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#094 - 📑Journal Club 37

Hello Friends 👋

We have another exciting episode of Journal Club for you this week. We apologize for the late release this morning, but this week has just been bananas for both Daphna and me. Service, calls, covid, it almost felt like this recording was not meant to happen. Yet, here we are and the content of the articles we have selected for you today is fantastic. We talk about neurodevelopmental outcomes, rates of diagnostic errors in the NICU, new approach to seizures, anti VEGF for ROP and risk of pulmonary hypertension, maternal vitamin A supplementation, and much more. We hope you enjoy listening to this episode as much as we enjoyed recording it. In the meantime, remember to send us stories of how the podcast had an impact on a patient or a family you took care of. You can send us email/voice notes, etc, no need for names/locations, just a heartwarming story. We will give the people who send those a leg up on our end-of-year giveaway.

Enjoy the rest of your weekend! - Ben


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

The International League Against Epilepsy New Classification of Neonatal Seizures. Mizrahi EM, Pressler RM; Task Force on Neonatal Seizures, Commission on Classification and Terminology, International League Against Epilepsy (ILAE).Pediatrics. 2022 Nov 1;150(5):e2022058114. doi: 10.1542/peds.2022-058114.

Long-Term Outcome of Necrotizing Enterocolitis and Spontaneous Intestinal Perforation. Vaidya R, Yi JX, O'Shea TM, Jensen ET, Joseph RM, Shenberger J, Gogcu S, Wagner K, Msall ME, Thompson AL, Frazier JA, Fry R, Singh R; ELGAN-ECHO Study Investigators.Pediatrics. 2022 Nov 1;150(5):e2022056445. doi: 10.1542/peds.2022-056445.

Maternal vitamin A supplementation and lung function in offspring. Checkley W, West KP Jr, Wise RA, Baldwin MR, Wu L, LeClerq SC, Christian P, Katz J, Tielsch JM, Khatry S, Sommer A.N Engl J Med. 2010 May 13;362(19):1784-94. doi: 10.1056/NEJMoa0907441.

Neurodevelopmental outcomes of extremely preterm infants fed an exclusive human milk-based diet versus a mixed human milk + bovine milk-based diet: a multi-center study. Hair AB, Patel AL, Kiechl-Kohlendorfer U, Kim JH, Schanler RJ, Hawthorne KM, Itriago E, Abrams SA, Blanco CL.J Perinatol. 2022 Nov;42(11):1485-1488. doi: 10.1038/s41372-022-01513-3. Epub 2022 Sep 28.

Pulmonary Hypertension in Preterm Infants Treated With Laser vs Anti-Vascular Endothelial Growth Factor Therapy for Retinopathy of Prematurity. Nitkin CR, Bamat NA, Lagatta J, DeMauro SB, Lee HC, Patel RM, King B, Slaughter JL, Campbell JP, Richardson T, Lewis T.JAMA Ophthalmol. 2022 Nov 1;140(11):1085-1094. doi: 10.1001/jamaophthalmol.2022.3788.

Antenatal Corticosteroid Exposure is Associated with Childhood Mental Disorders in Late Preterm and Term Infants. Lin YH, Lin CH, Lin MC, Hsu YC, Hsu CT.J Pediatr. 2023 Feb;253:245-251.e2. doi: 10.1016/j.jpeds.2022.09.050. Epub 2022 Oct 4.

Frequency of diagnostic errors in the neonatal intensive care unit: a retrospective cohort study. Shafer GJ, Singh H, Thomas EJ, Thammasitboon S, Gautham KS.J Perinatol. 2022 Oct;42(10):1312-1318. doi: 10.1038/s41372-022-01359-9. Epub 2022 Mar 4.


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

Ben 0:59

Hello, everybody. Welcome back to another episode of the incubator is to journal club. We're very happy to be here Daphna. Are you tell us. I know how you're doing. We just

Daphna 1:11

Well, I was it's my turn. But my family and I are quarantining after. So, so long. We've been, we've been hit by COVID. But here we are. It's still record from home.

Ben 1:27

I feel like I feel like now that you you were caught by COVID. I feel like there's no one left on this. Like you were so careful. So the fact that Yeah, well,

Daphna 1:36

what are we gonna do?

Ben 1:38

You know, and yet, you're here for Journal Club.

Daphna 1:41

I'm here because that's dedication.

Ben 1:46

Without I don't want to, I want to be mindful of your time today. So I want to make a few announcements. Today, we are releasing the first episode of the journal clubs in Portuguese. Very, very exciting out in Cuba. Dora. I don't know if I'm pronouncing that correctly. But yet the show is on all the different podcast platforms. And and we're very thankful we were able to partner with Dr. Mariana Gonzales, the Olivera and Dr. Morales, shoo, shoo in. And they're both from Brazil. And they've taken on this project. And we're very excited. So this is after the after the Spanish version of the podcast, we now have the Portuguese one French is coming up very soon. Stay tuned for that announcement. So that's just very exciting. And, yeah, it's just a lot of fun.

Daphna 2:47

It kind of seems unbelievable, like when we first started talking about putting it in other languages, this is like, very exciting to be at this point.

Ben 2:55

Absolutely. And we're completely indebted to the people who are partnering with us on this journey. So so for sure. And the last thing I wanted to mention was that we are still looking for all the stories you can share with us about the podcast and how that has impacted. One instance, I don't think you don't have to, we don't have to pretend like the podcast impacts your day to day life. But if you have a story where the podcast coincided with something that happened to you and your unit or one of your patients and, and the podcast was helpful in any way, please send us those messages, we'll want to read them on our end of your show. You don't have to give us your name where you're from, you don't have to give us any of that just just tell us the story. And we'll be happy to share that. And we will most likely give people who send us the stories, some form of perk in our end of year giveaway, which is quite well sponsored this year. So there's gonna be some cool gifts, whether I'm not really at liberty to say but you know, it could be a MacBook Pro, it could not be something else, I don't know. But anyway. So that's not a car. It's not a car, but it is going to be a significant prize. And so that's it you've been incentivized. Nothing else we need to talk about we will have, like we've said before, a few episodes coming up before the end of the year. With explaining a little bit what we're doing, especially when it comes to the upcoming conference, the Delphi neonatal innovation conference we're putting together for end of March, we're going to talk about the NICU relation between projects that we're doing with Rick Doty. We're also going to have on the amazing people from Ibnu to kickstart the Article of the year. So they're going to, we're not we're going to we're going to basically give them the floor and they're going to they're going to tell you about the articles that are running and you'll be voting and they'll they'll tell us who won eventually. So this is a lot of fun. But some things to look forward to on the podcast, we're very, this is the whole reason why we created this so that people could could start utilizing it. And so we're very excited about that. And the EB Neo people are definitely a great source of inspiration for us from the early work that they've done on Twitter. So very humbling for us. Yeah, there's more stuff coming up. We're talking to folks at PHS about doing things with them for 2023. Stay tuned for that. And that's it. I think, without further ado, we can get into Journal Club. Anything else that I forgot? Definitely.

Daphna 5:35

Now, I think you nailed it. All right.

Ben 5:38

So I'm going to start today and I have some, I was lucky to pick articles that are very, very interesting. And I'm gonna let you pick which one you want me to present first, I have a paper that made some some buzz on Twitter about like the use of and anti VEGF, you know, and pulmonary hypertension, have a paper that looked at the frequency of diagnostic errors in the NICU. Interesting, I noted another paper about the effects of maternal vitamin A supplementation on lung function in the offspring. And then there's another paper on the new definition and and assessment for neonatal seizures. Which one do you want to start with? I pick you can pick whichever they're all very cool.

Daphna 6:23

I thought you were gonna do a paper and post hemorrhagic facilitation.

Ben 6:28

No, I saved that paper. Just because I didn't have time to review it foi. And those papers just like got the most of my attention.

