 1:12:11

called mortality and neuro the mental outcome of infants with spontaneous intestinal perforation, a systematic review and meta analysis.

Unknown Speaker 1:12:21

So basically, they wanted to know babies who have a sip less than 32 weeks. What are their neural metal outcome? They looked at the northern metal outcome after one year of correct adjust of correct age. And they were able to basically find 18 cohort studies which included 13,000 infants.

Unknown Speaker 1:12:39

The meta analysis of unadjusted odds ratio showed that SIP was significantly as I thought they were going to say, let me just say this before, you know how the authors have to tell you what they hypothesize. I hypothesize, we're gonna say snip. Not too bad. Just so you know. Meta Analysis of unadjusted odds ratios showed that the SIP was significantly associated with the increased odds of mortality, cerebral palsy composite outcome of death or disability, visual impairment and hearing impairment. However, pooling of adjusted odds ratio found significant association only for mortality, the adjusted odds ratio was 2.27.

Unknown Speaker 1:13:20

And the level of evidence was low to very low. So their conclusion was that sippin very preterm infant is associated with higher odds of mortality, severe disability and death or disability.

Unknown Speaker 1:13:34

Actually, I forgot to mention that it was as if it was associated with a significant decision with for mortality, it for severe disability and the composite outcome of death or disability. I'm sorry, I missed that in my notes. So yeah, that was that's an interesting meta analysis. I mean, we've had to deal with a seminar unit not too long ago. So it was actually I was actually interested to see that paper. You have another one? I did. I thought this was since we, you know, we've been talking a lot about long term outcomes. And and this is the era of the neonatal kidney. There was an article in pediatric research higher blood pressure and adolescent boys after very preterm birth and fetal growth restriction out of Sweden. And this is something I think we keep asking and keep wondering, so

Unknown Speaker 1:14:28

they had this very preterm infants. And basically the results were that there were no group differences in prevalence of hypertension or in these measurements of arterial stiffness. But specifically in boys, these adolescent boys diastolic and mean arterial blood pressures increased from term,

Unknown Speaker 1:14:52

term gestation, to preterm gestation, so the preterm babies had higher blood pressures than the term babies and those preterm

Unknown Speaker 1:15:00

On fetal growth restricted babies had the highest of all the blood pressures, both in the daytime 24 hour mean arterial, arterial blood pressures. Interestingly, in girls, no group differences were observed. So I think this still, you know, is concerning for this increased cardiovascular risk. But I was happy to see that the blood pressures overall, were not so different. And we've already talked about this, that those growth restricted babies are a group all in their own.

Unknown Speaker 1:15:40

Your turn? Are you dumb? I'm actually a bit more pessimistic than you on this. Oh, yeah, no, I think it still predicts, I thought the studies on this arterial stiffness were interesting. And those were slightly different also.

Unknown Speaker 1:15:59

And also, it was looking at it in adolescence. And what does that translate to down the road beyond adolescence is something that some of the data has already started to show might be problematic. Okay. Well, I'm not going to dwell too much on that. My last paper that I wanted to review is also published in the Archives, and it's called nasal High Flow therapy to optimize stability during intubation. The nosy pilot trial, first author, Jason giving, I'm giving a 10 out of 10 for the nosy pilot.

Unknown Speaker 1:16:31

It's fun to say, yeah.

Unknown Speaker 1:16:34

So this was basically what they wanted to know was.

Unknown Speaker 1:16:39

Would babies be deciding more or less if they were on high flow nasal cannula during an intubation? So we've been trialed about CPAP. And so I think it was interesting to take a look at that. So I guess I was really excited to see the title. But then when you start delving into the study, you realize it's a small study. So it's not as as as large of a research paper as I would have anticipated. It's a double blinded, randomized control pilot trial that was conducted in a single center between October 2020 and October 2021. And basically,

Unknown Speaker 1:17:14

they randomly assign babies to either have a nasal high flow of six liters per minutes on 100%, oxygen versus nasal have flow zero liter, applied during intubation. In babies who were stratified then by gestational ages.