Daphna 6:37

Okay, I then I wanted to hear about the diagnostic errors. I knew

Ben 6:41

it. It's a crazy paper. The title of the paper is frequency of diagnostic errors in the neonatal intensive care unit, a retrospective cohort study. first author is Grant Schaefer. It's in the Journal of parasitology parasitology. And it comes from the US. I think there is a clear intent not to mention which hospital this is from because I think, first of all, I'm amazed that anybody allowed this review process to happen within their own unit. It's, it's, I mean, it's impressive, because it shows a tremendous amount of transparency and a willingness to to look systemically at what could be fixed to get better outcomes. So I don't know.

Daphna 7:21

Yeah, yeah. Not the review process, but then that they wrote it up. I mean, that's absolutely. And, and that's how we all learn. Right, exactly.

Ben 7:29

And so the the background is not earth shattering. It mentions that diagnostic error in health care remains relatively unstudied, that's very true. In contrast to errors in treatments such as medication error, hospital acquired infection, wrong site surgery, but like clinicians making the wrong diagnosis or making a mistake is not something that's really looked at looked at. Not surprisingly, they say the incidence and the impact of diagnostic errors in neonatology remains relatively unknown. Patients in the NICU are vulnerable to diagnostic errors, which tend to be more lethal with increased acuity of patient illness. So the way they frame this paper is that they wish to determine the frequency of diagnostic errors in patients admitted to the NICU and examine the associated processes break down the process breakdowns that would warrant intervention. So how did they go on to do that? So the study was conducted in a 173 bed level for NICU or coronary care Children's Hospital with 1700 to 2100 admission every year, the hospital has about 6000 deliveries with an admission rate of about 20%. The sample that they collected consisted of 600 consecutive inborn ie born and managed at the institution admitted to the NICU between January 1 2017 And July 20 2017. So how did they define what is the diagnostic error? Right, so the diagnostic error were defined as missed opportunities to make a correct or a timely diagnosis. The conceptual approach used the following previously established criteria to determine the prevalence of the diagnostic error. There was number one a case analysis that revealed evidence of a missed opportunity to make a correct or timely diagnosis. That is something could have been done differently. Second, was a missed opportunity. And that was framed within the context of an evolving diagnostic process. That is, the particular point in time when the error occurred, there was a failure to implement a correct action or there was an incorrect action. And then number three, the opportunity itself could have been missed by the clinician care team or health system. A preventable delay in diagnosis may occur due to factors outside the clinicians control. So how did they identify a diagnostic error? So basically, they did record a record revenue reviews and they used what's called the safer DX instrument, the safer diagnostic instrument, which is a structured medical review medical record review tool with the robust validity. And basically, it's 11 question that you go through to evaluate the various aspects of the diagnostic process. They have these questions actually in the paper. So you can go back I mean, I can I can read them to you to question number one is the documented admission, maternal history and lab work was suggestive of either an alternative diagnosis or should have prompted additional diagnostic workup which was not considered in the assessment. So they have a bunch of questions like that there's 11 of them. And the 12 question, which is the last one asks the reviewer to make a determination regarding the presence of an error and says, Well, the last question is, in conclusion, based on all the above question, the episodes of care under review had a diagnostic error. And on the Likert scale, they could be classified as Yes, unclear or no, if it was one to two, four, no, three to four for unclear five to six, five to six, four, yes. All 600 records were screened by your primary reviewer, which was a NICU fellow for any diagnostic error at the time, from the time of delivery through the first seven days of admission, so they only looked at the first week. And they say that they picked the first seven days, because of two reasons. Number one, because he said many patients have prolonged stays in the NICU. And it's not really feasible to perform a detailed evaluation of a patient's entire record, if that time period was over the course of months or years. Second, they said the period surrounding the surrounding and I think that's the that's the most salient point that they're making is around the time of the admission, it's really when you require a significant amount of diagnostic reasoning. And you assume that the key diagnostic decisions would be made within the first seven days of admission. And even if that's not always perfectly true, it's mostly true, I think, right? I mean, it's usually the first seven days that you get on sort of tracks based on the patient's presentation. So the patient's records, the patient's record was also examined beyond the initial seven days just to determine if an error that or if an error that occurred during that seven day period was detected at a later date. Then all the charts that were flagged as Yes, meaning Yes, there was an error. And there was a random selection of charts that had either a no one unclear, then underwent a secondary review by your senior neonatologist. The secondary reviewer included the Section Chief of neonatology and three medical directors of the sections academic NICUs. So yeah, so a very thorough process. And they were hoping that if there was any issues with the fellows assessment, the doing a sampling of random nose and uncleared would cover that. The secondary reviewer use the same process to review the charts just like the primary reviewer. And then if there was agreement, so that's the interesting thing. So what if they agreed, then, if they agreed both of them in terms of whether there was a diagnostic error, then it was considered final. So what happened if there was a discordance? So if there's a discordance between the primary and the secondary reviewer, then the record was discussed as a group and the group review involved all four secondary reviewers with access to both the primary and the secondary review results. And they came to a final consensus as to whether or not a diagnostic error had occurred. So I mean, when you read all this, and you said it 600 charts, I don't know how much time it must have taken them. Like this sounds like an awful amount of time. But we're all the more the world the better for it. Because this is this is great. So

Daphna 13:29

it's it's an interesting review process right between the fellow and the Division Chief. But it works for them. So yeah.

Ben 13:41

So what were the results, so the primary review classified 37 charts as Yes, diagnostic error, oops, present 16 as unclear and 547 as noted medical error. The secondary review evaluated 77 charts, which was 100% of the ones that were classified as an error that was 37. And then about like 12.5% of the unclear 7% of the ones out now, the raw agreement between the primary and the secondary review was 83%, with statistically substantial agreement between reviewers, so I think it was pretty high, but I was still surprised I was expecting it closer to 90 and then even above that. And so the main result is that after group consensus review of the 13 discordant charts 37 diagnostic errors were confirmed, which totals which is about which is an issue not about which is exactly 6.2% of study patients with a frequency of point nine diagnostic errors per 100 patient days in this patient sample. So if you were wondering, how what is the rate of diagnostic Arizona for seven days, Nikki was 6.2%. That's what the number they got to what were these errors. So the identify diagnostic errors were then classified by what kind of process breakdown led to this error. The most common process breakdown were missed maternal history findings, followed by incomplete physical exams. And in all honesty, I don't think I'm perfect on either one of those. And that was a very strong reminder to be careful. And they actually have a table that's quite long, you can review it in the paper where you can actually look at all the different issues and what was missed. And, and it's true that we'll talk about that the most common main disease categories that were the cause was infectious disease followed by renal disease. In three of the cases, the error potentially contributed to the patient's death. Of note, all three deaths related to delayed identification and treatment of infections in the setting of missed evidence of maternal or placental infection, at the time of delivery. The conclusion of the paper is that inboard patient during the first seven days of NICU admission, are at high risk of serious diagnostic error with a frequency of 6.2% in their study. And that's the main finding here and the main takeaway points, I think of the paper, they're the findings. Their findings suggest that inadequate handoff between obstetric and neonatology team, as well as incomplete physical exams are common process breakdowns leading to diagnostic errors in this population. Future work should address key aspect of current neonatology practice that leads to this breakdown, such as barrier to extracting critical information from maternal records, and over reliance on diagnostic testing in place of physical exam. I think you can ask a lot of questions about this data, right? The way the study was designed, you can have a lot of questions. But surprisingly, the conclusions rang very true to my day to day experience in the NICU. Where it's definitely the I'm going to be honest with you, it's definitely two of my weakest aspects of the care that I deliver in the NICU. It's it's very difficult to get a an accurate, timely maternal history between all the times where we don't have her records yet, they're gonna get them faxed. And it's like, did you check on them before you signed out? Or did you write? Or did that just like fall through the crack? Or a quick physical exam? Because you're still doing other stuff? And so yeah,

Daphna 17:27

yeah. Yeah, I would say, Yeah, I'm not I'm not surprised and surprising that this was it, I think, you know, we know that transitions of care such a weak spot such a vulnerable spot for, for information to be missed. And this is especially true, I think, in in the NICU and in the newborn nursery, you know, there a lot of data is collected during those months of pregnancy. However, once you have that many months, you get, but you know, was there something in that prenatal ultrasound, or, you know, not either the maternal Serologies, they got a bunch of urine cultures, and then one of them was positive, you know, and so much of that does not get handed off. And in a lot of places, the only thing you get are the Serologies, unless it's been passed off, you may not get a full maternal chart. So I think you said it's a reminder of how, how can we better solidify that that communication? And then obviously, obviously, a physical exam is important, you know?

Ben 18:35

Yeah. I mean, there was some findings that were very concerning. Like, it was like, an imperforate anus or like, like, like a spinal bifida where it's like, you didn't really turn around the baby. And it's like, I do do that, right. But it's like, oh, like, what if like, one slipped through the rackets. It's missed its

Daphna 18:53

opportunity. Somebody, somebody asks you a question while you're doing the physical exam and your, your, your routine is disrupted, which happens basically every minute. But I did. I told her president that once I said, we're, you do not want to miss it imperfect, and it's in the delivery room. You better at least check that before you work at it.

Ben 19:16

That's a good tip. That's a very good

Daphna 19:19

There you go. Thank you. Okay, well, I'm gonna shift gears a little bit. And the first paper I'm going to review I thought was actually really interesting because we've reviewed some papers along the same vein in the last few months, and certainly in the last two years, lots of papers have been coming out about antenatal steroid exposure. So this is antenatal corticosteroid exposure is associated with Childhood Mental disorders in late preterm and term infants. Authors II said sudden and Chun ting shoe. This is a preprint in the Journal of Pediatrics and it's coming to us from Taiwan. So like I said, we've been talking about this issue of corticosteroid timing, and is there a downside to, to providing it at different gestational ages? And if you get it and then you don't deliver preterm what happens or if you get it early in pregnancy? You know, what, when is the optimal time? Is there an optimal timing? And if it's not optimal, then then what's the downside? So, this was exactly their objective. And this was a population based cohort study using the Taiwan national health insurance research database. And of note the Taiwan National Health Insurance provides a single payer mandatory coverage. So it enrolls approximately 99.99% of the population. So it really is like a population based study. They enrolled all singleton live births between 2004 and 2010. And they follow them up for six years. They looked at the animal antenatal exposure as defined by the ACOG guidelines to beta methadone doses or for dexamethasone doses, and then they stratified the exposure timing by before 20 weeks 20 to 34 weeks and after 34 weeks. And again, they were looking specifically at this at these babies who deliver in the late preterm or the term gestation. And then the primary outcome was ending Childhood Mental disorder using ICD nine codes. And then the secondary outcomes included seven specific subgroups characterized as the following mild and moderate and intellectual disabilities, severe and profound intellectual disability, developmental delay, Autism Spectrum Disorders, attention deficit, hyperactivity, disturbance of emotions and tic disorders. And then they verify the diagnosis of mental disorders by using the same diagnosis code in at least three outpatient visits or one inpatient diagnosis, so I thought that was pretty good. And they had a total of 1,163,443 infants included in the analysis. And 16,847 infants are 1.45% were exposed to antenatal corticosteroid treatment, mothers in the exposed group. And so those moms who received steroids were more advanced age, higher C section rate, more chronic disease and more pregnancy related complications. They lower birth, infants with lower birth weight, lower Apgar scores and higher proportion of male infants. They had a similar family monthly income, and among the start exposed group, actually 73% were born at term. So I thought that was particularly interesting. And anyways, I'll get to that in the discussion. But I was wondering about what like what does like for our hospital? How many babies get exposed to stories and then do deliver it term? I have not asked that question before.

Ben 23:02

And that's something that we had reviewed on previous episodes and in specific articles. I think it was an article by reichen and colleagues, where they had shown that like, if you give steroids and they don't deliver preterm, there's, there's where there are worse outcomes.

Daphna 23:16

Yeah, so remember that as we discuss the outcomes on this paper. So, the unadjusted cute that will just get into the rest of the details the unadjusted cumulative rates for any Childhood Mental disorder was statistically significantly higher for the quarter code stair corticosteroid exposed children in the entire cohort in the term group and in the late preterm group in comparison with the non exposed in the early preterm group, in contrast, so babies born like less than 34 weeks in contrast, there was no significant difference in the incidence rates between exposure and non exposure groups. So I'll tell you the numbers. So after adjusting for covariates, the children exposed to antenatal steroids compared with non exposed subjects. So the whole cohort had still had a higher risk of developing Childhood Mental disorders with an adjusted hazard ratio of 1.13 and then after stratifying, the infants the term I want to make sure I get this right the corticosteroid exposure increased risk of all diseases in the term group adjusted hazard ratio of 1.11 and the late preterm adjusted hazard ratio of 1.15. Again, the corticosteroid exposure did not increase risk in the early preterm group. And then they again looked at the different sub diagnoses. So in the entire cohort, antenatal corticosteroid use was associated with developmental delay adjusted hazard ratio 1.09 Attention Deficit Hyperactive tivity has a ratio of 1.11 disturbance of emotions 1.18. And any little corticosteroid treatment increased the risk of ADHD not only in turn born groups but also in the late preterm groups. In the early preterm group, although the steroid exposure did tend to increase the risk of most of these diseases, it did not reach statistical significance. So that they wanted to look at didn't matter when you got the steroids. So I thought this was particularly interesting in light of the paper that you just talked about. So, when comparing the timing of administration prescribing antenatal corticosteroids in the early stage of pregnancy, less than 28 Weeks was associated with a notably increased risk of Childhood Mental disorder, just adjusted hazard ratio 1.22. And interestingly, the effects decline along with the increasing gestational age at which there was exposure to antenatal corticosteroids. So for the whole group, it was hazard ratio of 1.13. Before 28 weeks, it was 1.2 to between 28 to 34 weeks 1.12 and beyond 34 weeks of gestation. 1.05. And that's an that's different than the paper we reviewed, where it seemed like the babies who got the later steroid exposure had the worst outcomes. But regardless, there's definitely something going on with any look, corticosteroid exposure, we know that it predicts better outcomes in the preterm group. But if you get it and you're not born preterm, there's there's definitely something to some things to worry about. I guess I would say. Yeah. So I guess we just have to start looking at

Ben 27:01

what are we doing definite tell us, we have to start I'm at a loss. I'm at a loss with these papers. It's like, what are we? Starting from questioning? You start even questioning like, do we really need steroids for better respiratory outcomes? Like, which, like, it'd be interesting. How do you put these two things in terms of long term?

Daphna 27:18

Well, I think we have to look at the group of babies who get steroids and then which ones deliver and which ones don't deliver, right? And then find out how we can be we I guess it's not how our obstetric colleagues can be better at predicting which babies will actually deliver early. And, you know, I mean, I go in there full force, like what's the steroid situation like, did you guys get them on right? So maybe I can back off. But when you need them, you really need them, you know,

Ben 27:49

it definitely helps us move. Yes, neonatologist are very reliant on these anti natal steroids.

Daphna 27:55

And you know, that's what all the papers have showed. Certainly, like in the in the NICU, it doesn't matter when you got them or when you were born. It's helpful. Yeah, it's, it's the prolonged effects, right. Okay. Okay, your turn,