Unknown Speaker 1:17:34

Let me just look at something

Unknown Speaker 1:17:38

because I wanted to I wrote it down somewhere.

Unknown Speaker 1:17:47

Yeah, I think one of the, one of the issues obviously is

Unknown Speaker 1:17:53

randomizing babies. That's the question that I had, right? I mean, and then I know that question is going to come up, but

Unknown Speaker 1:18:02

if you if you okay, I'm gonna, I'm trying to be tactful. This is rapid review here, not being a rabbit. I'm sorry. But basically, is it is it the proper random is a proper control group to put a nasal cannula in the nose and not turning on flow or you know, just actually causing obstruction? Right, that's the question, but I'm going to let the Twittersphere get mad and discuss that. The primary outcome was How long were the babies with sat levels beef below 75% to the time of successful intubation, so they enrolled 43 infants 50 intubation episodes,

Unknown Speaker 1:18:39

the in babies less than three, four weeks, the median duration of s of saturation below 75% was 29 seconds versus 43 seconds in the control. That was not statistically significant. The median duration of sets below 75% in babies were above 34 weeks of gestation was zero seconds in 00 seconds in both group. So the pilot study showed at least that it was feasible, and that there were no significant differences noted in the oxygen saturation between the groups. Obviously, it's not powered to detect difference and larger high powered studies are warranted as the author's mentioned. But yeah, cool, little trial. That's all I have for you today. Do you have one more? I do have one more just for people to look at. It's actually

Unknown Speaker 1:19:26

a currently a journal pre proof we have here for the Journal of Pediatrics. I think that neonatologist have an opportunity to be more what's the word versed in ethics discussions, and so I thought this was a cool case review can expire drugs be used ethically in low and middle income countries? A case on treating pediatric hemophilia, lead author Tracy Kelly, and so this sorry, this coming to us from the University of Virginia, I think

Unknown Speaker 1:20:00

And it was just a neat way for them to lay out the case, we don't see a lot of these ethics cases in our neonatal journals. And so I think it's a good way to conceptualize many of the ethical challenges that we have in medicine. So I just thought it was a good exercise. So I will, I will leave it at that for people to review at their leisure. It's a it's a spicy one. It's basically the thought of don't hold back any punches in that article. So yeah, glad you mentioned it. And, you know, I think, I think it does speak to especially in neonatal care, how wide this

Unknown Speaker 1:20:41

chasm of inequity is between high income countries and low and middle income countries. So

Unknown Speaker 1:20:51

this was fun. That's also 100 in the bag.

Unknown Speaker 1:20:55

All right. Yeah. Thank you to everybody for sticking with us and recommending the podcast to other people. That's how we grow and given us great ideas about episodes and stay tuned for the conference. Right? We are, we are the product of our environment. So thank you for thank you for everybody on Twitter to continue to share interesting articles. Interesting stuff, for sure. Thank you for everybody who sent out recommendations for four guests. Dr. Lemons last week was an example of that. We're just here to try to make this available seamlessly to as many people as possible. Our audience has grown tremendously. We're very excited to bring you another 100 episodes in the coming two years. And stay tuned this week for a special episode on the conference. It will be

Unknown Speaker 1:21:44

a banger like this will be I am so excited about this conference. Like no idea. You have no idea.

Unknown Speaker 1:21:54

It's like my dream conference. So

Unknown Speaker 1:21:58

right. Now we just have to deliver. Alright, we just had to deliver definitely in charge. So it'll be fine.

Unknown Speaker 1:22:06

We have a great team working on the conference. So okay, answering to Daphna. All right,

Unknown Speaker 1:22:16

guys, all right. Get some rest, buddy. Bye, everybody.

Unknown Speaker 1:22:21

Thank you for listening to the incubator podcast. 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 or through our website at WWW dot v dash incubator that org

Unknown Speaker 1:22:56

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 professional. Thank you

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