Ben 28:10

my turn. Okay. Next paper that I want to go into. I'm going to talk about this paper. Let's just get into it. This is a paper that caused a lot of buzz. It's based published in JAMA ophthalmology. It's called pulmonary hypertension in preterm infants treated with laser versus anti vascular endothelial growth factor therapy, for retinopathy of prematurity. first author is Christopher Nutkin. And the set of authors is who's who of famous names in neonatology Sarah dimauro. And really, Ravi Patel, Brian King, Jonathan slaughter, Peter Campbell, Troy Richardson, Nick damnit, John, the gada. And last author is none other than Tamra Lewis. So Impressive, impressive group of authors. What's the what's the deal here? Right. ROP is a leading cause is is is a leading cause of acquired blindness, right? And treatment options involve laser photocoagulation. But intravitreal Bevacizumab, right which is anti veg F is now considered an effective therapy, especially when you have aggressive ROP. And anti VEGF therapy has several ocular advantages compared with laser including the potential for increased visual fields and lower degrees of refractive error. Now, if you We did talk about it in the neonatology review podcast, this is a therapy that was adopted really quickly because of its amazing outcomes. And there's a paucity of safety data about the effects on organ systems beyond the eye for sure. Intra vitreal Bevacizumab lowers your serum VEGF levels for up to two weeks and thus may be inhibiting vascular development in rapidly developing organ system. Hint Hint The lungs and the brain. disrupted pulmonary vascular bed development can be then considered as potentially an off target toxicity of intravitreal anti VEGF therapy. So they're asking, is there an association with increased risk of developing pulmonary hypertension in preterm infants with ROP following treatment with anti VEGF therapy compared to laser treatment? The study design is that they ended up doing a retrospective cohort review or database review. And the database that we use was the Pediatric Health Information System. The pH is which is an administrative database containing hospitalization data from 49 Children's Hospital in 27 states plus Washington DC, they included all infants admitted to sites participating in a database from 2010 to 2020, with a billing charge for NICU services, and these kids were considered eligible. Infants with documented gestational ages between 23 and 32 weeks were included. That makes sense considering ROP screening guidelines. They excluded babies with major congenital anomalies, no diagnosis code for op no treatment for RP, infants receive both laser and anti VEGF therapy in the same hospitalization. And additionally, because they assessed for the presence of the primary outcome, basically seven days after RP treatment, and we'll talk about that infants for whom day of therapy could not really be determined or who were discharged or transferred. Fewer than two days post RP treatment were then excluded as the cannot really assess for the initiation of pulmonary vasodilators. And then the patients were, quote unquote, followed until discharge, which is where probably the data collection stopped. They had a bunch of clinical and demographic variables. Look at the paper. I'm not going to go through all of them and the primary exposure was the basically the type of ROP therapy either laser photocoagulation, or anti VEGF therapy, meaning Bevacizumab Ranibizumab, or athlete percept. So what was the primary outcome that they were looking at? The primary outcome was the initiation of first pulmonary vasodilator treatment, ie inhaled nitric oxide. So Delafield bosentan Miller, known people Prost an all or treat, Prost, Anil, and the initiation of this first pulmonary vasodilator treatment beginning at least seven days after RP treatment. Why did they choose seven days they give two reasons seven days was chosen as a plausible minimum duration needed for systemic VEGF suppression to manifest as pulmonary hypertension. Right? If you give right it makes sense. And then second, they said that the history of treatment with pulmonary vasodilator prior to ROP therapy was not considered exclusionary and did not influence classification of the primary outcome. secondary outcome was hospital length of stay and NICU length of stay in case the kids move from the NICU to the PICU. Okay, so let's look at their results. At the end of the day, 1577 infants met all study eligibility criteria 689 infants were treated with laser 888 with anti VEGF therapy. What they did also so you have this group that's completely unbalanced in terms of numbers, but they then did a propensity score matching and gender and generated a cohort of 982 infants, where basically you had half in one arm and half in the other. So so in the data, if you go through the paper, you'll have one set of table that has just the raw numbers and then the propensity scores match table, and that will be important in how the data was analyzed later on. Most of the infants were born between 22 and 26 weeks of gestation, and birth weight range between 407 150 grams. infants were first treated for ROP at a median, just postmenstrual age of 36.4 weeks, infants received anti VEGF treatment had significantly younger gestational age at birth, lower birth weight, and were less likely to be inborn compared to infants receiving laser photocoagulation. Okay, some of the outcomes. significantly increasing proportions of infants were treated with anti VEGF therapy compared with laser over the study period with anti VEGF therapy becoming the predominant therapy beginning in 2015. And that goes back to a lot of that data that came out originally with great outcomes of anti VEGF therapy. But they did mention that this was not uniform across all the different sites, right. Some sites were more using the entire Jeff more than others, and so it was not really completely uniform. Okay, in the full cohort of about 1600 Kids 107 infants, which is about 7% were diagnosed with pulmonary hypertension by pulmonary receipt of receipt of pulmonary vasodilator. An additional 83 infants which is about 5%. were diagnosed by ICD nine ICD 10 diagnosis code and were included in the secondary pulmonary hyper Attention. So then a fill in I know where the most commonly prescribed video dilator and the median time between ROP therapy and the day of first PAH medication was about 24 days. Okay, the primary results in the unmatched analysis, patients who received anti VEGF therapy were more likely to receive pulmonary vasodilators following ROP treatment compared with patient receive liquid receiving laser photocoagulation. And that was 8.3% versus 4.8% with a P value of 0.01. Quite impressive. In the unadjusted propensity score matched cohort, more infants to receive anti VEGF therapy were treated for pulmonary hypertension 7.7% versus 4.7%. This difference, however, was attenuated after adjustment for site and year. And then the last clinic utilized statistical significance. So that's very important, right? So so the attenuation is a big, big deal. Looking at secondary outcomes, in the unadjusted analysis of the full cohort length of NICU stay was 114 days among infants on the anti VEGF therapy compared with 95 days among the babies who received laser. And length of hospital stay was 123 days among the kids who received anti VEGF compared to 114 days, more than kids who received laser we should use significant and you think, oh my god, laser is better. But remember, they said, the kids who had the anti VEGF were smaller they were they were lower weights. So then in the propensity score matched cohort, length of stay was 105 versus one or two, again, no longer significant and length of hospital stay was 118 versus 111. Again, barely reaching significance.

Another interesting outcome was BPD. So in the entire cohort, great tutor 3d pdf 36 Weeks was diagnosed in 37.7%. among infants without BPD, there was no difference in pulmonary vasodilator use who received anti VEGF compared to those who received laser photocoagulation. I think that's interesting. Among the patients with BPD, there was no difference in pulmonary vasodilator use between elephants received anti VEGF therapy, compared with those who received laser photocoagulation. There was not a significant interaction between the types of RP treatment and BPD. So what are the conclusion of this paper? I'm going to read you the conclusions of the of the article they said In summary, anti VEGF therapy for RP was associated with a statistically not significant, which was an interesting phrasing, I think some people commented on on Twitter, but potentially clinically important increase in the rate of treatment for pulmonary hypertension. And that goes back to some of the findings that they that they had in the unadjusted analysis that then got a bit attenuated. And I'll talk about that in a second. Because I think there's a lot of on unpacking that needs to be done here. Our findings suggest that exposure to ni VEGF may be associated with incident pulmonary hypertension, although they say and I quote, We cannot exclude the possibility of residual confounding based on systemic comorbidities, unmeasured association between the probability of receiving anti VEGF therapy and developing pH, meaning since you're already super small, maybe already a bit sicker when you're in the anti VEGF group. So maybe that's why you're developing pulmonary hypertension, right? Or hospital variation in ROP, or PAH treatment practices are really they're saying it could be the chicken could be the egg, we have no way of knowing based on the data. Alternative to Bevacizumab such as Ranibizumab may have a smaller impact because they're talking about the effect on the vascular growth, that's more interest more short term with the randomizer bitmap, I'm not gonna get into that it's in the discussion, feel free to read it. And then then they talk about some of the issues of the study which none of the issues but the issues in in creating these kinds of studies. So they're saying because of the rarity of the outcome randomized trials to evaluate pulmonary hypertension are unlikely to be definitive due to the adequate inadequate power and families may be unwilling to randomize their children to a trial with harm as an endpoint, completely agree with that. pharmacovigilance studies such as ours may be the strongest available evidence, neonatal clinicians, and the conclusion is very Tamra Lewis, I really liked it. It was like neonatal clinicians should continue to partner with families to evaluate possible adverse effects of anti VEGF therapy, evaluate the relative the relative systemic risks of difference in anti VEGF agent and consider the potential harm of these medications alongside their potential benefits. I think that was excellent to put there. But the bottom line is, yeah, how are we going to get data on this subject? Right? It's it's very, very hard. We're talking about treatment for something that can lead to blindness. So yeah, I think they're correct. It's going to be very hard to generate a trial that's gonna enroll so many babies that we're going to have a definitive answer and to convince parents to be potentially be willing to be in a in a treatment arm and control and a control group. It's just very difficult. And this data has a lot of issues. It's a data review, right, a database review, and we all know that they are issues however, It's a large number of, of, of data points that could be very valuable. So I have to say that thanks to their diligence that they did this propensity score matching cohorts, I feel good that hopefully the effects are not significant. But it's definitely something that should be probably disclosed to families and discuss with families, as they mentioned. But overall, I think this was very, very valuable information, because it doesn't appear as they say that better or more better design studies can potentially be coming in the near future. So for the time being, I think I agree with them. This is probably the best data we have.

Daphna 40:45

Yeah, it's, it's interesting, right? Because even the even the kind of indications for anti VEGF versus laser, I mean, those are changing right there. And they're not the same. And so how does that play into this? You know, it's interesting that they picked pulmonary hypertension as they were thinking about that signal, when really the you know, ROP itself is this kind of dysregulated vasculature. So I think that's interesting, too. I, you know, not something that I had previous really thought about, yeah, I

Ben 41:15

mean, could you design I mean, in an ideal world, right, let's say you have an infinite amount of patience, you could study would you want to know, levels of VEGF already? Lower? Like, all these things are very interesting. Like, are you suppressing the last little gotta factors? But yeah, I mean, yeah, I think sometimes we get into tough discussions and criticize studies, because we say, Oh, this study could have been designed better. But then you have to look at the feasibility of designing. Right. It's like,

Daphna 41:49

what are you Yeah, this is not this is a, you know, in real life stead.

Ben 41:54

Absolutely. Absolutely. And we have to not lose sight of the fact that designing the studies may not be possible in this day and age, just just almost impossible. Now. Yeah, but great work. I really like the paper. I think it's very, very helpful. The graphs are amazing, I think, really kudos for them because in the bar graphs, they have both the not the unadjusted and the adjusted graphs for laser versus VEGF both without the propensity score matching with the propensity score matching so very thorough, very transparent. I really liked it. This episode is so proudly sponsored by record me 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 Great paper.

Daphna 42:46

All right, shall we? Yeah. My next fever is neurodevelopmental outcomes of extremely preterm infants fed and exclusive human milk diet, versus a mixed human milk plus bovine milk based diet, a multicenter study, lead author Amy B. Hare, senior author, Cynthia Blonko. This is the journal apparent etiology. And it's actually a multicenter study. So it's a retrospective multicenter cohort study. There are six different centers where infants underwent a neurodevelopmental assessment between 18 to 20 months that 18 to 22 months corrected age using the Bailey skills of infant development three, so the BSIT three, and they basically did this retrospective evaluation as to whether the infant's received exclusive human milk and including their fortification or a bovine milk based diet. So either formula or bovine associated fortifier. So, again, they looked at these former preterm infants between 2006 and 2010. And like I said, they were retrospectively classified into these two cohorts. And so in the exclusive human milk based diet, they had mother's own milk, potentially supplemented with donor human milk when the mom's own milk was unavailable and fortified with a donor human milk based fortifier. And again, the bovine only cohort received the bovine co cohort received mother's own milk fortified with the powdered bovine milk base fortified or preterm formula if mother's own milk was unavailable. Interestingly, some of these infants and if 75 or 30%, in this cohort study, actually participated in two randomized control trials of of this exact question, and these were these the original proactive trials. And so some of them were supposed To get their Bayley follow ups and they were then included in this analysis. But the remaining 70% of the babies were not a part of those trials. And it was just retrospective based on parent report, or for some of them, Nikki documentation of milk exposure. So they had a total of 252 infants 101 In the human milk group, and 151 in the bovine exposed group, there was no statistical differences in gestational age, birth weight or sex between the groups. So for the primary outcome, there was no difference in surgical neck between the groups, P value point five however, the human milk group had a lower incidence of medical neck than the bovine group 2% versus 9% P value, point oh three of follow up, there were no differences in weight, length, or head circumference between the human milk group and the bovine group at 18 to 22 months. And then they looked at the Bailey scores. So the mean, Bailey cognitive scores were significantly higher in the human milk compared to the bovine group 96.5 plus or minus 15.1, versus 89.6 plus or minus 14.1, an adjusted P score of point 01. There's also an estimated difference of approximately seven points, they looked at the mean language scores at 5.5 plus or minus 15. And the human male compared to 82.2, plus or minus 14.1. And the Bobine group, this also met statistic, this did not meet statistical significance P value of point oh, seven. But but I've noticed they they put point o seven here, but the adjusted P value on the table is point o nine. Regardless, you can just you can do with that what you'd like the mean, motor scores were 92.9 plus or minus,

Ben 47:07

at least they falling on the same side on the same side, both on the on the non statistically significant, but it would have been an issue if one was point o three, and the other one was point o seven. Great.

Daphna 47:17

So the mean, motor scores were 92.9 plus or minus 11.7. And the human milk group compared to 91.4, plus or minus 14.6. And the bovine group, again, not statistically significant adjusted P value of point, one, eight. This is also not the same p value, the adjusted P value here is point three, two, but again, both are not statistically significant. So their takeaway was that first, that there was a difference in medical neck, but not surgical neck, that the human milk only group had a kind of a protective factor, and that an exclusive human milk based diet was associated with higher total cognitive Bailey three scores at 18 to 22 months. So there you go. Yeah.

Ben 48:14

I was mostly formula fed. I'm wondering what,

Daphna 48:18

what you could have been, if only it won't be got more best.

Ben 48:23

Yeah, I'm looking at I'm looking at these, like, seven points on the cognitive composite score. And I'm like, man, you know,

Daphna 48:33

imagine how good you'd be.

Ben 48:35

Don't get me started. But anyway, yeah. I mean,

Daphna 48:40

you'd be playing chess for money. Now.

Ben 48:42

Maybe Maybe. Can you imagine as be one of these famous? Yeah. Anyway? Yeah. I mean, I don't have much to say it's, it's, it's almost logical at this point. Right. You expect it? I was, I was actually curious to see if the outcomes were going to be different. And yet, no, they're they're always falling on the same path. Breast milk as best I mean, that's it. Nothing

Daphna 49:07

else. I think, I think the real, the real, the real problem is, is, you know, how do we get more breast milk? It's, it's not easy to acquire breast milk. And I've no, this was not all, you know, mom's own milk and included donor milk for sure. So that's obviously something to consider. But then it's really, you know, they were looking at the Florida fire specifically.

Ben 49:40

Okay, I have to have to keep going because I have articles. Yeah, we gotta hustle. Absolutely. And the article that I'm gonna do next is, I guess, I'm going to do the seizure definition thing. I like seizure research. And it's, in my opinion, it's a big paper. So it's called the International League against epilepsy, new classification of neonatal seizures. So strap on your seatbelt. And let's go. First author is Eli Mizrahi is published in pediatrics and it's basically from the task force on neonatal seizures commission on classification and terminology, International League against epilepsy. So yeah, it's an official document. What I what I understood basically, is that there was no I have to What did you understand? And maybe I'm wrong.

Daphna 50:27

But are you sure you understood it? Right? That's the question.

Ben 50:30

The paper understood great. But it was weird to see it as a perspective in pediatrics. In in the journal epilepsia was a special report that's called the International League against epilepsy classification of seizure and epilepsies. And it's called modification for seizure in the neonate. position paper by the IL IL a task force on neonatal seizure. Right. And it's a long paper. And it's I think it's really aimed at neurologists, right. And this paper in pediatrics first, like a cliff note for the pediatrician slash neonatologist. And I looked at both, and they cover and this paper in pediatrics covers most of it. And so I'm gonna go over that. And then I guess we can link the output the special report in the, in the in the website, and you can decide if you want to read both. But so there's a new classification for how to push neonatal seizures. It's a big, big deal. What's the rationale and why that so they are talking about obviously, the image of brain of the neonate manifests clinical events of epileptic origin differently than more developed brains, right? We know that the way, seizures presented a newborn are completely different. And previous classifications of neonatal seizures were based on contemporary methodology, and it included either clinical observation only, you had like a routine short term EEG, which we all know never catches the freaking seizure. You had video EEG recording and continuous EEG monitoring. Now, obviously, they talked about these findings that are really unique to the neonatal period. And they're mentioning that EEG video studies revealed that clinical recognition is unreliable in identifying seizures consistently associated with electrographic events. And that, and they're, I think, being very kind here. And they're saying that more than 50% of neonatal seizures are electrographic only. And I had read data, I think, if I'm not wrong in the fanaroff, and Martin textbook, they're going as high as 80%. Meaning you your clinical assessment is never very reliable, we're not getting that. Right. And so these findings have prompted reliance on continuous EEG monitoring to provide seizure surveillance and assess electrographic seizure burden, the new, I'm gonna stop calling them the International League against epilepsy. By the way, it sounds like an Avenger movie,

Daphna 52:52

I was just gonna say that they really sound like superheroes. I was very smart of them.

Ben 52:57

Good for them. But I'm gonna say the ILA because it's otherwise too long. But the new ILA classification is based on the recognition of electrographic seizure activity, categorized as either electro clinical or electrographic only. And so how do they approach this? This scenario, you have in the first box, it's basically a flowchart, you have first box critically ill or with clinical suspicion, second box, you must get a video EEG or amplitude integrated EEG, right? And then you have two options, either no seizures, and then that the pathway ends, or then you go into seizures, and then it's asking you is it electro clinical, meaning you have also clinical signs, or it's just electrographic. And then they have the different signs that would classify as electro clinical and I'm gonna get into them in a minute. So the initial application of this classification is the identification of infants infants, who either may be considered at risk for developing seizures or who have been observed to have abnormal clinical events being suspected for seizure. This then prompts the institution of EEG or if not available, amplitude, integrated EEG and subsequent management. In this classification, the critical EEG finding is electrographic seizure activity. Now, what are the clinical features of electro clinical these are motor motor findings meaning, autumn, Autumn autumn Madison's? automatisms, sorry, thank you. Clonic movements, epileptic spasms, myoclonic movements, tonic movements, right. So we know that then you have non motor motor, which would be autonomic or behavioral arrest. And then you would have sequential which is multiple consecutive clinical features during a given seizures or something that's unclassified right? Now, they're recognizing that this new strategy, which involves EEG, right, there's no pathway in this in this. There's no option in this pathway where you can actually diagnose clinical seizures and treat This classification, they say provides precision for diagnosis management by utilizing EEG as a biomarker for these events, whether electro clinical or electrographic. Only. With this approach, a significant proportion of seizures that would otherwise go undetected will be diagnosed and potentially treated. These classification may also refine the characterization of the wide range of motor and non motor decision manifestation, allowing for greater accuracy in diagnosis compared with clinical observation. Now, the big limitation and dimension this is that it's based on EEG. And although it is available in many high resource, neonatal centers, accessibility may still be problematic in some hospitals, and not often available globally in resource resource limited areas. The the ILA II recognizes that, although the classification will improve healthcare, for some, it underscores the need for ag to achieve this goal. And so they're like, yeah, the ideal scenario is that you have an EEG and your diagnosis with your EEG, but what are you going to do for all the other people who don't have quick access. And so then they talk about the impact of these new strategies, and they offer a solution for that. And they talk about the successful application of this classification requires a new strategy in healthcare for neonates, including a shift from clinical observation for seizure surveillance, to the identification of infants with risk factors for developing seizures. And there's a mega Venn diagram that's in the original consensus statement that I'll post on Twitter, basically, it gives you bubbles of various sizes based on the risk factors. And these include a few things which are HIV, not surprising, infectious, vascular, metabolic genetic brain malformation, or unknown. Yeah, it's a lot of things. Yeah, I mean, yeah, and it's all the things, it's always all the things. In addition, the duration of monitoring of a risk infant is also currently variable, although 24 hours is usually considered to be an acceptable duration for screening for seizures. So that was important also that like they're mentioning, and they're committing, they're sort of committing to this 24 hour time to make if you monitor the for 24 hours, and there's no seizures. You did your job. But I mean, it's fairly reasonable that that's a reasonable timeframe, right, you shouldn't aim for 4872 24, they seem to say, and then they build the second algorithm, to look at levels of diagnostic certainty on the basis of available EEG. And I'm just going to walk you through. So basically, you have a baby that is either at high risk of seizures, or a baby with a clinical event, right? So you have these two options. And then the algorithm asks you Do you have an EEG available? Right? And you can say yes, and then you'll have two options. Either you have a continuous EEG correlate or a an amplitude integrated EEG correlates. And we don't really care about that, because the answer is pretty self self evident. But if you don't have an EEG available, so then it asks you, was the event observed by an experienced personnel? And if this is a complicated question, it's a complicated question. But listen, I really appreciate that they the right, they could have just said, Hey, you should use you should use an EEG and tough tough luck if you don't have an EEG. So the fact that they they recognize that it would, it would create health disparities was great, the fact that they offered an opportunity for the people who don't have access, I think was was great, too. So the answer here is yes or no. If it says no meaning it wasn't, it was experienced by the nurse who graduated last week, right? It says, you get to a level four, which is you have insufficient evidence. And and and that's it. Now let's say it was observed by like the nurse that's retiring next week, who has seen all the kids, then it asks you is it a focal Clonic or a focal tonic? And then it says, it's a level to be it becomes a probable diagnosis of seizure? Or is it like something else, and then it says it's a possible diagnosis of seizure, and that's a level three. Now they're saying this application is helpful in clinical management in which EEG is not available. The clinical recognition of clinical events with the greatest diagnostic certainty such as focal Clonic, and focal tonic seizures require treatment with anti seizure medication. So That's level two B, whereas automatism, or isolated autonomic events are not seizure and should not be treated. The strategy also includes staff staff training to enhance the recognition of various types of clinical events. In addition, advocacy at the institutional level to improve the availability of EEG or AEG is an important strategy goal. So go go pester your administrators. The conclusion is that this new classification of neural seizure shifts the seizure diagnosis and ongoing surveillance from clinical observation to EEG recording, I think that's the main takeaway, allowing for greater accuracy in the detection of electro clinical or electrographic seizures only. It provides greater precision in treating confirmed and preventing the unnecessary treatment of clinical events which I have done many times determine to be of non epileptic origin. The classification is a new tool for both for both advancing and ice my I forgot to pace the last part of that of that sentence, but I have it here for both advancing sorry, investigations and refining practice parameters of infected infants. Pugh. It's a big deal. Now, what do you think?

Daphna 1:00:30

Yeah, I mean, really my takeaway, which should not have required this, but my takeaway is that if you're even thinking about it, you should put the EEG because we miss so many. But seeing it laid out in this little algorithm makes it I think what's so obvious,

Ben 1:00:48

right, what made it what made it interesting to me was the fact that like, let's say you have a baby, that has a great four ivh, right, which is a risk factor. And you're like, Okay, now. Now, this baby is doing some funny movements. And it's the middle of the night. And it's like, if I want to get an EEG, it's going to take me some time, whatever, right? To just start the front of arm, right? That's the question. And this paper is telling, you know, you get the EEG. And then you'll see, right. And I think, I think that's a huge shift. Because,

Daphna 1:01:28

I don't know, I think it could easily say, what if you didn't have the EEG in the middle of the night?

Ben 1:01:34

Well, then, but then, but you know, like, but Right, but what I'm saying is, you know how it is, even if you have EEG, like you have to call the EEG tech, right? And if they're not on site, they have to come from home, and then you have a baby that's doing these funny movements, right? And you're wondering, like, alright, like, this kid is if this kid is seizing, and I'm wasting two hours for the guy to come, right? Am I doing harm? I mean, that's the that's the that's usually the crux of the issue. Am I doing harm by letting potentially this kid sees for two hours while I wait for the EEG? And, and I think what I take away from this paper is that our clinical assessment of seizure is not good. And that's just you need to rely on EEG. Now, where we have the luxury that that's a luxury, I

Daphna 1:02:17

think your scenario would take us down this no route. No. Was it observed by an experienced personality? Yes. Was it focal? Clonic or focal tonic? Yes, yes. Then probable diagnosis of seizure.

Ben 1:02:33

Right. But we do have, but that's for the people who don't, I mean, technically, yes. But we have the luxury of having both video EEG and amplitude modulated EEG. So that's not really an issue. But I mean, anyway, it's interesting. Yeah. It's an interesting, it's interesting. I really enjoyed reading this paper.

Daphna 1:02:49

Yeah. That's good. All right. And my other takeaway is that if you're going to form an association or a group, you should give yourself a super cool name like a league. Yeah, for sure. Okay, we have time for more. Yeah, I

Ben 1:03:03

have one more than any more to I'll be quick, though. Yeah, I'll be quick to

Daphna 1:03:08

Okay. This is long term outcome. I got all long term outcome papers. I'm not mad about it. But

Ben 1:03:13

I felt bad about it just because I picked from the list before you and I was like, I was too it's too eager to read the ones that I picked. And I saw that it left you with a bunch of Northern metal stuff. And I was like, You know what, maybe she'll it'll be

Daphna 1:03:24

fine. Long term outcome of necrotizing enterocolitis and spontaneous intestinal perforation. I was a little nervous when I read this because oh gosh, oh, yeah. What's it gonna say? So, lead author Ruben. Vodka and anchoring author Rajnath Singh. This is coming to us from the Elgin echo studies in the journal Pediatrics. So what were they looking at, they wanted to see what was the Anthro Anthro pro rhetoric and neurodevelopmental outcome data at 10 and 15 years so good as infants with a history of neck fire, necrotizing, enterocolitis, and spontaneous intestinal perforation. So they derive their data from the LDN study, the extremely low gestational age newborn study, which is a prospective longitudinal study designed to identify characteristics and exposures that increase the risk of neurologic disorders in extremely low gestational age, newborns born preterm. So they're looking at babies born between 23 to 27 weeks gestational age, and between 2002 and 2004. They had a 1506 infants born in 14 participating institutions across five states in the United States. And so for the current study, children were categorized into four groups either medical neck, surgical neck sip, and the fourth group was no neck or sip, based on diagnoses made during the day acute hospitalization. So the primary outcome was the anthropometric data. So height weight head circumference, the secondary outcomes, again, they looked at 10 years and 15 years they looked at the motor function. So, using the gross motor function classification system, they looked at cognitive outcomes at 10 years with the school age differential ability scales to and the nonverbal reasoning subscales. So, they average the scores to create a full scale IQ, and at 15 years they use the Wechsler abbreviated Scale of Intelligence. And then they also looked at ADHD symptoms using the child symptom inventory for at 10 years and the mini international neuropsychiatric interview for children and adolescents at 15 years. I thought that was an interesting choice for diagnostic tool for ADHD, but that's what they used. So there like a HUD, tons of other resources. Like most pediatricians are using things like the Vander Bell, things like that. Anyways, that's what yeah, it was consistent across all all the all the children. So they had, I told you 1506 infants enrolled in the overall LDN study. They had 1200 22 infants who survived until discharge, and then they had 966. Eligible for follow up assessment at 10 years, and a total of 889 or 92%, participated in the comprehensive neurodevelopmental and neuro behavioral assessments at 10 years, and 694 71.8% completed the 15 year assessments. I think that's pretty impressive. So they started the group's 76% of infants had no neck or sip. 14.7 had medical neck 5.3 had surgical neck 3.4 had sip, and they had about, like I said, a 55 to 60% of each of those groups in the 15 year follow up. Infants with sip and surgical neck are more likely male had lower gestational age, and lower birth weight compared with infants with no neck or sip. Infants with medical neck had similar baseline demographic characteristics compared with infants with no neck or sip. So then they looked at the babies with medical neck children who had medical neck had similar weight, BMI, height and head circumference compared with those children without neck or SIP at both 10 and 15 years, and they had similar neurodevelopmental outcomes, and they looked at surgical neck. Children who had surgical neck tended to weigh less and be shorter at 10 years and children with no neck or sip. They were not statistically significant. However, at 15 years, children who had surgical neck have lower average weight scores, lower BMI scores, and lower height scores and children with no neck or sip, and they remain significant after correcting for the seeable attrition, and though adjusting for confounding variables. They had no differences found at either 10 or 15 years of age between the neurodevelopmental outcomes with surgical neck and then they looked at SIP at age 10 years children who had SIP tended to have lower weight and height compared with no neck or sip. But the results were not significant after adjusting for confounding variables. And then when adjusting for sample attrition, children with SIP had lower average weight and lower height than children no neck or SIP at age 10 years. At age 15 years, children who had SIP had similar weight, BMI and height as children who did not have neck or sip. And children who had SIP had IQ scores and classifications that did not differ from those of children with no neck or sip. So the study takeaway is the results are very encouraging, and that these babies who have these gi comorbidities will catch up in all facets, their growth and neurodevelopment. So I thought that it's not what I anticipated. I'll be honest.

Unknown Speaker 1:09:23


Ben 1:09:24

what was what would you what were you were anticipating that they would?

Daphna 1:09:29

I was I was worried that there would be differences, that some of these babies would have worse growth outcomes, and that that might impact their nerve development.

Ben 1:09:45

Yeah, it's interesting, but I mean, no, no, it's interesting. I hear what you're saying. I'm happy to hear that the northern mental outcomes were good, but it's it was depressing that they That's still sort of even even for growth, like it's still follows them so far out.

Daphna 1:10:06

Yes. And that, you know, that's a, that 10 year time point is not an easy time to be in school, right and be small or whatever. But it seems like by 15 years, they were able to catch up. So that's good.

Ben 1:10:23

It's a long time, but I think yeah.

Daphna 1:10:26

Yeah, no, I mean, elementary school is not an easy time. Bumping into, you know, middle schools is really not an easy tech, obviously. So.

Ben 1:10:39

Okay, then, my last paper. It's a very cool paper. It's published in the New England Journal of Medicine. It's not really a neonatal paper, but it is kind of important for us. It's called the maternal vitamin A supplementation and lung function in offspring. first author is William Checkley. And it's data coming from the pile. So if you're playing, I don't know if you guys like there's this game your friend, we play flags, you should just like show flags, and you have to guess the pile is always fun, because it's the one with the two little triangles. So it's always easy to recognize. But anyway, I digress.

Daphna 1:11:14

That's the game. You just show

Ben 1:11:16

you just like flags like yeah, you should just find some countries that

Daphna 1:11:20

that's like something school children play like,

Ben 1:11:23

yeah, hopefully that doesn't my house. We played a lot of games with a dictionary, basically. So in the dictionary, there's like a bunch of flags in the back cover. So we would play and then we would play this game that we used to call dictionary and I'm sure that people either be played where you open the dictionary randomly you read a definition, and you have to guess what the word is. It's actually fun.

Daphna 1:11:40

It does sound fun. I definitely never played that game. That's why you're so much smarter than

Ben 1:11:47

I know. I'm not been smarter than you are. And yeah, I mean, yeah, we had. Yeah, we. We may met when my parents bought their home, we got robbed and they stole the TV. My parents said, we're not replacing it. So it was

Daphna 1:12:05

good. Yeah. It was a really good idea.

Ben 1:12:09

Those games became handy without the TV in any case, because stead you played dictionary because we didn't have it with the internet was in its early days. So yeah, there was no it's a lesson for us all. Oh my god. I don't know we have a TV now. All right. What's the point here results from animal research have shown that vitamin A plays a key role in mediating fetal growth morphogenesis maturation of multiple organ system including the respiratory system depletion of vitamin A from the diet of female rats before and during pregnancy is associated with a Genesis or hyperplasia of the lungs in the offspring data on the long term consequence of vitamin deficiency on lung on lung health and human population is lacking. The question that they were asking was, what are the effect if we gave anticipating mothers antenatal vitamin A on the lung function of their pre adolescent children in a chronically undernourished population in rural Nepal. So most of the of the discussion will be on the study design. Basically, there was an original vitamin A trial that they conducted in the Sarla he district of southern Nepal. In a densely populated low lying southern plains. This plane is known to be chronically undernourished, and having vitamin A deficiency. The staple of the diet is rice. It's supplemented with small amount of seasonal fruits, vegetables, lentil soup and occasional meat, fish and eggs. For the people who don't remember I had to just make sure the food sources for vitamin A are leafy green vegetables, tomatoes, peppers, cantaloupe, Mango beef liver, fish oils, milk, eggs, and other fortified foods. So the original study took place between 1994 1997 It was a double blind placebo controlled cluster randomized trial involving married women of childbearing age. The study was designed to determine the effects of weekly supplementation with either a low dose of vitamin A or beta carotene. Beta carotene is an intermediate in the in the production of vitamin A, on the rates of maternal death, slash related of maternal deaths related to pregnancy. They had 44 by 340 540-440-5000 women enrolled and they received weekly supplementation with 7000 microgram retinol equivalent of vitamin A 7000 microgram of retinol equivalents, beta carotene or placebo. The original study showed that if you supplemented vitamin A, or beta carotene resulted in a reduction in 44% in the rates of maternal death related to pregnancy. Neither supplements had an effect on infant mortality. Now in 2006, they revisited the household of the children whose mother participated in the original study. These infants were now between the age of nine and 13 years old, and the objective of the follow up trial was to determine whether there were differences in the forced expiratory volume in one second and the forced vital capacity FEV one and FVC among children. According to group assignment of their mothers during the original trial, they can they basically had technicians that went to their home and did spirometry. And they have a whole explanation as to which tech they used, how they trained everybody. So all that is in there, I'm just going to skip that if that's okay. Of the 1894 children who were alive at the end of the original trial 6% Were no longer living in the study area at the time of the follow up study and 6% had died. Of the 1658 children who were eligible to participate 1371, which is 83% underwent spirometry, which in October 2006, and March 2008. As compared with the 684 children from the original birth cohort who were not included in the follow up study, children who were contacted and who underwent spirometry, it's important we're less likely to be members of a low caste, less likely to live in a thatch or mud bamboo house, more likely to live in a household that owned land and livestock and more likely to have a father who was a farmer, which I think are indicators of higher socioeconomic status, as we would have it in more or more studies in our in developed countries, right. I think these are very important, obviously. What were the effects of maternal supplementation, children whose mother had received vitamin A had a higher value of FTD, one than those who received placebo. The FTD, one of children whose mother received vitamin A was an average 46 milliliter higher than that of children whose mother received placebo. After adjustment for age eight sex Body Mass Index CAS calendar month and spirometry, the adjusted FEV one of children whose mother received beta carotene was on average 14 ML higher than that of children whose mother received placebo. A similar comparison happened with FVC were after adjustment for the same factor that they did for Fe one the FVC of children whose mother received vitamin A was 46 million or higher than that of children who receive placebo and the adjusted FVC of children whose mother received beta carotene was 17 ML higher than that of children whose mother received placebo did not find a significant significant difference, significant between good difference in the ratio, which means which suggested that the lung size and the airway caliber were influenced proportionally by supplementation of vitamin A. One more piece of result, and then we can we can call it a day they measured postpartum serum retinol levels in 678 mothers. And that was very interesting. So supplementation with vitamin A or beta carotene was associated with significantly higher serum retinol level postpartum, nothing surprising there. without consideration of the mother's original group assignment, we found that FEV one FVC levels of the study children were linearly related to the post partum serum retinol level of their mothers after adjustment for height body mass, index, age, sex, caste, calendar month and spirometer. On average, FEV one increased by 99 males and FVC increased by 69. Males for every standard deviation increase in postpartum retinol level. Postpartum serum beta carotene levels were measured in 590 for mother, but did not find a significant association between the postpartum serum beta carotene level in the mother's and either Fe one or FEC. So basically, beta carotene doesn't work as well as vitamin A. Got it, but it's still very impressive that this is those relationships. summary is that in an area where, where there's chronic vitamin A deficiency maternal supplementation during and after pregnancy was critical. That was a critical determinant of long maturation among the offspring. Nine to 13 years later, early interventions involving vitamin A supplementation in communities where undernutrition is highly prevalent may have long lasting consequences for lung health. The big question is so right. And they sort of addressed that in the discussion. So I mean, for the people who are not familiar with our process, we sort of skip on the discussion a little bit because it's, it's too much of an opportunity for the author's to polish their edges, but they do address many times a lot of of important questions. And that was addressed in the discussion. So kudos to the authors for recognizing it and mentioning it. And they do say and I'm going to quote this paragraph because it's just well written this it is important to recognize that a mean increase of 46 ML in FEV one and in FVC corresponds to a change in the distribution of values in the study population of children and does not predict the level of benefits that is expected in an individual child in an in an individual child sorry, however, the magnitude of the effect observed in this study is slightly greater than the than than that associated with preventing exposure to parental smoking in school aged children. Because if you want correlates with overall longevity in the general adult population, any improvement in the distribution of values of if you want in a population may provide long term health benefits, benefits. And you can argue with them about that. But I think that is a great way of looking at it, and gives a gives a good perspective on how this study could improve outcomes for these children down the road. custody.

Daphna 1:20:22

Yes. And for me, it was, again, such a reminder about how much you know, parental health impacts the babies that we get in the unit. Right. And, I mean, there are places in in our country, right, that have, you know, unfortunate you need access to good nutritional food. And so, so it's interesting, right? It's not just this third world problem, right? Like, we have that right around our, our neighborhood impacts our own NICU.

Ben 1:21:03

Yeah. And it reminded me of these old like, you know, the older you go in your fanaroff, and Martin and like the origins of the ontology, it talks about, they call the Dutch famine studies where they looked at these mothers who were undernourished during feminine Holland and like the effects on the newborns. And there is no doubt that maternal health is hugely important for long term outcomes of these infants. And it was kind of neat to see an I guess, a study that that followed in these footsteps of looking at infant outcomes after a maternal pre delivery intervention.

Daphna 1:21:42

Yeah, for me, as a neonatologist, it made me really think like, what is my responsibility in, you know, getting our parents access to resources and nutritional counseling and things like that we have so many parents who we see not once but multiple times in the same NICU. Right. So this is such an opport, we have such an opportunity to impact the next baby by what we say or do in the NICU. But that was my takeaway was the big takeaway.

Ben 1:22:16

Agreed? And, yeah, none of this. I mean, this was this was a phenomenal study. And no, it's, it's, it's a big deal. And there's and and to be honest with you, looking at it a little bit more egocentric ly about vitamin A, I mean, for us, narratologists has been a whole discussion about like, is it helpful? BPD? Do we start with that for everybody? We do a risk based assessment. And it's nice to see that, that that link between vitamin A and pulmonary development is there, right? It's there. It's present. So

Daphna 1:22:53

yeah, and I and maybe that's the takeaway, baby, if you have, if you have sufficient vitamin A, adding more isn't gonna help. But if you're deficient, you know.

Ben 1:23:03

Yeah. And maybe that's the thing is, it's over the

Daphna 1:23:06

developing lung there, right? This is the developing lung. Exactly. And

Ben 1:23:10

it's like, oh, maybe the vitamin A supplementation should be prenatal prenatal thing. And so yeah, that's, that's really it. I think that's it. That's all we have for journal clubs. Yeah,

Daphna 1:23:20

we went way over. So wrap it up. That's okay.

Ben 1:23:23

We're the we want to thank everybody for supporting the podcast for listening. We've seen a huge growth in the number of listeners and, and we're very happy about that. And we're trying to give back to the community in the best ways we can. If as usual, if you have ideas, if you have guests that you want to suggest, please, we're one email away. Our email addresses nichy And for the people who have already emailed us, they will tell you, we are quick to respond. We make sure to address questions, concerns, and even suggestions. So feel free. Again, you can send us messages and if you want to participate in any way, remember that if you want to host a week of the neonatology review podcast that's something that's available. Yeah, that's, that's that's it. We're just very happy to be doing this. This is a lot of fun for us.

Daphna 1:24:10

Well, I have nothing to add. Here we go. You've left me speechless. All right, everybody.

Ben 1:24:24

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 podcast, 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 d dash This podcast is intense digit 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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